scalable green chemistry practices - igcw 2019 2013/pharma...1 scalable green chemistry practices...

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Scalable Green Chemistry Practices

ICGW-20136-8 December, 2013Renaissance Hotel

Mumbai, India

Life Research Hope

Rakeshwar BandichhorPh.D.

Director, API-R&D, Innovation PlazaIPDO, Dr. Reddy’s Laboratories, Hyderabad

India

http://www.drreddys.com/products/green-chemistry.html (Green Chemistry Website)

Nature Medicine 2013, 19, 1200-1203 (Finding Right Chemistry)

http://www.drreddys.com/products/green-chemistry.html




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Significance of Chemistry

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•Whatever you hear, see, smell, taste, and touch involves chemistry and chemicals(matter).•And all these processes involve intricate series of chemical reactions and interactionsin the biological system.• With such an enormous range of biological actions which are governed by chemistrytherefore it is essential to know about this subject at some level in order tounderstand the world around us.

>200 >1000 >7000Chemicals

Green Tea Coffee Cigarette

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Significance of Chemistry

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Chemistry Signifies Love and Hate Relationship-can’t live without it but can’t accept everything that it has.

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Green Chemistry

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•Evolving discipline it does mean that the definition of green may change tomorrowe.g. Grignard reaction was considered to be one of the best reactions but today it isbeing replaced with greener metal catalyzed transformations.

•It is a subject that deals prevention of waste in any activity around us by design.

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Industry Sectors

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Energy alternatives

Textile, printing, agro and construction

Electronics and semiconductors

Pharmaceutical, medical and biotech

Cosmetics

Retail and everyday commodity

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Complexity

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Abacavir, Acefylline, Acrivastine, Alendronate sodium, Alfuzosin, Almotriptan, Altretamine, Alvimopan, Amifostine, Amlodipine,Amprenavir, Anastrozole, Angiotensinamide, Aprepitant, Arformoterol, Aripiprazole, Atorvastatin calcium, Azacitidine, Azelastine,Bamifylline, Benazepril, Betaine hydrate, Bicalutamide, Bifonazole, Bromfenac sodium, Bupheniode, Buprenorphine, Cafedrine,Calcitonin, Candesartan cilexetil, Capecitabine, Caroxazone, Carvedilol, Cefpodoxime Proxetil, Celecoxib, Cetalkonium chloride,Cetirizine, Chlorobutanol, Choline salicylate, Choline theophyllinate, Ciclopirox, Cimetidine, Cinmetacin, Ciprofloxacin, Citalopram,Clomifene, Clomipramine, Clopidogrel hydrogensulfate, Danazol, Dantrolene, Dapoxetine, Darifenacin, Darunavir, Decitabine,Degarelix, Desloratadine, Desvenlafaxine, Dexamethasone valerate, Dexrazoxane, Dextromethorphan, Dezocine, Diazepam,Diethylstilbestrol, Dimestrol, Diprophylline, Domperidone, Donepezil hydrochloride, Doxazosin, Doxofylline, Doxylamine,Dronedarone, Duloxetine oxalate, Dutasteride, Elcatonin, Enalapril, Enalaprilat, Escitalopram oxalate, Esomeprazole, Eszopiclone,Ethinamate, Etofylline, Etravirine, Everolimus, Exemestane, Exenatide, Ezetimibe, Famotidine, Febuprol, Felodipine, Fenclofenac,Fenetylline, Fexofenadine hydrochloride, Finasteride, Flecainide, Fleroxacin, Fluconazole, Flunitrazepam, Fluoxetine, Fluticasonepropionate, Fluvastatin sodium, Fondaparinux sodium, Formocortal, Fosamprenavir, Fosfluconazole, Fosinopril, Fosphenytoinsodium, Galantamine, Gatifloxacin, Gemcitabine, Glimepiride, Granisetron, Hexestrol, Histrelin, Hydrochlorothiazide, Ibandronatesodium monohydrate, Ibuprofen, Ibuproxam, Icatibant, Imidafenacin, Indinavir sulfateIrbesartan, Irinotecan, Ixabepilone, Ketorolac,Lacidipine, Lacosamide, Lacosamide, Lamotrigine, Lansoprazole, Letrozole, Levetiracetam, Levocetirizine, Levofloxacin,Levosalbutamol, Linezolid, Liraglutide, Lomifylline, Lomustine, Lopinavir, Loratadine, Losartan potassium, Mabuprofen,Meclofenoxate, Melitracen, Meloxicam, Memantine, Meptazinol, Mesalazine, Metapramine, Metoprolol, Miglitol, Milnacipranhydrochloride, Minaprine, Mirtazapine, Mitiglinide, Modafinil, Montelukast sodium, Moxifloxacin hydrochloride, Naproxen,Naratriptan, Nateglinide, Nebivolol, Nicardipine, Nisoldipine, Nizatidine, Nomifensine, Olanzapine, Olmesartan medoxomil,Ondansetron, Oxaprozin, Oxcarbazepine, Oxitriptan, Paliperidone, Palonosetron, Pamidronic acid, Pantoprazole sodium, Parecoxibsodium, Paroxetine, Perindopril, Phenytoin, Pimefylline, Pimeprofen, Pioglitazone, Piproxen, Pitavastatin, Prednival acetate,Pregabalin, Primidone, Proxyphylline, Pyridofylline, Quetiapine fumarate, Quinapril hydrochloride, Rabeprazole sodium, Raloxifenehydrochloride, Ramipril, Ranitidine, Ranolazine, Rasagiline, Repaglinide, Retapamulin, Riluzole, Risedronate sodium, Risperidone,Ritonavir, Rivastigmine, Rizatriptan benzoate, Rocuronium bromide, Ropinirole, Rosiglitazone, Rosuvastatin calcium, Rupatadine,Salmeterol, Saxagliptin, Sertaconazole, Sertraline, Sildenafil, Simvastatin, Sitagliptin phosphate, Solifenacin, Sulindac, Sulpiride,Sumatriptan, Tacrolimus, Tadalafil, Talaporfin, Tamsulosin hydrochloride, Tapentadol, Telcagepant, Telmisartan, Tenoxicam,Terbinafine, Teriparatide, Thalidomide, Tipranavir, Tizanidine, Tolmetin, Tolterodine, Tolvaptan, Tomoxetine hydrochloride,Topiramate, Topotecan, Trandolapril, Triclocarban, Tripelennamine, Trospium chloride, Ulobetasol propionate, Valaciclovir,Valdecoxib, Valganciclovir hydrochloride, Valrubicin, Valsartan, Vardenafil hydrochloride, Venlafaxine, Voriconazole, Zafirlukast,Zalcitabine, Zaleplon, Ziprasidone hydrochloride, Zoledronic acid, Zolmitriptan, Zolpidem, Zonisamide

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Higher E Factor α Degree of Complexity ?

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1000 10000 1000000

100000000

0

2,00,00,000

4,00,00,000

6,00,00,000

8,00,00,000

10,00,00,000

12,00,00,000

1 2 3 4

Material Demand in Tonnage

100

50

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120

1 2 3 4

E-Factor in Kg

1. Pharma; 2. Fine; 3. Bulk; 4. Oil

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Net E-Factor

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100000500000

5000000

10000000

0

2000000

4000000

6000000

8000000

10000000

12000000

1 2 3 4

Net E-Factor in Kg

1. Pharma; 2. Fine; 3. Bulk; 4. Oil

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Approaches

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Approaches

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1. Consideration of GC (TP and GM) in design phase2. Minimize the number of steps while maintaining the desired cost

component intact3. Minimize or replace (Switch) non-green solvents4. Work through multi-disciplinary scientific interface (Collaboration)5. Renewable material based synthesis6. Net output based energy efficient waste (unavoidable) management7. Non-toxic and hazard free practices8. Continuous mode of Chemistry/Engineering (flow technology)9. In-expensive catalyst based transformations10. Opt for asymmetric transformations11. Use of immobilized recombinant enzymes for transformations with

very low dilutions12. Educate and prepare young generation considering intuitive

knowledge potential to take a lead in this field

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Approaches: Flow Technology

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• Conventional method• Several Disadvantages

- Time and labor intensive- A number of unit processes- Needs extensive optimization

• Emerging Technology• Advantages over batch process

- High surface area, precisely controlled conditions- Rapid screening of reaction

conditions- “Scale-out” instead of “Scale-up”- Safety

BATCH (space-resolved process)

FLOW MICROREACTION TECHNOLOGY(time-resolved process)

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Approaches: Biocatalysis

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Microbe, enzymecollection Seed Fermenter

Production Fermenter

Shake Flask Lab Fermenter

Screening Optimization CPP Production

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Innovative Research Since 2007

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Innovation

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1. Incremental2. Medium Size3. Process4. Technology based

a. Biocatalysisb. Continuous

5. Major

Types of Innovation

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Incremental: Reductive Amination

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Kumar, U. Tetrahedron Lett. 2012, 53, 4354-4356

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Mechanistic Considerations

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Generality of the Method

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Incremental: Acylation

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Kumar, U. Tetrahedron Lett. 2013, in print

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Substrate Reagent/catalyst Conditions TimeYield (%)

2l

cat. DMAP, Py/Ac2O CH2Cl2, Reflux 2 h 90

Zn(OTf)2 (0.1 mol%) /Ac2O

25-25 °C 60s 90

2j

Py/Ac2O 25-25 °C 3 h 87

Zn(OTf)2 (0.1 mol%) /Ac2O

25-25 °C 30s 92

Pyridine (Py)/AC2O Mediated vs Zn(OTf)2 Catalyzed Acylation

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Incremental: Amide Reduction

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Tetrahedron Lett. 2013, 54, 4908-4913. (Featured in R&DHighlights Published in Org.Proc.Res.&Dev. 2013, ASAP and being tracked in Article Usage

Dashboard)

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Mechanistic Considerations

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Medium Size: Enantioselective Grignard addition to Nitroolefin

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Prashanth Reddy, G. Tetrahedron Lett., 2013, 54, 3911-3915

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Medium Size: Enantioselective Grignard Addition to Nitroolefin

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Potential Application

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S.No. Catalyst R1/R2/X °Cer (R/S) (HPLC)

Yield (%)

1 CuTC/L1 6Mn/Me/Br -60 49.5/50.5 752 CuTC/L1 6Mn/Me/Br -20 49/51 753 CuI/L1 6Mn/Me/Br -60 45/55 704 CuI/L1 6Mn/Me/Br -20 48.6/51.4 705 Zn(OTf)2/L1 6Mn/Me/Br -60 49.5/50.5 706 Zn(OTf)2/L1 6Mn/Me/Br -20 49.5/50.5 707 CuTC/L2 6Mn/Me/Br -60 49/51 758 CuTC/L2 6Mn/Me/Br -20 49.5/50.5 759 CuI/L2 6Mn/Me/Br -60 49.3/50.7 70

10 CuI/L2 6Mn/Me/Br -20 49.7/50.3 7011 Zn(OTf)2/L2 6Mn/Me/Br -60 49.2/50.8 7012 Zn(OTf)2/L2 6Mn/Me/Br -20 49.6/50.4 7013 CuTC/L1 6Mn/Me/Cl -70 49.2/50.8 7014 CuTC/L1 6Mn/Me/Cl -20 49.3/50.7 7015 CuTC/L1 6Mn/Me/Cl -35 48/52 72

Screening

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Screening

S.No. Catalyst R1/R2/X °Cer (R/S) (HPLC)

Yield %

1 CuTC/L1 6Mn/Me/Cl -40 48.7/51.3 702 CuTC/L1 6Mn/Et/Cl -40 49/51 693 CuTC/L1 6Mn/iPr/Cl -40 51/49 674 CuTC/L1 6Mn/tBu/Cl -40 72/28 685 CuTC/L1 6Mn/tBu/Cl -70 77/23 69

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Screening

S.No. Catalyst R1/R2/X °C er (R/S) (HPLC) Yield %1 CuI/L3 6Mn/Me/Cl -70 49.2/50.8 682 CuI/L3 6Mn/Et/Cl -70 49.5/50.5 643 CuI/L3 6Mn/iPr/Cl -70 51.97/48.03 644 CuTC/L3 6Mn/tBu/Cl -70 61/39 625 CuI/L3 6Mn/tBu/Cl -70 98.5/1.5 626 CuI/L3 6Mn/tBu/Cl -70 97.9/2.1 647 CuI/L3 6Mn/tBu/Cl -70 97.9/2.1 658 CuI/L3 6Mn/tBu/Cl -70 97.8/2.2 639 CuI/L3

iBu/6Mn/Br -70 25/75 7510 CuTC/L3 6Mn/Ph/Cl -70 50.56/49.44 6211 CuTC/L3 6Mn/Benzyl/Cl -70 49.49/50.51 6612 CuI/L3 Ph/tBu/Cl -70 39.5/60.5 6013 CuI/L3 p-EtO-Ph/tBu/Cl -70 23/77 6514 CuI/L3 p-F-Ph/tBu/Cl -70 4/96 60

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Catalytic Cycle and Mechanistic Consideration

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Medium Size: Regioselective Methylation

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Sudhakar, Tetrahedron Lett., 2013, 54, 1661-1663

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Different Methods

Basic condition: No selectivityAcidic condition: N-1 (thermodynamic); N-2 (kinetic)

Trimethyloxonium tetrafluoroborate (Meerwein’s reagent) is considered to be the best reagent for regioselective methylation

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Generality of the Methods

This reagent is suitable to both EWG and EDG containing substrates

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Process Innovation: Grignard Reaction

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First reported synthesis of Citalopram 1

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Strategies for Process Improvements

1. Can we freshly prepare GR and use it in situ?2. Can we avoid the use of LAH or Sodium borohydride reagent?3. Can we avoid Copper cyanide?4. Can we avoid NaH during alkylation?5. Can we do most of the transformations at room temperature or

at least can we avoid higher temperature (>100 0C) ?6. Is it possible to telescope this process to all possible extent?7. ……………….etc

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Outline Towards Realizing the Strategies : One Pot Synthesis of Diol HBr

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Role of Solvents and Inherent KF

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Temperature Profile

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DoE: Full Factorial

1.Pre DoE experiments2.Based on domain knowledge, deciding on the

variable and response factors3.Use of software e.g. Design Expert4.Augmentation of initial results with the help of

Response Surface Model to arrive on the optimal conditions

5.Analysis of results by considering ANOVA variance method to derive significant model

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process variables low high process variables low high

BFB

(mol equiv.)1.2 1.5

CPA

(mol equiv.)1.8 3.0

Mg

(mol equiv.)1.2 1.5

Mg

(mol equiv.)2.0 4.0

Iodine

(% w/w)1 10

Iodine

(% w/w)1 10

Operable ranges for DoE based on pre-DoE experiments

Response Factors>75% yield and >98% purity

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Design space obtained for BFB and CPA Grignard reactions

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Optimized Conditions

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Work up Simplification

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Safety Consideration

1. Understanding the heat of reaction and adiabatic temperature rise

2. Comparison of the batch temperature profile inside the reactor (Tr) with the reactor jacket temperature profile (Tj) in isothermal mode reveals whether the reaction is instantaneous or not. (Exo or Endothermic)

3. Enthalpy can be calculated which indicates temperature rise in a given batch size

4. This helps to avoid accidents at a scale by keeping control system in place without compromising on process variables and responses

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Safety Consideration

For 100g input of 10; Temperature rise for BFB Grignard is from 0 °C to 3 °C, E=170.2 KJ andTad=146.69 °C; Temperature rise for CPA Grignard is from 0 °C to 1.5 °C, E=148.15 KJ andTad=91.2 °C. Recommendation: Rate of heat exchange must be controlled by keepingefficient cooling in Jacket

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Michael E Kopach <[email protected]> 05/10/2013 04:45 AMTo"[email protected]" <[email protected]>

CcSubjectCitalopram PaperDear Rakesh,From on Grignard practioner to another – this is an outstanding paper:http://pubs.acs.org/doi/abs/10.1021/op3002596

Best Regards,

Mike

Appreciation

Org.Proc.Res.&Dev. 2013, 17, 798-805.

http://pubs.acs.org/doi/abs/10.1021/op3002596

http://pubs.acs.org/doi/abs/10.1021/op3002596

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Technology Based Innovation: Biocatalysis

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Asymmetric Reduction of a Key Intermediate of Esclicarbazepine Acetate Using Whole Cell

Catalysis Science & Technology 2012, 2, 1602-1605. (One of the Hot Articles).

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Bioreduction of Ketone 1 by P. methanolica whole-cells in biphasic system at 30°C

95

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ss (

ee

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Effect of Substrate Concentration

0

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Co

nve

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n(%

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Time (h)

0.5g/l 1.0g/l 1.5g/l 2.0g/l 2.5g/l 3.0g/l

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Effect of Cell Concentration

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Output at a Scale with Optimized Conditions

1.Resting cells of P. methanolica (150.0 gl-1), H2O: hexane (2 L), glucose (0.5%)

2. Reaction at 30°C for 48 h 3. 85% isolated with >98% ee

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Technology Based Innovation: Flow Chemistry

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Application of Flow Technology in the Process Development of Prazoles

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Synthesis of Prazoles

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Continuous Flow Micromixing Reactor Set up

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Effect of Flow Rate on Conversion

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Batch vs Flow

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Batch vs Flow

First three entries are from Batch and last three belong to Flow

Org. Process Res. Dev., 2010, 14, 229–233 (DRL, India)Org. Process Res. Dev., 2013, 17, 1272–1276 (DRL, India)

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Major Innovation: Diastereoselective Reduction

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Hansen, K.B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E.J.J.; Armstrong III, J.D. J. Am. Chem. Soc. 2009, 131, 8798-8804

Precedented Approaches

Recently Developed Asymmetric Reduction Involving Biocatalysis is More Prefered

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Innovative Approaches

Strategy I Strategy II

Yield ??; dr ??

HSiCl3

Yield ??; dr ??

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Evolution of Concept

dr : 83:17undesired isomer

dr: 85:15desired isomer

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yield 85%; dr = 85:15

Required diastereomer crystallized with dr>99%

Bandichhor, R.; et al. WO 2011025932 A2 20110303

-90 0C: dr=93:07, Yield= >90%

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Major Innovation: Synthesis of Eribulin

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Target 64 to 20 Steps

Late Stage Breast Cancer (Two Chemotherapies and Treated WithAnthramycin and Taxane Class of Medicine)

HALAVEN is a clear, colorless, sterile

solution for intravenous administration. Each vial contains 1 mg of

eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).

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Assemble Once Again after Two

Years from Now to Hear the

Story about Eribulin

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Inspiration

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“A chain is as strong as its weakest link”

Reading Materials:1. Scalable Green Chemistry: Case Studies from the Pharmaceutical Industry2. Green Chemistry in the Pharmaceutical IndustryApart from Leading Journals1. OPRD2. Journal of Chemical Education

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Amit BiswasVilas DhahanukarApurba BhattacharyaDhileep K. KrishnamurthyP. Pratap ReddyArnabAmarNamrataDineshGade SrinivasDavid (Clinton Foundation)NagarajuUdaiSudhakarKiranPrasanthPallaviERRGangulaChirotech teamAll the Chemistry, PE and Formulation scientists at IPDO

The management of the Dr. Reddy’s Laboratories Ltd. is highly acknowledged for supporting the innovative research

Oliver (Regensburg)Marisa (Upenn)Burgess (College Station)

Acknowledgement

Department of Science and Technology

http://www.google.co.in/imgres?imgurl=http://www.moneylife.in/site/userimage/image/UGC.jpg&imgrefurl=http://www.moneylife.in/article/8/4462.html&usg=__XKO3sfVWwODl6rcZbnfZckSFH-s=&h=250&w=360&sz=11&hl=en&start=29&zoom=1&tbnid=IijJxTSffSSjVM:&tbnh=84&tbnw=121&ei=rjAZT7fcD8_qrQe87sXRDQ&prev=/search?q=UGC&start=21&hl=en&sa=N&gbv=2&tbm=isch&prmd=ivns&itbs=1

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Thank You

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scalable green chemistry practices - igcw 2019 2013/pharma...1 scalable green chemistry practices...

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