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ketan Parmar CH-2.pdf (D17197641) ketan Parmar CH-3.pdf (D17197701) Hitesh Shah-3.pdf (D15988435) Hitesh Shah-5.pdf (D15988456) ketan Parmar CH-4.pdf (D17197716) http://shodhganga.inflibnet.ac.in/jspui/bitstream/10603/44111/8/08_chapter%202.pdf http://www.ijdrt.com/ijdrt_journal/issue/May-June_2012_article5.htm http://rasayanjournal.co.in/vol-1/issue-2/3.pdf http://www.ijrpsonline.com/pdf/221.pdf http://derpharmachemica.com/vol7-iss7/DPC-2015-7-7-182-188.pdf http://www.researchgate.net/profile/Pradeep_Gupta/publication/232768047_Synthesis_Characterization_and_Spectral_Studies_of_Various_Newer_4-Benzyloxy-1H-indole-2-carboxylic_Acid_(Arylidene)-hydrazide/links/09e41509529f15398d000000.pdf?origin=publication_detail http://www.orientjchem.org/vol29no3/synthesis-physico-chemical-spectral-and-x-ray-diffraction-studies-of-znii-complex-of-pioglitazone-a-new-oral-antidiabetic-drug/ http://www.ajbpr.com/issues/volume1/issue2/107.pdf http://shodhganga.inflibnet.ac.in/bitstream/10603/44292/8/08_chapter%202.pdf http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/6/06_abstract.pdf http://parazite.pp.fi/hiveboard/picproxie_docs/000448477-J_Org_Chem_1986_51_22_4294-4295.pdf https://www.researchgate.net/profile/Deepika_Sharma5/publication/225532914_Biological_importance_of_imidazole_nucleus_in_the_new_millennium/links/00b7d5183822e557cd000000.pdf?origin=publication_list http://shodhganga.inflibnet.ac.in/bitstream/10603/41621/8/08_chapter%202.pdf http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/10/10_chapter%202.pdf http://www.chtf.stuba.sk/~szolcsanyi/education/files/Chemia%20heterocyklickych%20zlucenin/Prednaska%202/Doplnkove%20studijne%20materialy/Indole/Biological%20Importance%20of%20the%20Indole%20Nucleus%20in%20Recent%20Years%20-%20A%20Comprehensive%20Review.pdf http://shodhganga.inflibnet.ac.in/jspui/bitstream/10603/39787/11/11_chapter2.pdf http://ir.inflibnet.ac.in:8080/jspui/bitstream/10603/43984/8/08_chapter%202.pdf

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171

U R K N DU

NEWER ROUTES FOR SYNTHESIS OF SOME MEDICINAL COMPOUNDS & ITS CHARACTERIZATION A THESIS SUBMITTED TO THE HEMCHANDRACHARYA NORTH GUJARAT UNIVERSITY PATAN FOR THE DEGREE OF Doctor of Philosophy IN Chemistry BY MR. NIMESH DAHYABHAI THAKKAR UNDER THE GUIDANCE OF DR. PIYUSH J. VYAS ASSOCIATE PROFESSOR DEPARTMENT OF CHEMISTRY SHETH M. N. SCIENCE COLLEGE, PATAN (2015) CERTIFICATE This is to certify that Mr. NIMESH DAHYABHAI THAKKAR has been registered for the Ph.D. Degree at the Hemchandracharya North Gujarat University, Patan. He has completed his research work under my guidance. I certify that the work presented in this thesis entitled “NEWER ROUTES FOR SYNTHSIS OF SOME MEDICINAL COMPOUNDS & ITS CHARACTERIZATION” is original and it has not been submitted to other University or Institution for the award of any other degree. Place: Dr.P.J.Vyas Date: Associate Professor Department of chemistry Sheth M.N.Science College, Patan. Dr. Piyush J. Vyas Associate Professor Department of Chemistry Sheth M. N. Science College Patan. DECLARATION I hereby declare that the work embodied in the thesis entitled “NEWER ROUTES FOR SYNTHSIS OF SOME MEDICINAL COMPOUNDS & ITS CHARACTERIZATION” has been carried out by me under the supervision of Dr.P.J.Vyas, Associate Professor, Sheth M.N.Science College, Patan. I also affirm that this work has not been submitted to any other University or Institution for the award of any other degree. Place: THAKKAR NIMESH DAHYABHAI Date: ACKNOWLEDGEMENT Sometimes words are not sufficient to express our feelings. I feel myself most lucky to work under the guidance of Dr. P.J.Vyas, Associate Professor, Sheth M.N.Science College, Patan I take this opportunity to express my heartiest gratitude to my guide. It would not be possible to complete this journey of my research work without his inspiration, encouragement and invaluable guidance. I express my deepest gratitude towards my family. I owe special thanks to my father Dahyabhai Thakkar, my mother Geetaben Thakkar, my wife Hetal Thakkar, my hearbeat - my son Parth Thakkar, my brother in law Darshan Thakkar for their care, love, encouragement and endless support. I sincerely thankful to Dr.K.S.Parikh, Principal, Sheth M.N.Science College, Patan for his invaluable support and providing all the facilities as possible at Science - College carries out best research work. My sincere thanks to Dr. V.P.Prajapati for his moral support during research work. I am very thankful to Dr. M.P.Brahmbhatt and all the staff members of Department of chemistry, Sheth M.N.Science College, Patan for their kind guidance whenever needed. I am very much thankful to Mr. Devendrabhai Patel who helped me at each stage of my study. I am also thankful to laboratory staff for their kind cooperation and help during research work. I want to thanks my research colleagues Dr. Keyur Trivedi, Deep Joshi, and Rahul Kshtriya for their kind support and help during research work. Thakkar Nimesh D. Index

Chapter-1 Introduction Page Number 1.1 Indole synthesis; a review and proposed classification 1 1.2

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Biological importance of Indole nucleus in recent years; A comprehensive review. 9 1.3

Work done on (4-Benzyl-oxy)-1H-Indole 28 1.4 Brief review on Irbesartan and Pioglitazone hydrochloride 29 1.5 Research gap of about the Derivatization of (4-Benzyloxy)- 1H-Indole and novel improved route for synthesis of Irbesartan and Pioglitazone hydrochloride. 36 1.5 Objectives of the present work 37 1.6 The Present Work 38 Chapter-2 Materials and Methods 2.1 Elemental Analysis 43 2.2 Introduction to Spectrometry 43 2.3 Infrared Spectroscopy 44 2.4 Proton Nuclear Magnetic Resonance Spectroscopy 48 2.5 Mass Spectroscopy 52 2.6 General Remarks for the Experimental Techniques 52 2.7 High performance liquid chromatography [HPLC] 53 Chapter-3 Synthesis of (4-Benzyloxy)-1H-Indole Derivatives, Synthesis of Irbesartan and Pioglitazone hydrochloride by newer route Section-A Synthesis of Various (4-Benzyloxy)-1H-Indole Derivatives 3.1 Synthesis of Schiff base of (4-Benzyloxy)-1H-Indole (4a-h) 60 3.2 Synthesis of 2-Azetidinone

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U R K N DU 30_Nimesh Thakkar Final Thesis.pdf (D18439541)

derivatives of (4-Benzyloxy)- 1H-Indole (5a-h) 65 3.3 Synthesis of 4-Thiazolidinone derivatives of (4- Benzyloxy)-1H-Indole (6a-h) 67 3.4 Synthesis of 5-arylidine-4-thiazolidinone derivatives of (4- Benzyloxy)-1H-Indole (7a-h) 69 3.5 Synthesis of Tetrazole derivatives of (4-Benzyloxy)-1H- Indole (9a-h) 71 3.6 Synthesis of 1,3,5-Oxadiazine derivatives of (4-Benzyl oxy)-1H-Indole (10a-h) 74 Section-B Synthesis of Irbesartan by newer improved route 3.7 Preparation of Irbesartan 77 Section-C Synthesis of Pioglitazone hydrochloride by newer improved route 3.8 Preparation of Pioglitazone hydrochloride 81 Chapter-4 Characterization of (4-Benzyloxy)-1H-Indole Derivatives, Characterization of Irbesartan and Pioglitazone hydrochloride by newer route Section-A Characterization data of various (4-Benzyloxy)-1H- Indole Derivatives 4.1 Characterization of Schiff base of (4-Benzyloxy)-1H-Indole (4a-f) 84 4.2 Characterization of 2-Azetidinones of (4-Benzyloxy)-1H- Indole (5a-f) 97 4.3 Characterization of 4-Thiazolidinones of (4-Benzyloxy)- 1H-Indole (6a-f) 110 4.4 Characterization of 5-Arylidine-4-Thiazolidinones of (4- Benzyloxy)-1H-Indole (7a-f) 123 4.5 Characterization of 1-[N-acetamido-4-benzyloxy-1H- Indole]-5-substituted phenyl-1H-tetrazoles (9a-f) 136 4.6 Characterization of 3-[N-acetamido-4-benzyloxy-1H- Indole]- 2,6-diphenyl-1,3,5-oxadiazine-4-thione (10a-f) 149 Section-B Characterization data of Irbesartan prepared by newer route 4.7 Characterization of Irbesartan and its intermediate. 162 Section-C Synthesis of Pioglitazone hydrochloride by newer improved route 4.8 Characterization of Pioglitazone hydrochloride and its intermediate. 169 Chapter-5 Analytical method validation data of Active pharmaceutical ingredients and Antimicrobial activity of produced novel compounds Section-A Analytical method validation data of Active Pharmaceutical ingredients [i.e. Irbesartan and Pioglitazone hydrochloride] 5.1 Analytical method of Analysis for Pioglitazone hydrochloride 177 5.2 Analytical method of Analysis for Irbesartan 180 Section-B Antimicrobial and antifungal activity of produced novel compounds i.e. various (4-Benzyloxy)-1H-Indole derivatives 5.3 Determination of MIC by agar dilution method 183 5.4 Determination of Antimicrobial activity 184 5.5 Results and discussion 198 Chapter-6 Literature references References 200-208 Chapter-1 Introduction Chapter-1 Dept. of Chemistry, H. N. G.U. 1 Chapter-1 Introduction 1.1 Indole synthesis; a review and proposed classification The indole alkaloids, ranging from lysergic acid to vincristine, have long inspired organic synthesis chemists; hence interest in developing new methods for indole synthesis has burgeoned over the past few years. These new methods have been fragmented across the literature of organic chemistry. In this section, we present a framework for the classification of all indole syntheses. There are four bonds in the five-membered indole ring. In classifying methods for synthesis (Fig. 1), we have focused on the last bond formed. We have also differentiated, in distinguishing Type 1 versus Type 2 and Type 3 versus Type 4, between forming a bond to a functionalized aromatic carbon, and forming a bond to an aromatic carbon occupied only by an H. Type 5 has as the last step CeN bond formation, while with Type 6 the last step is CeC bond formation. In Type 7, the benzene ring has been derived from an existing cyclohexane, and in Type 8, the benzene ring has been built onto an existing pyrrole. Finally, in Type 9, both rings have been constructed. There are several name reactions associated with indole synthesis. We have tried to note these in context, and to group examples of a particular name reaction together. For convenience, the ‘name reaction’ indole syntheses mentioned in this review are: Bartoli indole synthesis Type 1 Bischler indole synthesis Type 5 Fischer indole synthesis Type 1 Hemetsberger indole synthesis Type 3 Julia indole synthesis Type 5 Larock indole synthesis Type 5 Chapter-1 Dept. of Chemistry, H. N. G.U. 2 LeimgrubereBatcho indole synthesis Type 5 Madelung indole synthesis Type 6 Nenitzescu indole synthesis Type 7 Reissert indole synthesis Type 5 Sundberg indole synthesis Type 5 While it might be sufficient to merely label the nine strategies 1 to 9, for ease of recollection we have also associated each strategy with the name of an early or well-known practitioner. The division of strategies is strictly operational. 1.1.1 Type 1 - Fischer strategy H N H N H

Type 1 synthesis involves aromatic C-H functionalization. Although C-H activation is thought of as a modern topic, the venerable Fischer indole syntesis falls under this heading. Paul R. Brodfuehrer and Shaopeng Wang of Bristol-Myers Squibb described [1] the convenient reaction of an aryl hydrazine 1 with dihydropyran 2 to give the 3-hydroxypropylindole. N H NH 2 SO 2 NHMe N H SO 2 NHMe OH O + ZnCl 2 (1) (2) (3)

3


Chapter-1 Dept. of Chemistry, H. N. G.U. 3 1.1.2 Type 2 - Mori strategy X N H

Mori strategy In a landmark paper in 1977, Miwako Mori, working with Yoshio Ban at Hokkaido University, reported [2] the first intramolecular Heck cyclization, converting the 2-bromoaniline derivative (1) into the N-acetyl indole (2) with a Pd catalyst. In 1980, Louis S. Hegedus at Colorado State University showed [3] that iodides were superior to bromides for the cyclization, and that free amines, such as (3) were compatible with the reaction conditions, forming (4). Br N O COOMe N O COOMe Pd Cat. TMEDA (1) (2)

I N H N H Pd Cat. Et 3 N (3) (4)

1.1.3 Type 3 - Hemetsberger strategy H N

Hemetberger strategy Chapter-1 Dept. of Chemistry, H. N. G.U. 4 The lead Type 3 approach is the Hemetsberger [4] indole synthesis, as, for instance, employed [5] by John K. MacLeod of Australia National University in his synthesis of cis-trikentrin A. The aldehyde was homologated to the azido ester (2) that was then heated to convert it into the indole (3). H O N 3 CO 2 Et EtONa CO 2 Et N 3 N H CO 2 Et (1) (2) (3)

1.1.4 Type 4 – Buchwald strategy X N

Buchwald strategy The development of transition-metal-mediated aryl halide amination opened the way to Type 4 indole synthesis. In 1998, Stephen L. Buchwald of MIT reported [6] that on exposure to benzylamine in the presence of a Pd catalyst, the dibromide smoothly cyclized to the indoline. Ammonium formate in the presence of Pd/C converted into the indole. Br Br N Ph N H NH 2 Ph Pd Cat. HCO 2 NH 4 Pd / C (1) (2) (3)

Chapter-1 Dept. of Chemistry, H. N. G.U. 5

1.1.5 Type 5 – Sundberg strategy NH 2

In 1969, Richard J. Sundberg of the University of Virginia reported [7] that ortho-azido styrenes, such as were converted on thermolysis into the corresponding indole. He later found [8] that heating ortho-nitro styrenes, such as with P(OEt) 3 also delivered the indole. Aryl migration dominated over alkyl migration, leading to new compound. Recently, Tom G. Driver of the University of Illinois, Chicago showed [9] that the azide version of the Sundberg indole synthesis could be carried out at lower temperature with a Rh catalyst. N 3 N H NO 2 N H P(OEt) 3

Chapter-1 Dept. of Chemistry, H. N. G.U. 6 1.1.6 Type 6 – Madelung strategy N

The Madelung indole synthesis, as exemplified by the cyclization of input to product, was originally carried out at elevated temperature with bases, such as NaNH2. Willam J. Houlihan of Sandoz, Inc. (now Novartis) showed [10] that, with BuLi, the cyclization was facile below room temperature. D. N. Reinhoudt of the University of Twente found [11] that phenylacetonitriles, such as could be cyclized under even milder conditions, to form product. N H O MeO Ph N H MeO Ph N H O CN N H CN n- Buli NaH / TMSCl t-BuOK Bond formation in the opposite direction has also been developed. William D. Jones reported [12] that a Ru complex catalyzed the conversion of the isonitrile into the indole derivative. This reaction may be proceeding by way of the Ru vinylidene complex. NC N H Ru Cat.

Chapter-1 Dept. of Chemistry, H. N. G.U. 7 1.1.7 Type 7 – Nenitzescu strategy O

Type 7 includes all routes to indoles from cycloalkane derivatives. The earliest such approach is the Nenitzescu indole synthesis, exemplified in a modern manifestation [13] by Daniel M. Ketcha of Wright State University and Lawrence J. Wilson of Procter & Gamble. The combination of the

4


benzoquinone with the resin- bound examine gave, after release from the resin, the indole. NBn OH NH 2 O O O N H P NHBn O TFA

1.1.8 Type 8 – Van Leusen strategy N H

Type - 8 indole syntheses include all those that proceed by way of the preformed N-containing five-membered ring. In 1986, Albert M. van Leusen of Groningen University established [14] a route to highly substituted indoles, based on the condensation of isonitriles, with unsaturated ketones, such as 2,3- bisalkenylpyrrole. Heating followed by aromatization with DDQ completed the synthesis of the indole. Chapter-1 Dept. of Chemistry, H. N. G.U. 8 NC ts O Ph N H O Ph N H O Ph DDQ

1.1.9 Type 9 – Kanematsu strategy The least developed approach to indoles is Type 9, the simultaneous construction of both rings of the indole. This route was pioneered in 1986 [15] by Ken Kanematsu of Kyushu University. Homologation of the allene led to the intramolecular DielseAlder cyclization product, that was readily aromatized to the indole. Ar O N O H Cl N Ar O O Cl CH 2 =O / CuBr iPr 2 NH DDQ

Three related approaches have been put forward since that time. Michael J. Martinelli, then at Lilly, established [16] that acetic anhydride-mediated decarboxylation led to a 1,3-dipole, that added in an intramolecular fashion to the alkyne, delivering the dihydro indole. In a complementary approach, A. Stephen K. Hashmi of Ruprecht-Karls-Universit€at Heidelberg found [17] that with catalytic AuBr 3 , cyclized efficiently. As outlined earlier in this review, both would be readily aromatized to the corresponding indoles. Chapter-1 Dept. of Chemistry, H. N. G.U. 9 O SiMe 3 N O Bu COOH N Bu O O N ts N OH ts Cat. AuCl 3 Ac 2 O

1.2


Biological importance of Indole nucleus in recent years; A comprehensive review.


Heterocyclic compounds are those cyclic compounds in which one or more of the ring carbons are replaced by another atom. The non-carbon atoms in such rings are referred to as ‘‘heteroatom.’’ Such bicyclic heterocyclic compounds containing pyrrole ring with benzene ring fused to α,β-position are known as Indoles. Indole has a benzene ring and pyrrole ring sharing one double bond. It is a heterocyclic system with 10 electrons from four double bonds and the lone pair from the nitrogen atom. Indole is an important heterocyclic system because it is built into proteins in the form of amino acid tryptophan, because it is the basis of drugs like indomethacin and because it provides the skeleton of indole alkaloids—biologically active compounds from plants including strychnine and LSD.

The incorporation of indole nucleus, a biologically accepted pharmacophore in medicinal compounds (Table 1), has made it versatile heterocyclic possessing wide spectrum of biological activities (

Table 2).

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In the present

study, we have made an attempt to collect biological properties of imidazole nucleus reported in the new millennium.

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The name indole is portmanteau of

the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began with the study of the dye indigo.

Indole is

an aromatic heterocyclic nucleus. It has a



bicyclic structure, consisting of a six-membered benzene ring fused to a five membered nitrogen containing

pyrrole ring through the 2- and 3-positions of the pyrrole nucleus. Indole is

called as benzopyrrole.

The indole ring is also found in many natural products such as the vinca alkaloids, fungal metabolites and marine natural products. Indole

is a popular component of fragrances. Indoles are a pervasive class of compounds found in abundance in biologically active compounds such as pharmaceuticals, agrochemicals and alkaloids. Since the first synthesis of indole in 1866, a number of synthetic methods for the construction of the indole nucleus have been devised. Indole myriad derivatives have, therefore, captured the attention of organic synthetic chemists. Medicine and biochemistry are also interested in many aspects of the indole chemistry.

N H Antiinflammatory and analgesic Anticancer Antihypertensive AntiHIV Antioxidant Antidiabetic Photochemotherapeutic Antidepressant, Transquilizing and Anticonvulsant Thrombin catalytic Opioid antagonist Antitubercular Insectisidal activity Antiviral Antibacterial Antifungal

Chapter-1 Dept. of Chemistry, H. N. G.U. 11 1.2.1


Anti-Inflammatory activity and analgesic activity Abele et al. synthesized isatin and indole oximes and carried outthe chemical reactions and biological activities of the synthesized compounds where the compound (1) was found to be most active analgesic and anti-inflammatory agent [18].

N CH 3 N O O MeO Cl CO 2 Me

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Kalaskar et al. synthesized indole-3-acetic acids and evaluated them for their in vivo anti-inflammatory activityThe compound 1,2-disubstituted-5- methoxyindole/benz(g)indole-3-acetic acid (4) showed significant

activity [19]. N CH 2 C 6 H 5 C 6 H 5 CH 2 COOH MeO


The synthesis and anti-inflammatory activity of heterocyclic indole derivatives was performed by Rani et al. The compound was found to be most potent (inhibition of oedema at 50 lg/Kg dose) [20].

Chapter-1 Dept. of Chemistry, H. N. G.U. 12 N N N COCH 3 OH

K. Hemalatha, G. Madhumitha and S. M. Roopan [21] reported mini review on Indole as a Core Anti-Inflammatory Agent. The selectivity of cyclooxygenase enzyme was estimated by altering the substituent at N-1 and C-3 positions of the indole ring. The results explored that all the compounds showed potent in-vitro inhibition against COX-2 enzyme than COX-1 enzyme. The compound 1-benzoyl-3-[(4-tri fluoromethylphenylimino)methyl]indole exhibited significant COX-2 inhibition and selectivity (COX-1 IC50 < 100 μM, COX- 2 IC50 = 0.32 μM) in the in-vitro determination using enzyme immune assay kit. Also it was supported by the energy of intermolecular interactions (E intermolecular = -12.50) calculated in the docking of compounds against COX-1/COX-2 active site [22]. N O N CF 3

The anti-inflammatory activity of various isatin semicarbazide derivatives were evaluated by carrageenan-induced paw edema test in rats. The compound containing trifluoro methyl substituent displayed significant anti-inflammatory activity at the dose of 10 and 20 mg/kg and one-third of ulcer index compared to the reference drug diclofenac and aspirin. It was concluded that the electron-withdrawing nature and the increased Chapter-1 Dept. of Chemistry, H. N. G.U. 13 lipophilicity of the substituent may be the reason for the potent activity compared to that of the other substituent [23]. N O O Cl NH O N H N CF 3

A Series of novel 1,3,4-oxadiazole and 1,2,4-triazole moieties substituted in the indole ring at C-3 position was evaluated for anti-inflammatory activity. Even though all the compounds exhibited remarkable activity, the compound was superior to the other compounds [24]. N H N N N NH 2 S NC

Amir et al prepared and screened for the biological activities of some 4-(1H- indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyr imidin-2-ones/thiones as potent anti- inflammatory agents [25]. N H NH N H S R

R = various substitution Mana et al synthesized a series of novel derivative of indole, containing the thiazole and isoxazole moieties, by isatin and evaluated for anti‐inflammatory Chapter-1 Dept. of Chemistry, H. N. G.U. 14 activitiey. Anti‐inflammatory activitiy was performed by carrageenan induced oedema method. The compound showed significant anti‐inflammatory activity [26]. N H S N N O O Cl O

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Anupam Srivastava [27] reported review on Indole as a versatile nucleus for pharmaceutical field.


Ashok Kumar

et al synthesized a series of novel substituted indole derivatives and were evaluated for their in vitro

anti-inflammatory activity. It was found that the compound 2-(p-chlorophenyl)-1-[4-(2-(p -chorophenyl)-4-oxo-thiazolidin-3-yl]-5- mercapto[1,2,4,]-trizole-3-yl-methyl]- 3[4,6-dibromo-2-carboxyphenyliminomethyl]- 5-methoxyindole had shown prominent anti-inflammatory activity at the three graded dose of 25, 50 and 100mg/kg [28]. N N N N Cl N Br Br SH N S O R

MeO COOH



Thirumurugan prakasam et al synthesized a various 2-(1H-indol-3-yl)-6- methoxy-4- pentylpyridine-3, 5-dicarbonitrile derivatives and was screened for their anti-inflammatory activity. Most of the compounds had shown potent anti- inflammatory activity [29]. N N H N O

N

Lalit Kumar, Bala Shashi and Jeet kamal [30] reported diverse pharmaceutical importance of indole derivatives. 1.2.2 Anti-Fungal


activity Some of the isatin and indole oximes synthesized by Abele et al. were found to be exhibiting high fungicidal activity where the oxime derivates of 2-substituted indoles and 3-substituted indoles demonstrated significant antifungal activity [31].

N R COR'' NOR'

N H CONHN NOH


Pandeya et al synthesized schiff bases of isatin and 5-methyl isatin with sulphadoxine and were evaluated for their in vitro antifungal activity against various fungal strains viz. Candida albicans, Candida neoformis, Histoplasma capsulatum, Microsporum audounii and Trichophyton mentagrophytes. It was found that the piperidino methyl compounds have shown prominent antifungal activity [32].

Chapter-1 Dept. of Chemistry, H. N. G.U. 16 N CH 2 R O R' N SO 2 NH N N OMe MeO

1.2.2 Anti-microbial

8



activity The

synthesis and antibacterial activity of some substituted 3-(aryl) and 3- (heteroaryl)

indoles were reported by Hiari et al. The most active compound was reported to be 3-(4-trifluoromethyl-2-nitrophenyl) indole (11) exhibiting MIC = 7 μg/cm 3 against Escherichia coli and Staphylococcus aureus [33].

N H CF 3 NO 2

Panwar et al. synthesis substituted azetidonyl and thiazolidinonyl-1,3,4-


thiadiazino[6,5-b]indoles as prospective antimicrobial agents. The compounds were found to exhibit most inhibitory effect against E. coli and S. aureus [34].

Chapter-1 Dept. of Chemistry, H. N. G.U. 17 Moreau et al synthesized a series of indolin-2-one derivatives substituted in the 3-position by an aminomethylene group bearing either an ornithine or a lysine residue. The antibacterial activities were tested against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans [35]. N H O N H H NH 2 HCl COOH

Kumar et al synthesized a series of 2-phenyl sulpha/substituted indoles by the interaction of sulpha/substituted anilines and phenacyl halide. The newly synthesized compounds were tested for antibacterial and anti-inflammatory activity [36]. N H X X = Cl, F, NO 2

1.2.3


Insecticidal activity Sharma et al investigated the insecticidal activity of synthesized novel indole derivatives. The compounds exhibited promising results against Spodoptera liture (eighth instar larvae) and Jeliothis armigera [37].


1.2.4

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Anticancer activity Garcia et al. synthesized pyrrolo[2,3-e] indole derivatives and evaluated them for possible in vitro cytotoxic activity. The most active compound was found to be, which shows best result in PC-3 (prostate) cell line [38].


A series of halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy were reported by Rossiter et al. These derivatives were oxidized by horse radish peroxidase (HRP) and toxicity against V79 Chinese hamster lung fibroblasts was determined and the compound was found to possess highest cytotoxicity and it was the best drug for targeted cancer therapy [39].

Chapter-1 Dept. of Chemistry, H. N. G.U. 19 Sigman et al synthesized and carried out the preliminary biological studies of 3-substituted Indoles accessed by a palladium-catalyzed enantioselective alkene defunctionalisation reaction. Evaluation of several of the compounds revealed promising anticancer activity against MCF-7 cells [40]. N OH O R2 R1

Hardik patel, Nilesh Darji, Jagath pillai and Bhagirath patel [41] reported recent advance in anti-cancer activity on indole derivatives.

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Fan Zhang et al synthesized in vitro anti-tumor activity of 2-amino-3 cyano-6-(1 H -indol-3- yl)-4-phenylpyridine derivatives [42].

R1

N N NH 2 R3 CN R2

1.2.5


Lipoxygenase inhibitor Zheng et al synthesized a series of indole derivatives as possible 5- lipoxygenase inhibitors. In all, four compounds exhibited the most potent inhibitory activity with IC50 values ranging from 0.74 lM to 3.17 lM [43].


1.2.6


10



HIV inhibitors The analogs of pyrimido[5,4-b]indoles were synthesized and biologically evaluated by Merino et al. for their possible HIV inhibitory activity. The derivative formed by substitution at position 2 in analog-I and derivative at position 2, 4 in analog II (formed in 65% and 64% maximum yield) were reported to be the inhibitors of wild and mutant HIV-1 RT types in an ‘‘in vitro’’ recombinant HIV-1 RT screening assay as well as anti-infectives in HLT4lacZ-1IIIB cells [44].


1.2.7


Antioxidant activity A series of indole derivatives were synthesized and biologically evaluated by Enien et al., and found that Indole-2 and 3-carboxamides were having antioxidant properties by Chemoluminesence and Electron spin resonance spin trapping. They further reported that the derivatives have strongest scavenging effect on OH - radicals, i.e., quenching <30%


and the derivatives have strongest effect on scavenging of superoxide radicals [45]. 1.2.8


Antituberculosis activity A new series of 1-Hindole-2,3-dione derivatives were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv by Karali et al. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3- thiosemicarbazones and its 1-morpholinomethyl derivatives exhibited significant inhibitory activity with MIC values * 75% [46].

Chapter-1 Dept. of Chemistry, H. N. G.U. 22 1.2.9 Antiviral activity Selvam et al prepared 4-[(1, 2-dihydro-2- oxo-3H-indol-3-ylidene)amino]- N- (4,6-dimethyl-2-pyrimidin-2-yl)benzenesul phonamide and its derivatives. The related compounds were tested for antiviral activity against influenza A (H1N1, H3N2, and H5N1) and B viruses in Madin Darby canine kidney (MDCK) cell culture [47]. N R R1 O N S N H O O N N

Dun Wang et al synthesized some new derivatives of 3-ethoxycarbonyl-6- bromo-5-hydroxyindoles and their antiviral activity was determined in cell culture with virus cytopathic effect assay [48]. SCH 2 COOC 2 H 5 R1 CH 2 NR 3 R 4 OH Br


11


Wang Dun et al synthesized various 2-arylthiomethyl-4-tertiary amino methyl substituted derivatives of 6-bromo-3-ethoxycarbonyl-5-hydroxyindole and evaluated their in vitro antiviral activity against laboratory-passaged isolates of human influenza A3 and respiratory syncytial virus (RSV) respectively in MDCK cell culture and eLa cell culture with virus cytopathic effect assay in comparison with amantadine and Abidol. The 50% inhibitory concentration (IC50) and the minimum inhibitory concentration (MIC) for the tested compouds against the above two virus were calculated with Reed and Muench Method and therapeutic index (TI) was obtained. Some compounds had shown significant antiviral activity [49].

Chapter-1 Dept. of Chemistry, H. N. G.U. 23 N H O O Br OH

1.2.10


Plant growth regulator The 3-substituted indole was reported to be a plant growth regulator by Abele et al. among the various isatin and indole oximes synthesized and evaluated by them [50]. 1.2.11 Antidepressant, tranquilizing and anticonvulsant activity


A series of N-substituted indoles were synthesized by Falco et al., and afterwards, in vitro screening and in vivo spontaneous motor activity in mice had revealed molecules with good in vitro affinities for the a1-subunit of GABAA receptor and potent in vivo induction of sedation and (44) was found most potent compounds [51].

Kumar et al synthesized some new pyrazolinyl /isoxazolinylindol-2-ones. These compounds were screened for their anticonvulsant activity against maximum electroshock induced seizures [52]. Chapter-1 Dept. of Chemistry, H. N. G.U. 24 R R N N N H X N N N N H 3 COC O N H COCH 3


Sharma Prince P et al synthesized a series of various 3-(1,3-benzothiazol-2- ylimino)-1,3- dihydro-2H-indol -2-one derivatives and it was found that compounds had shown prominent anticonvulsant activity [53]. N H O N N S

1.2.12

Cardiovascular activity


12


A number of benzopyranyl indoline and indole analogs were synthesized and evaluated for Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) opener activity by Lee et al. The compounds showed the best cardioprotective activity [54]. 1.2.13 Antihypertensive activity

M R Bell


synthesized a series of novel 7-azaindole-3-acetamidoxime and 7- azaindole-1-acetamidoxime and evaluated for its antihypertensive activity. These compounds have shown prominent antihypertensive properties [55].

Chapter-1 Dept. of Chemistry, H. N. G.U. 25 N H N NH 2 N OH N N NH 2 N OH

1.2.14 Antihystaminic


activity A number of indole amide derivatives bearing a side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well known antihistamines, were prepared and tested for the antihistaminic activity by Battaglia et al. The most active some compounds were tested in vivo for their ability to antagonize histamine induced cutaneous vascular permeability in rats [56]. 1.2.15

Photochemotherapetic


activity The synthesis and photochemotherapeutic activity of thiopyrano[2,3-e]indol- 2-ones was performed by Barraja et al., wherein the compound thiopyrano[2,3-e]- indol-2-ones showed the maximum phototoxicity on two cultured cell lines: HL-60 and LoVo [57].


1.2.16


Antidiabetic activity Some of the indole derivatives were evaluated for their insulin sensitizing and glucose lowering effects by Li et al. The indole derivative showed increase in activity of PPARc agents, which shows decreased serum glucose and contributing to

antidiabetic activity [58]. 1.2.17 Steriod 5α-

13



reductase inhibitor. A class of indole and benzimidazole derivatives were synthesized and evaluated for their inhibitory activity against rat prostatic 5a-reductase by Takami et al. The compounds were found to be showing most potent inhibitory activity against rat prostatic 5a-reductase with IC50 ¼ 9.6 6 1.0 nM and 19 6 6.2 nM, respectively [59].

Chapter-1 Dept. of Chemistry, H. N. G.U. 27 1.2.18


Thrombin catalytic activity The substituted 5-amide indoles were evaluated as inhibitors of thrombin catalytic activity by Iwanowicz et al. The compound was found to be the most potent inhibitor of thrombin catalytic activity with an inhibition constant, Ki ¼ 260 nM [60]. 1.2.19

Selective CB2 receptor antagonist


The preparation and evaluation of a class of CB2 receptor agonist based on a 1,2,3,4-tetrahydropyrrolo[3,4-b] indole moiety were reported by Page et al. The compound showed to be most potent CB2 receptor agonist [61,62].


1.3 Work done on (4-Benzyl-oxy)-1H-Indole. As per recent literature on indole derivatives, (4-Benzyl-oxy)-1H-Indole is a very important molecule for pharmaceutical science but still very few reference found to work on (4-Benzyl-oxy)-1H-Indo le, some of them shown below. Aasheesh kumar jain, Pradeep kumar gupta and Kumaran Ganesan [63] reported

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synthesis, characterization and spectral studies of various newer 4-benzyl oxy-1H-Indole-2-carboxylic acid (

ary lidine)-hydrazides. 4-

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14


-Benzyloxy-1H-indole-2-carboxylic_Acid_(Arylidene)-hydrazide/links/09e41509529f15398d000000.pdf?origin=publication_detail 100%

Benzyloxyindole-2- carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in alcoholic medium in refluxing conditions to give 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-hydrazides, important synthetic intermediates for the synthesis of a newer class of pharmacologically active compounds.

N

H

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O

N H NH 2 O N H

O N H N O O N H O N H N O N H O N H N O Cl N H O N H N O F N H O

N H

N

O

OH

David H. Lioyd and David E. Nichols [64] reported

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nickel boride / hydrazine hydrate reduction of aromatic and aliphatic nitro compounds; synthesis of 4- benzyloxy-indole and alpha alkyltryptamines.


1.4 Brief review on Irbesartan and Pioglitazone hydrochloride 1.4.1 Literature review on Irbesartan Following is the various Route of synthesis reported in the literature [65-67]. Scheme-1.1 [As per patent number EP 2194050 A1]


N H 2 CN

N H CN O X CN CN N

H O N H O N N CN O N H N N N N N O N

H O NH 2

O +

15


BuCOCl Yield = 100% Yield = 94% Yield = 69% Yield = 85% Yield = 85% Overall Yield = 46.86 %


Scheme-1.2 [As per patent number WO 2005/113518A1] NH 2 COOH N H COOH

O NH 2 CN CN

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NH

O N H O N N CN O N NH N N N N O N

NH N N N

N

O

Yield =55.10% Yield = 94.50% Yield = 65.61% Yield = 86.48% Overall Yield = 20.67 % Purification in IPA

Scheme-1.3 [As per patent number WO 2005/113518A1]


N NH N N N N O N N H O Br Br Br N N O N N N N

CPH 3 B(OH) 2 Overall Yield = 16.72 % HCl + + Yield = 76% Yield = 22%


Scheme-1.4 [As per patent number US 8106216]


N N O H Br CN CN

N N O / Xylene N N O N N N N C(Ph) 3 N N O N N N N

H +

NaH / DMF Bu 3 SuN 3 Trityl chloride / CH 2 Cl 2 CH 3 OH/THF/HCl II III IV V I

Following is the new route of synthesis of Irbesartan. Chapter-1 Dept. of Chemistry,

H. N. G.U. 32

16



N N O H Br CN CN

N N O N N O N N N N H N N O N N N N

H + 2-

butyl-1,3-diazaspiro[4,4]non-1-en-4-one Hydrochloride 4'-(bromomethyl)biphenyl-2-carbonitrile NaOH, TBAB, Toluene, water NaN 3 , TEA.HCl, NaNO2, Xylene Irbesartan Technical Liq. Ammonia, Sulfuric acid Irbesartan Pure Yield = 95% Yield = 85% Overall Yield = 80.75% Scheme-5 Novel and new route for synthesis of Irbesartan During the last few years, considerable attention has been devoted to various synthesis route of Irbesartan. But, existing route having some disadvantage, say Long route of synthesis, Use of very costly and number of reagents, having moderate yield and quality, having complicated workup procedure, time staking procedure and number of impurities generated [65]. Here, in this paper new route of Irbesartan reported which having only two steps route of synthesis, use of very cheap raw material and reagents, having excellent yield and quality and lastly having very simple reaction and workup procedure. Chapter-1 Dept. of Chemistry, H. N. G.U. 33

1.4.2 Literature review on Pioglitazone hydrochloride Following is the various Route of synthesis reported in the literature [68]. Scheme-1 [As per JCPR article, 4(6), 4323, 2012] N OH N O NO 2 F NO 2 N O NH 2 N O Br COOMe NH S N O O NH NH S N O O O O OMe N H 2 NH 2 S H 2 /Pd/C NaNO 2 / HBr Me 2 CO / MeOH NaOAc HCl H 2 O HCl Pioglitazone Pioglitazone Hydrochloride


Scheme-2 [As per JCPR article, 4(6), 4323, 2012] OH NH 2 COOH NH S N O O O N H 2 NH 2 S OH Br COOH NH S OH O NH NH S OH O O N OH NaOAc / EtOH NaNO 2 + HCl CuBr, H + ArSO 2 Cl NaOH / DCM HCl Pioglitazone Pioglitazone Hydrochloride Following is the new route of synthesis of Pioglitazone hydrochloride. Chapter-1 Dept. of Chemistry, H. N. G.U. 35 N OH OH CHO

N O CHO NH S O

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O NH S O O N O NH S O O N O NH S O O N

O

CH 3 SO 2 Cl TEA, Toluent, 0-5C 2,4-thiazolidinone Liq NH 3 , Methanol Reflux Methanol, water NaOH, NaBH 4 15-17C HCl HCl Pioglitazone Hydrochloride Pioglitazone

Scheme-3 Novel Route for synthesis of Pioglitazone HCl During the last few years, considerable attention has been devoted to various synthesis route of Pioglitazone hydrochloride. But, existing route having some disadvantage, say Long route of synthesis, Use of very costly and number of reagents, having moderate yield and quality, having complicated workup procedure, time staking procedure and number of impurities generated [69]. Here, new route of Pioglitazone hydrochloride reported which having only two steps route of synthesis, use of very cheap raw material and reagents, having excellent yield and quality and lastly having very simple reaction and workup procedure. Chapter-1 Dept. of Chemistry, H. N. G.U. 36 1.5 Research gap of about the Derivatization of (4-Benzyloxy)-1H- Indole and novel improved route for synthesis of Irbesartan and

17


Pioglitazone hydrochloride. As per the review about the Indole derivatives, It is a five-membered heterocycles containing one nitrogen in the ring and its derivatives have biological activities such as antibacterial, antifungal, antimycobacterial, anti-inflammatory, analgesic, anticancer, antihypertensive, anticonvulsant, antiviral, antidepressant, antiasthmatic, diuretic and hypoglycemic. All these facts were driving force to develop novel indole derivatives with wide structural variation. Thus indole derivatives plays pivotal role in medicinal chemistry. As part of interest in heterocycles derived from Schiff bases that have been explored for developing pharmaceutically important molecules, 2-azetidinones [70,71], 4-thiazolidinones [71,72], 2-pyrrole and 2-pyrrolidinones [73,74], and tetrazole [75] have played a pivotal role in medicinal chemistry. Moreover they have been studied extensively because of their ready accessibility, diverse chemical reactivity and broad spectrum of biological activity. The area in which heterocyclization of 4-Benzyl oxy-indole (BOIH) into above heterocycles has not been reported so far. Hence, it was thought to undertaken such study. Irbesartan is classified as an angiotensin II receptor type 1 antagonist invented by jointly by Sanofi-synthelabo and Bristol-Myers squibb. Angiotensin II receptor type 1 antagonists are widely used in treatment of diseases like hypertension, heart failure, myocardial infarction and diabetic nephropathy [76]. Pioglitazone hydrochloride, (RS)-5-(4-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl)thiazolidine-2,4-dione hydrochloride)

is an oral ant diabetic

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agent used in the treatment of type 2 diabetes

mellitus also known as non insulin dependent diabetes mellitus 1 (NIDDM) or adult onset diabetes

innovated by Takeda Pharma.


Pioglitazone decrease

insulin resistance in the periphery and liver,

resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output.

Currently, it

is

marketed under the trade name Actos [77].

Chapter-1 Dept. of Chemistry, H. N. G.U. 37 During the last few years, considerable attention has been devoted to various synthesis route of Irbesartan and Pioglitazone hydrochloride. But, existing route having some disadvantage, say Long route of synthesis, Use of very costly and number of reagents, having moderate yield and quality, having complicated workup procedure, time staking procedure and number of impurities generated [78]. Here, in this objective new route of Irbesartan and Pioglitazone hydrochloride reported which having only two steps route of synthesis, use of very cheap raw material and reagents, having excellent yield and quality and lastly having very simple reaction and workup procedure. 1.6 Objectives of the present work: In view of above review, the prime objectives of the present thesis are, Part-A New derivatives of (4-Benzyloxy)-1H-Indole containing an 2-azetidinone, 4- thiazolidinone, 5-arylidene derivatives, 1,3,5-oxadiazine and

18


tetrazole derivatives. In view of above review, the objectives of work is mainly focused on, ? To synthesis and characterization of N-methyl acid hydrazide derivatives of (4-Benzyloxy)-1H-Indole (3)? To synthesis and characterization of Schiff base of N-methyl acid hydrazide derivatives of (4-Benzyloxy)-1H-Indole (4) ? To synthesis and characterization of 2-azetidinone (5a-h), 4-thiazolidinone (6a-h), 5-arylidine (7a-h), Tetrazole (9a-h) and 1,3,5-oxadiazine (10a-h) derivatives of (4-Benzyloxy)-1H-Indole. ? All newly prepared compounds were tested for Antimicrobial activity against various plant pathogens. Part-B Irbesartan were prepared by newer improved route and characterized each stage by Characterization techniques like IR, NMR, Mass analysis and elemental Chapter-1 Dept. of Chemistry, H. N. G.U. 38 analysis. HPLC (High performance liquid chromatography) purity of prepared Irbesartan was tested. Part-C Pioglitazone hydrochloride was prepared by newer improved route (Schem-8) and characterized each stage by Characterization techniques like IR, NMR, Mass analysis and elemental analysis. HPLC (High performance liquid chromatography) purity of prepared Pioglitazone hydrochloride was tested. 1.7 The present work: According to the above objectives, research work was carried and distributed into following six chapters of the present thesis. Chapter-1 First chapter comprises the ? Literature review on Indole derivatives and work done on (4-Benzyloxy)-1H- Indole. ? Literature review on Active pharmaceutical ingredients like Irbesartan and Pioglitazone hydrochloride. ? Research gap of about the Derivatization of (4-Benzyloxy)-1H-Indole and novel improved route for synthesis of Irbasartan and Pioglitazone hydrochloride. ? Objectives and ? Present work or Chapterization. Chapter-2 Chapter‐2 comprises the details about techniques used to characterize the newly prepared compounds. Following are the list of techniques used, Chapter-1 Dept. of Chemistry, H. N. G.U. 39? Infrared spectroscopy (IR) ? Nuclear magnetic resonance spectroscopy (NMR) ? Mass analysis ? Elemental analysis ? High performance liquid chromatography (HPLC) Chapter-3 Chapter‐3 were comprised into three sections, Section-A This section was included the synthesis of N‐methyl acid hydrazide derivatives of (4‐Benzyloxy)‐1H‐Indole BOIH (3) and N‐methyl acid hydrazide derivatives of (4‐Benzyloxy)‐1H‐Indole (4a‐h).

NH O N O CH 2 COOC 2 H 5 N O CH 2 CONHNH 2 N O CH 2 CONHN Ar (4-Benzyloxy)-1H-Indole CAS Number = 20289-26-3 (1) ClCH 2 COOC 2 H 5 NH 2 NH 2 H 2 O (2) (3) BOIH (4a-h) ArCHO Ethanol / Conc. H 2 SO 4 Chapter-1 Dept. of Chemistry, H. N. G.U. 40 This section also include synthesis of 2‐azetidinone (5a‐h), 4‐ Thiazolidinone (6a‐h), 5‐arylidene derivatives (7a‐h), Tetrazole derivatives (9a‐ h) and 1,3,5‐oxadiazine derivatives (10a‐h) from N‐methyl acid hydrazide derivatives of (4‐Benzyloxy)‐1H‐Indole (4 a‐h).

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N O Cl Ar S N O Ar N O CH 2 CONHN Ar N O CH 2 CONHNH 2 N O CH 2 CONH N O CH 2 CONH N O CH 2

CONH S N O Ar Br (4a-h) Schiff bases of BOIH ClCH 2 COCl 2-Azetidinone derivative of BOIH (5a-h) 4-Thiazolidinones derivatives of BOIH (6a-h) (3) BOIH ArCHO Ethanol / Conc. H 2 SO 4 -HCl SHCH 2 COOH -H 2 O 4-Bromo benzaldehyde 5-Arylidine derivatives of 6a-h (7a-h) Chapter-1 Dept. of Chemistry, H. N. G.U. 41 N O CH 2 CONHN Ar N O CH 2 CONHN Ar Cl N O CH 2 CONH N N N N Ar N O CH 2 CONH N N O S Ar Ph (4a-h) Schiff bases of BOIH PCl 5 (8a-h) Chlorinated Schiff bases of BOIH NaN 3 Tetrazole derivatives of BOIH (9a-h) PhCONCS 1,3,5-Oxadiazine derivatives of BOIH (10a-h) Section-B This section includes the synthesis of Irbesartan by newer improved route. Section-C This section were included the synthesis of Pioglitazone hydrochloride by newer improved route. Chapter-4 Chapter‐4 comprises into three sections, Section-A This section includes the Characterization data of N‐methyl acid hydrazide derivatives of (4‐Benzyloxy)‐1H‐Indole BOIH (3), N‐methyl acid hydrazide derivatives of (4‐Benzyloxy)‐1H‐Indole (4a‐h), 2‐azetidinone (5a‐h), 4‐ Chapter-1 Dept. of Chemistry, H. N. G.U. 42 Thiazolidinone (6a‐h), 5‐arylidene derivatives (7a‐h), Tetrazole derivatives (9a‐h) and 1,3,5‐oxadiazine derivatives (10a‐h). SectionB This section includes the Characterization data of each stage of Irbesartan. This will also include the High performance liquid chromatography data of prepared Final Irbesartan. Section-C

19


This section includes the Characterization data of each stage of Pioglitazone hydrochloride. This will also include the High performance liquid chromatography data of prepared Final Pioglitazone hydrochloride. Chapter-5 Chapter‐5 includes method validation data of active pharmaceutical ingredients. Chapter-6 Chapter‐6 includes list of all references throughout the thesis.

Chapter-2 Materials And Methods Chapter-2 Dept. of Chemistry, H. N. G.U. 43 Chapter-2 Materials and Methods


The present chapter comprises characterization techniques used to characterize the produced compounds.

Following techniques used for characterization. ? Elemental analysis ? Infrared spectroscopy (IR) ? Nuclear magnetic resonance spectroscopy (NMR) ? Mass analysis ? High performance liquid chromatography (HPLC) 2.1

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Elemental Analysis The majority of organic compounds are composed of a relatively small number of elements. The most important ones are: carbon, hydrogen, oxygen, nitrogen, sulphur, chlorine, etc. Elementary quantitative organic analysis [79] is used to determine the content of carbon, hydrogen, nitrogen, and other elements in the molecule of an organic compound. 2.2

Introduction to

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Spectrometry

Fundamental to modern techniques of structure determination is the field of

spectroscopy the study of the interaction of matter and light (or other electromagnetic radiations). Spectroscopy has been immensely important to many areas of

chemistry and physics. For example, much of what is known about orbitals and bonding comes from spectroscopy. But spectroscopy is also important to the laboratory organic chemist

because it can be used to determine unknown molecular structures. Although this presentation of spectroscopy will focus largely on its applications, some fundamentals of spectroscopy theory must be considered first.

Chapter-2 Dept. of Chemistry, H. N. G.U. 44 2.3

Infrared Spectroscopy Infrared spectroscopic technique [80-83] is of a very importance

to organic chemists for the identification of the presence of functional groups in the organic compounds although it does not provide the complete information regarding the molecular structure of the organic compounds. However it is used for the characterization of the compounds. Infrared spectroscopic technique gives the information about the molecular vibrations or more precisely on the transitions between rotational and vibrational energy levels in the molecule and due to this characteristic; it is of immense help to organic

chemists.

20


When infrared light is passed through a sample, some of the

frequencies are absorbed while other frequencies are transmitted through the sample.

The absorption of infrared radiation depends on increasing the energy of vibration or rotation associated with co-valent bond in a molecule. Absorption

of

radiation in the infrared region results in the excitation of bond deformations, either stretching or bending. Various stretching and bending vibrations occur at certain quantized frequencies. When infrared light of that frequency is incident or impart on the

molecule, energy is absorbed and

the amplitude of that vibration is increased. “An infrared spectrum is obtained when the frequency of molecular vibrations corresponds to the frequency of the infrared radiations absorbed.” The material under study is usually in the form of a solid, a neat liquid or a solution. Sometimes, however, a compound in the gas or vapor phase is studied. Under these conditions, in addition to changes in vibrational energy, simultaneous changes in rotational energy can occur and consequently some fine structures may be observed on the vibrational band. Infrared spectrum of a compound represents its energy absorption pattern in the infrared region and is obtained by plotting percentage absorbance or transmittance of infrared radiation as a function of wavelength or wave



number over a particular range. Infrared spectroscopy is usually divided into three regions. ? Near infrared (overtone region) – between 12500cm -1 -4000cm -1

? Middle infrared (fundamental vibrational region) – between 4000cm- 1 - 667cm -1

? Far infrared (pure rotational region) – between 667cm -1 -50cm -1

The normal or middle infrared region is particularly meant for organic chemists since the vibrations induced in organic molecules are absorbed

in this region. This

fundamental vibrational region is divided into the functional group region (4000cm -1 -1400cm -1 ) and finger print region (1400cm -1 -667cm -1 ). The normal and far infrared regions contain absorptions due to fundamental harmonic and combination bands. The use of linear-in-frequency instruments results in a considerable expansion of the high frequency end of the infrared region, resulting in an increased ability to resolve bands and define their positions. The position of absorption in the spectrum is usually expressed in terms of wave number (cm -1 )

of the absorbed light. The infrared spectrum is the simplest, most rapid and often most reliable means for assigning a compound to its class. It can also provide a variety of information on structure, symmetry, purity,

structural and geometrical isomers and hydrogen bonding.

Chapter-2

21


Dept. of Chemistry, H. N. G.U. 46 2.3.1


Anticipated Infrared Frequencies for heterocyclized products based on BOIH.

The present thesis comprises the study of following heterocyclized products: ?

Benzyl oxy indole hydrazide (BOIH) ? Schiff Bases of BOIH ? 2-Azetidinones ? 4-Thiazolidinones ? Tetrazoles ? 1,3,5-Oxadiazine

Hence, prior to characterize these compounds by IR spectroscopy it is necessary to predict the anticipated frequencies of each moiety.

Benzyl oxy indole hydrazide (BOIH) BOIH

is a heterocyclic compound.

It is an aromatic compound thus it provides the IR frequencies. The bands

due to

C=N are appeared between 1620-1640 cm -1

region. Another bands of N-N as well as C-H stretching frequencies appeared at ~1040 and between 3250-3300 cm -1 region. Another band of aromatic ether appeared at 1250 cm -1 region.

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Schiff Bases: Acyclic unsaturated nitrogen compounds containing C=N bond is most commonly encountered in oximes and Schiff’s bases. Both the classes absorb in the region from 1690-1640 cm -1 , usually less strongly than carbonyl compounds but the oximes are distinguished by the presence of O-H stretching(free) absorptions between 3650 and 3600 cm -1 in dilute solution.

Chapter-2

Dept. of Chemistry, H. N. G.U. 47 2-


Azetidinones (β-lactams): Lactams exhibits the following characteristic absorption bands in their spectra. Lactams exhibit a strong N-H stretching bonded absorption in the solid state near 3200 cm -1 and a weaker band near 3100 cm -1 resulted due to the combination of C=O stretching and N-H in-plane bending absorptions [84,85]. The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Lactams (five membered ring lactams) absorb near 1750-1700 cm -1 . Unfused β-lactams absorb at 1760-1730 cm -1 while β -lactams fused to unoxidized thiazolidine rings absorbed at 1780-1710 cm -1 [86,87]. N-H in-plane bending, C-N stretching and N-H wagging vibrations: Cyclic mono substituted amide shows no band in the region from 1600-1500 cm -1

comparable to the 1550 cm -1 C-N-H in-plane bending band in the trans structure. The cis N-H in-plane bending vibration absorbs at 1490-1440 cm -1 and the C-N stretching vibration at 1350 cm -1 [88]. There is much less interaction between these modes compared to the trans form. The N-H out-of-plane bending (wagging) vibration appears

22


as a broad band near 800

cm -1 . 4-

Thiazolidinones: The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Thiazolidinones absorbs at 1730-1700 cm -1 [89].

Tetrazoles:



due to

C=N are appeared between 1620-1640 cm -1 region. Another bands of N-N stretching frequencies appeared at ~1040 cm -1 region. Chapter-2 Dept. of Chemistry, H. N. G.U. 48 1,3,5-oxadiazines: The functional groups of this heterocycle are C=N, C=S and C-O-C. The C=N present in the pyridine ring give the band at 1620 cm -1 . The C=S group of diazine ring appeared at 1350 cm -1 and –C-O-C- of the diazine ring arise


at 1300

cm -1 [90]. 2.4

Proton nuclear magnetic resonance

spectroscopy

Nuclear magnetic resonance (NMR) spectroscopy is supplementary technique to IR spectroscopy to get details characterization report about structure of organic compounds. Most widely studied nucleus is proton and then the technique is called NMR spectroscopy [91,92]. IR spectra give information about the functional group while NMR spectra provide information about the exact nature of proton and its environment. Thus this technique is

more useful in the elucidation of an organic compound. IR spectra of isomers may appear same but their NMR spectra will markedly differ. The phenomenon of nuclear magnetic resonance was first reported independently in 1946 by two groups of physicists: Block, Hansen and Packard at Stanford University detected a signal from the protons of water, and Purcell, Torrey and Pound at Harvard University observed a signal from the protons in paraffin wax. Block and Purcell were jointly awarded the Nobel Prize for physics in 1952 for this discovery. Since that time, the advances in NMR techniques leading to wide spread applications in various branches of science resulted in the Nobel Prize in chemistry in 1991. The applications of NMR in clinical, solid state and biophysical sciences are really marvelous. The proton magnetic

resonance (PMR) spectroscopy is the most important technique used for the characterization of organic compounds. It gives information about the different kinds of protons in the molecule. In other words it tells one about different kinds of environments of the hydrogen atoms in the molecule. PMR also

23


gives information about the number of protons of each type and the ratio of different types of protons in the molecule.

Chapter-2

Dept. of Chemistry, H. N. G.U. 49


It is well known that all nuclei carry a positive charge. In some nuclei this charge ‘spins’ on the nuclear axis, and

this

circulation of nuclear charge generates a magnetic dipole along the axis. Thus, the nucleus behaves like a tiny bar magnet. The angular

momentum of the spinning charge is described in terms of spin number (I). The magnitude of generated dipole is expressed in terms of nuclear

magnetic moment (μ).

The spinning nucleus of a hydrogen atom ( 1 H or proton) is the simplest and is commonly encountered in organic compounds. The hydrogen nucleus has a magnetic moment, μ = 2.79268 and its

spin number (I) is + ½. Hence, in an applied external magnetic field,

its magnetic moment may have two possible orientations. The orientations in which the

magnetic moment is aligned with the applied magnetic field is more stable (lower energy) than in

which the magnetic moment is aligned against the field (high energy). The energy required for flipping the proton from its lower energy alignment to the higher energy alignment depends upon the difference in energy (∆E) between the two states

and is equal to ∆E = (h μ) In principle, the substance could be placed in a magnetic field of constant strength, and then the spectrum can be obtained in the same way as an infrared or an ultraviolet spectrum by passing radiation of steadily changing frequency through the substance and observing the frequency at which radiations is absorbed. In practice,

however,

it has been found to be more convenient to keep the

radiation frequency constant and vary the strength of the magnetic field. At some value of the field strength the energy required to flip the proton matches the energy of the radiation, absorption occurs and a signal is obtained. Such a spectrum is called a nuclear magnetic resonance (NMR) spectrum.

Two types of NMR spectrometers are commonly encountered. They are: a) Continuous wave (CW) NMR spectrometer b) Fourier transform (FT) NMR spectrometer. The CW-NMR spectrometer detects the resonance frequencies of nuclei in a sample placed in a magnetic field by sweeping the frequency of RF radiation through a given range and directly recording the intensity of absorption as a function of

24




frequency. The spectrum is usually recorded and plotted simultaneously with a recorder synchronized to the frequency of the RF source. In FT-NMR spectroscopy, the sample is subjected to a high power short duration pulse of RF radiation. This pulse of radiation contains a broad band of frequencies and causes all the spin-active nuclei to resonate all at once at their Larmor frequencies. Immediately following the pulse, the sample radiates a signal called free induction decay (FID), which is modulated by all the frequencies of the nuclei excited by the pulse. The signal detected as the nuclei return to equilibrium (intensity as a function of time) is recorded, digitized and stored as an array of numbers in a computer. Fourier transformation of the data affords a conventional (intensity as a function of frequency) representation of the

spectrum. The first step in running NMR spectrum is the complete dissociation of a requisite amount of the sample in the appropriate volume of a suitable NMR solvent. Commonly used solvents are: CCl 4 , deuteron chloroform, deuteron DMSO, deuteron methanol, deuteron water, deuteron benzene, trifluroacetic acid.

TMS is generally employed as internal standard

for measuring the position of 1 H, 13 C, and 29 Si in the NMR spectrum because it gives a single sharp peak, is chemically inert and miscible with a large range of solvents, being

a

highly volatile, can easily be removed if the sample has to be recovered, does not involve in intramolecular association with the sample. 2.4.1

Interpretation of the NMR Spectra It is not possible to prescribe a set of rules which is applicable on all occasions. The amount of additional information available will most probably determine the amount of information it is necessary to obtain from the PMR spectrum. However, the following general procedure will form

a useful

initial approach to the interpretation of most spectra.

Chapter-2 Dept. of Chemistry, H. N. G.U. 51 ?

By making table of the chemical shifts of all the groups of absorptions in the spectrum. In some cases it will not be possible to decide whether a particular group of absorptions arises from separate sets of nuclei, or from a part of one complex multiplet. In such cases it is probably best initially to include them under one group and to note the spread of chemical shift values. ? By measuring and recording the heights of the integration steps corresponding to each group of absorptions. With overlapping groups of protons it may not be possible to measure these exactly, in which case a range should be noted. Work out possible proton ratios for the range of heights measured, by dividing by the lowest height and multiplying as appropriate to give integral values. ? By noting any obvious splitting of the absorptions in the table (e.g., doublet, triplet, etc.). For spectra which appear to show first-order splitting, the coupling constants of each multiplets should be determined by measuring the separation between adjacent peaks in the multiplet. Any other recognizable patterns which are not first order should be noted. ? By noting any additional information such as the effect of shaking with D 2 O, use of shift reagent, etc. ? By considering both the relative intensities and the multiplicities of the absorptions attempt to determine which groups of protons are coupled together. The magnitude of the coupling constant may give

25


indication of the nature of the proton involved. ? By relating the information obtained other information available on the compound under considerations.


0: ketan Parmar CH-2.pdf 95%

Mass Spectroscopy It is unlikely that the laboratory organic chemist will be required to record mass spectra of compounds produced in the laboratory as they will normally be obtained through a centralized service [93]. Probably the most common use of mass spectrometry by the organic chemist is for the accurate determination of molecular weight. A second important use is to provide information about the structure of compounds by an examination of the fragmentation pattern [94]. 2.6

General Remarks for the Experimental Techniques ?

Melting points ( o C) of all the compounds were measured

by capillary method. ? The

yields of all compounds reported are of crystallized.

All solvents used were distilled and dried. The purity of the compounds was checked by TLC.

Column chromatography was performed on silica gel (60-120 mesh). ?

C, H, N and S contents of all the compounds were recorded on Thermofinigen 1101 Flash elemental analyzer. ? IR spectra were recorded in KBr pellets on Nicolet 760D

spectrophotometer. ?

NMR

and CMR

spectra were recorded on Bruker NMR spectro-photometer. PMR ad CMR chemical shifts are recorded using TMS as an internal standard in CDCl 3 /D 6 -DMSO. ?

LC-MS of selected one sample of each series has been carried out on

LC- MSD Trap-SL 01046 instrument using

Acetonitrile solvent.

Chapter-2

Dept. of Chemistry, H. N. G.U. 53 2.7 High performance liquid chromatography [HPLC] Chromatography is a technique by which a mixture sample is separated into components. Although originally intended to separate and recover (isolate and purify) the components of a sample, today, complete chromatography systems are often used to both separate and quantify sample components. The term, “chromatography" was coined by the Russian botanist, Tswett, who demonstrated that, when a plant extract was carried by petroleum ether through a column consisting of a glass tube packed with calcium carbonate powder, a number of dyes were separated, as shown in Figure 1. He named this analysis method "Chromatographie" after "chroma" and "graphos", which are Greek words meaning "color" and “to draw," respectively [95]. Figure 1 : Diagram showing

26


Tswett's experiment "Chromatography" represents a separation technique; whereas a "chromatograph" is a system for performing chromatography. The chart displaying the time-dependent change in signal intensity as a result of the separation is called a "chromatogram”. As shown in Table 1, gas and liquid chromatography are common classifications that are based upon the mobile and stationary phases utilized for the separation. Chapter-2 Dept. of Chemistry, H. N. G.U. 54

Table 1 Type of chromatography Mobile phase Stationary phase Analysis Sample Types Gas Solid/Liquid Gas chromatography (GC) Samples those are gaseous at ordinary temperatures and samples that vaporize when heated Odorous samples such as petrochemicals, perfumes, and thinner are easier to analyze by GC. High molecular weight compounds are measured after pyrolysis. Liquid Solid/Liquid Liquid chromatography (LC) Liquid samples and solvent-soluble solid samples Compared to GC, LC has a wide range of measurement subjects. High molecular weight compounds can be analyzed, if soluble in solvent. Although the intended use of GC and LC are the same (i.e., separation and quantification), the measurement subjects are different, as the sample conditions differ at separation. The stationary phase typically indicates a column (fillers), while the mobile phase, which is referred to as the eluent in LC, indicates a vehicle to pour a sample into the column. How is a sample separated into its components in the column? The speed of a migrating sample component depends on whether the component has an affinity for the stationary or mobile phase. This affinity appears via various actions: adsorption, partition, ion exchange, etc. As shown in Figure 2, components that have a higher affinity for the mobile phase compared with the stationary phase migrate more rapidly, while components that have a higher affinity for the stationary phase are eluted from the column later. The order and resolution of the components emerging from the column depend on the type of selected stationary and mobile phases. Chapter-2 Dept. of Chemistry, H. N. G.U. 55

Figure 2: Diagram showing separation Chromatography is based on the principal that under the same conditions, the time between the injection of a component into the column and the elution of that component is constant. This characteristic is used to perform qualitative or quantitative analysis. Such analyses are explained here using the measurement of aspartame, a synthetic sweetener contained in beverages. Configuration of an HPLC system An HPLC system consists of a pumping unit, sample-injection unit, separation unit, detection unit, and data-processing unit. Each of these units is essential for performing the analysis. Chapter-2 Dept. of Chemistry, H. N. G.U. 56

Figure 3 : Configuration of an HPLC system It is necessary to pump the eluent at a constant flow rate and pressure. Conventional, analytical HPLC pumps are the most common type, but semi-micro and a preparative pumps are also used depending on the range of the eluent flow rate required. The pump is selected to suit the purpose of the analysis. Analyses were first performed using isocratic separations in which the eluent composition remains unchanged during the analysis. This technique is adequate for simple separations. When a sample contains many components, such as a sample for amino-acid analysis is analyzed, it is very difficult to separate all of the components effectively using only one eluent. A gradient analysis allows the composition of the eluent to be changed during the analysis. This often indicates that the concentration gradient is to be generated in a linear manner. However, if the eluent composition is changed in a stepwise fashion, this is called a step gradient . Chapter-2 Dept. of Chemistry, H. N. G.U. 57 Figure-4 illustrates the merits of gradient analysis. If eluent A is used, the components eluted earlier are clearly separated, but the components eluted later show broad peaks or may not elute from the column. In contrast, if eluent B is used, the former are insufficiently separated, while the latter show sharp peaks. In this case, a gradient analysis in which the eluent composition is changed from the A to B during the analysis can be used to improve the separation over time Figure 4 : Merits of gradient analysis Detection unit The components eluted from the column are detected, and the detection data are converted into an electrical signal. The detector is selected to suit the sample. Chapter-2 Dept. of Chemistry, H. N. G.U. 58

27


Table 2 Major types of detector UV detector The light source is a D2 lamp. This detector is used mainly to detect components having an absorption wavelength of 400 nm or less in the ultraviolet region. UV-VIS detector A D2 lamp and a W lamp are used as the light source. This detector is the effective in the detection of coloring components such as dyes and stains because of the coverage of the visible light region. Diode array detector Data of the spectrum from the ultraviolet to visible light range is also collected. Fluorescence (FL) detector Fluorescent substances can be detected specifically with high sensitivity. Differential refractive index (RI) detector Change in the refractive index is detected. Components absorbing no ultraviolet light can also be detected despite low sensitivity. Conductivity detector Mainly inorganic ions are detected by monitoring the conductivity. The electrochemical detector (ECD), evaporative light scattering detector (ELSD), Corona® Charged Aerosol Detector (CAD), and others are also used. In addition, the LC-MS system, in which the components separated by HPLC are further analyzed using a mass spectrometer, is becoming widely used because of its high sensitivity and the possibility of specific detection. Chapter-3 Synthesis of (4-Benzyloxy)- 1H-Indole Derivatives, Synthesis of Irbesartan and Pioglitazone hydrochloride by newer route. Chapter-3 Dept. of Chemistry, H. N. G.U. 59 Chapter-3 Synthesis of (4-Benzyloxy)-1H-Indole Derivatives, Synthesis of Irbesartan and Pioglitazone hydrochloride by newer route. The chapter-3 deals with the synthesis of various (4-Benzyloxy)-1H-Indole derivatives like Schiff base, 2-Azetidinones, 4-Thiazolidinones, 5-Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazole derivatives and remaining part comprise of synthesis of Irbesartan and Pioglitazone hydrochloride by newer route. The presence of azo methine [<C=N-] group is of great importance by considering the fact that it can be transformed into various heterocyclic ring compounds.


The availability of the presence and significant biological properties of the members known so far prompted the authors to

extend moieties like 2- azetidinones, 4-thiazolidinones, 5-Arylidines, 1,3,5-oxadiazine and Tetrazole derivatives. In this context, whole chapter is divided into three sections. Section – A comprises the synthesis of various (4-Benzyloxy)-1H-Indole derivatives like Schiff base, 2-Azetidinones, 4-Thiazolidinones, 5-Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazole derivatives. Section – B comprises the synthesis of Irbesartan by newer route Section – C comprises the synthesis of Pioglitazone hydrochloride by newer route. Chapter-3 Dept. of Chemistry, H. N. G.U. 60

Section-A Synthesis of Various (4-Benzyloxy)-1H-Indole Derivatives 3.1 Synthesis

of Schiff base of (4-Benzyloxy)-1H-Indole Theoretical consideration:


Organic chemists are frequently facing the problem of characterizing and ultimately elucidating the structure of organic compounds. The worker in the field of natural product has the prospects of isolating such compounds from their sources in a pure state and then determining their structure. On the other hand the synthetic organic chemist encounters new or unexpected compounds in the course of investigations. All

reactions were carried out under prescribed laboratory conditions. All the reactions requiring anhydrous conditions were conducted in flame dried apparatus. The solvents and reagents used in the synthetic work were of laboratory reagent grade and were purified by distillation and crystallization techniques wherever necessary and their melting points were checked with the available literature. Melting points of newly synthesized compounds were determined by open capillary method. The final product was purified by recrystalization. The reaction,

the reagents and the conditions of the reaction system are given in the following scheme 3.1

28


and 3.2 as follows,


3.1.1 Synthesis of (4-Benzyloxy)-1H-Indole BOIH (3) (4-Benzyloxy)-1H-Indole (1) (0.01


mole) and chloro ethyl acetate (0.01 mole) in acetone (5 ml) were taken in round bottom flask [100 ml]. Then charge K 2 CO 3 (0.005 mole) and mixture were refluxed for 5-8 hrs. The solution was filtered through hyflow bed and filtrate

ml


was distilled out to get crude solid product. This is in turn purified by dissolving in methanol and pure product fall out by adding water.

This


in turn filtered and washed with water and dried for 12 hrs at 50-55 0 C. The

newly compound (2) (0.01 mole) dissolved in absolute ethanol. Hydrazine hydrate (99%, 0.02M) and few drops of concentrated sulphuric acid were added. The reaction mixture was refluxed for 6 hours. The resulting solid obtained was filtered, dried and crystallized from ethanol [96, 97]. NH O N O CH 2 COOC 2 H 5 N O CH 2 CONHNH 2 (4-Benzyloxy)-1H-Indole CAS Number = 20289-26-3 (1) ClCH 2 COOC 2 H 5 NH 2 NH 2 H 2 O (2) (3) BOIH

Scheme 3.1 Chapter-3 Dept. of Chemistry, H. N. G.U. 62 3.1.2 Synthesis of N-methyl acid hydrazide derivatives of (4-Benzyloxy)-1H- Indole (4a-f). The Schiff bases of (4-Benzyloxy)-1H-I ndole (4a-f) were prepared by method reported [98-102]. Benzaldehyde derivative (Given in Table: 3.1) (0.01mole), N-methyl acid hydrazide derivatives of (4-Benzyloxy)-1H-Indole BOIH (3) (0.01mole) and ethanol (20 ml) were taken in a RBF [100ml], few drop of concentrated sulfuric acid was added.


The mixture was heated until a clear solution was obtained. The clear solution was kept overnight when respective Schiff base fall out which was filtered, washed by petroleum ether and air dried.

The resultant Schiff bases are designated as (4

a-f) and their details are shown

as follows.

Chapter-3 Dept. of Chemistry, H. N. G.U. 63 Table 3.1 List of Raw materials used for Schiff bases Formation of BOIH List of Raw Materials Structure Benzaldehyde CHO

2-Bromo benzaldehyde CHO Br

29


4-Chloro benzaldehyde CHO Cl

4-Nitro benzaldehyde CHO O 2 N

4-Hydroxy benzaldehyde CHO OH

4-Methoxy benzaldehyde CHO MeO

The formation of Schiff bases is presented in scheme 3.2. Chapter-3 Dept. of Chemistry, H. N. G.U. 64

NO 2 Cl Br OMe OH N O CH 2 CONHNH 2 N O CH 2 CONHN Ar Where, Ar = , , , , (3) BOIH (4a-h) ArCHO Ethanol / Conc. H 2 SO 4

Scheme 3.2 Chapter-3 Dept. of Chemistry, H. N. G.U. 65 3.2 Synthesis of 2-Azetidinone derivatives of (4-Benzyloxy)-1H- Indole (5a-f) Schiff base of Benzyl oxy indole hydrazide (BOIH) (4a-f) cyclo condense with chloro acetyl chloride in presence of 1, 4-dioxane solvent and Tri ethyl amine as a base to yield corresponding 2-Azetidinone derivatives (5a-f) [103-107]. The formation of 2-Azetidinone derivatives is presented in scheme 3.3. N O Cl Ar N O CH 2 CONHN Ar N O CH 2 CONH NO 2 Cl Br OMe OH (4a-h) Schiff bases of BOIH ClCH 2 COCl 2-Azetidinone derivative of BOIH (5a-h) -HCl Where, Ar = , , , ,

Scheme 3.3 Chapter-3 Dept. of Chemistry, H. N. G.U. 66

3.2.1 Synthesis of 1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-aryl azetidin-2-ones (5a-f) A mixture of N-methyl (4-Benzyloxy)-1H-Indole acid (substituted benzylidine)-hydrazide (4


a-f) (0.01

mole) and tri ethyl amine (TEA) (0.03mole) was dissolved in 1,4-dioxane (50 ml) cooled and stirred. To this well stirred cooled solution chloro acetyl chloride (0.012 mole) was added drop wise. The reaction mixture was stirred for 14 hrs at room temperature.

Excess of solvent was removed by distillation. The residue was poured over crushed ice


and then air dried. The product thus obtained was purified by column chromatography over silica gel using 20% ethyl acetate: 80%

n-hexane as eluent. Recrystalization from ether/n-hexane gave white powdered 1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-aryl azetidin-2-ones (5a-f), which were obtained in 45-65% yield. Chapter-3 Dept. of Chemistry, H. N. G.U. 67

3.3 Synthesis of 4-Thiazolidinone derivatives of (4-Benzyloxy)-1H- Indole (6a-f). Schiff base of Benzyl oxy indole hydrazide (BOIH) (4a-f) cyclo condense with mercapto acetic acid in presence of Di methyl formamide (DMF) solvent and anhydrous zinc chloride as a catalyst to yield corresponding 4-thiazolidinone derivatives (6a-f) [108-113]. The formation of 4-Thiazolidinone derivatives is presented in scheme 3.4. S N O Ar N O CH 2 CONHN Ar N O CH 2 CONH NO 2 Cl Br OMe OH (4a-h) Schiff bases of BOIH 4-Thiazolidinones derivatives of BOIH (6a-h) SHCH 2 COOH -H 2 O Where, Ar = , , , ,

30



3.3.1 Synthesis of 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-aryl-1,3- thiazolidin-4-ones (6a-f) A mixture of N-methyl (4-Benzyloxy)-1H-Indole acid (substituted benzylidine)-hydrazide (4a-f) (0.01 mole) in Di methyl formamide (50 ml) and Thioglycolic acid (0.87ml, 0.0125 mole) with a pinch of anhydrous zinc chloride was refluxed for about 8-9 hours. The Excess solvent was removed under vacuum and residue was poured into ice cold water and then neutralized with sodium bicarbonate solution. Solid separated was filtered and


dried. The product thus obtained was purified by column chromatography over silica gel using

n-hexane: ethyl acetate (7:3 V/V) mixture as eluent. The eluate was concentrated and the product crystallized from alcohol (Yield = 50-60%). Chapter-3 Dept. of Chemistry, H. N. G.U. 69 3.4 Synthesis of 5-arylidine-4-thiazolidinone derivatives of (4- Benzyloxy)-1H-Indole (7a-f). 4-Thiazolidinone derivatives of Benzyl oxy indole hydrazide (BOIH) (6a-f) condense with 4-bromo benzaldehyde in presence of ethanol solvent and sodium methoxide as a base to yield corresponding 5-arylidine-4-thiazolidinone derivatives (7a-f) [114-118]. The formation of 5-arylidine-4-Thiazolidinone derivatives is presented in scheme 3.5. S N O Ar N O CH 2 CONH N O CH 2 CONH S N O Ar Br NO 2 Cl Br OMe OH 4-Thiazolidinones derivatives of BOIH (6a-h) 4-Bromo benzaldehyde 5-Arylidine derivatives of 6a-h (7a-h) Where, Ar = , , , ,

Scheme 3.5 Chapter-3 Dept. of Chemistry, H. N. G.U. 70 3.4.1 Synthesis of N-[2-aryl-4-(4-bromo phenyl arylidene)-5-oxothiazolidin-3 yl]-(1H-4-benzyloxy-1H-indole)-acetic acid hydrazide (7a-f) A mixture of 4-thiazolidinone derivatives (6a-f) (0.01 moles) and 4-bromo benzaldehyde (0.01 moles) in ethanol (35 ml) in presence of sodium ethoxide were refluxed on a water bath for about 5 hrs and cooled. The solid separated was collected by filtration, dried and recrystallized from ethanol. Chapter-3 Dept. of Chemistry, H. N. G.U. 71 3.5 Synthesis of Tetrazole derivatives of (4-Benzyloxy)-1H-Indole (9a-f). Various Schiff bases of (4-Benzyloxy)-1H-Indole (4a-f) reacted with phosphorous pentachloride to yield corresponding imidoyl chloride derivatives (8a-f) which in turns heterocyclised with sodium azide yield corresponding tetrazole derivatives (9a-f). The synthetic route

0: Hitesh Shah-3.pdf 90%

is shown in Scheme-3.6.

Experimental procedure for the synthesis of this series compounds have been adopted

according to

reported methods [119].


NO 2 Cl Br OMe OH N O CH 2 CONHN Ar N O CH 2 CONHN Ar Cl N O CH 2 CONH N N N N Ar Where, Ar = , , , , (4a-h) Schiff bases of BOIH PCl 5 (8a-h) Chlorinated Schiff bases of BOIH NaN 3 Tetrazole derivatives of BOIH (9a-h)


3.5.1 Synthesis of 5-substituted phenyl – 1 - [(1H-4-benzyloxy-1H-indole)-acetic acid hydrazide]-1H-Tetrazole (9a-f) A mixture of Schiff bases (4a-f) (0.01 mole) and Phosphorous pentachloride [PCl 5 ]

31


(0.01 mole) was heated at 100 o C for 1 hour. When the evolution of fumes of HCl ceased, excess of PCl 3 was removed under reduced pressure and the residual imidoyl chloride (8a-f) was treated with an ice-cold solution of sodium azide (0.02 mole) in water (75 ml), sodium acetate (0.01 mole) and acetone (100 ml) with stirring. Stirring was continued for overnight, there after acetone was removed under reduced pressure. The remaining aqueous portion was extracted with chloroform and dried to give white crystals of product (9a-f) which is obtained in 50-70% yield. Chapter-3 Dept. of Chemistry, H. N. G.U. 74 3.6 Synthesis of 1, 3, 5-Oxadiazine derivatives of (4-Benzyloxy)-1H- Indole (10a-f). Various Schiff bases of (4a-f) on heterocyclization reaction with benzoyl isothiocyanate yield corresponding 1,3,5-oxadiazine derivatives (10a-f). The synthetic route




according to

reported

method [120]. N O CH 2 CONHN Ar N O CH 2 CONH N N O S Ar Ph NO 2 Cl Br OMe OH (4a-h) Schiff bases of BOIH PhCONCS 1,3,5-Oxadiazine derivatives of BOIH (10a-h) Where, Ar = , , , ,

Scheme 3.7 Chapter-3 Dept. of Chemistry, H. N. G.U. 75 3.6.1 Synthesis of 3-[(1H-4-benzyloxy-1H-indole)-acetic acid hydrazide]-2- substituted aryl-6-phenyl-1,3,5-oxadiazine-4-thione (10a-f) A mixture of Schiff bases of BOIH (4a–f) (0.01 mole), benzoyl isothiocyanate (0.01 mole), and tri ethyl amine (three-four drops) in 1,4-dioxane (20 ml) was refluxed for 2 hours. The separated solid that formed upon dilution with water (20 ml) was filtered, dried, and recrystallized from xylene to give yellow crystals of product (10a-f) which were obtained in 50-70% yield. Chapter-3 Dept. of Chemistry, H. N. G.U. 76

Section-B Synthesis of Irbesartan by newer improved route Irbesartan is classified as an angiotensin II receptor type 1 antagonist invented by jointly by Sanofi-synthelabo and Bristol-Myers squibb. Angiotensin II receptor type 1 antagonists are widely used in treatment of diseases like hypertension, heart failure, myocardial infarction and diabetic nephropathy [121]. Irbesartan is an orally active lipophilic drug and possesses rapid oral absorption. It causes reduction in blood pressure and is used in treatment of hypertension. Irbesartan delays progression of diabetic nephropathy and is indicated for the reduction of renal disease progression in patients with type 2 diabetes. It is jointly marketed by Sanofi-Aventis and Bristol- Myers Squibb under the trade name Aptovel®, Karvea® and Avapro® [122,123]. Irbesartan is also available in a combination formulation with a low dose thiazide diuretic, invariably hydrochlorothiazide, to achieve an additive antihypertensive effect. This section presents the development of efficient commercial process for the preparation of highly pure Active pharmaceutical ingredients (API) like Irbesartan. Irbesartan could be an attractive target for the generic industries. During the last few years, considerable attention has been devoted to various synthesis route of Irbesartan. But, existing route having some disadvantage, say Long route of synthesis, Use of very costly and number of reagents, having moderate yield and quality, having complicated workup procedure, time staking procedure and number of impurities generated [124]. Here, in this section new route of Irbesartan is reported which having only two steps route of synthesis, use of very cheap raw material and reagents, having excellent yield and quality and lastly having very simple reaction and workup procedure. Hence, the present communication comprises the study of new route for scalable process of Irbesartan presented in scheme 3.8. Chapter-3 Dept. of Chemistry,

H. N. G.U. 77

32



N N O H Br CN CN


H + 2-

butyl-1,3-diazaspiro[4,4]non-1-en-4-one Hydrochloride 4'-(bromomethyl)biphenyl-2-carbonitrile NaOH, TBAB, Toluene, water NaN 3 , TEA.HCl, NaNO2, Xylene Irbesartan Technical Liq. Ammonia, Sulfuric acid Irbesartan Pure Yield = 95% Yield = 85% Overall Yield = 80.75%

Scheme-3.8 Novel and new route for synthesis of Irbesartan 3.7 Preparation of Irbesartan 3.7.1 Preparation of Irbesartan Crude Charge 25 g 4’-(bromo methyl)biphenyl-2-carbonitrile, 21.2 g 2-Butyl-1,3- diazaspiro[4,4]-non-1-en-4one hydrochloride and 6 g TBAB in 75 ml toluene into this add sodium hydroxide solution [Prepared by dissolving 10 g NaOH in 40 ml water] and stir resulting slurry for 20 hours. Check TLC of reaction mass and then add 100 ml water, stirred and do layer separation. Take toluene layer distilled out toluene under vaccum till thick mass observed. Charge 125 ml Xylene, 12.5 g sodium azide, Chapter-3 Dept. of Chemistry, H. N. G.U. 78 26.5 g triethylamine hydrochloride and stirred. Heat reaction mass to 120-125 0 C and maintain for 24 hours. Check TLC of reaction mass and then cool to 25-30 0 C. charge 25 ml water and cool to 10-15 0 C. To this add sodium nitrite solution [by dissolving 13 g NaNO 2 in 130 ml water] then adjust pH 2.0 to 3.0 using dilute sulfuric acid [prepared by dissolving 16.5 ml H 2 SO 4 with 325 ml water]. Raise temperature to 25- 30 0 C, filter and dry at 50-55 0 C for 8 – 10 hours in Hot air oven to give Irbesartan crude (37.5 g) 3.7.2 Preparation of Irbesartan Pure Charge 35 g Irbesartan crude + 280 ml Water and stirrred, adjust pH 6.5 to 7.5 using liqour ammonia and stir. Further adjust pH 4.2 to 4.8 using dilute sulfuric acid and stir. Filter the slurry. Charge 140 ml special denature spirit (5-10% moisture containing ethanol) and heat to make clear solution and cool to 25-30 0 C, stir and filrer. Charge 140 ml special denature spirit (5-10% moisture containing ethanol) into wet cake and heat to reflux and cool to 35-40 0 C and filter. Dry wet cake under vacuum for 12 hours at 50-55 0 C to get 22.5 gm Irbesartan pure. Comparative data of various route of Irbesartan Source Overall yield % HPLC %Purity Number of steps EP Impurity - A Remarks EP 2194050A1 46.86 99.0% 05 0.20 - WO2005/113518A1 20.67 98-99% 05 0.20 - WO2005/113518A1 16.72 98-99% 02 0.15 Costly raw materials US8106216 Around 20-25% 98-99% 03 0.10 - Adopted ROS 80.75 99.0 – 99.5% 02 0.04 Cheaper raw materials Chapter-3 Dept. of Chemistry, H. N. G.U. 79

Section-C Synthesis of Pioglitazone hydrochloride by newer improved route Pioglitazone hydrochloride, (RS)-5-(4-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl)thiazolidine-2,4-dione hydrochloride)

is an oral ant diabetic



mellitus also known as non insulin dependent diabetes mellitus1 (NIDDM) or adult onset diabetes

innovated by Takeda Pharma.

33






Currently, it

is

marketed under the trade name Actos® [125]. It

is a white or almost white crystalline, odourless powder, practically tasteless, insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in

dimethylformamide. It exhibits slow gastrointestinal absorption rate and inter individual variation of its bioavailability [126].

This section covers the development of efficient commercial process for the preparation of highly pure Active pharmaceutical ingredients (API) like Pioglitazone hydrochloride. Pioglitazone hydrochloride could be an attractive target for the generic industries. During the last few years, considerable attention has been devoted to various synthesis route of Pioglitazone hydrochloride. But, existing route having some disadvantage, say Long route of synthesis, Use of very costly and number of reagents, having moderate yield and quality, having complicated workup procedure, time staking procedure and number of impurities generated [127]. Here, in this section new route of Pioglitazone hydrochloride reported which having only two steps route of synthesis, use of very cheap raw material and reagents, having excellent yield and quality and lastly having very simple reaction and workup procedure. Chapter-3 Dept. of Chemistry, H. N. G.U. 80 Hence, the present communication comprises the study of new route for scalable process of Pioglitazone hydrochloride presented in scheme 3.9. N OH OH CHO

N O CHO NH S O



O

CH 3 SO 2 Cl TEA, Toluent, 0-5C 2,4-thiazolidinone Liq NH 3 , Methanol Reflux Methanol, water NaOH, NaBH 4 15-17C HCl HCl Pioglitazone Hydrochloride Pioglitazone

Scheme-3.9 Novel and new route for synthesis of Pioglitazone hydrochloride Chapter-3 Dept. of Chemistry, H. N. G.U. 81

3.8 Preparation of Pioglitazone hydrochloride 3.8.1 Preparation of Pioglitazone Stage-1 Charge 5 gm NaOH and 30 ml water and stirred then charge 100 ml Methylene dichloride, 15 gm 5-ethyl-2-pyr idine ethanol, 6 gm Tetra butyl ammonium bromide and 23 gm p-toluene sulfonyl chloride and mixture were stirred for 2 hours at 25-30 0 C. To the reaction mixture add 12 gm 4-hydroxy benzaldehyde, 100 ml water and 8 gm sodium hydroxide and stirred reaction mixture at 40-50 0 C for 12 hours. Do layer separation. Dry Organic layer over Na 2 SO 4 and distilled out Methylene

34


dichloride to give 29 gm of 4-[2-(5-ethyl-2-pyridinyl)ethoxy]ben zaldehyde as oil. 3.8.2 Preparation of Pioglitazone Stage-2 Charge 27 gm oil of 4-[2-(5-ethyl-2 -pyridyl)ethoxy]benzaldehyde, 33 gm 2,4- thiazolidinone, 300 ml methanol and 14 ml concentrated aqueous ammonia, heat resulting mixture to reflux for 5 hours. The product crystal were separated was filtered and recrystallized from 1,2-dichloro ethane gives 21.6 gm 5-{4-[2-(5-ethyl-2- pyridyl)ethoxy]benzylidine}-2,4-thiazolidinone. 3.8.3 Preparation of Pioglitazone Base Charge 10gm 5-{4-[2-(5-ethyl-2- pyridyl)ethoxy]benzylidine}-2,4- thiazolidinone and 100 ml methanol and stirred. Charge 5 gm NaOH solution in 5 ml water into reaction mass and stirred. Charge 10 gm NaBH 4 (sodium borohydride) into reaction mass and cool to 15-17 0 C. Maintain reaction mass for 5-6 hours at 15-17 0 C. filter slurry to remove solid material and concentrate filtrate mother liquor under vacuum to get crude product, which is recrystallized from methanol to give 6.6 gm pure crystal of 5-{4-[2-(5-ethyl-2-pyri dyl)ethoxy]benzyl}-2,4-thiazolidinone. Chapter-3 Dept. of Chemistry, H. N. G.U. 82

3.8.4 Preparation of Pioglitazone Hydrochloride Charge Pioglitazone base 10 gm and 30 ml acetone and stirred. Cool reaction mixture to 5-10 0 C. Adjust pH of reaction mass to 2 to 3 by purging HCl gas. (HCl gas produce by adding sulfuric acid in sodium chloride), stir reaction mass for 60 minutes at 5-10 0 C. Filter resulting slurry and wash wet cake with 5 ml acetone. Dry under vacuum at 40-45 0 C for 5 hours Dry weight = 10 gm. Comparative data of various route of Pioglitazone Hydrochloride Source Overall yield % HPLC %Purity Number of steps EP Impurity-A Remarks JCPR article, 4(6), 4323, 2012 20-25% 98-99% 06 0.12 Use of number of raw materials JCPR article, 4(6), 4323, 2012 25-30% 98-99% 05 0.18 Use of number of raw materials Adopted ROS 70-75% 99.0 to 99.5% 04 0.06 Using cheaper and easily available raw materials Chapter-4 Characterization of (4-Benzyloxy)-1H-Indole Derivatives, Characterization of Irbesartan and Pioglitazone hydrochloride by newer route. Chapter-4 Dept. of Chemistry, H. N. G.U. 83 Chapter-4 Characterization of (4-Benzyloxy)-1H-Indole Derivatives, Characterization of Irbesartan and Pioglitazone hydrochloride by newer route. The chapter-3 deals with the synthesis of various (4-Benzyloxy)-1H-Indole derivatives like Schiff base, 2-Azetidinones, 4-Thiazolidinones, 5-Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazole derivatives and synthesis of Irbesartan and Pioglitazone hydrochloride by newer route [128-135]. Here, present chapter deals with the Characterization report of various (4- Benzyloxy)-1H-Indole derivatives prepared in chapter-3 and characterization report of Irbesartan and Pioglitazone hydrochloride which is prepared by newer route. In this context, whole chapter is divided into three sections. Section – A comprises the characterization data of various (4-Benzyloxy)-1H- Indole derivatives prepared in chapter-3. Section – B comprises the characterization data of Irbesartan and Section – C comprises the characterization data of Pioglitazone hydrochloride. Chapter-4 Dept. of Chemistry, H. N. G.U. 84 Section-A Characterization data of various (4-Benzyloxy)-1H-Indole Derivatives 4.1 Characterization of Schiff base of (4-Benzyloxy)-1H-Indole (4a-f) The Schiff base of (4-Benzyloxy)-1H-Indole (4a-f) was synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared Schiff base of BOIH (4a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 85

Compound-4a N O CH 2 CONHN

N-methyl (4-Benzyloxy)-1H-Indole acid benzylidine-hydrazide


Molecular Formula: C 24 H 21 N 3 O 2 Molecular Weight: 383 gm/mole Melting Point: 134-136 o C (Uncorrected) Yield: 90%

Elemental Analysis %C %H %N Calculated 75.19 5.48 10.96 Found 75.20 5.50 11.00

Infrared Spectral Features around cm -1 1620-1640

35


cm -1 (C=

N) 3030-3080cm -1 (C-H of Aromatic) 2815-2860cm -1 (C-H of -OCH 2 -) 1590-1610 cm -1 (C=O) 3450-3460 (

N-H stretching) 1391

cm -1 (-NCH 2 CO)


Mass in m/z (+Ve) Molecular ion peak was observed at 384.3

NMR spectral Features (δ, ppm) 6.1-8.5 (

multiplet, aromatic, Indole +


CH of CH=N protons) 2.93 (2H of –CH 2 CONH) 4.2 (S, 2H, OCH 2 ) 13 CMR spectral Features (δ, ppm) 115-129 Benzene & Indole 153 CH=N 162 C=O

of Amide 56 -CH 2 CONH Chapter-4

Dept. of Chemistry, H. N. G.U. 86 Figure 4.1 IR spectrum of compound 4a Chapter-4 Dept. of Chemistry, H. N. G.U. 87


Figure 4.2

NMR spectrum of compound 4a Figure 4.3 CMR spectrum of compound 4a Chapter-4

Dept. of Chemistry, H. N. G.U. 88 Figure 4.4 MASS spectrum of compound 4a Chapter-4

Dept. of Chemistry, H. N. G.U. 89 Compound-4b N O CH 2 CONHN Br

N-methyl (4-Benzyloxy)-1H-Indole acid-(4-Bromo benzylidine)-hydrazide


Molecular Formula: C 24 H 20 N 3 O 2 Br Molecular Weight: 462 gm/mole Melting Point: 156-158 o C (Uncorrected) Yield: 85%

Elemental Analysis %C %H %N %Br Calculated 62.33 4.32 9.09 17.31 Found 62.30 4.30 9.00 17.30


cm -1 (C=


36


N-H stretching) 1391 cm -1 (-NCH 2 CO) 1065 cm -1 (-C-

Br)








Dept. of Chemistry, H. N. G.U. 90 Figure 4.5 IR spectrum of compound 4b Chapter-4 Dept. of Chemistry, H. N. G.U. 91


Figure 4.6 NMR spectrum of compound 4b Figure 4.7 CMR spectrum of compound 4b Chapter-4 Dept. of Chemistry, H. N. G.U. 92 Figure 4.8 MASS spectrum of compound 4b Chapter-4

Dept. of Chemistry, H. N. G.U. 93 Compound-4C N O CH 2 CONHN Cl

N-methyl (4-Benzyloxy)-1H-Indole acid-(4-Chloro benzylidine)-hydrazide


Molecular Formula: C 24 H 20 N 3 O 2 Cl Molecular Weight: 417.5 gm/mole Melting Point: 152-155 o C (Uncorrected) Yield: 87%

Elemental Analysis %C %H %N %Cl Calculated 68.98 4.79 10.05 8.50 Found 69.00 4.80 10.00 8.50


cm -1 (C=



Cl)



37







Dept. of Chemistry, H. N. G.U. 94 Compound-4d N O CH 2 CONHN NO 2 N-methyl (4-Benzyloxy)-1H-Indole acid-(4-Chloro benzylidine)-hydrazide





cm -1 (C=



NO 2 )








Dept. of Chemistry, H. N. G.U. 95 Compound-4e N O CH 2 CONHN OH

N-methyl (4-Benzyloxy)-1H-Indole acid-(4-Hydroxy benzylidine)-hydrazide


38





cm -1 (C=



OH)


Mass in m/z (+Ve) Molecular ion peak was observed at 400.4 NMR spectral Features (δ, ppm) 6.6-8.5 (


CH of CH=N protons) 2.43 (2


H of –CH 2 CONH) 4.2 (S, 2H, OCH 2 ) 11.2 (S, H, OH) 13 CMR spectral Features (δ, ppm) 115-129 Benzene & Indole 153 CH=N 162 C=O

of Amide 56 -CH 2 CONH Chapter-4 Dept. of Chemistry, H. N. G.U. 96 Compound-4f N O CH 2 CONHN OMe N-methyl (4-Benzyloxy)-1H-Indole acid-(4-methoxy benzylidine)-hydrazide




cm -1 (C=



OCH 3 )




39



CH of CH=N protons) 2.43 (2H of –CH 2 CONH) 4.20 (S, 2H, OCH 2 ) 4.30 (S, H, OCH 3 ) 13 CMR spectral Features (δ, ppm) 115-129 Benzene &

Indole 153 CH=N 162 C=O


Dept. of Chemistry, H. N. G.U. 97 4.2 Characterization of 2-Azetidinones of (4-Benzyloxy)-1H-Indole (5a-f) The Azetidinone derivatives of (4-Benzyloxy)-1H-Indole (5a-f) were synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared azetidinones of BOIH (5a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 98 Compound-5a N O CH 2 CONH N O Cl

1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-Phenyl azetidin-2-ones



Elemental Analysis %C %H %N %Cl Calculated 67.90 4.78 9.14 7.72 Found 68.00 4.70 9.10 7.70 Infrared Spectral Features in cm -1 1697

cm -1

CO stretching of azetidinone Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 460.7 1


H-

NMR

spectral Features (δ, ppm) 7.4-7.8 (m, aromatic, Indole) 10.8 (s, 1H, -CONH) 4.2 (s, 2

H, OCH 2 ) 3.1 (d, 1H, C 3 -H azetidinones) 3.0 (d, 1H, C 4 -H azetidinones) 2.83 (s, 2H,

CH 2

CONH) 13 C-NMR spectral Features (δ, ppm) 114-130 Benzene &

Indole 48, 144, 153 β-lactam 169 CO of β-lactam Chapter-4 Dept. of Chemistry, H. N. G.U. 99 Figure 4.9 IR spectrum of compound 5a Chapter-4 Dept. of Chemistry, H. N. G.U. 100


Figure 4.10



40


Figure 4.12 MASS spectrum of compound 5a Chapter-4


Compound-5b N O CH 2 CONH N O Cl Br

1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-(4-bromo Phenyl) – azetidin-2-ones


Molecular Formula: C 26 H 21 N 3 O 3 Cl Br

Molecular Weight: 538.5 gm/mole Melting Point: 134-135 o C (Uncorrected) Yield: 65% Elemental Analysis %C %H %N %

Cl % Br Calculated 57.93 3.90 7.80 6.59 14.85 Found 58.00 3.90 7.80 6.50 14.80 Infrared Spectral Features

in cm -1 1697

cm -1 CO stretching of azetidinone Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 539.8 1


H-

NMR



CH 2


Indole 48, 143, 153 β-lactam 169 CO of β-lactam Chapter-4 Dept. of Chemistry, H. N. G.U. 103

Figure 4.13 IR spectrum of compound 5b Chapter-4 Dept. of Chemistry, H. N. G.U. 104


Figure 4.14 NMR spectrum of compound 5b Figure 4.15 CMR spectrum of compound 5b Chapter-4 Dept. of Chemistry, H. N. G.U. 105

Figure 4.16 MASS spectrum of compound 5b Chapter-4


Compound-5C N O CH 2 CONH N O Cl Cl

1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-(4-chloro Phenyl) – azetidin-2-ones

41



Molecular Formula: C 26 H 21 N 3 O 3 Cl 2 Molecular Weight: 494 gm/mole Melting Point: 170-173 o C (Uncorrected) Yield: 58%


cm -1



H-

NMR



CH 2



Compound-5d N O CH 2 CONH N O Cl NO 2 1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-(4-nitro Phenyl) – azetidin-2-ones




cm -1



H-

NMR


42



CH 2



Compound-5e N O CH 2 CONH N O Cl OH

1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-(4-hydroxy Phenyl) – azetidin-2-ones




cm -1


H-


NMR



CH 2

CONH) 11.2 (s, H, -OH) 13 C-NMR spectral Features (δ, ppm) 114-130

Benzene &

Indole 48, 143, 153 β-lactam 169 CO of β-lactam 157 Aromatic C-OH Chapter-4 Dept. of Chemistry, H. N. G.U. 109

Compound-5f N O CH 2 CONH N O Cl OMe 1-[N-acetamido-4-benzyloxy-1H-Indole]-3-chloro-4-(4-methoxy Phenyl) – azetidin-2-ones




43


cm -1



H-

NMR



CH 2

CONH) 3.7 (s, 3H, -OCH 3 ) 13 C-NMR spectral Features (δ, ppm) 114-130

Benzene &

Indole 48, 143, 153 β-lactam 169 CO of β-lactam 54 O-CH 3 Chapter-4 Dept. of Chemistry, H. N. G.U. 110 4.3 Characterization of 4-Thiazolidinones of (4-Benzyloxy)-1H- Indole (6a-f) The Thiazolidinone derivatives of (4-Benzyloxy)-1H-Indole (6a-f) were synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared thiazolidinones of BOIH (6a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 111

Compound-6a N O CH 2 CONH S N O

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-Phenyl-1,3-thiazolidin-4-ones


Molecular Formula: C 26 H 23 N 3 O 3 S Molecular Weight: 457 gm/mole

Melting Point: 158-160 o C (Uncorrected) Yield: 63%

Elemental Analysis %C %H %N %S Calculated 68.27 5.03 9.19 7.00 Found 68.30 5.00 9.20 7.00 Infrared Spectral Features in cm -1 1686

cm -1

CO of thiazolidinone Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 458.7 1


H-

NMR spectral Features (δ, ppm) 6.2-7.8 (m, Aromatic & Indole + NH of CONH) 5.35 (S, H, C 2 -H thiazolidinone) 3.1 (S, 2H, CH 2 thiazolidinone) 4.2 (S, 2H, -OCH 2 ) 2.93 (S, 2H, -CH 2


44


Indole 48, 56 CH 2 of thiazolidinone 169 CO of thiazolidinone Chapter-4 Dept. of Chemistry, H. N. G.U. 112

Figure 4.17 IR spectrum of compound 6a Chapter-4 Dept. of Chemistry, H. N. G.U. 113


Figure 4.18





Compound-6b N O CH 2 CONH S N O Br

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-bromo Phenyl)-1,3-thiazolidin-4-ones


Molecular Formula: C 26 H 22 N 3 O 3 SBr Molecular Weight: 536 gm/mole Melting Point: 134-135 o C (Uncorrected) Yield: 65% Elemental Analysis %C %H %N %

S %Br Calculated 58.20 4.10 7.83 5.97 14.92 Found 58.20 4.10 7.80 6.00 15.00 Infrared Spectral Features

in cm -1 1686

cm -1 CO of thiazolidinone Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 537.2 1


H-







45




Compound-6C N O CH 2 CONH S N O Cl

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-chloro Phenyl)-1,3-thiazolidin-4-ones


Molecular Formula: C 26 H 22 N 3 O 3 SCl Molecular Weight: 491.5 gm/mole Melting Point: 170-173 o C (Uncorrected) Yield: 58% Elemental Analysis %C %H %N %

S %Cl Calculated 63.47 4.47 8.54 6.51 7.22 Found 63.50 4.50 8.50 6.50 7.20 Infrared Spectral Features

in cm -1 1686

cm -1 CO of thiazolidinone Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 492.7 1


H-




Compound-6d N O CH 2 CONH S N O NO 2 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-nitro Phenyl)-1,3-thiazolidin-4-ones





cm -1



H-

46





Compound-6e N O CH 2 CONH S N O OH

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-hydroxy Phenyl)- 1,3-thiazolidin-4-ones





cm -1



H-

NMR

spectral Features (δ, ppm) 6.2-7.8 (m, Aromatic & Indole + NH of CONH) 5.35 (S, H, C 2 -H thiazolidinone) 3.1 (S, 2H, CH 2 thiazolidinone) 4.2 (S, 2H, -OCH 2 ) 2.93 (S, 2H, -CH 2


Benzene &

Indole 48, 56 CH 2 of thiazolidinone 169 CO of thiazolidinone 157 Aromatic C-OH Chapter-4 Dept. of Chemistry, H. N. G.U. 122

Compound-6f N O CH 2 CONH S N O OMe 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-methoxy Phenyl)- 1,3-thiazolidin-4-ones





47


cm -1



H-

NMR


CONH) 3.7 (S, 3H, -OCH 3 ) 13 C-NMR spectral Features (δ, ppm) 114-130 Benzene &

Indole 48, 56 CH 2 of thiazolidinone 169 CO of thiazolidinone 54 O-CH 3 Chapter-4 Dept. of Chemistry, H. N. G.U. 123

4.4 Characterization of 5-Arylidine-4-Thiazolidinones of (4-Benzyloxy)-1H-Indole (7a-f) The 5-Arylidine-4-Thiazolidinone derivatives of (4-Benzyloxy)-1H-Indole (7a-f) were synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared 5-Arylidine-4-thiazolidinones of BOIH (7a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 124

Compound-7a N O CH 2 CONH S N O Br

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-Phenyl-5-(4-bromo benzylidine)- 1,3-thiazolidin-4-ones



S %Br Calculated 63.46 4.16 6.73 5.12 12.82 Found 63.50 4.10 6.70 5.10 12.80 Infrared Spectral Features cm -1 1050

C-

Br of bromobenzene 3030 =C=CH- of arylidene Other bands as mentioned in parent 4-Thiazolidinone derivatives. Mass in m/z (+Ve) Molecular ion peak was observed at 625.1 NMR spectral Features (?, ppm) 6.12-7.85 (multiplet, aromatic & Indole) 3.54 (2H of –CH 2 CONH) 5.35 (H of C 2 H for thiazolidinone) 6.70 (H of =C=CH- in thiazolidinone) CMR spectral Features (?, ppm) 113-130 Aromatic 169 C=O (Thiazolidinone) 177 C=O of -CONH 46 CH of ring 36 CH 2 CONH 123 C-Br Chapter-4 Dept. of Chemistry, H. N. G.U. 125



Figure 4.26


48





Compound-7b N O CH 2 CONH S N O Br Br

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-bromo Phenyl)-5-(4-bromo benzylidine)-1,3-thiazolidin-4-ones


Molecular Formula: C 33 H 25 N 3 O 3 SBr 2 Molecular Weight: 703 gm/mole Melting Point: 185-187 o C (Uncorrected) Yield: 84% Elemental Analysis %C %H %N %


C-







Compound-7C N O CH 2 CONH S N O Br Cl

3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-chloro Phenyl)-5-(4-bromo benzylidine)-1,3-thiazolidin-4-ones


Molecular Formula: C 33 H 25 N 3 O 3 SBrCl Molecular Weight: 658.5 gm/mole Melting Point: 207-209 o C (Uncorrected) Yield: 83% Elemental Analysis %C %H %N %

S %

Br %Cl Calc. 60.13 3.79 6.37 4.85 12.14 5.39 Found 60.10 3.80 6.40 4.80 12.10 5.40 Infrared Spectral Features cm -1 1050

49


C-


Compound-7d N O CH 2 CONH S N O Br NO 2 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-nitro Phenyl)-5-(4-bromo benzylidine)- 1,3-thiazolidin-4-ones




C-

Br of bromobenzene 3030 =C=CH- of arylidene Other bands as mentioned in parent 4-Thiazolidinone derivatives. Mass in m/z (+Ve) Molecular ion peak was observed at 670.7 NMR spectral Features (?, ppm) 6.12-7.85 (multiplet, aromatic & Indole) 3.54 (2H of –CH 2 CONH) 5.35 (H of C 2 H for thiazolidinone) 6.70 (H of =C=CH- in thiazolidinone) CMR spectral Features (?, ppm) 113-130 Aromatic 169 C=O (Thiazolidinone) 177 C=O of -CONH 46 CH of ring 36 CH 2 CONH 123 C-Br Compound-7e Chapter-4 Dept. of Chemistry, H. N. G.U. 134 N O CH 2 CONH S N O Br OH 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-hydroxy Phenyl)-5-(4-bromo benzylidine)-1,3-thiazolidin-4-ones




C-

Br of bromobenzene 3030 =C=CH- of arylidene Other bands as mentioned in parent 4-Thiazolidinone derivatives. Mass in m/z (+Ve) Molecular ion peak was observed at 641.7 NMR spectral Features (?, ppm) 6.12-7.85 (multiplet, aromatic & Indole) 3.54 (2H of –CH 2 CONH) 5.35 (H of C 2 H for thiazolidinone) 6.70 (H of =C=CH- in thiazolidinone) 11.2 (s, H, -OH) CMR spectral Features (?, ppm) 113-130 Aromatic 169 C=O (Thiazolidinone) 177 C=O of -CONH 46 CH of ring 36 CH 2 CONH 123 C-Br 157 Aromatic C-OH Compound-7f Chapter-4 Dept. of Chemistry, H. N. G.U. 135 N O CH 2 CONH S N O Br OMe 3-[N-acetamido-4-benzyloxy-1H-Indole]-2-(4-methoxy Phenyl)-5-(4-bromo benzylidine)-1,3-thiazolidin-4-ones


50




C-

Br of bromobenzene 3030 =C=CH- of arylidene Other bands as mentioned in parent 4-Thiazolidinone derivatives. Mass in m/z (+Ve) Molecular ion peak was observed at 654.2 NMR spectral Features (?, ppm) 6.12-7.85 (multiplet, aromatic & Indole) 3.54 (2H of –CH 2 CONH) 5.35 (H of C 2 H for thiazolidinone) 6.70 (H of =C=CH- in thiazolidinone) 3.7 (s, 3H, -OCH 3 ) CMR spectral Features (?, ppm) 113-130 Aromatic 169 C=O (Thiazolidinone) 177 C=O of -CONH 46 CH of ring 36 CH 2 CONH 123 C-Br 54 O-CH 3 Chapter-4 Dept. of Chemistry, H. N. G.U. 136 4.5 Characterization of 1-[N-acetamido-4-benzyloxy-1H-Indole]-5- substituted phenyl-1H-tetrazoles (9a-f) The Tetrazole derivatives (9a-f) of (4-Benzyloxy)-1H-Indole were synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared Tetrazoles of BOIH (9a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 137


Compound-9a N O CH 2 CONH N N N N

1-[N-acetamido-4-benzyloxy-1H-Indole]-5-phenyl-1

H-tetrazoles

Molecular Formula: C 24 H 20 N 6 O 2 Molecular Weight: 424 gm/mole Melting Point: 160-162 o C (Uncorrected) Yield: 58% Elemental Analysis %C %H %N Calculated 67.92 4.71 19.81 Found 68.00 4.70 19.80 Infrared Spectral Features (cm -1 ) ~1040

N-

N of tetrazole 1385-1425 N=N of tetrazole Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 425.2 1 H NMR spectral Features (?, ppm) 7.0-9.12 (multiplet, aromatic) 13 C NMR spectral Features (?, ppm) 113-130 Aromatic 143 Tetrazole Chapter-4 Dept. of Chemistry, H. N. G.U. 138



Figure 4.34





Compound-9b N O CH 2 CONH N N N N Br

1-[N-acetamido-4-benzyloxy-1H-Indole]-5-(4-bromo phenyl)-1

51



H-tetrazoles

Molecular Formula: C 24 H 19 N 6 O 2 Br Molecular Weight: 503 gm/mole


Elemental Analysis %C %H %N % Br Calculated 57.25 3.77 16.70 15.90 Found 57.30 3.80 16.70 16.00 Infrared Spectral Features (cm -1 ) ~1040

N-




Figure 4.38





Compound-9C N O CH 2 CONH N N N N Cl

1-[N-acetamido-4-benzyloxy-1H-Indole]-5-(4-chloro phenyl)-1


H-tetrazoles

Molecular Formula: C 24 H 19 N 6 O 2 Cl Molecular Weight: 458.5 gm/mole


Elemental Analysis %C %H %N % Cl Calculated 62.81 4.14 18.32 7.74 Found 63.00 4.10 18.30 7.70 Infrared Spectral Features (cm -1 ) ~1040

N-


52


Compound-9d N O CH 2 CONH N N N N NO 2 1-[N-acetamido-4-benzyloxy-1H-Indole]-5-(4-nitro phenyl)-1


H-tetrazoles


N-


Compound-9e N O CH 2 CONH N N N N OH 1-[N-acetamido-4-benzyloxy-1H-Indole]-5-(4-hydroxy phenyl)-1


H-tetrazoles


N-

N of tetrazole 1385-1425 N=N of tetrazole Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 441.4 1 H NMR spectral Features (?, ppm) 7.0-9.12 (multiplet, aromatic) 11.2 (s, H, -OH) 13 C NMR spectral Features (?, ppm) 113-130 Aromatic 143 Tetrazole 157 Aromatic C-OH Chapter-4 Dept. of Chemistry, H. N. G.U. 148

Compound-9f N O CH 2 CONH N N N N OMe 1-[N-acetamido-4-benzyloxy-1H-Indole]-5-(4-methoxy phenyl)-1


H-tetrazoles


N-

N of tetrazole 1385-1425 N=N of tetrazole Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 455.4 1 H NMR spectral Features (?, ppm) 7.0-9.12 (multiplet, aromatic) 3.7 (s, 3H, -OCH 3 ) 13 C NMR spectral Features (?, ppm) 113-130 Aromatic 143 Tetrazole 54 O-CH 3 Chapter-4 Dept. of Chemistry, H. N. G.U. 149

53


4.6 Characterization of 3-[N-acetamido-4-benzyloxy-1H-Indole]- 2,6-diphenyl-1,3,5-oxadiazine-4-thione (10a-f) The 1,3,5-oxadiazine derivatives (10a-f) of (4-Benzyloxy)-1H-Indole were synthesized and details procedure was describe in chapter-3. Here, in this section describes the characterization data of prepared 1,3,5-oxadiazine of BOIH (10a-f). Chapter-4 Dept. of Chemistry, H. N. G.U. 150

Compound-10a N O CH 2 CONH N N O S

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2,6-diphenyl-1,3,5-oxadiazine-4-

thione




Elemental Analysis %C %H %N %S Calculated 70.32 4.76 10.25 5.86 Found 70.30 4.70 10.20 5.90 Infrared Spectral Features (cm -1 ) 1000-1400

C-

N of oxadiazine 1350 C=S of oxadiazine 1300 C-O-C

of oxadiazine Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 547.4 1 H NMR spectral Features (δ, ppm) 7.5-9.5 (Multiplet, aromatic) 4.3 (s, 1H, C 2 H of Oxadiazole) 13 C NMR spectral Features (δ, ppm) 148-152 Indole 110-130 Benzene 169 O – C = N 86 O – C – N 166 C = S Chapter-4 Dept. of Chemistry, H. N. G.U. 151



Figure 4.42





Compound-10b N O CH 2 CONH N N O S Br

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2-(4-bromo phenyl)-6-phenyl-1,3,5- oxadiazine-4-


thione

Molecular Formula: C 32 H 25 N 4 O 3 SBr Molecular Weight: 625 gm/mole


54



C-





Figure 4.46





Compound-10C N O CH 2 CONH N N O S Cl

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2-(4-chloro phenyl)-6-phenyl-1,3,5- oxadiazine-4-


thione

Molecular Formula: C 32 H 25 N 4 O 3 SCl Molecular Weight: 580.5 gm/mole



C-



Compound-10d N O CH 2 CONH N N O S NO 2

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2-(4-Nitro phenyl)-6-phenyl-1,3,5- oxadiazine-4-

thione

55






C-



Compound-10e N O CH 2 CONH N N O S OH

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2-(4-hydroxy phenyl)-6-phenyl-1,3,5- oxadiazine-4-

thione





C-


of oxadiazine Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 592.4 1


H NMR spectral Features (δ, ppm) 7.5-9.5 (Multiplet, aromatic) 4.3 (s, 1H, C 2 H of Oxadiazole) 5.2 (s, 1H of OH) 13 C NMR spectral Features (δ, ppm) 148-152 Indole 110-130 Benzene 169 O – C = N 86 O –

C – N 166 C = S 157 Aromatic C-OH Chapter-4 Dept. of Chemistry, H. N. G.U. 161

Compound-10f N O CH 2 CONH N N O S OMe

3-[N-acetamido-4-benzyloxy-1H-Indole]- 2-(4-methoxy phenyl)-6-phenyl-1,3,5- oxadiazine-4-

thione

56






C-


of oxadiazine Other bands as mentioned in parent Schiff base. Mass in m/z (+Ve) Molecular ion peak was observed at 577.4 1 H NMR spectral Features (δ, ppm) 7.5-9.5 (Multiplet, aromatic) 4.3 (s, 1H, C 2 H of Oxadiazole) 3.7 (s, 1H of OCH 3 ) 13 C NMR spectral Features (δ, ppm) 148-152 Indole 110-130 Benzene 169 O – C = N 86 O – C – N 166 C = S 54 O-CH 3 Chapter-4 Dept. of Chemistry, H. N. G.U. 162

Section-B Characterization data of Irbesartan prepared by newer route 4.7 Characterization of Irbesartan and its intermediate. Irbesartan was prepared by new route where 2-butyl-1,3-diazaspiro[4,4]non-1- en-4-one hydrochloride was condensed with 4'-(bromomethyl)biphenyl-2-carbonitrile in presence of NaOH, toluene and water to form condensed product (Intermediate-1) which under goes cyclization for tetrazole formation in presence of Sodium azide and TBAB (Tetra n-butyl ammonium bromide) to yield crude Irbesartan. Lastly crude product was purified in special denature spirit (5-10% moisture containing ethanol), Liq. Ammonia and sulfuric acid to yield Irbesartan pure. Hence, here in this section characterization data of Irbesartan pure was discussed. It includes IR, 1 H NMR, elemental and finally by Mass analysis. Prepared Irbesartan pure also analyzed by High performance liquid chromatography to know the quality of compounds and related substance i.e. impurity present in product. The HPLC graph depicted in figure 4.52. Route of Synthesis for Irbesartan depicted below, Chapter-4 Dept. of Chemistry,

H. N. G.U. 163


N N O H Br CN CN


H + 2-

butyl-1,3-diazaspiro[4,4]non-1-en-4-one Hydrochloride 4'-(bromomethyl)biphenyl-2-carbonitrile NaOH, TBAB, Toluene, water NaN 3 , TEA.HCl, NaNO2, Xylene Irbesartan Technical Liq. Ammonia, Sulfuric acid Irbesartan Pure Yield = 95% Yield = 85% Overall Yield = 80.75%

Scheme-4.1 Novel Route for synthesis of Irbesartan Chapter-4 Dept. of Chemistry, H. N. G.U. 164

Irbesartan pure N N O N N N N


57


H

Molecular Formula: C 25 H 28 N 6 O Molecular Weight: 428 gm/mole

Melting Point: 180-182 o C (Uncorrected) Yield: 80.75%

Elemental Analysis %C %H %N Calculated 70.00 6.53 19.60 Found 70.00 6.50 19.80 Infrared Spectral Features (cm -1 ) 1647

cm -1 (C=

O of O=C-N=) 3280

cm -1 (N-H of Tetrazole) 1040 cm -1 (

N-N of Tetrazole) 1450 cm -1 (N=N


of Tetrazole) 1590 cm -1 (C=N of Tetrazole) 1220 cm -1 (C-N of Tetrazole and Imidazole) 2810 cm -1 (N-CH 2 N-CH 2 Linkage) 3030-3080 cm -1 (C-H of Aromatic) Mass in m/z (+Ve) Molecular ion peak was observed at 429.5 1 H NMR spectral Features (δ, ppm) 0.86

ppm (CH 3 of Butane chain) 1.33 ppm (CH 2 of Butane chain) 3.5 ppm (CH 2 of N-CH 2 - linkage) 6.8 – 7.8 ppm (C-H of Aromatic) 2.12 ppm (N-H of Tetrazole) 1.51 ppm (CH 2 of cyclopentane) Chapter-4 Dept. of Chemistry, H. N. G.U. 165

Figure 4.49 IR spectrum of Irbesartan pure Chapter-4 Dept. of Chemistry, H. N. G.U. 166

Figure 4.50 NMR spectrum of Irbesartan pure Chapter-4 Dept. of Chemistry, H. N. G.U. 167

Figure 4.51 MASS spectrum of Irbesartan pure Chapter-4 Dept. of Chemistry, H. N. G.U. 168

Figure 4.52 HPLC graph of Irbesartan pure Chapter-4 Dept. of Chemistry, H. N. G.U. 169

Section-C Synthesis of Pioglitazone hydrochloride by newer improved route 4.8 Characterization of Pioglitazone hydrochloride and its intermediate. Pioglitazone hydrochloride was prepared by new route where 5-ethyl-2- pyridine ethanol were condensed with 4-hydroxy benzaldehyde in presence of methane sulfonyl chloride in presence of Tri ethyl amine and toluene at 0-5 0 C temperature to yield 4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzaldehyde as a oil. Further this oil condensed with 2,4-thiazolidinone in presence of Liq. Ammonia and methanol solvent to give 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidine}-2,4-thiazolidinone, which further reduced using sodium borohydride to give pure crystal of 5-{4-[2-(5- ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinone [Pioglitazone Base]. Pioglitazone base taken in acetone in resulting clear solution HCl gas was purged to give white crystals of Pioglitazone hydrochloride. Here in this section characterization data of Pioglitazone hydrochloride was discussed. It includes IR, 1 H NMR, elemental and finally by Mass analysis. Prepared Pioglitazone hydrochloride also analyzed by High performance liquid chromatography to know the quality of compounds and related substance i.e. impurity present in product. The HPLC graph depicted in figure 4.56. Route of Synthesis for Pioglitazone hydrochloride depicted below, Chapter-4 Dept. of Chemistry, H. N. G.U. 170

N OH OH CHO

N O CHO NH S O

58




O

CH 3 SO 2 Cl TEA, Toluent, 0-5C 2,4-thiazolidinone Liq NH 3 , Methanol Reflux Pioglitazone Methanol, water NaOH, NaBH 4 15-17C HCl HCl Pioglitazone Hydrochloride

Scheme-4.2 Novel Route for synthesis of Pioglitazone HCl Chapter-4 Dept. of Chemistry, H. N. G.U. 171

Pioglitazone hydrochloride NH S O O N O HCl


Molecular Formula: C 19 H 21 N 2 O 3 SCl Molecular Weight: 356.44 gm/mole Melting Point: 183-185 o C (Uncorrected) Yield: 73 %

Elemental Analysis %C %H %N %S Calculated 63.96 5.61 7.85 8.98 Found 64.00 5.60 7.80 9.00 Infrared Spectral Features (cm -1 ) 1730

cm -1 C=

O of S-CO-NH 1735 cm -1 CH-CO-NH 2850 cm -1 C-

O of –O-CH 2 - linkage 3410 cm -1 N-H of thiazolidinone 1670 cm -1 C=N of pyridine ring 2920 cm -1 CH 2 and CH 3 of Alkane chain Mass in m/z (+Ve) Molecular ion peak was observed at 357.3 1 H NMR spectral Features (δ, ppm) 8.00 ppm N-H of thiazolidinone ring 4.7 ppm CH of thiazolidinone ring 7.0 -7.6 ppm CH of Aromatic and Pyridine 0.91,1.33 ppm CH 3 and CH 2 proton 3.37 ppm -O-CH 2 - of linkage Chapter-4 Dept. of Chemistry, H. N. G.U. 172

Figure 4.53 IR spectrum of Pioglitazone Hydrochloride Chapter-4 Dept. of Chemistry, H. N. G.U. 173

Figure 4.54 NMR spectrum of Pioglitazone hydrochloride Chapter-4 Dept. of Chemistry, H. N. G.U. 174

Figure 4.55 MASS spectrum of Pioglitazone hydrochloride Chapter-4 Dept. of Chemistry, H. N. G.U. 175

Figure 4.56 HPLC graph of Pioglitazone hydrochloride Chapter-5 Analytical method validation data of Active pharmaceutical ingredients and Antimicrobial activity of produced novel compounds Chapter-5 Dept. of Chemistry, H. N. G.U. 176 Chapter-5 Analytical method validation data of Active pharmaceutical ingredients and Antimicrobial and Antifungal activity of produced novel compounds The chapter-4 deals with the characterization data of various (4-Benzyloxy)- 1H-Indole derivatives like Schiff base, 2-Azetidinones, 4-Thiazolidinones, 5- Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazole derivatives and Characterization data of Irbesartan and Pioglitazone hydrochloride by newer route. Here, present chapter deals with the Analytical method validation data of Irbesartan and Pioglitazone hydrochloride and Antimicrobial activity of various (4- Benzyloxy)-1H-Indole derivatives like Schiff base, 2-Azetidinones, 4- Thiazolidinones, 5-Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazoles. In this context, whole chapter is divided into two sections. Section – A comprises the Analytical method validation data of Irbesartan and Pioglitazone hydrochloride and Section – B comprises the Antimicrobial activity of various (4-Benzyloxy)- 1H-Indole derivatives like

59


Schiff base, 2-Azetidinones, 4-Thiazolidinones, 5- Arylidine derivatives, 1,3,5-Oxadiazines and Tetrazoles. Chapter-5 Dept. of Chemistry, H. N. G.U. 177

Section-A Analytical method validation data of Active Pharmaceutical ingredients [i.e. Irbesartan and Pioglitazone hydrochloride] 5.1 Analytical method of Analysis for Pioglitazone hydrochloride Specification: Impurity at RRT 0.7: Not more than 0.2% Impurity at RRT 1.4: Not more than 0.2% Impurity at RRT 3.0: Not more than 0.2% Any other individual impurities: Not more than 0.1% Total Impurities: Not more than 0.5% Method: Apparatus: HPLC, pH meter and Analytical balance Reagents and chemicals: ? Ammonium acetate ? Acetic acid ? Methanol (HPLC grade) ? Acetonitrile (HPLC grade) ? Distilled water Standards: Pioglitazone Hydrochloride WS Chapter-5 Dept. of Chemistry, H. N. G.U. 178

Mobile phase Preparation: Buffer preparation: Dissolve 7.7 gm of Ammonium acetate in 1000 ml of distilled water. Mobile Phase: Buffer: Acetonitrile: Acetic acid (25:25:1) System solubility solution: Accurately weigh and transfer about 25 mg of Pioglitazone hydrochloride WS and 6.5 mg of Benzophenone WS in 50 ml volumetric flask, dissolve in 20 ml methanol and make up to the mark with methanol. Take 1 ml of this solution in 20 ml volumetric flask and dilute up to the mark with mobile phase. Test Solution: Accurately weigh and transfer about 20 mg of Pioglitazone hydrochloride test sample in 100 ml of volumetric flask and dissolve it with 20 ml of methanol and mark up to the 100 ml with mobile phase. Standard solution: Accurately weigh and transfer about 20 mg of Pioglitazone hydrochloride WS in 100 ml of volumetric flask and dissolve it with 20 ml of methanol and mark up to the 100 ml with mobile phase (Test solution). Pipette 1 ml of this solution in 200 ml volumetric flask and dilute up to the mark with mobile phase. System suitability requirements: Resolution: Not less than 10 between Pioglitazone and benzophenone peak, system suitability solution. Chapter-5 Dept. of Chemistry, H. N. G.U. 179

Relative standard deviation: Not more than 2%, standard solution Chromatographic conditions: Column A stainless steel column, packed with octadecylsilanized silica gel, 4.6 mm X 15 cm, 5 μm Flow rate 0.7 ml / minute Detector An ultraviolet absorption photometer Wavelength 269 nm Injection volume 40 μl Run time 30 minutes Column temperature Constant at 25 0 C Retention time About 7 minutes Impurity at RRT About 0.7 with reference to pioglitazone Impurity at RRT About 1.4 with reference to pioglitazone Impurity at RRT About 3.0 with reference to pioglitazone Procedure: Sr. No. Injection sequence No. of injections 1 Blank 1 2 System suitability solution 1 3 Standard solution 6 4 Test solution 2 5 Blank 1 Calculation: % Impurity = R y / R s X 0.5 Where, R Y = Peak area of each Impurity from test solution R S = Pioglitazone peak area for standard solution Chapter-5 Dept. of Chemistry, H. N. G.U. 180

5.2 Analytical method of Analysis for Irbesartan Irbesartan is official in European Pharmacopoeia and United State Pharmacopoeia. Chromatographic methods The high-pressure liquid chromatography (HPLC)for residue determination and simultaneous estimation of single and combination drug and also used in impurity profiling. HPTLC method is widely usedchromatographic methods in the analysis of irbesartan in plasma and pharmaceutical dosage form. RP HPLC method also developed for determination of concentration of irbesartan in human serum and also for simultaneous determination in synthetic mixture, combination dosage form like hydrochlorthaizide, losartan, valsartan. UP-HPLC is used for determination of combination of hydrochlorthiazide and irbesartan. Stability indicating method Stability indicating method is used to check out the stability of drug in various conditions. Here Irbesartan is studied by RP-HPLC, HPTLC, and also LC/MS/MS for stability study. Chromatographic conditions: Column A stainless steel column, packed with octadecylsilanized silica gel, 4.6 mm X 15 cm, 5 μm Flow rate 0.7 ml / minute Detector An ultraviolet absorption photometer Wavelength 245 nm Injection volume 45 μl Run time 60 minutes Column temperature Constant at 25 0 C Retention time About 7 minutes Chapter-5 Dept. of Chemistry, H. N. G.U. 181

Mobile Phase: United state pharmacopeia Phosphate buffer (pH = 3.2) : acetonitrile (63:37 v/v) as mobile phase and column is (25mm X 4 mm, 2.5 micron) European pharmacopeia Solvent is used

60


0.1 M perchloric acid determining the end point potentiometrically Apparatus: HPLC, pH meter and Analytical balance Procedure: Sr. No. Injection sequence No. of injections 1 Blank 1 2 System suitability solution 1 3 Standard solution 6 4 Test solution 2 5 Blank 1 Chapter-5 Dept. of Chemistry, H. N. G.U. 182

Section-B Antimicrobial and Antifungal activity of produced novel compounds i.e. various (4-Benzyloxy)-1H-Indole derivatives In vivo tests are used as screening procedure for new agents and for testing the susceptibility of individual isolates from infections to determine which of the available drugs might be useful therapeutically. Due to the development of sulphonamides and penicillin’s in vivo measurement of susceptibility of microorganism to chemotherapeutic agents has been in use. In general any compound or drug which inhibits the growth or causes the death of micro-organisms is known as anti microbial agent. Any drug which inhibits the growth of bacteria and fungi it is said to possess bacteriostatic activity respectively. If it kills the bacteria or fungi, it is said to possess bactericidal or fungicidal activity. Important factors for the antimicrobial activity are size of inoculum, metabolic state of organisms, pH, Temperature, duration of infection, concentration of inhibitor and presence of interfering substances. In vivo tests are used as screening procedure for new antimicrobial agents and for testing the susceptibility of individual isolates from infections, to determine which of the available drugs might be useful therapeutically. Sensitivity testing is done to determine the range of microorganisms that are susceptible to the compound under specified conditions. It can be done by disk diffusion method. This method is suitable for the organisms that grow well overnight such as most of the common aerobes and facultative anaerobes and rapidly growing fungi. Several forms of disk diffusion methods have been adopted. Among the Kirby-bauer method is the official method of the USA Food and Drug Administration. Prior to the disk diffusion method, MIC of the test compounds was determined by agar dilution method [136,137]. Chapter-5 Dept. of Chemistry, H. N. G.U. 183

5.3 Determination of MIC by agar dilution method:

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Graded concentrations of the test compounds were prepared by serial dilution and added into appropriate agar medium. A suitably diluted suspension of

a


test organism was inoculated, in the form of tiny drops, on the surface of

the


agar medium. After incubation, presence / absence of the growth of organism on the agar medium was observed and from the results, the MIC of the test compounds was calculated. Procedure: Six test tubes were labeled 1 to 6

and 2 ml of dimethyl formamide (DMF) was transferred into tube 1 and 1 ml each in the remaining 5 tubes. All the


61


tubes were plugged with non-absorbent cotton wool and sterilized by autoclaving at 121 0 c for 20 minutes. 32 mg of the test compound was aseptically transferred and dissolved in tube-1. From this 1 ml of

the solution was transferred to the


test tube-2 and mixed well. This process is repeated 6 times and 1 ml of the solution from the tube 6 was discarded. 15 ml molten Mueller Hinton agar fluid sabouraud’s dextrose agar [138] was aseptically added into each test tube,


mixed well, aseptically poured into a sterile Petri dish and

the


medium was allowed to solidify. Each plate was divided into four quadrants. Each quadrants was inoculated with a different test organism 10 drops of suitably diluted suspension (10 6 cells/ml) of the test organism (bacterial cultures on

Mueller Hilton agar and


fungal culture on sabouraud’s agar) was inoculated on the surface of the agar medium, in the form of tiny droplets, using a sterile 1 ml syringe with 24 gauge needle. A positive control was prepared in a similar way except that the test compound was not added into the agar medium. A negative control was prepared in a similar way except that the test compound was not added and the tube was not inoculated with test organism. All plates were

incubated aerobically at 37 0 C for 24 hours and tubes inoculated with fungal cultures were incubated aerobically at 25 0 C for Chapter-5 Dept. of Chemistry, H. N. G.U. 184 48 hours. The tubes were observed for the presence or absence of growth in the form of colonies and the results are given in table. Concentration of the test compounds in Petri plates. 5.4 Determination of Antimicrobial activity: Modified Kirby-Bauer method was used for the evaluation of antimicrobial activity of the synthesized compounds. Circular paper disks of 6 mm diameter were impregnated with the specified amount of the test sample and were placed on a Mueller Hinton agar medium in a Petri plate, which was inoculated on its surface with one of the test organisms. After incubation, the plates were observed for the growth inhibition zones around paper disk. The diameter of the zone of inhibition is proportional to the antimicrobial activity of the substance. The diameters of the zones of inhibition were compared with that produced by the standard antibiotics [139]. All the test compounds were at 50 μg level. To obtain this, solutions containing 10 mg/ml of the test compounds were prepared in sterile dimethyl formamide (DMF) and 5 μl each of the solutions were added into each disk using a micropipette. Ampicillin (10 μg) was used as standard antibiotics. All solutions were prepared in aseptic conditions. Plate number 1 2 3 4 5 6 Concentration (μg/ml) 1000 500 250 125 63 31 Chapter-5 Dept. of Chemistry, H. N. G.U. 185

Preparation of Mueller Hinton agar/ sabouraud’s agar: (Composition of agar media)

62



The medium was prepared by dissolving the specified quantity of the dehydrated medium (Hi-media) in purified water and

was dispensed in 20 ml volumes into test tubes. The test tubes were closed with cotton plugs and sterilized

by autoclaving at 121 0 C (15 ibs/square inches) for 15 minutes. The contents of the tubes were poured aseptically into sterile Petri plates (90 mm diameter) and allowed to solidify.

Four different bacterial cultures viz., a staphylococcus aureus, Escherichia coli, pseudomonas aeruginosa and bacterial subtillis and one of the fungal culture, candida albicans were used as test organisms for evaluation of antibacterial and antifungal activity. Mueller


Hinton agar medium was used to inoculate bacterial cultures and Sabouraud’s dextrose agar medium was used for fungal

culrures. Each Petri plate containing Mueller Hinton agar medium was inoculated with one of the bacterial cultures by spreading a suitably diluted suspension of the organism (10 6 cells/ml) with a sterile cotton swab. One filter paper disk impregnated with the solution of the test compound was placed at three places of the plate at equal distance. Filter paper disk containing the standard drug (Ampicillin 10 μg) was placed at two places of the same plate. Composition of Mueller Hinton agar medium Composition of Sabouraud’s dextrose agar medium Beef Extract 300 ml Dextrose 40 g Casein hydrolysate 17.5 g Peptone 10 g Starch 1.5 g Agar 15 g Agar 17 g Distilled water 1000 ml Distilled water 1000 ml pH 5.6+0.2 pH 7.3 +0.2 Chapter-5 Dept. of Chemistry, H. N. G.U. 186 All the plates were kept in the refrigerator for 1 hour to allow the diffusion of the sample into the surrounding agar medium. Then the plates were incubated at 37 0 C for 24 hours. Diameter of the zones of inhibition wherever produced was measured and the average diameter for each sample was calculated. The diameters obtained for the standard antibiotic was also measured and the average diameter was compared with that produced by the test compounds. Similar procedure was carried out for the evaluation of antifungal activity using sabouraoud’s dextrose agar medium. The plates were incubated at 27 0 c for 48 hours. Chapter-5 Dept. of Chemistry, H. N. G.U. 187

Table:-5.1 Antibacterial Activity of Schiff base derivatives (4a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 4a 48 50 45 45 63 4b 41 62 55 54 68 4c 42 62 70 42 82 4d 68 70 74 81 86 4e 62 58 40 63 42 4f 81 70 70 83 68 Ampicillin 82 58 71 81 75 Table:-5.2 Antifungal Activity of Schiff base derivatives (4a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 4a 70 60 71 52 50 4b 60 68 64 52 68 4c 71 70 78 68 63 4d 68 67 63 76 72 4e 52 57 73 65 66 4f 53 65 61 75 63 Chapter-5 Dept. of Chemistry, H. N. G.U. 188

Table:-5.3 Antibacterial Activity of Azetidinone derivatives (5a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus Subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 5a 54 55 47 44 64 5b 40 66 58 55 68 5c 45 65 71 42 83 5d 70 77 74 80 86 5e 64 60 41 63 41 5f 82 72 71 84 68 Ampicillin 84 56 72 80 77 Table:-5.4 Antifungal Activity of Azetidinone derivatives (5a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 5a 75 61 72 54 52 5b 65 71 65 52 68 5c 74 70 78 68 64 5d 71 68 64 77 72 5e 55 57 73 65 67 5f 54 64 60 74 62 Chapter-5 Dept. of Chemistry, H. N. G.U. 189

63


Table:-5.5 Antibacterial Activity of Thiazolidinone derivatives (6a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 6a 52 54 49 42 58 6b 72 76 72 82 70 6c 65 67 70 70 68 6d 42 68 58 59 50 6e 65 58 40 65 40 6f 80 73 70 82 55 Ampicillin 84 57 73 80 77 Table:-5.6 Antifungal Activity of Thiazolidinone derivatives (6a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 6a 55 61 65 55 54 6b 65 72 65 58 68 6c 74 70 78 68 64 6d 58 60 62 55 60 6e 55 57 65 65 62 6f 54 62 60 63 62 Chapter-5 Dept. of Chemistry, H. N. G.U. 190

Table:-5.7 Antibacterial Activity of 5-Arylidine derivatives (7a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 7a 41 67 58 59 50 7b 62 58 42 64 40 7c 45 63 70 43 83 7d 71 75 75 80 85 7e 43 68 55 56 50 7f 64 57 40 65 42 Ampicillin 65 60 70 75 80 Table:-5.8 Antifungal Activity of Thiazolidinone derivatives (6a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 7a 55 62 63 55 54 7b 63 72 63 57 68 7c 74 70 78 68 65 7d 65 65 64 75 72 7e 55 55 70 65 67 7f 70 74 72 78 84 Chapter-5 Dept. of Chemistry, H. N. G.U. 191

Table:-5.9 Antibacterial Activity of Tetrazole derivatives (9a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 9a 52 54 48 45 63 9b 42 66 58 55 68 9c 46 64 70 43 82 9d 71 75 75 80 86 9e 65 62 41 62 40 9f 81 70 70 85 68 Ampicillin 85 56 72 78 76 Table:-5.10 Antifungal Activity of Tetrazole derivatives (9a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 9a 74 60 71 53 51 9b 65 70 65 52 68 9c 75 72 77 67 65 9d 70 68 64 77 72 9e 55 55 72 65 66 9f 56 63 60 75 61 Chapter-5 Dept. of Chemistry, H. N. G.U. 192

Table:-5.11 Antibacterial Activity of 1,3,5-Oxadiazine derivatives (10a-f) Compounds Zone of Inhibition Gram +Ve Gram –Ve Bacillus subtilis Staphylococcus aureus Klebsiella promioe Salmonella typhi E.coli 10a 53 55 50 42 57 10b 73 76 70 80 70 10c 65 68 72 70 67 10d 43 68 58 57 50 10e 65 58 40 65 42 10f 81 72 72 80 55 Ampicillin 85 57 73 80 77 Table:-5.12 Antifungal Activity of 1,3,5-Oxadiazine derivatives (10a-f) Compounds Zone of Inhibition at 1000 ppm (%) Penicillium Expansum Botrydepladia Thiobromine Nigrospora Sp. Trichothesium Sp. Rhizopus Nigricum 10a 56 60 65 56 57 10b 65 72 64 58 58 10c 75 71 78 67 64 10d 58 60 60 55 62 10e 54 57 65 66 62 10f 55 60 63 64 60 Chapter-5 Dept. of Chemistry, H. N. G.U. 193

Figure 5.1 Antibacterial activities of Schiff base derivatives Figure 5.2 Antibacterial activities of Azetidinone derivatives Chapter-5 Dept. of Chemistry, H. N. G.U. 194

Figure 5.3 Antibacterial activities of Thiazolidinone derivatives Figure 5.4 Antibacterial activities of 5-arylidine derivatives Chapter-5 Dept. of Chemistry, H. N. G.U. 195

Figure 5.5 Antibacterial activities of Tetrazole derivatives Figure 5.6 Antibacterial activities of 1,3,5-Oxadiazine derivatives Chapter-5 Dept. of Chemistry, H. N. G.U. 196

Figure 5.7 Antifungal activities of Schiff base and Azetidinone derivatives Figure 5.8 Antifungal activities of Thiazolidinone and 5-Arylidine derivatives Chapter-5 Dept. of Chemistry, H. N. G.U. 197

Figure 5.9 Antifungal activities of Tetrazole and 1,3,5-Oxadiazine derivatives Figure 5.10: Antimicrobial activity of compound 5a to 5f and 6a to 6f (B.Subtillis) Chapter-5 Dept. of Chemistry, H. N. G.U. 198

5.5 Results and discussion: The compounds tested for antibacterial and antifungal

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activity are listed in Table-5.1 – 5.12 show size of zone of inhibition of bacterial growth procedure by test compounds for broad range of antimicrobial activity inhibiting growth of Gram- positive bacterial strains S. aureus and K. Promioe, and Gram-negative bacterial strains E.Coli and S. Typhi.

Comparison of antibacterial activity of produced compounds with that of standard antimicrobial drugs reveals that the produce compounds (Schiff

base to various cyclic products)


shows moderate to good activity against all four bacterial strains.

Among

Schiff base derivatives (4a-f) (Table-5.1) compounds 4d and 4f shows good antimicrobial activity. Among Azetidinone derivatives (5a-f) (Table-5.3) compound 5b and 5c shows good antimicrobial activity. Among Thiazolidinone derirvatives (6a-f) (Table-5.5) compound 6b and 6c

shows good antimicrobial activity. Among 5-Arylidine derivatives (7a-f) (Table-5.7) compound 7b, 7c and 7d

shows good antimicrobial activity. Among Tetrazole derivatives (9a-f) (Table-5.9) compound 9b and 9c shows good antimicrobial activity. Among 1,3,5-oxadiazine derivatives (10a-h) (Table-5.11) compound 10b and 10c shows good antimicrobial activity. Chapter-5 Dept. of Chemistry, H. N. G.U. 199 Other prepared compounds shows moderate activity compared to standard drugs against all four bacterial strains S. aureus and K. Promioe, and Gram-negative bacterial strains E.Coli and S. Typhi. The fungicidal activity also studied in vitro. Among all the compounds 5a, 5c, 5d, 6c, 7c, 9d and 10c showed more activity as antifungal. Chapter-6 Literature references Chapter-6 Dept. of Chemistry, H. N. G.U. 200 Chapter-6 Literature references [1] P. R. Brodfuehrer, B. C. Chen, T. R. Sattelberg, J. Org. Chem., 62, 9192 (1997). [2] M. Mori, K. Chiba, Y. Ban, Tetrahedron Lett., 1037 (1977). [3] R. Odle, B. Blevins, M. Ratcliff, J. Org. Chem., 45, 2709 (1980). [4] H. Hemetsberger, D. Knittel, H. Weidmann, Monatsh. Chem., 101, 161 (1970). [5] J. K. MacLeod, L. C. Monahan, Tetrahedron Lett., 29, 391 (1988). [6] K. Aoki, A. J. Peat, S. L. Buchwald, J. Am. Chem. Soc., 120, 3068 (1998). [7] R. J. Sundberg, L. S. Lin, D. E. Blackburn, J. Heterocycl. Chem., 6 441 (1969). [8] R. J. Sundberg, T. J. Yamazaki, J. Org. Chem., 32, 290 (1967). [9] M. Shen, B. E. Leslie, T. G. Driver, Angew. Chem., Int. Ed., 47, 5056 (2008). [10] W. J. Houlihan, V. A. Parrino, Y. J. Uike, J. Org. Chem., 46, 4511e4515 (1981). [11] E. O. M. Orlemans, A. H. Schreuder, P. G. M. Conti, Tetrahedron, 43, 3817 (1987). [12] W. D. Jones, W. P. Kosar, J. Am. Chem. Soc., 108, 5640 (1986). [13] D. M. Ketcha, L. J. Wilson, D. E. Portlock, Tetrahedron Lett., 41, 6253 (2000). [14] J. Moskal, A. M. van Leusen, J. Org. Chem., 51, 4131 (1986). [15] K. Hayakawa, T. Yasukouchi, K. Kanematsu, Tetrahedron Lett., 27, 1837e1840 (1986). Chapter-6 Dept. of Chemistry, H. N. G.U. 201 [16] D. R. Hutchison, N. K. Nayyar, Tetrahedron Lett., 37, 2887 (1996). [17] A. S. K. Hashmi, M. Rudolph, Eur. J. Chem., 14, 6672 (2008). [18] E. Abele, R. Abele, O. Dzenitis, E. Lukevics, Chem Heterocycl. Compd 39, 3 (2003). [19] G. P. Kalaskar, M. Girisha, M. G. Purohit, B. S. Thippeswamy and B. M. Patil, Indian J Heterocycl Chem., 16, 325 (2007). [20] P. Rani, V. K. Srivastava and A. Kumar, Eur. J. Med. Chem., 39, 449 (2004). [21] K. Hemalatha, G. Madhumitha and S. M. Roopan, Chem. sci. Rev. and letters, 2(5), 287 (2013). [22] K. J. Bhardwaj and H. Z. Knaus, Bioorg Med Chem Lett 22, 2154 (2012). [23] C. R. Prakash, S. Raja, G. Saravanan, Chinese Chem Lett, 23, 541 (2012). [24] G. H. Manda, Chinese Chem Lett 24, 127 (2013). [25] M. Amir, S. Akhtar Javed, Harish Kumar, Acta pharm., 58, 467 (2008). [26] Supriya mana, nilanjan pahari, neeraj k. Sharma and priyanka, The

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68


Hit and source - focused comparison, Side by Side:

Left side: As student entered the text in the submitted document. Right side: As the text appears in the source.

Instances from: ketan Parmar CH-2.pdf


Mass Spectroscopy It is unlikely that the laboratory organic chemist will be required to record mass spectra of compounds produced in the laboratory as they will normally be obtained through a centralized service [93]. Probably the most common use of mass spectrometry by the organic chemist is for the accurate determination of molecular weight. A second important use is to provide information about the structure of compounds by an examination of the fragmentation pattern [94]. 2.6

General Remarks for the Experimental Techniques ?

Melting points ( o C) of all the compounds were measured

by capillary method. ? The

yields of all compounds reported are of crystallized.

All solvents used were distilled and dried. The purity of the compounds was checked by TLC.

Column chromatography was performed on silica gel (60-120 mesh).?


The source document can not be shown. The most likely reason is that the submitter has opted to exempt the document as a source in Urkund's Archive.

69


C, H, N and S contents of all the compounds were recorded on Thermofinigen 1101 Flash elemental analyzer. ? IR spectra were recorded in KBr pellets on Nicolet 760D

spectrophotometer. ?

NMR

and CMR

spectra were recorded on Bruker NMR spectro-photometer. PMR ad CMR chemical shifts are recorded using TMS as an internal standard in CDCl 3 /D 6 -DMSO. ?

LC-MS of selected one sample of each series has been carried out on


H of –CH 2 CONH) 4.2 (S, 2H, OCH 2 ) 11.2 (S, H, OH) 13 CMR spectral Features (δ, ppm) 115-129 Benzene & Indole 153 CH=N 162 C=O

of Amide 56 -CH 2 CONH Chapter-4 Dept. of Chemistry, H. N. G.U. 96 Compound-4f N O CH 2 CONHN OMe N-methyl (4-Benzyloxy)-1H-Indole acid-(4-methoxy benzylidine)-hydrazide






70


cm -1 (C=




CH of CH=N protons) 2.43 (2H of –CH 2 CONH) 4.20 (S, 2H, OCH 2) 4.30 (S, H, OCH 3 ) 13 CMR spectral Features (δ, ppm) 115-129 Benzene &

Indole 153 CH=N 162 C=O





Molecular Formula: C 26 H 21 N 3 O 3 Cl Br

Molecular Weight: 538.5 gm/mole Melting Point: 134-135 o C (Uncorrected) Yield: 65% Elemental Analysis %C %H %N %

Cl % Br Calculated 57.93 3.90 7.80 6.59 14.85 Found 58.00 3.90 7.80 6.50 14.80 Infrared Spectral Features

in cm -1 1697



144: ketan Parmar CH-2.pdf 33% 144: ketan Parmar CH-2.pdf 33%

71


H NMR spectral Features (δ, ppm) 7.5-9.5 (Multiplet, aromatic) 4.3 (s, 1H, C 2 H of Oxadiazole) 5.2 (s, 1H of OH) 13 C NMR spectral Features (δ, ppm) 148-152 Indole 110-130 Benzene 169 O – C = N 86 O –



W. Kemp, Organic Spectroscopy, ELBS (1996). [81] B.

Oteorge, Infrared Spectroscopy, Heyden, London (1972). [82] L. J. Bellamy, The Infrared Spectra of Complex Molecules, Metheuen, London (1980). [83] E. Merck, FTIR Atlas, VCH-Verlag/Ischatt, Weinheim, Germany (1987). [84]

P. R. Griffith, FTIR Spectrometry, Wiley, Chichester (1956). [85]



72




The availability of the presence and significant biological properties of the members known so far prompted the authors to




H-

NMR



CH 2





H-

NMR




73



CH 2



H-

NMR



CH 2





H-

NMR




74



CH 2



H-

NMR



CH 2

CONH) 3.7 (s, 3H, -OCH 3 ) 13 C-NMR spectral Features (δ, ppm) 114-130

Benzene &




H-



75





H-






H-






H-



76





H-

NMR



Benzene &




H-

NMR




77


CONH) 3.7 (S, 3H, -OCH 3 ) 13 C-NMR spectral Features (δ, ppm) 114-130 Benzene &


Molecular Formula: C 33 H 25 N 3 O 3 SBrCl Molecular Weight: 658.5 gm/mole Melting Point: 207-209 o C (Uncorrected) Yield: 83% Elemental Analysis %C %H %N %

S %

Br %Cl Calc. 60.13 3.79 6.37 4.85 12.14 5.39 Found 60.10 3.80 6.40 4.80 12.10 5.40 Infrared Spectral Features cm -1 1050

C-




H-tetrazoles

Molecular Formula: C 24 H 19 N 6 O 2 Br Molecular Weight: 503 gm/mole


Elemental Analysis %C %H %N % Br Calculated 57.25 3.77 16.70 15.90 Found 57.30 3.80 16.70 16.00 Infrared Spectral Features (cm -1 ) ~1040




78


H-tetrazoles

Molecular Formula: C 24 H 19 N 6 O 2 Cl Molecular Weight: 458.5 gm/mole


Elemental Analysis %C %H %N % Cl Calculated 62.81 4.14 18.32 7.74 Found 63.00 4.10 18.30 7.70 Infrared Spectral Features (cm -1) ~1040



H-tetrazoles





H-tetrazoles





79


H-tetrazoles




H

Molecular Formula: C 25 H 28 N 6 O Molecular Weight: 428 gm/mole

Melting Point: 180-182 o C (Uncorrected) Yield: 80.75%

Elemental Analysis %C %H %N Calculated 70.00 6.53 19.60 Found 70.00 6.50 19.80 Infrared Spectral Features (cm -1 ) 1647

cm -1 (C=

O of O=C-N=) 3280



80


Instances from: Hitesh Shah-3.pdf




according to

reported methods [119].






according to

reported









81


cm -1 (C=



Molecular Formula: C 24 H 20 N 3 O 2 Br Molecular Weight: 462 gm/mole Melting Point: 156-158 o C (Uncorrected) Yield: 85%

Elemental Analysis %C %H %N %Br Calculated 62.33 4.32 9.09 17.31 Found 62.30 4.30 9.00 17.30


cm -1 (C=






Elemental Analysis %C %H %N %Cl Calculated 68.98 4.79 10.05 8.50 Found 69.00 4.80 10.00 8.50


cm -1 (C=



82







cm -1 (C=








cm -1 (C=




83





cm -1




Molecular Formula: C 26 H 21 N 3 O 3 Cl 2 Molecular Weight: 494 gm/mole Melting Point: 170-173 o C (Uncorrected) Yield: 58%


cm -1








84


cm -1




cm -1






cm -1








85





S %Br Calculated 58.20 4.10 7.83 5.97 14.92 Found 58.20 4.10 7.80 6.00 15.00 Infrared Spectral Features




Molecular Formula: C 26 H 22 N 3 O 3 SCl Molecular Weight: 491.5 gm/mole Melting Point: 170-173 o C (Uncorrected) Yield: 58% Elemental Analysis %C %H %N %

S %Cl Calculated 63.47 4.47 8.54 6.51 7.22 Found 63.50 4.50 8.50 6.50 7.20 Infrared Spectral Features









86



















123: Hitesh Shah-3.pdf 90% 123: Hitesh Shah-3.pdf 90%

87


Molecular Formula: C 33 H 25 N 3 O 3 SBr 2 Molecular Weight: 703 gm/mole Melting Point: 185-187 o C (Uncorrected) Yield: 84% Elemental Analysis %C %H %N %

















88






Elemental Analysis %C %H %N %S Calculated 70.32 4.76 10.25 5.86 Found 70.30 4.70 10.20 5.90 Infrared Spectral Features (cm -1) 1000-1400

C-





thione

Molecular Formula: C 32 H 25 N 4 O 3 SBr Molecular Weight: 625 gm/mole



C-



89




thione

Molecular Formula: C 32 H 25 N 4 O 3 SCl Molecular Weight: 580.5 gm/mole



C-







Elemental Analysis %C %H %N %S Calculated 64.97 4.23 11.84 5.41 Found 65.00 4.20 11.80 5.40 Infrared Spectral Features (cm -1) 1000-1400

C-



90







C-








C-




91



Molecular Formula: C 19 H 21 N 2 O 3 SCl Molecular Weight: 356.44 gm/mole Melting Point: 183-185 o C (Uncorrected) Yield: 73 %

Elemental Analysis %C %H %N %S Calculated 63.96 5.61 7.85 8.98 Found 64.00 5.60 7.80 9.00 Infrared Spectral Features (cm -1 ) 1730

cm -1 C=

O of S-CO-NH 1735 cm -1 CH-CO-NH 2850 cm -1 C-



92


Instances from: Hitesh Shah-5.pdf


NMR



CH 2



93




Compound-9a N O CH 2 CONH N N N N

1-[N-acetamido-4-benzyloxy-1H-Indole]-5-phenyl-1

H-tetrazoles




94


Instances from: http://shodhganga.inflibnet.ac.in/jspui/bitstream/10603/44111/8/08_chapter%202.pdf


Elemental Analysis The majority of organic compounds are composed of a relatively small number of elements. The most important ones are: carbon, hydrogen, oxygen, nitrogen, sulphur, chlorine, etc. Elementary quantitative organic analysis [79] is used to determine the content of carbon, hydrogen, nitrogen, and other elements in the molecule of an organic compound. 2.2


Elemental analysis: The majority of organic compounds are composed of a relatively small number of elements. The most important ones are: carbon, hydrogen, oxygen, nitrogen, sulphur, halogens etc. Elementary, quantitative organic analysis is used to determine the content of carbon, hydrogen, nitrogen, and other elements in the molecule of an organic compound.


It is well known that all nuclei carry a positive charge. In some nuclei this charge ‘spins’ on the nuclear axis, and

this

circulation of nuclear charge generates a magnetic dipole along the axis. Thus, the nucleus behaves like a tiny bar magnet. The angular

momentum of the spinning charge is described in terms of spin number (I). The magnitude of generated dipole is expressed in terms of nuclear

magnetic moment (μ).

The spinning nucleus of a hydrogen atom ( 1 H or proton) is the simplest and is commonly encountered in organic compounds. The hydrogen nucleus has a magnetic moment, μ = 2.79268 and its

spin number (I) is + ½. Hence, in an applied external magnetic field,


It is well known that all nuclei carry a positive charge. In some nuclei this charge ‘spins’ on the nuclear axis, and this circulation of nuclear charge generates a magnetic dipole along the axis. Thus, the nucleus behaves like a tiny bar magnet. The angular momentum of the spinning charge is described in terms of spin number (I). The magnitude of generated dipole is expressed in terms of nuclear magnetic moment (μ). The spinning nucleus of a hydrogen atom ( 1 H or proton) is the simplest and is commonly encountered in organic compounds. The hydrogen nucleus has a magnetic moment, μ = 2.79268 and its spin number (I) is + ½. Hence, in an applied external magnetic field, its magnetic moment may have two possible orientations. The orientations in which the magnetic moment is aligned with the applied magnetic field is more stable (lower energy) than in which the magnetic moment is aligned against the field (high energy). The energy required for flipping the proton from its lower energy alignment to the higher energy alignment depends upon the difference in energy (∆E) between the two states and is equal to hμ(∆E = h μ). In principle, the substance could be placed in a magnetic

95


its magnetic moment may have two possible orientations. The orientations in which the

magnetic moment is aligned with the applied magnetic field is more stable (lower energy) than in

which the magnetic moment is aligned against the field (high energy). The energy required for flipping the proton from its lower energy alignment to the higher energy alignment depends upon the difference in energy (∆E) between the two states

and is equal to ∆E = (h μ) In principle, the substance could be placed in a magnetic field of constant strength, and then the spectrum can be obtained in the same way as an infrared or an ultraviolet spectrum by passing radiation of steadily changing frequency through the substance and observing the frequency at which radiations is absorbed. In practice,

however,

it has been found to be more convenient to keep the

radiation frequency constant and vary the strength of the magnetic field. At some value of the field strength the energy required to flip the proton matches the energy of the radiation, absorption occurs and a signal is obtained. Such a spectrum is called a nuclear magnetic resonance (NMR) spectrum.

Two types of NMR spectrometers are commonly encountered. They are: a) Continuous wave (CW) NMR spectrometer b) Fourier transform (FT) NMR spectrometer. The CW-NMR spectrometer detects the resonance frequencies of nuclei in a sample placed in a magnetic field by sweeping the frequency of RF radiation through a given range and directly recording the intensity of absorption as a function of

field of constant strength, and then the spectrum can be obtained in the same way as an infrared or an ultraviolet spectrum by passing radiation of steadily changing frequency through the substance and observing the frequency at which radiations is absorbed. In practice, Chapter-2 51 however, it has been found to be more convenient to keep the radiation frequency constant and vary the strength of the magnetic field. At some value of the field strength the energy required to flip the proton matches the energy of the radiation, absorption occurs and a signal is obtained. Such a spectrum is called a nuclear magnetic resonance (NMR) spectrum. Two types of NMR spectrometers are commonly encountered. They are: a) Continuous wave (CW) NMR spectrometer b) Fourier transform (FT) NMR spectrometer. The CW-NMR spectrometer detects the resonance frequencies of nuclei in a sample placed in a magnetic field by sweeping the frequency of RF radiation through a given range and directly recording the intensity of absorption as a function of

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Instances from: http://www.ijdrt.com/ijdrt_journal/issue/May-June_2012_article5.htm


Fan Zhang et al synthesized in vitro anti-tumor activity of 2-amino-3 cyano-6-(1 H -indol-3- yl)-4-phenylpyridine derivatives [42].

R1


Fan Zhang et al. (2011), synthesized in vitro anti-tumor activity of 2-amino-3 cyano-6-(1 H -indol-3-yl)-4-phenylpyridine derivatives.5

Compound R1

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Instances from: http://rasayanjournal.co.in/vol-1/issue-2/3.pdf


Graded concentrations of the test compounds were prepared by serial dilution and added into appropriate agar medium. A suitably diluted suspension of


Graded concentration of the test compound should be prepared by serial dilutions and added in to an appropriate agar medium. A suitably diluted suspension of






agar medium. After incubation, presence / absence of the growth of organism on the agar medium was observed and from the results, the MIC of the test compounds was calculated. Procedure: Six test tubes were labeled 1 to 6


agar medium. After incubation presence/absence of the growth of organism on the agar medium was observed and from the results, the MIC of the test compound was calculated. Six test tubes were labeled 1 to 6.


tubes were plugged with non-absorbent cotton wool and sterilized by autoclaving at 121 0 c for 20 minutes. 32 mg of the test compound was aseptically transferred and dissolved in tube-1. From this 1 ml of


tubes were plugged with non-absorbent cotton and sterilized by autoclaving at 121°C for 20 minutes. 32 mg of the test compound was aseptically transferred and dissolved in tube-1. From this 1 ml of

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98


test tube-2 and mixed well. This process is repeated 6 times and 1 ml of the solution from the tube 6 was discarded. 15 ml molten Mueller Hinton agar fluid sabouraud’s dextrose agar [138] was aseptically added into each test tube,

test tube-2 and mixed well. This process is repeated 6 times and 1ml of solution from tube-6 was discarded. 15 ml molten Muller Hinton agar/fluid Sabouraud′s dextrose agar was aseptically added into each test tube,


mixed well, aseptically poured into a sterile Petri dish and


mixed well aseptically poured into a sterile Petri dish and


medium was allowed to solidify. Each plate was divided into four quadrants. Each quadrants was inoculated with a different test organism 10 drops of suitably diluted suspension (10 6 cells/ml) of the test organism (bacterial cultures on


medium was allowed to solidify. Each plate was divided into four quadrants. Each quadrant was inoculated with different test organism. 10 drops of suitably diluted suspension (10 6 Cfu/ml) of the test organisms (bacterial cultures on


fungal culture on sabouraud’s agar) was inoculated on the surface of the agar medium, in the form of tiny droplets, using a sterile 1 ml syringe with 24 gauge needle. A positive control was prepared in a similar way except that the test compound was not added into the agar medium. A negative control was prepared in a similar way except that the test compound was not added and the tube was not inoculated with test organism. All plates were


fungal cultures on Sabouraud′s agar) was inoculated on the surface of agar medium, in the form of tiny droplets, using a sterile 1ml syringe with 24-gauze needle. A positive control was prepared in a similar manner except with the test compound not adding in to the agar medium. A negative control was prepared in a similar way except the text compound was not added and the tube was not inoculated with test organism. All plates were

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99


The medium was prepared by dissolving the specified quantity of the dehydrated medium (Hi-media) in purified water and

was dispensed in 20 ml volumes into test tubes. The test tubes were closed with cotton plugs and sterilized

by autoclaving at 121 0 C (15 ibs/square inches) for 15 minutes. The contents of the tubes were poured aseptically into sterile Petri plates (90 mm diameter) and allowed to solidify.

The medium was prepared by dissolving the specified quantity of the dehydrated medium in purified water and was dispersed in 20ml volumes in to test tubes. The test tubes were closed with cotton plugs and were sterilized by autoclaving at 121°C (15 lb psig) for 15 minutes. The contents of tubes were poured aseptically in to sterile Petri dishes (90mm diameter) and allowed to solidify.


Hinton agar medium was used to inoculate bacterial cultures and Sabouraud’s dextrose agar medium was used for fungal


Hinton agar medium was used to inoculate bacterial cultures and Sabouraud′s dextrose agar medium was used for fungal

100


Instances from: http://www.ijrpsonline.com/pdf/221.pdf


The name indole is portmanteau of

the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began with the study of the dye indigo.

Indole is

an aromatic heterocyclic nucleus. It has a


The name indole is portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began with the study of the dye indigo. Indole is an aromatic heterocyclic nucleus. It has a


bicyclic structure, consisting of a six-membered benzene ring fused to a five membered nitrogen containing

pyrrole ring through the 2- and 3-positions of the pyrrole nucleus. Indole is

called as benzopyrrole.

The indole ring is also found in many natural products such as the vinca alkaloids, fungal metabolites and marine natural products. Indole

is a popular component of fragrances. Indoles are a pervasive class of compounds found in abundance in biologically active compounds such as pharmaceuticals, agrochemicals and alkaloids. Since the first synthesis of indole in 1866, a number of synthetic methods for the construction of the indole nucleus have been devised. Indole myriad derivatives have, therefore, captured the attention of organic


bicyclic structure, consisting of a six-membered benzene ring fused to a five membered nitrogen containing pyrrole ring through the 2- and 3-positions of the pyrrole nucleus. Indole is called as benzopyrrole. The indole ring is also found in many natural products such as the vinca alkaloids, fungal metabolites and marine natural products. 1 Indole is a popular component of fragrances. 2 Indoles are a pervasive class of compounds found in abundance in biologically active compounds such as pharmaceuticals, agrochemicals and alkaloids. Since the first synthesis of indole in 1866, a number of synthetic methods for the construction of the indole nucleus have been devised. Indole myriad derivatives have, therefore, captured the attention of organic synthetic chemists. Medicine and biochemistry are also interested in many aspects of the indole chemistry. 3

101


synthetic chemists. Medicine and biochemistry are also interested in many aspects of the indole chemistry.


Ashok Kumar

et al synthesized a series of novel substituted indole derivatives and were evaluated for their in vitro

anti-inflammatory activity. It was found that the compound 2-(p-chlorophenyl)-1-[4-(2-(p -chorophenyl)-4-oxo-thiazolidin-3-yl]-5- mercapto[1,2,4,]-trizole-3-yl-methyl]- 3[4,6-dibromo-2-carboxyphenyliminomethyl]- 5-methoxyindole had shown prominent anti-inflammatory activity at the three graded dose of 25, 50 and 100mg/kg [28]. N N N N Cl N Br Br SH N S O R


Ashok Kumar et al synthesized a series of novel substituted indole derivatives and were evaluated for their in vitro anti-inflammatory activity. It was found that the compound 2-(p-chlorophenyl)-1- [4-(2-(p-chorophenyl)-4-oxo-thiazolidin-3-yl]-5-mercapto[1,2,4,]-trizole-3-yl-methyl]-3[4,6- dibromo-2-carboxyphenyliminomethyl]-5-methoxyindole had shown prominent anti-inflammatory activity at the three graded dose of 25, 50 and 100mg/kg p.o. 4 N N H 3 CO Br COOH Br N N N HS N S O R


Thirumurugan prakasam et al synthesized a various 2-(1H-indol-3-yl)-6- methoxy-4- pentylpyridine-3, 5-dicarbonitrile derivatives and was screened for their anti-inflammatory activity. Most of the compounds had shown potent anti- inflammatory activity [29]. N N H N O


Thirumurugan prakasam et al synthesized a various 2-(1H-indol-3-yl)-6-methoxy-4- pentylpyridine-3,5-dicarbonitrile derivatives and was screened for their anti-inflammatory activity. Most of the compounds had shown potent anti-inflammatory activity. 6 N N N O


Pandeya et al synthesized schiff bases of isatin and 5-methyl isatin with sulphadoxine and were evaluated for their in vitro antifungal activity against various fungal strains viz. Candida albicans, Candida


Pandeya et al synthesized schiff bases of isatin and 5-methyl isatin with sulphadoxine and were evaluated for their in vitro antifungal activity against various fungal strains viz. Candida albicans, Candida

102


neoformis, Histoplasma capsulatum, Microsporum audounii and Trichophyton mentagrophytes. It was found that the piperidino methyl compounds have shown prominent antifungal activity [32].

neoformis, Histoplasma capsulatum, Microsporum audounii and Trichophyton mentagrophytes. It was found that the piperidino methyl compounds have shown prominent antifungal activity. 17


Wang Dun et al synthesized various 2-arylthiomethyl-4-tertiary amino methyl substituted derivatives of 6-bromo-3-ethoxycarbonyl-5-hydroxyindole and evaluated their in vitro antiviral activity against laboratory-passaged isolates of human influenza A3 and respiratory syncytial virus (RSV) respectively in MDCK cell culture and eLa cell culture with virus cytopathic effect assay in comparison with amantadine and Abidol. The 50% inhibitory concentration (IC50) and the minimum inhibitory concentration (MIC) for the tested compouds against the above two virus were calculated with Reed and Muench Method and therapeutic index (TI) was obtained. Some compounds had shown significant antiviral activity [49].


Wang Dun et al synthesized various 2-arylthiomethyl-4-tertiary amino methyl substituted derivatives of 6-bromo-3-ethoxycarbonyl-5-hydroxyindole and evaluated their in vitro antiviral activity against laboratory-passaged isolates of human influenza A3 and respiratory syncytial virus (RSV) respectively in MDCK cell culture and HeLa cell culture with virus cytopathic effect assay in comparison with amantadine and Abidol. The 50% inhibitory concentration (IC 50 ) and the minimum inhibitory concentration (MIC) for the tested compouds against the above two virus were calculated with Reed and Muench Method and therapeutic index (TI) was obtained. Some compounds had shown significant antiviral activity. 19 3-


Sharma Prince P et al synthesized a series of various 3-(1,3-benzothiazol-2- ylimino)-1,3- dihydro-2H-indol -2-one derivatives and it was found that compounds had shown prominent anticonvulsant activity [53]. N H O N N S

1.2.12


Sharma Prince P et al synthesized a series of various 3-(1,3-benzothiazol-2-ylimino)-1,3- dihydro-2H-indol-2-one derivatives and it was found that compounds had shown prominent anticonvulsant activity. 13 3-(1,3-benzothiazol-2-ylimino)-1,3-dihydro-2H-indol-2-one H N O N S

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synthesized a series of novel 7-azaindole-3-acetamidoxime and 7- azaindole-1-acetamidoxime and evaluated for its antihypertensive activity. These compounds have shown prominent antihypertensive properties [55].

synthesized a series of novel 7-azaindole-3-acetamidoxime and 7-azaindole-1- acetamidoxime and evaluated for its antihypertensive activity. These compounds have shown prominent antihypertensive properties. 18

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Instances from: http://derpharmachemica.com/vol7-iss7/DPC-2015-7-7-182-188.pdf


O

N H NH 2 O N H

O N H N O O N H O N H N O N H O N H N O Cl N H O N H N O F N H O

N H

N

O


O N H NH 2 O HO O NH O POCl 3 N N O O N H O Hydrolysis EtOH/HCl N N O O H 2 N N N O O N Ar-CHO EtOH/H 2 SO 4 Ar 1 N N O O

N Ar H Cl H O 2-Azetidinones(4a-h) N N O

O N H O N N O


N H 2 CN

N H CN O X CN CN N

H O N H O N N CN O N H N N N N N O N


N Ar H Cl H O 2-Azetidinones(4a-h) N N O

O N H O N N O

O H 2 N N N O O N


The mixture was heated until a clear solution was obtained. The clear solution was kept overnight when respective Schiff base fall out which was filtered, washed by petroleum ether and air dried.


The mixture was heated until a clear solution was obtained. The clear solution was kept overnight when respective Schiff base fall out which was filtered, washed by petroleum ether and air dried. The

105


The resultant Schiff bases are designated as (4

a-f) and their details are shown

resultant Schiff bases are designated as 2a-h and their details are shown


a-f) (0.01

mole) and tri ethyl amine (TEA) (0.03mole) was dissolved in 1,4-dioxane (50 ml) cooled and stirred. To this well stirred cooled solution chloro acetyl chloride (0.012 mole) was added drop wise. The reaction mixture was stirred for 14 hrs at room temperature.


a-h) (0.002 mole) and triethyl amine (TEA) (0.004 mole) was dissolved in 1,4-dioxane (50 ml), cooled, and stirred. To this well-stirred cooled solution chloroacetyl chloride (0.004 mole) was added drop wise within a period of 30 minutes. The reaction mixture was then stirred for an additional 3 hours and left at room temperature


and then air dried. The product thus obtained was purified by column chromatography over silica gel using 20% ethyl acetate: 80%


and then air-

dried. The product thus obtained was purified by column chromatography over silica gel using 30%

ethyl acetate: 70%


dried. The product thus obtained was purified by column chromatography over silica gel using


dried. The product thus obtained was purified by column chromatography over silica gel using 30%

106


Instances from: http://www.researchgate.net/profile/Pradeep_Gupta/publication/232768047_Synthesis_Characterization_and_Spectral_Studies_of_Various_Newer_4-Benzyloxy-1H-indole-2-carboxylic_Acid_(Arylidene)-hydrazide/links/09e41509529f15398d000000.pdf?origin=publication_detail


synthesis, characterization and spectral studies of various newer 4-benzyl oxy-1H-Indole-2-carboxylic acid (


Synthesis, Characterization and Spectral Studies of Various Newer 4-Benzyloxy-1H-indole-2- carboxylic Acid (


Benzyloxyindole-2- carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in alcoholic medium in refluxing conditions to give 4-benzyloxy-1H-indole-2-carboxylic acid (arylidene)-hydrazides, important synthetic intermediates for the synthesis of a newer class of pharmacologically active compounds.


benzyloxyindole-2-carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in alcoholic medium in refluxing conditions to give 4-Benzyloxy-1H-indole-2-carboxylic acid (arylidene)- hydrazides, important synthetic intermediates for the synthesis of a newer class of pharmacologically active compounds.

107


Instances from: http://www.orientjchem.org/vol29no3/synthesis-physico-chemical-spectral-and-x-ray-diffraction-studies-of-znii-complex-of-pioglitazone-a-new-oral-antidiabetic-drug/



mellitus also known as non insulin dependent diabetes mellitus 1 (NIDDM) or adult onset diabetes


agent used in the treatment of type 2 diabetes mellitus also known as non‐insulin‐dependent diabetes mellitus1 (NIDDM) or adult‐onset diabetes.





Currently, it

is

marketed under the trade name Actos [77].


Pioglitazone decrease insulin resistance in the periphery and liver, resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Currently, it is marketed under the trade name Actos®2.



108



mellitus also known as non insulin dependent diabetes mellitus1 (NIDDM) or adult onset diabetes

agent used in the treatment of type 2 diabetes mellitus also known as non‐insulin‐dependent diabetes mellitus1 (NIDDM) or adult‐onset diabetes.





Currently, it

is

marketed under the trade name Actos® [125]. It

is a white or almost white crystalline, odourless powder, practically tasteless, insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in

dimethylformamide. It exhibits slow gastrointestinal absorption rate and inter individual variation of its bioavailability [126].


Pioglitazone decrease insulin resistance in the periphery and liver, resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Currently, it is marketed under the trade name Actos®2.

It is a white or almost white crystalline, odourless powder, practically tasteless, insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. It exhibits slow gastrointestinal absorption rate and inter individual variation of its bioavailability3.

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Instances from: http://www.ajbpr.com/issues/volume1/issue2/107.pdf


activity are listed in Table-5.1 – 5.12 show size of zone of inhibition of bacterial growth procedure by test compounds for broad range of antimicrobial activity inhibiting growth of Gram- positive bacterial strains S. aureus and K. Promioe, and Gram-negative bacterial strains E.Coli and S. Typhi.

Comparison of antibacterial activity of produced compounds with that of standard antimicrobial drugs reveals that the produce compounds (Schiff


activity are listed in Table-III show size of zone of inhibition of bacterial growth procedure by test compounds for broad range of antimicrobial activity inhibiting growth of gram-positive bacterial strains B. Subtillis and S. Aureus, and gram-negative bacterial strains E. Coli and P. Aeruginosa. Comparison of antimicrobial activity of produced compounds with that of standard antimicrobial drugs reveals that the produce compounds (Schiff


shows moderate to good activity against all four bacterial strains.

Among


shows moderate to good activity against all four bacterial strains. Among

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Instances from: http://shodhganga.inflibnet.ac.in/bitstream/10603/44292/8/08_chapter%202.pdf


number over a particular range. Infrared spectroscopy is usually divided into three regions. ? Near infrared (overtone region) – between 12500cm -1 -4000cm -1

? Middle infrared (fundamental vibrational region) – between 4000cm- 1 - 667cm -1

? Far infrared (pure rotational region) – between 667cm -1 -50cm -1

The normal or middle infrared region is particularly meant for organic chemists since the vibrations induced in organic molecules are absorbed

in this region. This

fundamental vibrational region is divided into the functional group region (4000cm -1 -1400cm -1 ) and finger print region (1400cm -1 -667cm -1 ). The normal and far infrared regions contain absorptions due to fundamental harmonic and combination bands. The use of linear-in-frequency instruments results in a considerable expansion of the high frequency end of the infrared region, resulting in an increased ability to resolve bands and define their positions. The position of absorption in the spectrum is usually expressed in terms of wave number (cm -1 )

of the absorbed light. The infrared spectrum is the simplest, most rapid and often most reliable means for assigning a compound to its class. It can also provide a variety of information on structure, symmetry, purity,


number over a particular range. Infrared spectroscopy is usually divided into three regions. • Near infrared (overtone region) – between 12500 cm -1 - 4000 cm -1

• Middle infrared (fundamental vibrational region) – between 4000 cm -1 - 667 cm -1

• Far infrared (pure rotational region) – between 667 cm -1 - 50 cm -1

The normal or middle infrared region is particularly meant for organic chemists since the vibrations induced in organic molecules are absorbed in this region. This fundamental vibrational region is divided into the functional group region (4000 cm -1 - 1400 cm -1 ) and finger print region (1400 cm -1 - 667 cm -1 ). The normal and far infrared regions contain absorptions due to fundamental harmonic and combination bands. The use of linear-in-frequency instruments results in a considerable expansion of the high frequency end of the infrared region, resulting in an increased ability to resolve bands and define their positions. The position of absorption in the spectrum is usually expressed in terms of wave number (cm -1 ) of the absorbed light. The infrared spectrum is the simplest, most rapid and often most reliable means for assigning a compound to its class. It can also provide a variety of information on structure, symmetry, purity, structural and geometrical isomers and hydrogen bonding. Chapter-2

111


structural and geometrical isomers and hydrogen bonding.

Chapter-2



due to


It is an aromatic compound thus it provides the IR frequencies. The bands due to


frequency. The spectrum is usually recorded and plotted simultaneously with a recorder synchronized to the frequency of the RF source. In FT-NMR spectroscopy, the sample is subjected to a high power short duration pulse of RF radiation. This pulse of radiation contains a broad band of frequencies and causes all the spin-active nuclei to resonate all at once at their Larmor frequencies. Immediately following the pulse, the sample radiates a signal called free induction decay (FID), which is modulated by all the frequencies of the nuclei excited by the pulse. The signal detected as the nuclei return to equilibrium (intensity as a function of time) is recorded, digitized and stored as an array of numbers in a computer. Fourier transformation of the data affords a conventional (intensity as a function of frequency) representation of the

spectrum. The first step in running NMR spectrum is the complete dissociation of a requisite amount of the sample in the appropriate volume of a suitable NMR solvent. Commonly used solvents are: CCl


frequency. The spectrum is usually recorded and plotted simultaneously with a recorder synchronized to the frequency of the RF source. In FT-NMR spectroscopy, the sample is subjected to a high power short duration pulse of RF radiation. This pulse of radiation contains a broad band of frequencies and causes all the spin-active nuclei to resonate all at once at their Larmor frequencies. Immediately following the pulse, the sample radiates a signal called free induction decay (FID), which is modulated by all the frequencies of the nuclei excited by the pulse. The signal detected as the nuclei return to equilibrium (intensity as a function of time) is recorded, digitized and stored as an array of numbers in a computer. Fourier transformation of the data affords a conventional (intensity as a function of frequency) representation of the spectrum. The first step in running NMR spectrum is the complete dissociation of a requisite amount of the sample in the appropriate volume of a suitable NMR solvent. Commonly used solvents are: CCl 4 , deuteron chloroform, deuteron DMSO, deuteron methanol, deuteron water, deuteron

112


4 , deuteron chloroform, deuteron DMSO, deuteron methanol, deuteron water, deuteron benzene, trifluroacetic acid.

TMS is generally employed as internal standard

for measuring the position of 1 H, 13 C, and 29 Si in the NMR spectrum because it gives a single sharp peak, is chemically inert and miscible with a large range of solvents, being

a

highly volatile, can easily be removed if the sample has to be recovered, does not involve in intramolecular association with the sample. 2.4.1

Interpretation of the NMR Spectra It is not possible to prescribe a set of rules which is applicable on all occasions. The amount of additional information available will most probably determine the amount of information it is necessary to obtain from the PMR spectrum. However, the following general procedure will form

a useful

initial approach to the interpretation of most spectra.

Chapter-2 Dept. of Chemistry, H. N. G.U. 51 ?

By making table of the chemical shifts of all the groups of absorptions in the spectrum. In some cases it will not be possible to decide whether a particular group of absorptions arises from separate sets of nuclei, or from a part of one complex multiplet. In such cases it is probably best initially to include them under one group and to note the spread of chemical shift values. ? By measuring and recording the heights of the integration steps corresponding to each group of absorptions. With overlapping

benzene, trifluroacetic acid. TMS is generally employed as internal standard for measuring the position of 1 H, 13 C, and 29 Si in the NMR spectrum because it gives a single sharp peak, is chemically inert and miscible with a large range of solvents, being a highly volatile, Chapter-2 HNGU, PATAN 42 can easily be removed if the sample has to be recovered, does not involve in intramolecular association with the sample. 2.4.1 Interpretation of the NMR Spectra It is not possible to prescribe a set of rules which is applicable on all occasions. The amount of additional information available will most probably determine the amount of information it is necessary to obtain from the PMR spectrum. However, the following general procedure will form a useful initial approach to the interpretation of most spectra. • By making table of the chemical shifts of all the groups of absorptions in the spectrum. In some cases it will not be possible to decide whether a particular group of absorptions arises from separate sets of nuclei, or from a part of one complex multiplet. In such cases it is probably best initially to include them under one group and to note the spread of chemical shift values. • By measuring and recording the heights of the integration steps corresponding to each group of absorptions. With overlapping groups of protons it may not be possible to measure these exactly, in which case a range should be noted. Work out possible proton ratios for the range of heights measured, by dividing by the lowest height and multiplying as appropriate to give integral values. • By noting any obvious splitting of the absorptions in the table (e.g., doublet, triplet, etc.). For spectra which appear to show first-order splitting, the coupling constants of each multiplet should be determined by measuring the separation between adjacent peaks in the multiplet. Any other recognizable patterns which are not first order should be noted. • By noting any additional information such as the effect of shaking with D 2 O, use of shift reagent, etc. Chapter-2 HNGU, PATAN 43 • By considering both the relative intensities and the multiplicities of the absorptions attempt to determine which groups of protons are coupled together. The magnitude of the coupling

113


groups of protons it may not be possible to measure these exactly, in which case a range should be noted. Work out possible proton ratios for the range of heights measured, by dividing by the lowest height and multiplying as appropriate to give integral values. ? By noting any obvious splitting of the absorptions in the table (e.g., doublet, triplet, etc.). For spectra which appear to show first-order splitting, the coupling constants of each multiplets should be determined by measuring the separation between adjacent peaks in the multiplet. Any other recognizable patterns which are not first order should be noted. ? By noting any additional information such as the effect of shaking with D 2 O, use of shift reagent, etc. ? By considering both the relative intensities and the multiplicities of the absorptions attempt to determine which groups of protons are coupled together. The magnitude of the coupling constant may give indication of the nature of the proton involved. ? By relating the information obtained other information available on the compound under considerations.

constant may give indication of the nature of the proton involved. • By relating the information obtained other information available on the compound under considerations. 2.5


Organic chemists are frequently facing the problem of characterizing and ultimately elucidating the structure of organic compounds. The worker in the field of natural product has the prospects of isolating such compounds from their sources in a pure state and then determining their structure. On the other hand the synthetic organic chemist encounters new or unexpected compounds in the course of investigations. All

reactions were carried out under prescribed laboratory conditions. All the reactions requiring anhydrous conditions were conducted in flame dried apparatus. The solvents and reagents used in the synthetic work were of laboratory reagent grade and were purified by distillation and crystallization techniques wherever necessary and


Organic chemists are frequently facing the problem of characterizing and ultimately elucidating the structure of organic compounds. The worker in the field of natural product has the prospects of isolating such compounds from their sources in a pure state and then determining their structure. On the other hand the synthetic organic chemist encounters new or unexpected compounds in the course of investigations. All reactions were carried out under prescribed laboratory conditions. All the reactions requiring anhydrous conditions were conducted in flame dried apparatus. The solvents and reagents used in the synthetic work were of laboratory reagent grade and were purified by distillation and crystallization techniques wherever necessary and their melting points were checked with the available literature. Melting points of newly synthesized compounds

114


their melting points were checked with the available literature. Melting points of newly synthesized compounds were determined by open capillary method. The final product was purified by recrystalization. The reaction,

the reagents and the conditions of the reaction system are given in the following scheme 3.1

were determined by open capillary method. The final product was purified by recrystallization. The reaction, the reagents and the conditions of the reaction system are given in the following scheme 2.1


Figure 4.2


Dept. of Chemistry, H. N. G.U. 88 Figure 4.4 MASS spectrum of compound 4a Chapter-4


Figure 2.6 NMR Spectrum of Compound SMO-02 Figure 2.7 CMR Spectrum of Compound SMO-02 Chapter-2 HNGU, PATAN 64 Figure 2.8 MASS Spectrum of Compound SMO-02 Chapter-2


Figure 4.6 NMR spectrum of compound 4b Figure 4.7 CMR spectrum of compound 4b Chapter-4 Dept. of Chemistry, H. N. G.U. 92 Figure 4.8 MASS spectrum of compound 4b Chapter-4





115


Figure 4.10











Figure 4.18








116






Figure 4.26













117


Figure 4.34






Figure 4.38







Figure 4.42






118



Figure 4.46







of Tetrazole) 1590 cm -1 (C=N of Tetrazole) 1220 cm -1 (C-N of Tetrazole and Imidazole) 2810 cm -1 (N-CH 2 N-CH 2 Linkage) 3030-3080 cm -1 (C-H of Aromatic) Mass in m/z (+Ve) Molecular ion peak was observed at 429.5 1 H NMR spectral Features (δ, ppm) 0.86


of ring 1635 cm -1 C=N stretching of ring 1040 cm -1 C-N stretching of ring 1330 cm -1 S=O stretching 1140 cm -1 C=S stretching of ring 2965 cm -1 C-H stretching of ring NMR spectral Features (δ, ppm) 6.16-8.22 (m, Aromatic proton + CH=N proton), Mass in m/z Molecular ion peak was observed at 380.46 13 CMR spectral Features (δ, ppm) 115-130


T. Miyazawa, ibid, 4, 155 (1960). [89] F. B. Dains, J. Am. Chem. Soc., 55, 3857 (1933). [90]


T. Miyazawa, (1960) ibid, 4, 155. [12] F. B. Dains (1933) J. Am. Chem. Soc., 55, 3857. [13]

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Instances from: http://shodhganga.inflibnet.ac.in/bitstream/10603/19311/6/06_abstract.pdf


N O Cl Ar S N O Ar N O CH 2 CONHN Ar N O CH 2 CONHNH 2 N O CH 2 CONH N O CH 2 CONH N O CH 2


N

O 2 N 53 54 55 56 Methanol N O 2 N 57 OCH 3 O OCH 3 CH 3 N H 2 N 58 OCH 3 O OCH 3 CH 3 N H N 59 OCH 3 O OCH 3 CH 3 O O N H N 60 OCH 3 O OH CH 3

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nickel boride / hydrazine hydrate reduction of aromatic and aliphatic nitro compounds; synthesis of 4- benzyloxy-indole and alpha alkyltryptamines.


Nickel Boride/Hydrazine Hydrate: Reduction of Aromatic and Aliphatic Nitro Compounds. Synthesis of 4-(Benzy1oxy)indole and a-Alkyltryptamines

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Instances from: https://www.researchgate.net/profile/Deepika_Sharma5/publication/225532914_Biological_importance_of_imidazole_nucleus_in_the_new_millennium/links/00b7d5183822e557cd000000.pdf?origin=publication_list


NH

O N H O N N CN O N NH N N N N O N

NH N N N


NH O 69 N N N Cl H 2 N 70 N N F 3 C 71 N N N N N + O - O 72 N N N N


N NH N N N N O N N H O Br Br Br N N O N N N N


N NH 3 2 N N OCH 3 O N H O H N N H O O O N N N N


N N O H Br CN CN

N N O / Xylene N N O N N N N C(Ph) 3 N N O N N N N

H +


N

N H N Br O H N N

O NH O H

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H 3


N N O H Br CN CN


H + 2-


N

N H N Br O H N N

O NH O H


H 3


N N O H Br CN CN


H + 2-


N

N H N Br O H N N

O NH O H


123


H 3


N N O H Br CN CN


H + 2-


N

N H N Br O H N N

O NH O H


H 3

124




The present chapter comprises characterization techniques used to characterize the produced compounds.


The present chapter comprises two sections. Section-I comprises characterization techniques used to characterize the produced compounds (


Anticipated Infrared Frequencies for heterocyclized products based on BOIH.

The present thesis comprises the study of following heterocyclized products: ?

Benzyl oxy indole hydrazide (BOIH) ? Schiff Bases of BOIH ? 2-Azetidinones ? 4-Thiazolidinones ? Tetrazoles ? 1,3,5-Oxadiazine

Hence, prior to characterize these compounds by IR spectroscopy it is necessary to predict the anticipated frequencies of each moiety.

Benzyl oxy indole hydrazide (BOIH) BOIH

is a heterocyclic compound.


due to


Anticipated Infrared Frequencies for Heterocyclised products based on NTOH. The present thesis comprises the study of following heterocyclized products: 2-(3-flourophenyl)-1,2,4-[3,2-b]-triazolo-Odz-6-thione aceto hydrazide (NTOH) b) Schiff Bases of AOD c) 2-Azetidinones d) 4-Thiazolidinones e) 2H-Pyrrole-2-Ones f) 2-Pyrrolidinones Hence, prior to characterize these compounds by IR spectroscopy it is necessary to predict the anticipated frequencies of each moiety. 2-(3-flourophenyl)-1,2,4-[3,2-b]-triazolo-Odz-6-thione (NTOH): NTOH is a heterocyclic compound.

It is an aromatic compound thus it provides the IR frequencies. The bands due to

125



mole) and chloro ethyl acetate (0.01 mole) in acetone (5 ml) were taken in round bottom flask [100 ml]. Then charge K 2 CO 3 (0.005 mole) and mixture were refluxed for 5-8 hrs. The solution was filtered through hyflow bed and filtrate


mole) and 0.01 mole chloro acetic acid in acetone (5 ml) were taken in round bottom flask [100 ml]. Then charge K 2 CO 3 (0.005 mole) and mixture were refluxed for 5-8 hrs. The 39 39 solution was drinkable through celite bed and filtrate






in turn filtered and washed with water and dried for 12 hrs at 50-55 0 C. The


in turn filtered and washed with water and dried for 12 hrs. at 50 0 -55 0 C. The





Mass in m/z Molecular ion peak was observed at 435.4 13 C-NMR spectral Features (δ, ppm) 114-125



126
















Mass in m/z (+Ve) Molecular ion peak was observed at 400.4 NMR spectral Features (δ, ppm) 6.6-8.5 (




The chemistry of Penicillin”, p.390, Princeton Press, Princeton, N. J (1949). [87]


The chemistry of Penicillin”, p.390, Princeton Press, Princeton, N. J. 8.

127






O S NH O O N O S NH O O N O CHO S NH O O + N









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Biological importance of Indole nucleus in recent years; A comprehensive review. 9 1.3


Biological Importance of the Indole Nucleus in Recent Years: A Comprehensive Review


Biological importance of Indole nucleus in recent years; A comprehensive review.


Biological Importance of the Indole Nucleus in Recent Years: A Comprehensive Review


Heterocyclic compounds are those cyclic compounds in which one or more of the ring carbons are replaced by another atom. The non-carbon atoms in such rings are referred to as ‘‘heteroatom.’’ Such bicyclic heterocyclic compounds containing pyrrole ring with benzene


Heterocyclic compounds are those cyclic compounds in which one or more of the ring carbons are replaced by another atom. The non-carbon atoms in such rings are referred to as ‘‘heteroatoms.’’ Such bicyclic heterocyclic compounds containing pyrrole ring with benzene

129


ring fused to α,β-position are known as Indoles. Indole has a benzene ring and pyrrole ring sharing one double bond. It is a heterocyclic system with 10 electrons from four double bonds and the lone pair from the nitrogen atom. Indole is an important heterocyclic system because it is built into proteins in the form of amino acid tryptophan, because it is the basis of drugs like indomethacin and because it provides the skeleton of indole alkaloids—biologically active compounds from plants including strychnine and LSD.

The incorporation of indole nucleus, a biologically accepted pharmacophore in medicinal compounds (Table 1), has made it versatile heterocyclic possessing wide spectrum of biological activities (

Table 2).

In the present

study, we have made an attempt to collect biological properties of imidazole nucleus reported in the new millennium.

ring fused to a,b-position are known as Indoles. Indole has a benzene ring and pyrrole ring sharing one double bond. It is a heterocyclic system with 10 electrons from four double bonds and the lone pair from the nitrogen atom. Indole is an important heterocyclic system because it is built into proteins in the form of amino acid tryptophan, because it is the basis of drugs like indomethacin and because it provides the skeleton of indole alkaloids—biologically active compounds from plants including strychnine and LSD. The incorporation of indole nucleus, a biologically accepted pharmacophore in medicinal compounds (Table 1), has made it versatile heterocyclic possessing wide spectrum of biological activities (Table 2). In the present study, we have made an attempt to collect biological properties of imidazole nucleus reported in the new millennium.


Anti-Inflammatory activity and analgesic activity Abele et al. synthesized isatin and indole oximes and carried outthe chemical reactions and biological activities of the synthesized compounds where the compound (1) was found to be most active analgesic and anti-inflammatory agent [18].


Anti-inflammatory and analgesic activity. Abele et al. synthesized isatin and indole oximes and carried out the chemical reactions and biological activities of the synthesized compounds where the compound (1) was found to be most active analgesic and anti-inflammatory agent [1].

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Kalaskar et al. synthesized indole-3-acetic acids and evaluated them for their in vivo anti-inflammatory activityThe compound 1,2-disubstituted-5- methoxyindole/benz(g)indole-3-acetic acid (4) showed significant


Kalaskar et al. synthesized indole-3-acetic acids and evaluated them for their in vivo anti-inflammatory activity. The compound 1,2-disubstituted-5-methoxyindole/ benz(g)indole-3-acetic acid (4) showed significant


The synthesis and anti-inflammatory activity of heterocyclic indole derivatives was performed by Rani et al. The compound was found to be most potent (inhibition of oedema at 50 lg/Kg dose) [20].


The synthesis and anti-inflammatory activity of heterocyclic indole derivatives was performed by Rani et al. The compound (5) was found to be most potent (inhibition of oedema at 50 lg/Kg dose) [4].


activity Some of the isatin and indole oximes synthesized by Abele et al. were found to be exhibiting high fungicidal activity where the oxime derivates of 2-substituted indoles and 3-substituted indoles demonstrated significant antifungal activity [31].


activity. Some of the isatin and indole oximes synthesized by Abele et al. were found to be exhibiting high fungicidal activity where the oxime derivates of 2-substituted indoles (8) and 3-substituted indoles (9) demonstrated significant antifungal activity [1].

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activity The

synthesis and antibacterial activity of some substituted 3-(aryl) and 3- (heteroaryl)

indoles were reported by Hiari et al. The most active compound was reported to be 3-(4-trifluoromethyl-2-nitrophenyl) indole (11) exhibiting MIC = 7 μg/cm 3 against Escherichia coli and Staphylococcus aureus [33].


activity. The synthesis and antibacterial activity of some substituted 3-(aryl) and 3-(heteroaryl) indoles were reported by Hiari et al. The most active compound was reported to be 3-(4-trifluoromethyl- 2-nitrophenyl) indole (11) exhibiting MIC * 7 lg/cm 3 against Escherichia coli and Staphylococcus aureus [7].


thiadiazino[6,5-b]indoles as prospective antimicrobial agents. The compounds were found to exhibit most inhibitory effect against E. coli and S. aureus [34].


thiadiazino[6,5-b]indoles as prospective antimicrobial agents. The compounds (12) and (13) were found to exhibit most inhibitory effect against E. coli and S. aureus [8].



132


Insecticidal activity Sharma et al investigated the insecticidal activity of synthesized novel indole derivatives. The compounds exhibited promising results against Spodoptera liture (eighth instar larvae) and Jeliothis armigera [37].

Insecticidal activity. Sharma et al. investigated the insecticidal activity of synthesized novel indole derivatives. The compounds (14) and (15) exhibited promising results against Spodoptera liture (eighth instar larvae) and Jeliothis armigera [9].


Anticancer activity Garcia et al. synthesized pyrrolo[2,3-e] indole derivatives and evaluated them for possible in vitro cytotoxic activity. The most active compound was found to be, which shows best result in PC-3 (prostate) cell line [38].


anticancer activity [1]. Garcia et al. synthesized pyrrolo[2,3-e] indole derivatives and evaluated them for possible in vitro cytotoxic activity. The most active compound was found to be (21), which shows best result in PC-3 (prostate) cell line [11]. 494


A series of halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy were reported by Rossiter et al. These derivatives were oxidized by horse radish peroxidase (HRP) and toxicity against V79 Chinese hamster lung fibroblasts was determined and the compound was found to possess highest cytotoxicity and it was the best drug for targeted cancer therapy [39].


A series of halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy were reported by Rossiter et al. These derivatives were oxidized by horse radish peroxidase (HRP) and toxicity against V79 Chinese hamster lung fibroblasts was determined and the compound (22) was found to possess highest cytotoxicity and it was the best drug for targeted cancer therapy [12].

133



Lipoxygenase inhibitor Zheng et al synthesized a series of indole derivatives as possible 5- lipoxygenase inhibitors. In all, four compounds exhibited the most potent inhibitory activity with IC50 values ranging from 0.74 lM to 3.17 lM [43].


Lipoxygenase inhibitor. Zheng et al. synthesized a series of indole derivatives as possible 5-lipoxygenase inhibitors. In all, four compounds 24, 25, 26, and 27 exhibited the most potent inhibitory activity with IC 50 values ranging from 0.74 lM to 3.17 lM [14].


HIV inhibitors The analogs of pyrimido[5,4-b]indoles were synthesized and biologically evaluated by Merino et al. for their possible HIV inhibitory activity. The derivative formed by substitution at position 2 in analog-I and derivative at position 2, 4 in analog II (formed in 65% and 64% maximum yield) were reported to be the inhibitors of wild and mutant HIV-1 RT types in an ‘‘in vitro’’ recombinant HIV-1 RT screening assay as well as anti-infectives in HLT4lacZ-1IIIB cells [44].


HIV inhibitors. The analogs of pyrimido[5,4- b]indoles were synthesized and biologically evaluated by Merino et al. for their possible HIV inhibitory activity. The derivative (28) formed by substitution at position 2 in analog-I and derivative (29) at position 2, 4 in analog II (formed in 65% and 64% maximum yield) were reported to be the inhibitors of wild and mutant HIV-1 RT types in an ‘‘in vitro’’ recombinant HIV-1 RT screening assay as well as anti-infectives in HLT4lacZ-1 IIIB cells [15].



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Antioxidant activity A series of indole derivatives were synthesized and biologically evaluated by Enien et al., and found that Indole-2 and 3-carboxamides were having antioxidant properties by Chemoluminesence and Electron spin resonance spin trapping. They further reported that the derivatives have strongest scavenging effect on OH - radicals, i.e., quenching <30%

Antioxidant activity. A series of indole derivatives were synthesized and biologically evaluated by Enien et al., and found that Indole-2 and 3-carboxamides were having antioxidant properties by Chemoluminesence and Electron spin resonance spin trapping. They further reported that the derivatives 30 and 31 have strongest scavenging effect on OH * radicals, i.e., quenching <30%


and the derivatives have strongest effect on scavenging of superoxide radicals [45]. 1.2.8


and the derivatives 31 and 32 have strongest effect on scavenging of superoxide radicals [16].


Antituberculosis activity A new series of 1-Hindole-2,3-dione derivatives were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv by Karali et al. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3- thiosemicarbazones and its 1-morpholinomethyl derivatives exhibited significant inhibitory activity with MIC values * 75% [46].


Antituberculosis activity. A new series of 1H- indole-2,3-dione derivatives were synthesized and evaluated for in vitro antituberculosis activity against Myco- bacterium tuberculosis H37Rv by Karali et al. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones and its 1-morpholinomethyl (36, 37, 38, and 39) derivatives exhibited significant inhibitory activity with MIC values *75% [18].

135



Plant growth regulator The 3-substituted indole was reported to be a plant growth regulator by Abele et al. among the various isatin and indole oximes synthesized and evaluated by them [50]. 1.2.11 Antidepressant, tranquilizing and anticonvulsant activity


Plant growth regulator. The 3-substituted indole (42) was reported to be a plant growth regulator by Abele et al. among the various isatin and indole oximes synthesized and evaluated by them [1]. Antidepressant, tranquillizing, and anticonvulsant activity.


A series of N-substituted indoles were synthesized by Falco et al., and afterwards, in vitro screening and in vivo spontaneous motor activity in mice had revealed molecules with good in vitro affinities for the a1-subunit of GABAA receptor and potent in vivo induction of sedation and (44) was found most potent compounds [51].


A series of N-substituted indoles were synthesized by Falco et al., and afterwards, in vitro screening and in vivo spontaneous motor activity in mice had revealed molecules with good in vitro affinities for the a 1 -subunit of GABA A receptor and potent in vivo induction of sedation and (44) was found most potent compounds [19].


A number of benzopyranyl indoline and indole analogs were synthesized and evaluated for Cardioselective anti-ischemic ATP-


A number of benzopyranyl indoline and indole analogs were synthesized and evaluated for Cardioselective anti-ischemic ATP-

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sensitive potassium channel (KATP) opener activity by Lee et al. The compounds showed the best cardioprotective activity [54]. 1.2.13 Antihypertensive activity

sensitive potassium channel (K ATP ) opener activity by Lee et al. The compounds (46) and (47) showed the best cardioprotective activity [20]. Antihypertensive activity.


activity A number of indole amide derivatives bearing a side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well known antihistamines, were prepared and tested for the antihistaminic activity by Battaglia et al. The most active some compounds were tested in vivo for their ability to antagonize histamine induced cutaneous vascular permeability in rats [56]. 1.2.15


activity. A number of indole amide derivatives bearing a side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well known antihistamines, were prepared and tested for the antihistaminic activity by Battaglia et al. The most active compounds 49, 50, 51, 52, 53, and 54 were tested in vivo for their ability to antagonize histamine induced cutaneous vascular permeability in rats [21].


activity The synthesis and photochemotherapeutic activity of thiopyrano[2,3-e]indol- 2-ones was performed by Barraja et al., wherein the compound thiopyrano[2,3-e]- indol-2-ones showed the maximum phototoxicity on two cultured cell lines: HL-60 and LoVo [57].


activity. The synthesis and photochemotherapeutic activity of thiopyrano[2,3- e]indol-2-ones was performed by Barraja et al., wherein the compound thiopyrano[2,3-e]-indol-2-ones (56) showed the maximum phototoxicity on two cultured cell lines: HL-60 and LoVo [23].

137



Antidiabetic activity Some of the indole derivatives were evaluated for their insulin sensitizing and glucose lowering effects by Li et al. The indole derivative showed increase in activity of PPARc agents, which shows decreased serum glucose and contributing to


Antidiabetic activity. Some of the indole derivatives were evaluated for their insulin sensitizing and glucose lowering effects by Li et al. The indole derivative (57) showed increase in activity of PPARc agents, which shows decreased serum glucose and contributing to


reductase inhibitor. A class of indole and benzimidazole derivatives were synthesized and evaluated for their inhibitory activity against rat prostatic 5a-reductase by Takami et al. The compounds were found to be showing most potent inhibitory activity against rat prostatic 5a-reductase with IC50 ¼ 9.6 6 1.0 nM and 19 6 6.2 nM, respectively [59].


reductase inhibitor. A class of indole and benzimidazole derivatives were synthesized and evaluated for their inhibitory activity against rat prostatic 5a-reductase by Takami et al. The compounds (64) and (65) were found to be showing most potent inhibitory activity against rat prostatic 5a-reductase with IC 50 ¼ 9.6 6 1.0 nM and 19 6 6.2 nM, respectively [29].



138


Thrombin catalytic activity The substituted 5-amide indoles were evaluated as inhibitors of thrombin catalytic activity by Iwanowicz et al. The compound was found to be the most potent inhibitor of thrombin catalytic activity with an inhibition constant, Ki ¼ 260 nM [60]. 1.2.19

Thrombin catalytic activity. The substituted 5-amide indoles were evaluated as inhibitors of thrombin catalytic activity by Iwanowicz et al. The compound (67) was found to be the most potent inhibitor of thrombin catalytic activity with an inhibition constant, K i ¼ 260 nM [31].


The preparation and evaluation of a class of CB2 receptor agonist based on a 1,2,3,4-tetrahydropyrrolo[3,4-b] indole moiety were reported by Page et al. The compound showed to be most potent CB2 receptor agonist [61,62].


The preparation and evaluation of a class of CB2 receptor agonist based on a 1,2,3,4-tetrahydropyrrolo[3,4-b] indole moiety were reported by Page et al. The compound (71) showed to be most potent CB2 receptor agonist [35]. 500


H. Panwar, R. Verma, V. K. Srivastava, A. Kumar, Indian J Chem., 45B, 2099 (2006). [34] Y. Hiari, A. M. Qaisi, M. M. Abadelah, W. Voelter, Monatshefte Fur Chemie 137, 243 (2006). [35]


H.; Verma, R. S.; Srivastava, V. K.; Kumar, A. In- dian J Chem 2006, 45B, 2099. [8] Hiari, Y. M. A.; Qaisi, A. M.; Abadelah, M. M.; Voelter, W. Monatshefte Fur Chemie 2006, 137, 243. [9]



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J Heterocycl. Chem., 1, 189 (1992). [38] L. C. Garcia, R. Martinez, Eur J Med Chem, 37, 261 (2002). [39] S. Rossiter, L. K. Folkes, P. Wardman, Bioorg. Med. Chem. Lett., 12, 2523 (2002). [40]


J Chin Chem Soc 2006, 53, 647. [11] Garcia, L. C.; Martinez, R. Eur J Med Chem 2002, 37, 261. [12] Rossiter, S.; Folkes, L. K.; Wardman, P. Bioorg Med Chem Lett 2002, 12, 2523. [13]

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Spectrometry

Fundamental to modern techniques of structure determination is the field of

spectroscopy the study of the interaction of matter and light (or other electromagnetic radiations). Spectroscopy has been immensely important to many areas of

chemistry and physics. For example, much of what is known about orbitals and bonding comes from spectroscopy. But spectroscopy is also important to the laboratory organic chemist

because it can be used to determine unknown molecular structures. Although this presentation of spectroscopy will focus largely on its applications, some fundamentals of spectroscopy theory must be considered first.


Infrared Spectroscopy Infrared spectroscopic technique [80-83] is of a very importance

to organic chemists for the identification of the presence of functional groups in the organic compounds although it does not provide the complete information regarding the molecular structure of the organic compounds. However it is used for the characterization of the compounds. Infrared spectroscopic technique gives the information about the molecular vibrations or more precisely on the transitions


Spectrometry Fundamental to modern techniques of structure determination is the field of spectroscopy, the study of the interaction of matter and light (or other electromagnetic radiations). Spectroscopy has been immensely important to many areas of chemistry and physics. For example, much of what is known about orbitals and bonding comes from spectroscopy. But spectroscopy is also important to the organic chemist because it can be used to determine unknown molecular structures. Although this presentation of spectroscopy will focus largely on its applications, some fundamentals of spectroscopic theory must be considered first. Chapter 2 Department of Chemistry, S.P.U. 51 2.1.3 Infrared Spectroscopy Infrared spectroscopic technique 1-4 is of an immense importance to organic chemists for the identification of the presence of functional groups in the organic compounds although it does not provide the complete information regarding the molecular structure of the organic compounds. However it is used for the identification of the compounds. Infrared spectroscopic technique gives the information about the molecular vibrations or more precisely on the transitions between rotational and vibration energy levels in the molecule and due to this characteristic; it is of immense help to organic chemists. When infrared light is passed through a sample, some of the frequencies are absorbed while other frequencies are transmitted through the sample. The absorption of infrared radiation results in increasing the energy of vibration or rotation associated with covalent bond in a molecule. Absorption of radiation in the infrared region results in the excitation of bond deformations, either stretching or bending. Various stretching and bending vibrations occur at certain quantized frequencies. When infrared light of that frequency is incident or impart on to the molecule, energy is

141


between rotational and vibrational energy levels in the molecule and due to this characteristic; it is of immense help to organic

chemists.

When infrared light is passed through a sample, some of the

frequencies are absorbed while other frequencies are transmitted through the sample.

The absorption of infrared radiation depends on increasing the energy of vibration or rotation associated with co-valent bond in a molecule. Absorption

of

radiation in the infrared region results in the excitation of bond deformations, either stretching or bending. Various stretching and bending vibrations occur at certain quantized frequencies. When infrared light of that frequency is incident or impart on the

molecule, energy is absorbed and

the amplitude of that vibration is increased. “An infrared spectrum is obtained when the frequency of molecular vibrations corresponds to the frequency of the infrared radiations absorbed.” The material under study is usually in the form of a solid, a neat liquid or a solution. Sometimes, however, a compound in the gas or vapor phase is studied. Under these conditions, in addition to changes in vibrational energy, simultaneous changes in rotational energy can occur and consequently some fine structures may be observed on the vibrational band. Infrared spectrum of a compound represents its energy absorption pattern in the infrared region and is obtained by plotting percentage absorbance or transmittance of infrared radiation as a function of wavelength or wave

absorbed and the amplitude of that vibration is increased. “An infrared spectrum is obtained when the frequency of molecular vibrations corresponds to the frequency of the infrared radiations absorbed.” The material under study is usually in the form of a solid, a neat liquid or a solution. However, a compound in the gas or vapor phase is studied. Under these conditions, in addition to changes in vibrational energy, simultaneous changes in rotational energy can occur and consequently some fine structures may be observed on the vibrational band. Infrared spectrum of a compound represents its energy absorption pattern in the infrared region and is obtained by Chapter 2 Department of Chemistry, S.P.U. 52 plotting percentage absorbance or transmittance of infrared radiation as a function of wavelength or wave

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Schiff Bases: Acyclic unsaturated nitrogen compounds containing C=N bond is most commonly encountered in oximes and Schiff’s bases. Both the classes absorb in the region from 1690-1640 cm -1 , usually less strongly than carbonyl compounds but the oximes are distinguished by the presence of O-H stretching(free) absorptions between 3650 and 3600 cm -1 in dilute solution.

Chapter-2


Schiff Bases Acyclic unsaturated nitrogen compounds containing C=N bond is most commonly encountered in oximes and Schiff‟s bases. Both the classes absorb in the region from 1690-1640 cm -1 , usually less strongly than carbonyl compounds but the oximes are distinguished by the presence of O-H stretching(free) absorptions between 3650 and 3600 cm -1 in dilute solution. Chapter 2


Azetidinones (β-lactams): Lactams exhibits the following characteristic absorption bands in their spectra. Lactams exhibit a strong N-H stretching bonded absorption in the solid state near 3200 cm -1 and a weaker band near 3100 cm -1 resulted due to the combination of C=O stretching and N-H in-plane bending absorptions [84,85]. The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Lactams (five membered ring lactams) absorb near 1750-1700 cm -1 . Unfused β-lactams absorb at 1760-1730 cm -1 while β -lactams fused to unoxidized thiazolidine rings absorbed at 1780-1710 cm -1 [86,87]. N-H in-plane bending, C-N stretching and N-H wagging vibrations: Cyclic mono substituted amide shows no band in the region from 1600-1500 cm -1

comparable to the 1550 cm -1 C-N-H in-plane bending band in the trans structure. The cis N-H in-plane bending vibration absorbs at


Azetidinones (β-lactams) Lactams exhibits the following characteristic absorption bands in their spectra. Lactams exhibit a strong N-H stretching bonded absorption in the solid state near 3200 cm -1 and a weaker band near 3100 cm -1 resulted due to the combination of C=O stretching and N-H in-plane bending absorptions [6]. The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Lactams (five membered ring lactams) absorb near 1750-1700 cm -1 . Unfused β-lactams absorb at 1760-1730 cm -1 while β-lactams fused to unoxidized thiazolidine rings absorbed at 1780- 1710 cm -1 [7,8]. N-H in-plane bending, C-N stretching and N-H wagging vibrations: Cyclic mono substituted amide shows no band in the region from 1600-1500 cm -1 comparable to the 1550 cm -1 C-N-H in-plane bending band in the trans structure. The cis N-H in-plane bending vibration absorbs at 1490-1440 cm -1 and the C-N stretching vibration at 1350 cm -1 [9]. There is much less interaction

143


1490-1440 cm -1 and the C-N stretching vibration at 1350 cm -1 [88]. There is much less interaction between these modes compared to the trans form. The N-H out-of-plane bending (wagging) vibration appears

as a broad band near 800

cm -1 . 4-

Thiazolidinones: The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Thiazolidinones absorbs at 1730-1700 cm -1 [89].

between these modes compared to the trans form. The N-H out-of- plane bending (wagging) vibration appears as a broad band near 800 cm -1 . 4-Thiazolidinones The carbonyl stretching vibration absorbs near 1650 cm -1 in six or seven membered rings as in the case of acyclic trans structure. Thiazolidinones absorbs at 1730-1700 cm -1 [10,13]. 2-


at 1300

cm -1 [90]. 2.4

Proton nuclear magnetic resonance

spectroscopy

Nuclear magnetic resonance (NMR) spectroscopy is supplementary technique to IR spectroscopy to get details characterization report about structure of organic compounds. Most widely studied nucleus is proton and then the technique is called NMR spectroscopy [91,92]. IR spectra give information about the functional group while NMR spectra provide information about the exact nature of proton and its environment. Thus this technique is

more useful in the elucidation of an organic compound. IR spectra of isomers may appear same but their NMR spectra will markedly differ.


at 561 cm -1 [11,12]. 2.4 Proton Nuclear Magnetic Resonance Spectroscopy Nuclear magnetic resonance (NMR) spectroscopy is supplementary technique to IR spectroscopy to get details information about structure of organic compounds. Most widely studied nucleus is proton and then the technique is called PMR spectroscopy. IR spectra give information about the functional group while NMR spectra provide information about the exact nature of proton and its environment. Thus this technique is more useful in the elucidation of an organic compound. IR spectra of isomers may appear same but their NMR spectra will markedly differ. The phenomenon of nuclear magnetic resonance was first reported independently in 1946 by two groups of physicists: Block, Hansen and Packard at Stanford University detected a signal from the protons of water, and Purcell, Torrey and Pound at Harvard University observed a signal from the protons in paraffin wax. Block and Purcell were jointly awarded the Nobel Prize for physics in 1952 for this discovery. Since that time, the advances in NMR techniques

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The phenomenon of nuclear magnetic resonance was first reported independently in 1946 by two groups of physicists: Block, Hansen and Packard at Stanford University detected a signal from the protons of water, and Purcell, Torrey and Pound at Harvard University observed a signal from the protons in paraffin wax. Block and Purcell were jointly awarded the Nobel Prize for physics in 1952 for this discovery. Since that time, the advances in NMR techniques leading to wide spread applications in various branches of science resulted in the Nobel Prize in chemistry in 1991. The applications of NMR in clinical, solid state and biophysical sciences are really marvelous. The proton magnetic

resonance (PMR) spectroscopy is the most important technique used for the characterization of organic compounds. It gives information about the different kinds of protons in the molecule. In other words it tells one about different kinds of environments of the hydrogen atoms in the molecule. PMR also

gives information about the number of protons of each type and the ratio of different types of protons in the molecule.

leading to wide spread applications in various branches of science Chapter 2 Page 55 resulted in the Nobel Prize in chemistry in 1991. The applications of NMR in clinical, solid state and biophysical sciences are really marvelous. The proton magnetic resonance (PMR) spectroscopy is the most important technique used for the characterization of organic compounds. It gives information about the different kinds of protons in the molecule. In other words it tells one about different kinds of environments of the hydrogen atoms in the molecule. PMR also gives information about the number of protons of each type and the ratio of different types of protons in the molecule.




CH of CH=N protons + H of Pyrimdine + H of SO 2 NH) 3.85 (3H, singlet, OCH 3 ) 13 CMR spectral Features ( , ppm) 114-131 Benzene 134 Ar-Cl 160 CH=N 162-169 pyrimidine 163 -C – O 56



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R. M. Fikry, N. A. Ismael, A. A. El-Bahnasawy, A. A. Sayed El-Ahl, Phosphorous, Sulfur, and Silicon, 179, 1227 (2004). [73]


R.M.Fikry, N.A.Isamael, A.A.E.Bahnsawy, A.A.Sayed El. Ahl., Phos. Sulfur and Silicon., 179, 1227 (2004). 14.





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