chapter-i -...

CHAPTER-I

An improved process for the preparation

of Dronedarone Hydrochloride

Introduction

10

Introduction

Atrial fibrillatio (AF or Afbi) is the most common cardiac rhythm disturbance and

is responsible for substantial morbidity, requiring hospitalization. It is growing

like an epidemic in western countries with an estimated prevalence of 3.8% of the

population aged over 60 years and 9% in respect of population aged over 80

years.1 It is expected to affect 30 million North Americans and Europeans by

2050.2

In AF, the normal electrical impulses usually originate in the roots of the

pulmonary veins, leading to irregular conduction of impulses to the ventricles

which generate the heartbeats. AF may be treated with medication and there are

two major treatment strategies available i.e. Rate control and Rhythm control.3

Rate control lowers the heart rate closer to normal; usually 60 to 100 bpm,

without trying to convert to a regular rhythm. This can be done with:

Beta blockers (preferably the “cardioselective” beta blockers such as

Metoprolol, Atenolol, Bisoprolol, Nebivolol).

Non-dihydropyridine calcium channel blockers (i.e. Diltiazem or

Verapamil).

Cardiac glycosides (i.e. Digoxin–which have limited use i.e. only

given to sedentary elderly patient).

Rhythm control is also called „Cardioversion‟ which is a non-invasive conversion

of an irregular heartbeat to a normal heartbeat using electrical or chemical means.

Electrical cardioversion involves the restoration of normal heart

rhythm through the application of Direct current (D.C.) electrical

shock.

Chemical cardioversion is performed with drugs, such as

Procainamide, Dofetilide, Idutilibe, Propafenone, Amiodarone and

Dronedarone.

11

History of Dronedarone Hydrochloride

Amiodarone (1; Figure–1), a benzofuran derivative synthesized in 1962 as a

coronary vasodilator, is now recognized as one of the most effective drugs in the

treatment of both atrial and ventricular arrhythmias.4

It is a multi channel blocker

and exerts a very complex electro pharmacologic effects, including classes I, II,

III and IV antiarrhythmic actions, with marked difference between short–term and

long–term effects.5 Chronic use of Amiodarone and its active metabolite

desethyl–amiodarone can cause adverse effects on thyroid such as

hypothyroidism or thyrotoxicosis, pulmonary toxicity and hepatic toxicity. 3, 6

Amiodarone is an iodinated benzofuran derivative (as seen in Figure–1). Due to

presence of the iodo–substituent, it is lipophilic and have a long half–life up to

100 days and causes thyroid dysfunction and accumulation in adipose tissue and

other organs like liver, lung, cornea, skin.2, 7–11

Figure−1

O

O

O

N R

I

I

1

R = Et, Amiodarone, R = H, Desethyl amiodarone

Since most of the unfavourable properties of Amiodarone are due to the presence

of iodine functionality, to improve the safety and tolerability, several non–

iodinated benzofuran derivatives have been synthesised. Of these modified

analogues, Dronedarone is the most advanced candidate in clinical development.

12

Structure of Dronedarone Hydrochloride

Dronedarone Hydrochloride (2; Figure–2) is a white fine powder, which is

practically insoluble in water and freely soluble in DCM, Chloroform and

methanol. Its empirical formula is C31H44N2O5S.HCl with a relative molecular

weight 593.2. Structure of Dronedarone Hydrochloride is provided in figure−2.

Figure−2

O

O

O

NHS

O O

N .HCl

Dronedarone Hydrochloride (2)

Dronedarone Hydrochloride (2) is a modified synthetic analogue of Amiodarone

with two molecular changes; i.e., it lacks the iodine functionality of Amiodarone

but has an additional sulphonamide group placed on benzofuran ring which

decreases lipophilicity, resulting in a shorter life-time and lower tissue

accumulation.

Dronedarone Hydrochloride is a potent blocker of multiple ion current and US

food and drug administration has approved it for treatment of AF on July 2, 2009.

13

Literature Review

A thorough literature search on Dronedarone Hydrochloride revealed that due to

the usefulness of this molecule, various synthetic process/routs have been

developed for its commercial production.

Gubin et al.12

[Product patent route, 1993]

Jean Gubin and co−workers synthesised Dronedarone Hydrochloride by using

2-hydroxy 5-nitro benzyl bromide (3) as key raw material which, on reaction with

triphenyl phosphine (TPP) in chloroform gave Wittig salt 4. Now condensation

of valeroyl chloride with Wittig salt 4 using pyridine as base, followed by

intramolecular Wittig reaction in toluene afforded nitro benzofuran derivative 5.

Friedel−Craft acylation reaction of nitro benzofuran 5 with p-anisoyl chloride, in

presence of stannic chloride yielded compound 6. Now demethylation was

achieved in EDC in presence of aluminium chloride to obtain intermediate 7

(Scheme−1).

Scheme−1

OH

Br

NO2

OH

PPh3

NO2

+

-Br

O

O2N

O

O2N

O

O

O

O2N

O

OH

3 4 5

6 7

a b

c d

Reagents and conditions: (a) TPP, CHCl3, reflux, 30 min; (b) i) valeroyl

chloride, pyridine, CHCl3, reflux, 2 h; ii) Et3N, toluene, reflux, 3 h;

(c) p-anisoyl chloride, SnCl4, DCM, 23 °C, 24 h; (d) AlCl3, EDC, reflux, 20 h.

14

Further condensation of chloro compound 42 with benzofuran 7 in MEK and

K2CO3 provided nitro compound 8. Reduction of nitro group to amine was

accomplished by catalytic hydrogenation in presence of PtO2 as catalyst in

ethanol and finally Dronedarone free base was synthesised using methane

sulfonyl chloride and Et3N in DCM. Purification of free base was performed by

column chromatography followed by hydrochloride salt formation in ethyl acetate

using hydrogen chloride in ether to furnish Dronedarone Hydrochloride (2) as

shown in scheme−2.

Scheme−2

O

O2N

O

OH

O

O2N

O

ON

O

O

ON

NH2

O

O

ON

NHS

O OO

O

ON

NHS

O O

.HCl

7 8

92 (free base) 2

a b

c d

N

Cl

+

42

Reagents and conditions: (a) K2CO3, MEK, reflux, 20 h; (b) PtO2/H2, EtOH,

RT, 20 min; (c) MsCl, Et3N, DCM, RT, 20 h; (d) HCl−ether, ethyl acetate, 45

min.

Generation of extensive amount of side product like TPPO during cyclization via

intramolecular Wittig reaction, use of class 1 solvent like EDC and formation of

mutagenic13

intermediate 7 were major disadvantages of this route.

15

Wolfgang M et a l 14

[synthesis of nitro benzofuran from methyl salicylate]

Wolfgang M. reported an alternative synthesis of nitro benzofuran derivative 5

exploiting methyl salicylate (10) as raw material which was condensed with

methyl-2-bromohexanoate (43) in acetonitrile and K2CO3 was used as base to

obtain diester compound 11 which on saponification with NaOH in MeOH

afforded diacid derivative 12. The cyclised compound 13 was prepared from

diacid derivative 12 by using acetic anhydride and sodium acetate in acetic acid,

under reflux condition, further deacylation by 6.0 N HCl in EtOH afforded keto

compound 14. Nitration of 14 was accomplished by employing nitrating mixture

(i.e. H2SO4 and HNO3) to furnish nitro compound 15. Further reduction of 15 by

NaBH4 in EtOH followed by aromatization in presence of H2SO4 in EtOH

resulted in nitro benzofuran intermediate 5 as shown in scheme−3.

Scheme−3

OH

O

O O

O

O

O

O

O

O

OH

O

OH

10 11 12

a bc

O

OAc

O

O

O

OO2N

d e

13 14 15

O

OHO2N

f O

O2N

g

16 5

Reagents and conditions: (a) methyl 2-bromohexanoate, K2CO3, ACN, reflux

16 h; (b) NaOH, MeOH, 40 °C 1h; (c) Ac2O, AcOH, NaOAc, reflux 4 h; (d) 6.0

N HCl, EtOH, reflux 4 h; (e) H2SO4, HNO3, 5 °C; (f) NaBH4, EtOH, reflux 2 h;

(g) H2SO4, EtOH, reflux, 4 h.

16

Schlama Thierry et al 15

Schlama and co-workers prepared nitro benzofuran 5 in four steps from

Salicylaldehyde (17) which was condensed with methyl 2-bromohexanoate (43)

to give ester 18. This was followed by ester hydrolysis to afford acid 19.

Nitration of acid derivative 19 followed by cyclization using acetic anhydride

furnished the desired nitro benzofuran intermediate 5 (Scheme−4).

Scheme−4

OH

O

H O

O

H

O

O

O

O

H

O

OH

17 18 19

a b

c d O

O2N

5

O

O

H

O

OH

O2N

20

Reagents and conditions: (a) methyl 2-bromohexanoate, K2CO3, DMF, 80 °C, 4

h; (b) H2SO4, HNO3, 5 °C; (c) i) 50.0% NaOH, water, 50 °C, 2h; ii) conc. HCl,

water; AcOH, NaOAc, reflux 4h; (d) Ac2O, K2CO3, 130 °C, 5h.

Several other methods were reported for the preparation of benzofuran derivatives

like condensation of 2-iodo phenol with acetylene derivatives in presence of CuI,

base and Pd/C or Pd(OAc)2,16, 17

reaction of β-keto ester with 1-bromo-2-iodo

benzene,18

cyclization of keto derivatives. 19−21

Also other methodologies were

reported through which one can synthesize required nitro benzofuran 5. 22−27

17

Kretzschmar Gerhard and co-workers 28

[Synthesis of intermediate 7]

Recently Kretzschmar Gerhard and co-workers reported the synthesis of key

intermediate 7. Acylation of phenol 21 by using valeroyl chloride gave

intermediate 22 which on cyclization in presence of tri-n-butyl amine and

molecular sieve / Fe-BEA type zeolite in xylene at reflux afforded intermediate 6.

Demethylation of 6 was carried out with dry HCl in tri-n-butyl amine

hydrochloride or using 1-butyl-4-methypyridinium tetrafluoroborate as ionic

solvent is reported as described in scheme−5.

Scheme−5

O2N

OHO

OO2N

OO

O

O

O

O

O

O2N

O

O

OH

O2N

2122

67

a

b

c

Reagents and conditions: (a) i) K2CO3, acetone, water, 40−50 °C, 1h; ii)

valeroyl chloride, acetone, -10 °C, 30 min; (b) tri-n-butyl amine, molecular sieves

or Fe-BEA type zeolite, xylene reflux, 8 h; (c) tri-n-butyl amine hydrochloride or

ionic liquid, 150 °C, 15−20 h.

The reagent and solvents involved in this process were relatively less toxic. Use

of recovered catalyst like molecular sieves at cyclization stage clearly indicated

that Kretzschmar and co-workers focused their attention on green chemistry

which was very important feature of this scheme. However requirement of high

18

temperature at cyclization and demethylation step (150 °C) was the major

concerns due to which we decided to avoid this route for commercial scale

synthesis of intermediate 7.

Shoutteeten A. and co-workers et a l 29

[preparation of intermediate 7].

Shoutteeten A. and co-workers reported preparation of key intermediate 7 by

starting from nitro compound 23. Acid catalyzed rearrangement of nitro

compound 23 using acetic acid and conc. H2SO4 at reflux was used to produce

benzofuran 24. Conversion of benzofuran 24 to corresponding acid chloride 25

by treatment with SOCl2 followed by reaction with p-anisole at 0 to 5 °C afforded

intermediate 6. Insitu demethylation of intermediate 6 was carried out using

AlCl3 at 60 °C to arrive at desired intermediate 7(Scheme−6).

Scheme−6

O

OH

O

O2N

O

O

O

O2N

6

b

c d

O

ClO

O2N

23 24

O

OHO

O2N

25

a

O

O

OH

O2N

7

Reagents and conditions: (a) AcOH, H2SO4, reflux 2 h; (b) SOCl2,

chlorobenzene, 80 °C, 9 h; (c) AlCl3, chlorobenzene, 0−5

°C, 1 h; (d) AlCl3,

chlorobenzene, 60 °C, 7 h.

19

Michel Biard and La Mure et a l 30

[FeCl3 route].

Michel Biard and La Mure reported the synthesis of Dronedarone Hydrochloride

(2) starting from nitro benzofuran 5 which on Friedel-Craft acylation with acid

chloride 29, produced intermediate 8. This reaction was carried out in DCM at 20

to 22 °C by employing FeCl3 as Lewis acid. Catalytic reduction of nitro group

was achieved by using PtO2 in EtOH followed by sulfonamide formation using

MsCl and Et3N in DCM. Hydrochloride salt formation of Dronedarone free base

was carried out in ethyl acetate using Hydrogen chloride in ether.

Main feature of this route was preparation of side chain, (Acid chloride 29)

prepared in 3 steps starting from methyl paraben (26). methyl paraben (26) was

condensed with chloro compound 42 in DMF using K2CO3 at 100 °C followed by

alkaline ester hydrolysis using 20% aqueous NaOH in MeOH under reflux. Lastly

acid chloride formation was effected for intermediate 29 with SOCl2 in

chlorobenzene (Scheme–7).

The major advantage of this route was formation of mutagenic intermediate 7 was

eliminated. Use of relatively mild and safe Lewis acid FeCl3 instead of already

reported catalysts like AlCl3 and SnCl4 for critical Friedel-Craft acylation step

was the salient feature of this route.

20

Scheme−7

OH

OO

O

OHO

N

O

ClO

N.HCl

+

O

O2N

26

28295

89

2 (free base)

e

g

d

O

O2N

O

O

N

O

O

O

NH2

N

O

O

O

NHS

O O

N

2

O

O

O

NHS

O O

N .HCl

N

Cl

+

42

a

b

c

O

OO

N

27

f

.HCl

Reagents and conditions: (a) K2CO3, DMF, 100 °C, 1 h; (b) 20.0% aq. NaOH,

MeOH, 65 °C, 2 h; (c) SOCl2, cat. DMF, chlorobenzene, 85 °C, 1 h; (d) FeCl3,

DCM, 20−22 °C, 1.5 h; (e) PtO2/H2, EtOH, RT, 20 min; (f) MsCl, Et3N, DCM,

RT, 20 h; (g) HCl−ether, ethyl acetate, 45 min.

21

Fino, N and co-workers et a l 13

[sulfonamide route].

Fino and co-workers started their synthesis from conversion of nitro benzofuran

derivative 5 (Scheme–8) into respective sulfonamid intermediate 31 by first

reducing nitro group using PtO2/ H2 or Pd/C and ammonium formate to obtain

respective amino benzofuran 30. Which was then treated with MsCl in mixture of

THF and MTBE using aq. ammonia to afford sulfonamide 31. Acid chloride 29

was then coupled with sulfonamide 31 using FeCl3 to afford Dronedarone free

base which was further converted in Dronedarone Hydrochloride (2) using conc.

HCl in IPA.

Scheme−8

O

ClO

N.HCl

O

O2N

29

5

2 (free base)

e

O

NH2

30

O

NHS

O O +

a or b c

d

31

O

O

O

NHS

O O

N

2

O

O

O

NHS

O O

N .HCl

Reagents and conditions: (a) PtO2/H2, EtOH, 20–50 °C; (b) Pd/C, HCOONH4,

EtOH, 50 °C, 5 h; (c) MsCl, aq. NH3, THF, MTBE, 20 °C; (d) FeCl3, DCM,

20−22 °C, 2 h; (e) conc. HCl, IPA.

22

Monahnarangam S. and co-workers et a l 31

Monahnarangam S. and co-workers reported synthesis of intermediate 7 from

nitro benzofuran 5 with little modification i.e. they had used AlCl3 for

Friedel−Craft acylation instead of reported SnCl4. Further O-alkylation of

intermediate 7 was performed by using 1-Bromo-3-chloropropane and K2CO3 in

DMF to provide chloro derivative 32.

Transfer hydrogenation (Pd/C and HCOONH4) was employed for nitro to amine

functional group transformation which resulted in compound 33 as described in

scheme−9.

Scheme−9

O

O2N

O

O2N

O

O

5

a b

c

O

O2N

O

OH

d

6 7

O

O2N

O

OCl

O

O

OCl

NH2

32 33

Reagents and conditions: (a) p-anisoyl chloride, AlCl3, DCM, 25 °C, 4 h; (b)

AlCl3, chlorobenzene, 85 °C, 4 h; (c)1-bromo-3-chloropropane, K2CO3, DMF, 25

°C, 20 h; (d) Pd/C, HCOONH4, IPA, 50 °C, 30 min.

Sulfonamide formation was carried out in biphasic mixture of water and DCM

using MsCl and NaHCO3 as base. Lastly coupling of di-n-butylamine with

sulfonamide 34 followed by hydrochloride salt formation by ethyl acetate−HCl

provided Dronedarone Hydrochloride (2) as disclosed in scheme−10.

23

Scheme−10

a b

c

.HCl

2

O

O

O

NHS

O O

N

O

O

O

NHS

O O

N

O

O

OCl

NH2

O

O

O

NHS

O O

Cl

33 34

2 (free base)

Reagents and conditions: (a) MsCl, NaHCO3, DCM, 35 °C, 6 h; (b) di-n-butyl

amine, DMF, 125 °C, 4 h; (c) EtOAc-HCl, EtOAc, 25 °C, 2 h.

Sada M. and co-workers et a l 32

[Dimesyl route]

Sada, M. and co-workers successfully completed synthesis of Dronedarone

Hydrochloride in four steps starting from readily available intermediate 7.

Coupling of intermediate 7 with 3-chloro-1-propanol in presence of TBAB, KI,

and base K2CO3 in DMF yielded compound 35. Catalytic reduction of compound

35 into amino derivative 36 was accomplished by Pd/C and H2. Dimesyl

intermediate 37 was synthesised by using MsCl and pyridine in DCM, 37 on

treatment with di-n-butyl amine gave Dronedarone free base which was

subsequently converted into Dronedarone Hydrochloride (2) as depicted

scheme−11.

24

Scheme−11

O

O2N

O

OH

O

O2N

O

OOH

O

O

O

NH2

OH

O

O

O

NHS

O O

OMs

a bc

7 35 36

37

de

2 (free base) 2

O

O

O

NHS

O O

N

O

O

O

NHS

O O

N

Reagents and conditions: (a) 3-chloro-1-propanol, K2CO3, KI, TBAB, DMF, 85

°C, 5 h; (b) Pd/C, H2 MeOH, 40 °C; (c) MsCl, pyridine, DCM, RT, 24 h; (d) di-n-

butyl amine, ACN, reflux 5 h;(e) conc. HCl. acetone.

Arie Gutman and co-workers et a l 33

[p-Anisidine route]

Arie Gutman and co-workers reported synthesis of Dronedarone Hydrochloride

(2) in three stages i.e. synthesis of sulfonamide 31, preparation of acid chloride 29

and coupling of these intermediates to afford 2.

Inexpensive p-anisidine (38) was used in the synthesis of sulfonamide 31. Acetic

anhydride was employed for N-acetyl protection of p-anisidine (38) to afford

acetamide compound 39, Friedel-Craft acylation of acetamide 39 with 2-

bromohexanoyl chloride along with insitu demethylation resulted in bromo

intermediate 40 as presented in Scheme−12.

25

Scheme−12

O

NH2

O

NH

O

OH

NH

O

Br

O

3839 40

O

NH2

30

HCl.

O

NHS

O O

31

a b c

d

Reagents and conditions: (a) Ac2O, DCM, hexane, 25−30 °C, 1 h; (b) 2-bromo

hexanoyl chloride, AlCl3, DCM-CH3NO2, RT, overnight; (c) i) NaHCO3, MeOH,

reflux 2 h; ii) NaBH4, MeOH, 0−5 °C; iii) dil. HCl, MeOH, reflux, 5 h; (d) MsCl,

toluene, reflux, 2 h.

Preparation of amino benzofuran 30 from bromo compound 40 was

accomplished in four steps following a sequence of chemical transformations like

cyclization (using NaHCO3), reduction of carbonyl group (by NaBH4),

aromatization and deprotection (both steps were acid catalyzed). Free base of

amino benzofuran 30 on treatment with MsCl in toluene, at reflux condition,

furnished sulfonamide 31.

Preparation of acid chloride 29 started with O-alkylation of methyl paraben (26)

with 1,3-dibromo propane at reflux condition in MEK by using K2CO3 as base.

Condensation of bromo ester 41 with di-n-butyl amine gave intermediate 27

followed by acid catalysed ester hydrolysis to afford acid 28. Conversion of acid

28 to the corresponding acid chloride 29 was accomplished with SOCl2 in DCM

(Scheme−13).

26

Scheme−13

OO

OH

OO

O Br

OO

O N

OHO

O N

ClO

O N

a b

c d

26 27

.HCl .HCl

2829

41

Reagents and conditions: (a) 1,3-dibromo propane, K2CO3, MEK, reflux 6 h;

(b) di-n-butyl amine, toluene, reflux, 3 h; (c) conc. HCl, reflux 5 h; (d) SOCl2,

DCM, reflux, 1 h.

Dronedarone free base was prepared by drop wise addition of SnCl4 into the

mixture of acid chloride 29 and sulfonamide 31 in DCM at 0−5 °C to provide

crude Dronedarone free base. This crude free base was further purified by column

chromatography and treated with hydrogen chloride 10% solution in ethyl acetate

to obtain Dronedarone Hydrochloride (2) as per scheme−14.

27

Scheme−14

O

NHS

O O +

ClO

O N.HCl

O

NHS

O O

ON

O

O

NHS

O O

ON

O

.HCl

31 29

2 (free base) 2

a

b

Reagents and conditions: (a) SnCl4, DCM, 25 °C, 2 h; (b) HCl 10% sol

n in

EtOAc, EtOAc, 0−5 °C, 1 h.

Condensation of sulfonamide 31 and acid chloride 29 was low yielding reaction

and accompanied with high impurity formation, hence required chromatographic

purification due to which this process was not commercially viable.

Present Work

28

Present work

The retro synthetic analysis depicted in scheme−15 suggested that Dronedarone

(2) can be assembled from the two critical fragments namely benzofuran

derivative 46 and the acid 47. Benzofuran derivative 46 and the acid 47 can be

condensed which would give the coupled product 45. Intermediate 45 inturn

could be converted to the immediate precursor 44 of Dronedarone by replacing

−Cl group of 45 with dibutyl amine.

Scheme−15

O

O

ON

NHS

O OO

O

ON

NHProt

O

O

OCl

NHProt

O

NHProt

+

OHO

O Cl

244

45

4647

Finally, the protection group on intermediate 44 can be removed and sulfonamide

formation can be effected to arrive at the target compound (2).

The acid fragment 47 could be obtained from very common and economically

available raw material 4-hydroxymethyl benzoate (26), which is also known as

methyl paraben as shown in scheme−16.

29

Scheme−16

OHO

O Cl

OO

O Cl

OO

OH

48 4726

The synthesis of benzofuran moiety 46 could be achieved from commercially

available and inexpensive raw material p-anisidine (38) by following literature

procedure33

with obligatory changes as shown in scheme−17.

Scheme−17

OH

NH

O

Br

O

40

O

NH2

O

NH2

3830

O

NHProt

46

p-anisidine (38) can be converted to the benzofuran 30 via bromo intermediate 40

and finally can be shielded with suitable protecting group.

With this intention, we started our synthetic campaign towards the benzofuran

derivative 30 using p-anisidine (38) as the starting material. Accordingly, N-

acetylation of p-anisidine (38) was achieved by using acetyl chloride as

acetylating reagent instead of reported acetic anhydride as shown in scheme−18.

Scheme−18

O

NH2

O

NH

O

38 39

i) CH3COCl/ NaOH

ii) acetone/ water

90%

30

During the optimization of reaction conditions for the synthesis of acetamide 39,

various solvents like DCM, EtOAc, THF, DMF, toluene, acetone and

acetone−water mixture were examined. Combination of acetone−water (1:4) was

found to be the best media because the compound 39 was insoluble in this solvent

system. Hence, after completion of reaction, isolation of pure product was

achieved by simple filtration followed by water wash without any additional work

up. Structure of 39 was confirmed by 1H NMR and mass [m/z: 166.0 (M+H)

+]

spectrum.

Condensation of 2-bromo hexanoyl chloride by Friedel-Craft acylation with insitu

demethylation using AlCl3 as Lewis acid provided the formation of bromo

compound 40. As use of AlCl3 was beneficial due to insitu demethylation no

other Lewis acids were tried for this conversion (Scheme−19).

Scheme−19

O

NH

O

OH

NH

O

Br

O

3940

2- bromo hexanoyl chloride

AlCl3 DCM-nitromethane

82%

Conversion of bromo compound 40 into desired amino benzofuran hydrochloride

30 was carried out in three insitu chemical transformations. Initially bromo

compound 40 was refluxed with NaHCO3 in methanol to obtain cyclic keto

compound 49, followed by reduction of carbonyl group was achieved by using

NaBH4 to obtain hydroxyl compound 50 as shown in scheme−20.

31

Scheme−20

OH

NH

O

Br

O

NH

O

O

O

40 49

NH

O

OH

O

NH2

O

HCl.

30

NaHCO3 MeOH NaBH4

dil. HCl

75%

50

Finally, dehydration and deprotection were completed by using dil. HCl in single

step to afford essential amino benzofuran hydrochloride 30 as described in

scheme−20. Presence of signal for one proton as singlet at 6.69 ppm in 1H NMR

and mass spectrum [m/z: 190.0 (M+H)+] confirmed the structure of amino

benzofuran 30.

After successful synthesis of key intermediate 30, we focused our attention on the

other fragment 47 required for the preparation of Dronedarone Hydrochloride. As

shown in the retro scheme−16 for arriving at the acid intermediate 47, we decided

to use methyl paraben (26) as starting material. Initially, we tried alkylation of

methyl paraben (26) with 1,3-dibromo propane as per literature condition,33

unfortunately the outcome of this reaction was not satisfactory as formation of

considerable amount of dimeric biproduct (51) was observed along with desired

alkylated product 41 (Scheme−21).

Scheme−21

OO

OH

+ Br Br

OO

O Br

+

O O

OO OO

K2CO3/DMF

26 1,3-Dibromo propane 41 51

32

In order to minimize the dimeric impurity formation, we decided to use 1-bromo-

3-chloro propane (BCP) instead of 1,3-Dibromo propane for alkylation reaction.

Accordingly, methyl paraben (26) was treated with BCP using K2CO3 as base and

various solvent systems such as THF, acetone, DMF, MIBK and under heating

condition heating condition using BCP as alkylating reagent and solvent. Best

result was observed by addition of catalytic amount of DMF in to the reaction

mixture under neat condition during which formation of dimeric impurity 51 was

minimized. After work up and simple purification from cyclohexane the desired

alkylated product 48 was isolated in more than 90% with high purity

(Scheme−22).

Scheme−22

OO

OH

OO

O Cl

OHO

O Cl

ClO

O Cl

26 48 47 52

BCP

K2CO3/DMF

88% 88%

NaOH/HCl

MeOHSOCl2/DCM

After several experiments we were able to optimize the quantity of BCP to be

used in reaction up to 3.2 eq. which was finalized for scale up batch. Structure of

chloro compound 48 was confirmed by 1H NMR. In

1H NMR spectrum, protons

of –CH2Cl, and –OCH2 group resonated at 3.75 ppm (t, 2H) and 4.17 ppm (t, 2H)

respectively.

Saponification of methyl ester of chloro compound 48 was achieved with NaOH

in MeOH−water. During this hydrolysis step methoxy impurity was observed in

the range of 2−5% along with desired acid 47. At this stage we felt that

presence/contamination of this impurity 53 in the acid 47 is not going to pose the

problem as this impurity is not going to involve in the amination step so could be

easily removed during the salt the formation at later stage of synthesis

(Scheme−23).

33

Scheme−23

OO

O Cl

OHO

O Cl

+

O O

OHO

48 47 53 (2-5%)

NaOH

MeOH/water

Using our optimized conditions we could achieve 88% yield of the required acid

fragment (47) having around 2% of impurity 53 and decided to proceed further

(without trying further purification).

Once we had both the fragments amino benzofuran hydrochloride 30 and acid 47

(or acid chloride 52), the next thing left was the coupling of amino benzofuran

hydrochloride 30 with acid 47 as shown in scheme−24.

Scheme−24

O

NH2

+

OHO

O Cl

O

NH2

O

OCl

F-C acylation

30 47 54

Prior to trying any Friedel-Craft reaction of 30 and 47 we felt that the protection

of amino group of benzofuran 30 could interfere in the Friedel-Craft reaction and

would result in amide formation. With this intention, we decided to protect the

amine group of benzofuran 30 before the Friedel-Craft reaction.

Literature survey on Dronedarone33

indicated that use of the desired sulfonamide

derivative 31 was blocked. Also use of several other protecting group like amide

34

and carbamates was restricted hence, we decided to evaluate the utility of

phthalimido group for protection of aminobenzofuran 30. This approach is

advantageous because,

phthalimido protection is stable for wide verity of reaction conditions.34, 35

The required reagent phthalic anhydride is inexpensive and available at

bulk scale.

Deprotection of phthalimido group can be achieved under very mild

conditions using aqueous solution of monomethyl amine or hydrazine

hydrate.36

Accordingly, hydrochloride salt of amino benzofuran 30 was treated with aqueous

NaHCO3 and free base 30 was extracted in toluene. Further this solution of 30 in

toluene, phthalic anhydride and catalytic Et3N were added and reaction mass was

refluxed for 1.5 h with azeotropic distillation of water (Scheme−25).

Scheme−25

O

NH2

O

N

O

O

30 55

Phthalic anhydride

Et3N/toluene

93%

After completion of reaction, reaction mass was diluted with cyclohexane product

was isolated by filtration in excellent yield (93%). In 1H NMR presence of

additional signals for four protons in aromatic region at 7.76−7.80 ppm (2H) and

7.93−7.97 ppm (2H) confirmed the structure of phthalimido derivative 55. As

we got excellent yield and purity, further optimization was not required.

Friedel−Craft acylation of phthalimido compound 55 with acid 47 or acid chloride

52 was the most critical reaction of our synthetic scheme and hence, we decided

to make this transformation more efficient (less impurity formation) high yielding

and simpler with respect to Lewis acid catalysts generally used for the

Friedel−Craft reaction (Scheme−26).

35

Scheme−26

O

N

O

O

+

XO

O Cl

O

N

O

O

O

OCl

Lewis acid

55 47 or 52 56

where, X = -OH or -Cl

Accordingly, we intended to examine various Lewis acid systems for catalysing

the critical conversion; the results of our efforts are summarized in table−1.

Table−1

Sr. No. −X Lewis acid Condition Result Ref

1 -Cl AlCl3 DCM, -20 °C, 1h 68%

a 37

2 -Cl FeCl3 DCM, reflux, 6 h NA 37

3 -OH ZnCl2−Al2O3 DCM, reflux, 5 h NA 38

4 -Cl SnCl4 DCM, 0 to 25 °C, 1h 80%

a 37

5 -Cl ZnO DCM, 25 °C, 24 h NA 39

6 -OH P2O5−Al2O3 EDC, reflux, 24 h NA 40

7 -OH P2O5−SiO2 EDC, reflux, 24 h NA 41

8 -Cl Zn(OTf)2.6H2O CH3NO2, 25

°C, 24 h NA 42

a

Isolated yields.

Even though variety of Lewis acids were examined, only AlCl3 and SnCl4 were

found to be effective. Best results were obtained by using 3.0 eq. of SnCl4

(table−1, Entry−4) for Friedel-Craft acylation from which chloro compound 56

was obtained in 80% yield. Structure of chloro compound 56 was confirmed by

1H NMR. The disappearance of singlet at 6.69 ppm due to benzofuran and

appearance of additional peaks due to the other fragment in 1H NMR spectrum

confirmed the structure of compound 56.

36

Chloro compound 56 was further converted to desired Dronedarone

Hydrochloride (2) successfully as shown in scheme−27.

Scheme−27

2

O

N

O

O

O

OCl

56

O

NH

O

ON

SO O

.HCl

Even though the final product was completely devoid of any metal contamination

(tin content was below detection limit in API) and overall yield and purity of

Dronedarone Hydrochloride (2) was good, because of the risk involved in

industrial scale handling of SnCl4 and the resulting large quantity of toxic tin

waste, we intended to eliminate the use of SnCl4 in our commercial

manufacturing process of Dronedarone Hydrochloride (2).

With this intention we decided to focus on non-metallic catalyst for the

Friedel−Craft acylation. During our search we came across a report 43

in which

use of poly phosphoric acid (PPA) and P2O5 for affecting this transformation was

discussed. When we tried the same conditions for the condensation of

phthalimido compound 55 with acid derivative 47, the desired product chloro

compound 56 was isolated in good yield. Encouraged by these results, we looked

for better condition which can be used on commercial scale.

Eaton‟s reagent (1:10 P2O5 in MSA) discovered by P. E. Eaton in 1973 could to

be a good alternative to PPA or PPA−P2O5 as it overcomes the critical drawbacks

of PPA due to its lower viscosity, easy handling and product isolation does not

require any special complex separation procedures.44

Many synthetic schemes45–48

involving Eaton‟s reagent are not only more

economical but also more environment friendly and offer a number of distinct

advantages such as,

37

Safety on industrial scale.

Avoids additional medium required because the raw materials often

dissolve in the reagent rapidly.49

High-purity products with excellent yields.

The distinctive physical and chemical properties of Eaton‟s reagent makes it a

very useful reagent in many reactions with different applications.44−57

Several uses of Eaton‟s reagent from the literature have been described in the next

few schemes to demonstrate the ability of Eaton‟s reagent to accomplish these

kinds of transformations.

Scheme−28

NHOMe

OMe

O

O

OMe

Eaton's reagent

OMe

NH

O

O

OMe

Zewge described a high-yielding methodology for the cycloacylation of aniline

derivatives to 4-quinolones in the presence of Eaton's reagent (Scheme−28).51

Scheme−29

OH

OHOH

+

O

OH

OH O

OH

OH

O

Eaton's reagent

Preparation of biologically active Xanthones derivatives (novel anti-HIV agent)

using Eaton‟s reagent was published by Shi, Lee and co-workers. 52

(Scheme−29)

38

Scheme−30

Eaton's reagent

N

O

I

NH

EtO O

O

OEt

NH

OEt

O O

I

N

O

Dorow and Co-workers developed a route for the synthesise of Pyrrolquinolone

PHA-529311 in which cyclization was accomplished by using Eaton‟s reagent as

depicted in scheme−30.

Scheme−31

NH2

+O

O

O

Oref - 55 N

HO

OH

Im and his colleagues prepared 4-hydroxy quinolinone, an important hetrocyclic

member from aniline in excellent yield by using Eaton‟s reagent.55

(Scheme−31).

Scheme−32

Cl

O

NH

(CH2O)n, Eaton's

ref - 48 N

O

Cl

Yang and his colleagues reported a scalable approach for the cyclization of

substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one utilizing

Eaton‟s reagent48

(Scheme−32).

From the preceding lines it is clearly evident that, Eaton‟s reagent could be an

excellent alternative to the most recent condition (PPA−P2O5) worked for us,

hence we decided to try this reagent for our transformation. Prior to its use in our

scheme we thought to check its utility for the Friedel−Craft reaction involving the

known fragments sulfonamide 31 and acid derivative 28, the results could give us

39

an idea about its performance in comparison with reported conditions for the same

fragments. Consequently we carried out condensation of sulfonamide 31 with

acid derivative 28 by using Eaton‟s reagent and we got desired Dronedarone

Hydrochloride (2) with good yield and purity.

Accordingly, commercial Eaton‟s reagent (5 volumes, 7.7% Solution) was used

for the coupling of phthalimido compound 55 with acid 47 and we were pleased

to see a much better reaction profile when compared to all other conditions

including PPA−P2O5 and the isolated yield of the desired product was 75%.

According to Eaton,44

methanesulfonic anhydride is formed in this mixture while

other species are also present, such as PPA and mixed anhydride of PPA and

MSA.49

Hence it is clear that completion of reaction is dependent on mole

equivalents of P2O5 (which gives methanesulfonic anhydride and mixed

anhydride) and not on volumes of Eaton‟s reagent. By considering this fact, in

an attempt to reduce the volumes and to increase the efficiency of reaction, we

conducted several experiments, in which volume of MSA was not changed and

only the quantity of P2O5 was altered. From all our efforts, we concluded that 2.5

mol. Eq. of P2O5 is optimum quantity to get best results with respect to yield and

reaction time, the results are summarized in Table−2.

Table−2

Sr. No Mol .eq. of P2O5 time Result

1 0.33 36 h In complete reaction

2 0.5 36 h In complete reaction

3 1.0 24 h 70%

4 1.5 12 h 72%

5 2.0 4 h 73%

6 2.5 1 h 75%

7 3.0 50 min 75%

8 4.0 50 min 72%

40

After successfully finding a better, non-hazardous, non-metallic, commercially

available reagent and an optimized condition for the critical Friedel-Craft

acylation, we could generate enough quantity of the intermediate 56. Now the,

only thing left for us was the transformation of chloro derivative 56 to final

Dronedarone Hydrochloride (2) which was planned following a series of simple

transformations as shown in scheme−33.

Scheme−33

O

N

O

O

O

OCl

O

N

O

O

O

ON

O

NH2

O

ON

O

O

ON

NHS

O O

.HCl

5657

582

The first thing to be taken care of was the displacement of –Cl group of

compound 56 with the desired di-n-butyl amine. When this amination was tried,

we found out the conversion to be sluggish as the reaction took almost 72 h at 100

°C using 2 eq. of di-n-butyl amine in DMF. Hence the reaction condition was

optimized and we found that addition of 1 eq. of KI and catalytic amount of PTC

(TBAB or TBAI) accelerated the rate of reaction dramatically and the reaction

was completed in 6 h. Further, various solvents like toluene, MEK, MIBK,

acetone and DMF were tried and out of all these solvents, we found that DMF

was most appropriate solvent for this conversion. After all these experiments,

41

amination of chloro derivative 56 using di-n-butyl amine under the optimized

conditions was successfully furnished amino derivative 57 in excellent yield.

During process development amine compound 57 was isolated as its

hydrochloride salt, but later on we decided to use the free base (viscous oil) as it

is and proceeded for the next step (Scheme−34).

Scheme−34

O

N

O

O

O

OCl

O

N

O

O

O

ON

56 57

Di-n-butyl amine

TBAB, KI, DMF

Deprotection of Phthalimido group has been reported using various reagents like

hydrazine hydrate, mono methyl amine, NaBH4−AcOH, out of which commercial

monomethyl amine 40% aq. solution was one of the most economical reagent,

and hence was selected as the reagent of choice for our deprotection. During

process development this reagent worked very well in first stroke, and after

completion of reaction amine 58 was isolated as oil. Hence, other conditions

were not examined.

As per the regulatory requirement, for any API process the precursor of API

should have maximum possible purity and should fulfil QA requirements. So it

was necessary to develop a purification method for this particular intermediate

58. But as amino compound 58 was oil, it was very difficult to develop a

convenient purification method. At initial stage column chromatography was

employed for the purification of the free base 58, but as use of column

chromatography for purification is exorbitant technique for commercial synthesis,

we decided not to adopt this technique for purification and find out the better

alternative. Also, another issue associated with use of the free base 58 was the

observed colour change of purified free base (oil) from pale yellow to the light

42

brown during the holding time study, which raised some doubt about stability of

compound.

Hence, we decided to eliminate these issues at such an advanced stage which

could later prove crucial and jeopardize our process. We thought, suitable salt

formation of amino compound 58 was the easiest and immediate solution to these

problems. Accordingly we examined various organic acids like citric acid,

fumaric acid, benzoic acid, salicylic acid, oxalic acid, acetic acid, tartaric acid,

methanesulfonic acid and mineral acids like HCl, HBr, H2SO4 and HNO3 for the

salt formation process. Out of all these acids, only oxalic acid worked well and

we could isolate the corresponding dioxalate salt as crystalline solid while in all

other cases, either sticky mass or no crystallization of the salt was observed.

Isolation of amino compound 58 as dioxalate salt resolved the complications in

purification. Efficient recrystallization of the dioxalate salt of 58 was achieved

from methanol to afford a purity of >99%. Holding time study of dioxalate salt of

58 was performed and found that of the salt was stable at ambient condition for at

least one month. Finalised reagents and conditions are summarized in

scheme−35.

Scheme−35

O

N

O

O

O

ON

O

NH2

O

ON

57free base 58

Mono methyl amine

Oxalic acid

IPA

O

NH2

O

ON

.2COOH

COOH

58

MeOH

43

The only thing left to complete our synthesis was the sulfonamide formation of

the amino group of 58. The major concern in this step was the formation of

disulfonamide impurity 59, which was well documented.59, 60

As per ICH guide

lines, the limit for known impurity like 59 is 0.15% and hence it was essential to

control its formation during reaction itself. In this direction before initiating work

for this step, we synthesised and isolated this impurity using excess

methanesulfonyl chloride (2.5 equiv) and DIPEA as base in DCM which is

described in scheme−36.

Scheme−36

O

NH2

O

ON

.2COOH

COOH

O

O

ON

NHS

O O

582 (minor)

O

O

ON

NS

O O

S

O

O

+

58 (major)

MsCl

DIPEA

DCM

In 1H NMR spectrum a singlet integrating for 6H was observed at 3.35 ppm and

mass [ (M+H)+

= 635.0] confirmed the structure of disulfonamide impurity.

In an effort to arise at the best conditions for the mesylation reaction, various

solvents such as DCM, chloroform, THF, toluene, ethyl acetate and acetone were

screened and it was observed that in chlorinated solvents like DCM and

chloroform, disulfonamide impurity 59 formation started from the beginning of

the reaction, while in case of other solvents like THF, ethyl acetate and acetone, it

started forming after major product formation. However, in toluene reasonably

less impurity formation with completion of reaction was observed. Thus toluene

was found to be the suitable solvent for this conversion.

After solvent selection, further fine tuning of the process was required. Organic

bases such as DIPEA, Et3N, pyridine and N-methyl morpholine were screened at

44

various temperatures between -5 to 50 °C to find out the best condition for

minimal disulfonamide formation (Scheme−37).

Scheme−37

O

NH2

O

ON

.2COOH

COOH

O

O

ON

NHS

O O

.HCl

58

2

MsCl/Et3N

toluene

55%

O

O

ON

NHS

O O

free base 2

dil. HCl/DCM

From all our efforts, we concluded that adding 1.05 equiv. of MsCl dropwise in

presence of Et3N in toluene at -5 to 5 °C gives the best results with high yield of

Dronedarone free base and negligible impurity formation (59). We wanted to

take advantage of the fact that Dronedarone hydrochloride is soluble in

chlorinated solvents like DCM, CHCl3 and decided to affect the salt formation

using dilute HCl. Accordingly Dronedarone free base in DCM was treated with

dilute HCl and the resulting salt was extracted in to DCM. Removal of solvent

and treating the crude mass (viscous oil) with EtOAc:IPA (9:1) provided

Dronedarone Hydrochloride as filterable solid. At this stage purity of API was

99% having 0.5% impurity 59, and hence further purification was needed to

comply the ICH norms. This problem was resolved by single recrystallization of

99% pure Dronedarone Hydrochloride from acetone, which afforded Dronedarone

Hydrochloride (2) with purity more than 99.5% and any individual impurity less

than 0.1%.

45

Conclusion

In conclusion we have, developed a industrially feasible, commercial process for

the manufacturing of antiarrhythmic drug Dronedarone Hydrochloride (2) as

shown in scheme.

Scheme

O

N

O

O

O

OCl

O

N

O

O

O

ON

O

NH2

O

ON

.2COOH

COOH

O

O

ON

NHS

O O

.HCl

5657

58

2

i) Di-n-butyl amine

70%

ii) TBAB, KI

iii) DMF

i) Mono methyl amine

ii) Oxalic acid/ MeOH

i) MsCl/Et3N

ii) dil. HCl/DCM

55%

O

NH2HCl.

O

N

O

O

30

55

i) Phthalic anhydride

ii) Et3N/toluene

93%

+

COOH

OCl

47

Eaton's reagent

75%

Our process has several distinct advantages over reported routes:

46

The API was synthesised in good overall yield with very high HPLC

purity, and complies the ICH guidelines.

Critical n-1 intermediate (amino derivative 58) was isolated in its purest

and stable form as dioxalate salt.

Best condition for final mesylation reaction under which minimal

formation of disulfonamide 59 was achieved.

Elimination of Hazardous/Toxic metal catalyst (Lewis acids) for the

critical Friedel-Craft acylation reaction was accomplished.

Utility of simple and commercial Eaton‟s reagent was demonstrated in

critical Friedel-Craft acylation step successfully.

Experimental

47

Experimental

Preparation of N-(4-methoxyphenyl)acetamide (39).

O

NH

O

To the stirred suspension of p-anisidine (100.0 g, 0.812 mol) in acetone (50.0

mL), NaOH (98.0 g, 1.225 mol) dissolved in D. M. water (400.0 mL), was

charged at 5 to 10 °C. Acetyl chloride (96.0 g, 1.223 mol) was charged drop

wisely controlling exotherm up to 25 °C. After complete addition of acetyl

chloride suspension was stirred for additional 2 h at 25 to 30 °C and product was

filtered followed by water wash (100.0 mL x 3) and lastly washing with

cyclohexane (100.0 mL x 2). Wet cake was dried at 50 °C to get acetamide

intermediate 39 (121.0 g, 90%).

mp: 127−128 °C; m/z: 166.0 (M+H)

+ ;

1H NMR (400 MHz, CDCl3): δ 2.12 (s,

3H), 3.77 (s, 3H), 6.82 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.56 (brs,

1H); 13

C NMR (100 MHz, CDCl3): 24.0, 55.3, 113.8, 122.0, 131.0, 156.2, 168.7.

Preparation of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide (40).

OH

NH

O

O

Br

To the stirred solution of acetamide 39 (100.0 g, 0.605 mol) in DCM (250.0 mL)

charged AlCl3 (242.5 g, 1.819 mol) portion wise under inert atmosphere by

controlling exotherm up to 25 °C followed by subsequent addition of nitro

48

methane (113.5 g, 1.859 mol) and 2-bromohexanoyl chloride (155.0 g, 0.726 mol)

at 5 to 10 °C. After stirring the reaction at ambient temperature for 4 h, second lot

of AlCl3 (80.7 g, 0.605 mol) was charged and reaction mass was stirred at

ambient temperature for overnight. Reaction was quenched by careful addition of

reaction mass over ice-cold water followed by distillation of solvents. After

complete distillation of DCM resulting suspension was filtered and solids were

washed with D.M. water (100.0 mL x 2) followed by toluene wash (100.0 mL).

Wet cake was dried at 50 °C to get bromo compound 40 (164.0 g, 82%).

mp: 136−138 °C; m/z: 328.1 (M+H)

+ ;

1H NMR (400 MHz, CDCl3): δ 0.92 (t, J =

7.0 Hz, 3H), 1.34−1.49 (m, 4H), 2.09−2.17 (m, 2H), 2.19 (s, 3H), 5.14 (t, J = 7.0

Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 7.21 (s, 1H), 7.42 (dd, J = 8.9 Hz, J = 2.3 Hz

1H), 8.19 (d, J = 2.3 Hz, 1H), 11.82 (s, 1H); 13

C NMR (100 MHz, CDCl3): 13.8,

22.2, 24.1, 29.4, 32.8, 46.4, 116.4, 119.0, 121.3, 129.3, 129.9, 160.0, 168.7, 198.6.

Preparation of 2-butyl-5-aminobenzofuran hydrochloride (30).

O

NH2HCl.

Bromo compound 40 (100.0 g, 0.305 mol) was added portion wise to the

suspension of NaHCO3 (51.2 g, 0.610 mol) in MeOH (500.0 mL). The

suspension was refluxed for 2 h. Reaction mass was cooled at 5 °C and charged

solution NaBH4 (4.7 g, 0.123 mol) dissolved in 1% NaOH solution (15.0 mL)

drop wisely over a period of 1 h. After stirring for 2 h at 5 °C reaction mass was

acidified by adding 6.0 N HCl solution (750.0 mL) followed by stirring at 80 °C

for 6 h. After completion of hydrolysis, suspension was chilled at 10 °C and

filtered after 2 h. Washing of wet cake with chilled ethyl acetate (50.0 mL x 2)

followed by drying obtains amino benzofuran hydrochloride 30 with good yield

(51.5 g, 75%).

mp: 190−193 °C; m/z: 190.0 (M+H)

+ ;

1H NMR (400 MHz, DMSO_d6): δ 0.90 (t,

J = 7.4 Hz, 3H), 1.30−1.39 (m, 2H), 1.62−1.69 (m, 2H), 2.77 (t, J = 7.4 Hz, 2H),

49

6.69 (s, 1H), 7.23 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.57−7.61 (m, 2H), 10.45 (brs,

3H); 13

C NMR (100 MHz, DMSO_d6): 13.9, 21.9, 27.6, 29.4, 102.6, 111.9,

115.4, 118.6, 126.1, 129.8, 153.4, 162.0.

Preparation of 2-(2-butyl-1-benzofuran-5-yl)-1H-isoindole-1,3(2H)dione

(55).

O

N

O

O

Amino benzofuran hydrochloride 30 (100.0 g, 0.443 mol) was slowly added to a

stirred mixture of NaHCO3 (50.0 g, 0.595 mol), water (300.0 mL) and toluene

(150.0 mL) by controlling frothing. After 30 min, layers were separated and the

organic layer was washed with water (100.0 mL). Phthalic anhydride (66.0 g,

0.445 mol) and Et3N (4.5 g, 0.044 mol) was sequentially added to the organic

layer containing the free amine and the reaction mass was refluxed for 1.5 h with

azeotropeic removal of water. The reaction mixture was allowed to cool at 75 °C

where upon cyclohexane (300.0 mL) was added and the mixture was cool down to

20 °C and stirred for 1 h. The precipitated solids were filtered, washed with

cyclohexane (100.0 mL) and dried at 50 °C to afford phthalimido compound 55

(132.0 g, 93%).

mp: 150 −152 °C; m/z: 320.1 (M+H)+

; 1H NMR (400 MHz, CDCl3): δ 0.96 (t, J =

7.4 Hz, 3H), 1.38−1.47 (m, 2H), 1.70−1.78 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 6.42

(s, 1H), 7.20 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.49−7.52 (m, 2H), 7.76−7.80 (m,

2H), 7.93−7.97 (m, 2H); 13

C NMR (100 MHz, CDCl3): 13.6, 22.1, 28.0, 29.6,

102.0, 111.1, 118.9, 121.8, 123.5, 126.0, 129.6, 131.7, 134.1, 153.8, 161.1, 167.6.

50

Preparation of methyl 4-(3-chloropropoxy)benzoate (48).

OO

O Cl

Sodium methylparaben (26) (100.0 g, 0.574 mol) and powdered K2CO3 (40.0 g,

0.289 mol) were mixed with solution of 1-Bromo-3-chloro propane (BCP) (290.0

g, 1.842 mol), DMF (10.0 mL) and heated at 90 °C for 6 h. After completion of

reaction above suspension was cooled and quenched with D. M. water (200.0

mL), layers were separated and organic layer was washed with D. M. water

(200.0 mL). Excess of 1-bromo-3-chloro propane was distilled out completely

under reduced pressure and resultant residue was diluted with cyclohexane (200.0

mL) followed by cooling of the reaction mass to 0−5 °C was done to crystallized

the product. The precipitated solids were filtered, washed with chilled

cyclohexane (50.0 mL x 2) and dried under vacuum at ambient temperature to

give chloro compound 48 as low melting solid (120.0 g, 91%).

mp: 58−60 °C; m/z: 228.8 (M+H)+

; 1H NMR (400 MHz, CDCl3): δ 2.22−2.28

(m, 2H), 3.75 (t, J = 6.3 Hz, 2H), 3.88 (s, 3H), 4.17 (t, J = 5.8 Hz, 2H), 6.91 (d, J

= 14.5 Hz, 2H), 7.98 (d, J = 14.5 Hz, 2H); 13

C NMR (100 MHz, CDCl3): 31.8,

41.1, 51.6, 64.2, 113.8, 122.5, 131.4, 162.2, 166.5.

Preparation of 4-(3-chloropropoxy)benzoic acid (47).

O Cl

OHO

Chloro compound 48 (100.0 g, 0.437 mol) was added to a mixture of MeOH

(400.0 mL) and 20.0% w/v aq. NaOH solution (100.0 mL) and refluxed for 2 h.

51

After completion of saponification, reaction mass was diluted with water (300.0

mL) followed by acidification by drop wise addition of conc. HCl (60.0 mL). The

resulting precipitate was filtered, washed with D.M. water (100.0 mL x 2)

followed by cyclohexane (50.0 mL x 2) and dried under vacuum at 50 °C to give

chloro acid derivative 47 (82.5 g, 88%).

mp: 154−157 °C; m/z: 213.0 (M+H)

+ ;

1H NMR (400 MHz, DMSO_d6): δ

2.15−2.21 (m, 2H), 3.79 (t, J = 6.4 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 7.03 (d, J =

8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 12.64 (brs, 1H); 13

C NMR (100 MHz,

DMSO_d6): 31.9, 42.4, 65.1, 114.9, 123.3, 132.1, 162.7, 167.8.

Preparation of 3-[4-(3-chloropropoxy)benzoyl]2-n-butyl-1-benzofuran-5-yl-

1H-isoindole-1,3(2H)dione (56).

O

N

O

O

Cl

O

O

Procedure−I : Friedel-Craft acylation using SnCl4 as lewis acid.

To the mixture of phthalimido derivative 55 (100.0 g, 0.313 mol) in DCM (250.0

mL), anhydrous SnCl4 was added at 5 °C. Acid chloride 52 (76.52 g, 0.328 mol)

in DCM (250.0 mL) and added slowly to the reaction mixture at 0 to 5 °C.

Reaction mixture was stirred for 1 h at 5 °C followed by at 25 to 30 5

°C for 1 h.

The reaction mixture was quenched by pouring on to ice cold water (450.0 mL)

by keeping temperature of reaction mixture below 20 °C. Layers were separated

after stirring for 30 min. Organic layer was consecutively washed with 2.0 N HCl

solution (450 mL x 2) and 5.0% NaHCO3 solution (450.0 mL). Solvent was

distilled off and residue was slurred with MeOH (800.0 mL) and solids were

52

filtered, washed with MeOH (200.0 mL) and dried at 45 °C to furnish chloro

compound 56 (129.5 g, 79.0%).

Procedure−II : application of Eaton’s reagent.

Eaton‟s reagent was prepared by adding P2O5 (111.2 g, 0.783 mol) portion wise to

methane sulfonic acid (425.0 mL) under nitrogen atmosphere and stirred for 30

min at 25 to 35 °C. To this, chloro acid 47 (70.33 g, 0.328 mol) was added and

allowed to stir for 15 min, and then phthalimido derivative 55 (100.0 g, 0.313

mol) was charged and stirred for 1 h at 35 °C. After complete consumption of

starting material, reaction was quenched by pouring reaction mass in to a mixture

of water (1.0 L) and DCM (200.0 mL) below 15 °C and layers were separated.

Organic layer was washed with 5% NaHCO3 solution (2 x 400.0 mL) followed by

water wash (400.0 mL). DCM was distilled off and the residue was slurred with

methanol (800.0 mL) and the solids were filtered, washed with methanol (200.0

mL) and dried at 45 °C to furnish chloro compound 56 (121.2 g, 76.0%).

mp: 109−110 °C; m/z: 516.1 (M+H)

+ ;

1H NMR (400 MHz, CDCl3): δ 0.90 (t, J =

7.4 Hz, 3H), 1.32−1.41(m, 2H), 1.73−1.80 (m, 2H), 2.22−2.29 (m, 2H), 2.95 (t, J

= 7.5 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.97 (d, J = 8.8

Hz, 2H), 7.29 (dd, J = 8.7 Hz, J = 2.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.59 (d,

J = 8.7 Hz, 1H), 7.76−7.78 (m, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.86−7.94 (m, 2H);

13C NMR (100 MHz, CDCl3): 13.55, 22.16, 27.70, 29.93, 31.88, 41.15, 64.38,

111.40, 114.15, 116.75, 120.11, 123.15, 123.47, 126.98, 127.66, 131.49, 131.57,

134.15, 152.65, 162.47, 165.90, 167.22, 189.46; Anal. Calcd for C30H26ClNO5 :

C, 69.83; H, 5.08; N, 2.71 Found: C, 70.08; H, 5.09; N, 2.72.

53

Preparation of 3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-butyl-1-

benzofuran-5-yl-1H-isoindole-1,3(2H)dione hydrochloride (57).

O

N

O

O

N

O

O

.HCl

Chloro compound 56 (100.0 g, 0.193 mol), KI (32.2 g, 0.194 mol), TBAB (5.0 g,

0.015 mol), Di-n-butyl amine (50.1 g, 0.388 mol) and DMF (150.0 mL) were

heated to 85 °C for 14 h. Reaction mixture was cooled to 25 °C and water (600.0

mL), DCM (150.0 mL) were added. Layers were separated, organic layer was

sequentially washed with 2.0 N HCl (2 x 150 mL), D.M. water (2 x 500.0 mL)

DCM was distilled completely and residue was diluted with IPA (400.0 mL)

followed by cooling of reaction mass to 0 to 5 °C. This was done to crystallize

the product. The precipitated solids were filtered, washed with chilled IPA (2 x

50.0 ml) and dried under vacuum at 50 °C, in this manner hydrochloride salt of

compound 57 was afforded as off- white solid (100.0 g, 85.0%).

mp: 109−110 °C; m/z: 609.1 (M+H)

+ ;

1H NMR (400 MHz, DMSO_d6): δ 0.80 (t,

J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H), 1.21−1.36 (m, 6H), 1.57−1.71 (m, 6H),

2.08−2.18 (m, 2H), 2.81 (t, J = 7.4 Hz, 2H), 3.05−3.10 (m, 4H), 3.22−3.26 (m,

2H), 4.17 (t, J = 5.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.7 Hz, J =

2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.79−7.85 (m, 3H), 7.88−7.96 (m, 4H), 9.47

(brs, 1H); 13

C NMR (100 MHz, DMSO_d6): 13.46, 13.57, 19.46, 21.65, 23.02,

25.05, 27.37, 29.46, 48.96, 51.93, 65.28, 111.59, 114.65, 116.51, 120.15, 123.45,

124.47, 127.19, 127.76, 131.15, 131.54, 131.60, 134.75, 152.35, 162.34, 164.72,

167.36, 189.30; Anal. Calcd for C38H44N2O5.HCl : C, 70.74; H, 7.03; N, 4.34

Found: C, 70.58, H, 7.09, N, 4.22.

54

Preparation of 5-Amino-3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-butyl-

1-benzofuran dioxalate (58).

O

NH2

O

ON

.2COOH

COOH

Procedure−I : Deprotection of 3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-

butyl-1-benzofuran-5-yl-1H-isoindole-1,3(2H)dione hydrochloride.

Amino compound 57 (100.0 g, 0.164 mol) was added to the mixture of IPA

(400.0 mL) and methylamine 40% aqueous solution (100.0 mL) and resulting

suspension was heated for 1 h at 75 °C followed by distillation of excess

methylamine and solvent under reduced pressure. The residue was diluted with

IPA (400.0 mL) and oxalic acid dihadrate (41.3 g, 0.328 mol) was added and

stirred at 65 °C for 30 min. The reaction mixture was cooled to 5

°C and stirred

for 1 h. The precipitated solids were filtered and washed with IPA (100.0 mL)

followed by acetone (100.0 mL) and dried at 50 °C to furnish dioxalate salt 58

(97.0 g, 90.0%).

Procedure−II : One pot preparation from 3-[4-(3-chloropropoxy)benzoyl]2-

n-butyl-1-benzofuran-5-yl-1H-isoindole-1,3(2H)dione.

Chloro compound 56 (100.0 g, 0.193 mol), KI (32.2 g, 0.194 mol), TBAB (5.0 g,

0.015 mol), Di-n-butyl amine (50.1 g, 0.388 mol) and DMF (150.0 mL) were

heated to 85 °C for 14 h. Reaction mixture was cooled to 25 °C, water (600.0

mL), DCM (150.0 mL) were added. Layers were separated, organic layer was

sequentially washed with 2.0 N HCl (150 mL), D.M. water (500.0 mL x 2)

55

followed by saturated NaHCO3 solution (250.0 mL). DCM was distilled

completely to afford amino compound 57 as oil. IPA (400.0 mL) followed by

methylamine 40% aqueous solution (100.0 mL) was added and mixture was

heated for 1 h at 75 °C. Reaction mixture was concentrated under vacuum. The

residue was diluted with IPA (500.0 mL) and oxalic acid dihadrate (49.0 g, 0.388

mol) was added and stirred at 65 °C for 30 min. The reaction mixture was cooled

to 5 °C and stirred for 1 h. The predicated solids were filtered and washed with

IPA (100.0 mL) followed by acetone (100.0 mL) and dried at 50 °C to furnish

crude dioxalate salt 58 (105.0 g, 82.0%) with purity 95%.

Recrystalization of crude dioxalate salt 58 from MeOH results in pure product

with purity more than 99% by HPLC and individual impurity less 0.5% (90.0 g,

70.0%).

mp: 166−170 °C; m/z: 479.2 (M+H)+

; 1H NMR (400 MHz, DMSO_d6): δ 0.79 (t,

J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H), 1.19−1.24 (m, 2H), 1.28−1.37 (m, 4H),

1.57−1.65 (m, 6H), 2.12−2.18 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H), 3.04−3.09 (m,

4H), 3.20−3.24 (m, 2H), 4.17 (t, J = 5.9 Hz, 2H), 6.53 (d, J = 2.0 Hz, 1H), 6.59

(dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.7 Hz,

1H), 7.76 (d, J = 8.8 Hz, 2H); 13

C NMR (100 MHz, DMSO_d6): 13.63, 13.73,

19.64, 21.85, 23.16, 25.17, 27.44, 29.75, 49.07, 52.05, 65.39, 107.01, 111.55,

114.73, 116.46, 127.61, 131.59, 131.65, 141.06, 148.03, 162.35, 163.68, 164.22,

190.10; Anal. Calcd for C34H46N2O11 : C, 61.99; H, 7.04; N, 4.25 Found: C,

61.91; H, 7.15; N, 4.41.

56

Preparation of Dronedarone Hydrochloride (2).

O

O

ON

NHS

O O

.HCl

Dioxalate salt 58 (100.0 g, 0.152 mol) was added portionwise to the stirred

mixture of water (300.0 mL) DCM (300.0 mL) and NaHCO3 (56.6 g, 0.674 mol).

Above suspension was stirred for 30 min. Inorganic solids were filtered and

layers were separated. Organic layer containing precursor free amine was washed

with water (2 x 200.0 mL). DCM was distilled out. To this residue toluene

(300.0 mL) was added followed by Et3N (23.0 g, 0.227 mol) and chilled at -5 °C.

Methane sulfonyl chloride (18.3 g, 0.159 mol) was added dropwise at -5 to 5 °C

and stirred for 30 min. After completion of reaction on TLC, reaction mass was

quenched by adding 5.0% aqueous NaHCO3 (300.0 mL) and layers were

separated, washed with water (200.0 mL). Toluene was distilled out and the

residue was stirred with a mixture of DCM (300.0 mL), conc. HCl (30.0 mL) and

D. M. water (300.0 mL) for 30 min.

After layer separation, organic layer was washed with D. M. water (200.0 mL x

2). DCM was distilled out and to the residue mixture of ethyl acetate and IPA

(1.0 L, 9:1) was added and stirred at 25 °C for 4 h. The reaction mixture was

cooled at 5 °C and stirred for 2 h. Suspension was filtered to afford Dronedarone

Hydrochloride crude (67.0 g, 75.0%). Recrystallisation of crude product from

acetone results in Pure Dronedarone Hydrochloride (2) with purity more than

99.5% by HPLC and any individual impurity less than 0.10% (54.0 g, 60.0%).

57

mp: 143 °C; m/z: 557.3 (M+H)+

; 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 7.4

8Hz, 3H), 0.9 (t, J = 7.3 Hz, 6H), 1.34−1.45 (m, 6H), 1.72−1.84 (m, 6H),

2.38−2.45 (m, 2H), 2.91 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H), 3.03−3.07 (m, 4H),

3.22−3.27 (m, 2H), 4.24 (t, J = 5.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.18 (d, J =

2.1 Hz, 1H), 7.31 (dd, J = 8.8 Hz, J = 2.1 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H),

7.66 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 11.93 (s, 1H); 13

C NMR (100 MHz,

CDCl3):13.23, 13.35, 19.70, 21.95, 23.32, 24.75, 27.57, 29.67, 38.15, 49.84,

52.08, 64.72, 111.12, 113.99, 115.18, 116.38, 119.75, 127.42, 131.30. 131.50,

133.06, 151.14, 161.77, 165.55, 189.79; Anal. Calcd for C31H45ClNO5S : C,

62.77; H, 7.56; N, 4.72; S, 5.40 Found: C, 62.83; H, 7.46; N, 4.91; S, 5.60.

Preparation of Disulfonamide impurity (59).

O

O

ON

NS

O O

S

O

O

Dioxilate salt 58 (10.0 g, 0.015 mol) was added portion wise in to the stirred

mixture of water (30.0 mL), DCM (30.0 mL) and NaHCO3 (5.6 g, 0.067 mol).

Suspension was stirred for 30 min. and resulting inorganic solids were filtered

followed by layer separation. Organic layer was washed with D. M. water (20.0

mL x 2) and dried over MgSO4. To the reaction mass Et3N (4.5 g, 0.045 mol)

was added and solution was chilled at -5 °C. Methane sulfonyl chloride (4.3 g,

0.037 mol) was added dropwise at -5 to 5 °C and stirred for 30 min. After

complete conversion on TLC, reaction was quenched by adding saturated

NaHCO3 solution (30.0 mL) and layers were separated; organic layer was washed

with D.M. water (20.0 mL). DCM was distilled out and resulting product was

purified by column chromatography. (Eluting phase:-m CHCl3: MeOH; 99:1) to

afford disulfonamide impurity 59 as gummy solid (6.2 g, 65.0%).

58

m/z: 635.0 (M+H)+

; 1H NMR (400 MHz, CDCl3): δ 0.85−0.92 (m, 9H),

1.28−1.37 (m, 6H), 1.38−1.46 (m, 4H), 1.67−1.75 (m, 2H), 1.94−1.99 (m, 2H),

2.45 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 3.35 (s,

6H), 4.09 (t, J = 6.1 Hz, 2H), 6.95 93 (d, J = 8.6 Hz, 2H), 7.25 (dd, J = 8.6 Hz, J

= 1.7 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.6

Hz, 2H); 13

C NMR (100 MHz, CDCl3):13.52, 13.96, 20.55, 22.18, 26.76, 27.83,

28.96, 29.91, 42.50, 50.25, 53.75, 66.43, 111.92, 114.18, 116.76, 123.85, 126.48,

128.44, 128.89, 131.00, 131.66, 153.90, 163.23, 166.16, 189.30.

Spectra

59

1H NMR spectrum of Compound 39 in CDCl3

13C NMR spectrum of Compound 39 in CDCl3

60

Mass spectrum of compound 39


61



62

1H NMR spectrum of Compound 30 in DMSO_d6

13

C NMR spectrum of Compound 30 in DMSO_d6

63



64



65



66



67

13C NMR spectrum of Compound 47 in DMSO_d6


68


13

C NMR spectrum of Compound 56 in CDCl3

69



70

13



71


13


72



73

13



74


13


75


References

76

References

1) Hohnloser, S.H.; New pharmacological options for patients with atrial

fibrillation: the ATHENA trial.; 62(05), 2009, 479−481.

2) Dobromir, D.; Stanley, N. Lancet, 2010, 375, 1212−1223.

3) Patel, P.B.; Patel, K. C.; Mehta, H. R. IRJP, 2011, 2 (3), 59−65.

4) Singh, B. N.; j. Cardiovasc. Pharmacol. 52, 2008, 300.

5) Kodama, I.; Kamiya, K.; Toyama; j. Cardiovasc. Res. 35, 1997, 13.

6) Zimetbaum, P. N.; Engl. J. Med., 2007, 356, 935.

7) Patel, P. D.; Bhuriya, R.; Patel, D.D.; Arora, B.L.; Singh, P. P..; Arora, R. R.

Dronedarone for atrial Fibrillation: a new therapeutic agent. Vascular Health

and Risk management, 2009, 5, 635−642.

8) Nattel, S.; Singh, B. N.; Am. J. Cardiol., 84 (9A), 1999, 11R−19R.

9) Wyse, D. G.; Waldo A. L.; Di Marco, J. P. S.; N.; Engl. J. Med., 2002, 347,

1825−1833.

10) Hohnloser, S.H.; Kuck K. H.; Lilienthal, j. Lancet, 2000, 356, 1789−1794..

11) Van Gelder, I. C.; Hagens, V. E.; Bosker, H. A. N.; Engl. J. Med., 2002, 347,

1834−1840.

12) Gubin, J.; Chatelaine, P.; Lucchetti, J.; Chaster.; Rosseels, G.; Henri, I.; U. S.

Patent 5,223,510, 1993.

13) Fino, N.; Leroy, C.; U. S. Patent 6,828,448 B2, 2004.

14) Wolfgang, M.; . U. S. Patent 6,984,741 B2, 2006.

15) Schlama, T.; . U. S. Patent 6,555,697 B1, 2003.

16) Pal, M.; Subramaniam, V.; Rao, K. K.; Tetrahedron letters, 2003, 44,

8221−8225.

17) Pu, Y. M.,; Grieme, T.; Gupta, A.; Plata, D.; Bhatia, A.V.; Cowart, M.; Ku, Y.

Y.; Org. Process Res. Dev. 2005, 9 (1), 45−50.

18) Lu, B.; Wang, B.; Zhang, Y.; Ma, D.; j. Org. Chem. 2007, 72, 5337−5341.

19) Chen, C. Y.; Dormer, P. G.; j. Org. Chem. 2005, 70, 6964−6967.

20) Carril, M.; San Martin, R.; Tellitu, I. M.; Dominguez. Org. Lett. 2006, 8,

1467−1470.

21) Ackermann, L.; Kespar, T.; j. Org. Chem. 2007, 72, 6149−6153.

77

22) Van Otterlo W. A. L.; Morgans, G. L.; Madeley, L. G.; Kuzvidza, Z.;Moleele,

S. S.; Thornton, C. B.; de Koning; Tetrahedron, 2005, 61, 7746−7755.

23) Anderson, K. W.; Ikawa, T.; Tundel. R. E.; Buchwald, S. L.; j. Am. Chem.

Soc. 2006, 128, 10694−10695.

24) Dudley M. E.; Morshed M. M.; Hossain, M. M.; Synthesis, 2006, 1711−1714.

25) De Luca, L.; Giacomelli, G.; Nieddu, G.; j. Org. Chem. 2007, 72, 3955−3957.

26) Takeda, N.; Miyata, O.; Naito, T.; Eur. j. Org. Chem. 2007, 1491−1507.

27) Eidamshaus, C.; Burch, J. D.; Org. Lett. 2008, 10, 4211−4214.

28) Kretzschmar, G.; Kraft, V.; Rossen, K.; Graser, J. U. S. Patent 2012/0077995

A1, 2012.

29) Shoutteeten, A.; Bleger, F.; Mordacq, F.; 2007/0155831 A1, 2007.

30) Biard, M.; La Mure.; U. S. Patent 6,846,936 B2, 2005.

31) Mohanarangam, S.; Satyanarayana, B.; Elati, C. R.; Vijaybhaskar, B.; Reddy

P.P. journal of the Chinese chemical society, 2011, 58, 841−845.

32) Sada, M.; Nardi, A.; Maiorana, S.; WO 2011/104591 A1, 2011.

33) Gutaman, A.; Nisnevich, G.; Yudovitch, L.; U. S. Patent 7,312,345 B2, 2007.

34) Kukoiju, S.; Steven, R. L.; j. Am. Chem. Soc. 1975, 97(19), 5582−5583.

35) Ceric, H.; Sindler-Kulyk, M. ARKIVOC, 2009, No. (vii) 237−246.

36) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic

Synthesis, 4th

ed.; Wiley-Interscience: Hoboken, NJ, 2007; pp 790−793.

37) Olah, G. A.; Friedel-Crafts and related reactions; Wiley-Interscience; New

York, 1964, p 3.

38) Dang, W.; Xu, Y.; Gou, Q.; Chin. Chem. Lett. 2005, 16, 327−330.

39) Sarvari, M. H.; Sharghi, H. j. Org.Chem. 2004, 69, 6953−6956.

40) Hajipour, A. R.; Zarei, A.; Khazdooz, L.; Ruoho, A. E. Synth. Commun. 2009,

39 (15), 2702−2722.

41) Zarei, A.; Hajipour, A. R.; Khazdooz, L. Tetrahedron Lett. 2008, 49,

6715−6719.

42) He, F.; Wu, H.; Chen, J.; Su, W.; Synth. Commun. 2008, 38 (2), 255−264.

43) Mizuno, A.; Miya, M.; Kamei, T.; Shibata, M.; Tatsuoka, T.; Nakanishi, K.;

Takiguchi, C.; Hidaka, T.; Yamaki, A.; Inomata, N. Chem. Pharm. Bull. 2000,

48 (8), 1129−1137.

44) Eaton, P. E.; Carlson, G. R.; Lee, J. T.; j. Org. Chem. 1973, 38 (23),

4071−4073.

78

45) Wu, Z.; Wei, G.; Lian, G.; Yu, B.; j. Org.Chem. 2010, 75, 5725−5728.

46) Scott, P. E.; Bradshaw, J. S. j. Org.Chem. 1980, 45, 4716−4720.

47) Li, Y.; Zang, C.; Sun, M.; Gao, W.; j. Heterocycl. Chem. 2009, 46, 1190−1194.

48) Ulysse, L. G.; Yang, Q.; McLaws, M. D.; Daniel, K.; Keefe, G.; Peter, R.;

Haney, B. P.; Org. Process Res. Dev. 2010, 14, 225−228.

49) So, Y.-H.; Heeschen, J.-P. j. Org.Chem. 1997, 62, 3552−3561.

50) Ghinet, A.; Hijfet, N. V.; Gautret, P.; Rigo, B.; Oulyadi, H.; Rousseau, J.

Tetrahedron, 2012, 68, 1109−1116.

51) Zewge, D.; Chen, C.; Deer, C.; Dormer, P. G.; Hughes, D. L.; j. Org.Chem.

2007, 72, 4276−4279.

52) Zhou, T.; Shi, Q.; Chen, C.-H.; Huang, L.; Ho, P.; Susan L. Morris-Natschke;

Lee, K. H.; Euro. J. Med. Chem. 2012, 47, 86–96.

53) R. L. Dorow,* Paul M. Herrinton,* Richard A. Hohler, Mark T. Maloney, Michael

A. Mauragis, William E. McGhee, Jeffery A. Moeslein, JosephW. Strohbach, and

Michael F. Veley Org. Process Res. Dev. 2006, 10, 493−499.

54) Pandit, C. R.; Polniaszek, R. P.; Thottathil, J. K.; Syn. Comm. 2002, 32 (15),

2427−2432.

55) Im, I.; Lee, E. S.; Choi, S. J.; Lee, J. Y.; Kim,Y.-C. Bioorganic and Medicinal

chemistry lett. 2009, 19(13), 3632−3636.

56) Borse, A.; Patil, M.; Patil, N.; Shinde, R. ISRN Organic Chemistry, 2012, Vol

2012, page 6.

57) Zhao, D.; Hughes, D. L.; Bender, D. R.; DeMarco, A. M.; Reider, P. J.; j. Org.

Chem. 1997, 62, 3001.

58) Ren, R. X.; Zueva L. D.; Ou, W.; Tetrahedron letters, 2001, 42, 8441−8443.

59) Dumas, D. J.; U. S. Patent 5,990,315, 1999.

60) Srivastav, S.; Crasto, A. M.; Gharpure, M. M.; Deore, D. B.; Nareyanan, S. B.;

WO/2012/007959 A1, 2012.

http://www.sciencedirect.com/science/article/pii/S0223523411007641

http://www.sciencedirect.com/science/article/pii/S0223523411007641

http://www.tandfonline.com/action/doSearch?action=runSearch&type=advanced&result=true&prevSearch=%2Bauthorsfield%3A%28Pandit%2C+Chennagiri+R.%29

chapter-i -...

Documents