Green Chemistry Innovation in the Synthesis of Medicines · 1 Green Chemistry Innovation in the...

1

Green Chemistry Innovation in the Synthesis

of Medicines

198th OMICS Group Conference International Summit on Past and Present Research Systems

of Green Chemistry August 25-27, 2014

Hilton Philadelphia Airport, USA

Life Research Hope

Rakeshwar Bandichhor Ph.D.

Director, API-R&D, Innovation Plaza IPDO, 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

2

Significance of Chemistry

Life Research Hope

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

>200 >1000 >7000 Chemicals

Green Tea Coffee Cigarette

Value added

products from nature

Understanding of life processes and

chemical matter at molecular level

Resource stressed planet

NN

NO

O

O H

H

HN

NN

N

N

N

HH

H

H

HH

N

NN

O

O

O

H

H

H

NN

NN

N

N

HH

HH

H

HN

N

NO

O

O

H

H

H

NN

NN

N

N

H

H

HH

HH

Utility Science Core and Integrative Science Sustainability Science

Evolving Path of Chemistry

3

Significance of Chemistry

Life Research Hope

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

-To quote Linus Pauling, Nobel Laureate in chemistry, from a 1983 UC Berkeley lecture: Chemistry is wonderful! I feel sorry for people who don't know anything about chemistry. They are missing an important source of happiness -- that of satisfying one's intellectual curiosity. The world is wonderful. Chemistry is an important part of it.

4

Green Chemistry

Life Research Hope

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

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

CHALLENGESOPPORTUNITIES

SKILL SETS

ENERGYENVIRONMENT

EDU

CA

TIO

N

GREENCHEMISTRY ???

5

Industry Sectors

Life Research Hope

Energy alternatives

Textile, printing, agro and construction

Electronics and semiconductors

Pharmaceutical, medical and biotech

Cosmetics

Retail and everyday commodity

6

Complexity

Life Research Hope

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, Fluticasone propionate, Fluvastatin sodium, Fondaparinux sodium, Formocortal, Fosamprenavir, Fosfluconazole, Fosinopril, Fosphenytoin sodium, Galantamine, Gatifloxacin, Gemcitabine, Glimepiride, Granisetron, Hexestrol, Histrelin, Hydrochlorothiazide, Ibandronate sodium 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, Milnacipran hydrochloride, 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, Parecoxib sodium, Paroxetine, Perindopril, Phenytoin, Pimefylline, Pimeprofen, Pioglitazone, Piproxen, Pitavastatin, Prednival acetate, Pregabalin, Primidone, Proxyphylline, Pyridofylline, Quetiapine fumarate, Quinapril hydrochloride, Rabeprazole sodium, Raloxifene hydrochloride, 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

O

Me

O

OO

O

OO

H

H

O

HO

OMe

H2N

OH

Eribulin19 stereocenters

O

H

H

O

O

H

H

O

O

H

HMe

O

O

MeH

H

O

O

Me

O

OO

O

OO

H

H

O

Me

HO

HHO

HOH

Halichondrin B

7

Higher E Factor α Degree of Complexity ?

Life Research Hope

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

5 0.1

0

20

40

60

80

100

120

1 2 3 4

E-Factor in Kg

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

8

Net E-Factor

Life Research Hope

100000 500000

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

9

Approaches

Life Research Hope

Eco-friendly

IPChallenges

(IP-free)

ConsistentQuality

Low Cost

Application of recent

trends i.e.OC, OM, BC

etcScalable

Solvents & Reagents

Control of Impurites

Consistent in Polymorphic

forms

Scalable Synthesis ofGenric API

Engineering Challengs

Safe

Process

Speed of Development

Organic Chemistry

Understanding the Pivotal Role of Organic Chemistry in Addressing the Challenges

10

Approaches

Life Research Hope

1. Consideration of GC (TP and GM) in design phase 2. Minimize the number of steps while maintaining the desired cost

component intact 3. Minimize or replace (Switch) non-green solvents 4. Work through multi-disciplinary scientific interface (Collaboration) 5. Renewable material based synthesis 6. Net output based energy efficient waste (unavoidable) management 7. Non-toxic and hazard free practices 8. Continuous mode of Chemistry/Engineering (flow technology) 9. In-expensive catalyst based transformations 10. Opt for asymmetric transformations 11. Use of immobilized recombinant enzymes for transformations with

very low dilutions 12. Educate and prepare young generation considering intuitive

knowledge potential to take a lead in this field

11

Approaches: Flow Technology

Life Research Hope

• 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)

12

Approaches: Biocatalysis

Life Research Hope

Microbe, enzyme collection Seed Fermenter

Production Fermenter Shake Flask Lab Fermenter

Screening Optimization CPP Production

13

Innovative Research Since 2007

Life Research Hope

N

AcO

O NH2

Esclicarzepine

Catal. Sci. Technol., 2012, 2, 1602-1605

HN

OH HN O

HN

O

O

NS

N

O

HN

OH HN O

N

O

O

HN

O

S

N

Ritonavir Lopinavir

Tetrahedron Lett. 2011, 52, 6968-6970

N

OCH2CF3

NH

NS

O

DexlansoprazoleTetrahedron Lett., 2011, 52, 5464-5468

N O

NH2

O

Levetiracetam

Green Chem. Lett. Rev. 2010, 3, 225-230

O

N

HN

OO

Amtolmetin

O

O

Org.Proc.Res.&Dev., 2010, 40, 362-368

Pioglitazone

O

SNH

O

O

N

Et

Org.Proc.Res.&Dev., 2009, 13, 1190-1194

NN

Cl

ClCl

O HN

N

Rimonabant

Monatsh. Chem., 2008, 139, 1091-1094

N

O

OCF3

CF3

NHN

NH

F

O

Aprepitant

Tetrahedron Lett., 2007, 48, 8001-8004

O

NC

F

N

HBr

Citalopram

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

BnNH

EtO2C

O

N

CO2H

HH

Ramipril

Synthetic Commun. 2011, 41, 1186-1191

NN

N

NH

N

Rizatriptan

Org.Proc.Res.&Dev. 2009, 13, 683-689

14

Innovation

Life Research Hope

1. Incremental 2. Medium Size 3. Process 4. Technology based a. Biocatalysis b. Continuous 5. Major

Types of Innovation

BIGIMPACT

15

Incremental: Reductive Amination

Life Research Hope

OH

R

catalyst

reagentNHR1

R

catalystNR1

H

R

reagent

Direct

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

16


Life Research Hope

R H

O

Fe(OTf)3 R H

OLA

NH2R1

R H

OLA

NH

R1

H

R H

OLA

NH

R1

H

R1N

HR

H2O

(TfO)3Fe OH

H

NaBH4

R1NH

R

Mechanistic Considerations

Class 1 (toxic) Class 2 (less toxic) Class 3 (non-toxic)Pt, Pd, Ir , Rh, Ru, Os

Mo, Ni, Cr , V Cu, Mn, T i, Sc Zn, Fe

17


Life Research Hope

H2NR11 mol% Fe(OTf)3

1 eq. NaBH4

O

R

NR1

R

R, R1 = alkyl,aryl or heterocyclic

NH

Ph NH

3a 90% 3b 90%

NH

Ph3c 92%

NH

Ph

3d 90%

NHPh

Cl

3e 80%

NHPh

CF3

NHPh

F

3f 88%

NHPh

O

3g 90% 3h 90%

NHPh

EtO

3i 82%

OCH3

H3CO

NHPh

3j 87%

NH

C2H5O3k 88%

NH

Ph

C2H5O

3l 89%

NH

Ph

NO2

3m 92%

NH

Ph

O2N

3o 90%

NH Ph

3n 89%

NH

Ph

OCH3

H3CO

3p 90%

NH

Ph

OH

O2N

3q 90%

NH

Ph

CF3

3r 89%

HN

CF3

3s Cinacalcet 80%

O

O

OO

O

HN

Ph3t Aliskiren intermediate 88%

1 2 3 (a-t)

Cl

Generality of the Method

Supe

rfast

Acyl

ation

Less than a minute

18

Incremental: Acylation

Life Research Hope

Kumar, U. Tetrahedron Lett. 2013, in print

Pyridine

Catalytical

Conventional

Zn(OTf)2, 25 °C

Ac2O, DMAP

Ac2O

0-5 °C

ROH ROAcAcetylation

OR

O CH3

O

H3C

OLA

H

Zn(OTf)2

Less Toxic

low cost, stable

Rapid recation time

High yield

19


Life Research Hope

Ac2O0.1 mol% Zn(OTf)2

Neat or CH2Cl2, 25 0C

R = alkyl, benzyl, phenyl; X=O, S

1 2 3 (a-i)

R XH R XAc

OAc

3a 98%

OAc

3b 95%

OAc

3c 98%

OAc OAc

O2N Br

OAc

OCF3

F3COAc

3d 93% 3e 94%

3f 97% 3g 98%

SAc

OAc

3h 95% 3i 98%

O

AcO

3j 92%

OAc

F

O

N O

O

3k 98%

N

AcO

H2N O

3l 90%

OAc

3m 85%


20


Life Research Hope

Substrate Reagent/catalyst Conditions Time Yield (%)

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

21

Incremental: Amide Reduction

Life Research Hope

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

Dashboard)

N

O

R3R2

R1

TMSClLAH

N R3R2

R1

HH

DCM0-10 oC, 30 min

22


Life Research Hope

N

O

R3R2

R1

TMSCl (LA)N

OTMS

R3R2

R1ClLAH

N

OTMS

R3R2

R1

AlH3

TMSOAlH3

N R3R2

R1

H LAHN R3R2

R1

HH

Mechanistic Considerations

23


Life Research Hope


O

N

Cl N

O

N

N N

Cl

Cl

O

N NO

O

F3C

CF3

O

NH

Cl

O

HN

NH

O

OCF3

CF3

O

N

1b, 85% 2b, 78% 3b, 79% 4b, 77% 5b, 81%

6b, 75% 7b, 77% 8b, 81% 9b, 74%

10b, 84% 11b, 79%

24


Life Research Hope

Generality of the Method O

Cl

N

HH

1b', 85%, 99% de

O

Cl

N

HH

1b'', 79%, 99% de

N

SNH2

HN

12b, 77%, 98.5% ee

N

SNH2

HN

13b, 72%, 98.5% ee

O

NH

Cl

14b, 81%, 99% ee

O

NH

Cl

15b, 79%, 99% ee

O

Cl

NH

16b, 82%, 98.5% ee

O

Cl

NH

17b, 79%, 98.5% ee

25


Life Research Hope

26

Medium Size: Enantioselective Grignard addition to Nitroolefin

Life Research Hope

R1 NO2 NO2

R26 mol% L3

1.2 eq of R2MgXMTBE, 3 h

R1

5 mol% Cu(I)

upto 97% ee

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

27

Medium Size: Enantioselective Grignard Addition to Nitroolefin

Life Research Hope

O

CHO

O

NO2Nitromethane

O

NO2

97%

80%

NH4OAc, AcOH

MeMgCl Toluene

NH4Cl H2O

Naproxen

O

Br

MgTHFNO2

5 °C,1h

Potential Application

28


Life Research Hope

R1 NO2 NO2

R220 mol% catalyst1.2 eq of R2MgX THF, 8 h

R1

S.No. Catalyst R1/R2/X °C er (R/S) (HPLC) Yield (%)

1 CuTC/L1 6Mn/Me/Br -60 49.5/50.5 75 2 CuTC/L1 6Mn/Me/Br -20 49/51 75 3 CuI/L1 6Mn/Me/Br -60 45/55 70 4 CuI/L1 6Mn/Me/Br -20 48.6/51.4 70 5 Zn(OTf)2/L1 6Mn/Me/Br -60 49.5/50.5 70 6 Zn(OTf)2/L1 6Mn/Me/Br -20 49.5/50.5 70 7 CuTC/L2 6Mn/Me/Br -60 49/51 75 8 CuTC/L2 6Mn/Me/Br -20 49.5/50.5 75 9 CuI/L2 6Mn/Me/Br -60 49.3/50.7 70

10 CuI/L2 6Mn/Me/Br -20 49.7/50.3 70 11 Zn(OTf)2/L2 6Mn/Me/Br -60 49.2/50.8 70 12 Zn(OTf)2/L2 6Mn/Me/Br -20 49.6/50.4 70 13 CuTC/L1 6Mn/Me/Cl -70 49.2/50.8 70 14 CuTC/L1 6Mn/Me/Cl -20 49.3/50.7 70 15 CuTC/L1 6Mn/Me/Cl -35 48/52 72

N N

OO

PPh2PPh2

FePCy2

Ph2P

L3: [(S)-1-[(Rp)-2-(Dicyclohexyl-phosphino)-ferrocenylethyl]diphenylphosphine]

L1: (SS)-isopropyl bisoxazoline

L2: (R)-BINAP

Screening

29


Life Research Hope

Screening

R1 NO2 NO2

R220 mol% catalyst1.2 eq of R2MgX

MTBE, 8 hR1

N N

OO

PPh2PPh2

FePCy2

Ph2P



L2: (R)-BINAP

S.No. Catalyst R1/R2/X °C er (R/S) (HPLC) Yield %

1 CuTC/L1 6Mn/Me/Cl -40 48.7/51.3 70 2 CuTC/L1 6Mn/Et/Cl -40 49/51 69 3 CuTC/L1 6Mn/iPr/Cl -40 51/49 67 4 CuTC/L1 6Mn/tBu/Cl -40 72/28 68 5 CuTC/L1 6Mn/tBu/Cl -70 77/23 69

30


Life Research Hope

Screening

R1 NO2 NO2

R220 mol% catalyst1.2 eq of R2MgX

MTBE, 8 hR1

N N

OO

PPh2PPh2

FePCy2

Ph2P



L2: (R)-BINAP

S.No. Catalyst R1/R2/X °C er (R/S) (HPLC) Yield % 1 CuI/L3 6Mn/Me/Cl -70 49.2/50.8 68 2 CuI/L3 6Mn/Et/Cl -70 49.5/50.5 64 3 CuI/L3 6Mn/iPr/Cl -70 51.97/48.03 64 4 CuTC/L3 6Mn/tBu/Cl -70 61/39 62 5 CuI/L3 6Mn/tBu/Cl -70 98.5/1.5 62 6 CuI/L3 6Mn/tBu/Cl -70 97.9/2.1 64 7 CuI/L3 6Mn/tBu/Cl -70 97.9/2.1 65 8 CuI/L3 6Mn/tBu/Cl -70 97.8/2.2 63 9 CuI/L3 iBu/6Mn/Br -70 25/75 75

10 CuTC/L3 6Mn/Ph/Cl -70 50.56/49.44 62 11 CuTC/L3 6Mn/Benzyl/Cl -70 49.49/50.51 66 12 CuI/L3 Ph/tBu/Cl -70 39.5/60.5 60 13 CuI/L3 p-EtO-Ph/tBu/Cl -70 23/77 65 14 CuI/L3 p-F-Ph/tBu/Cl -70 4/96 60

31


Life Research Hope

CuI/TC

R2MgX

R1

NCuR2

L

L

O

OMgBr

SCO2

R1

N OO

R1

R2

NO

OMg

Br

H2O

R1

R2

NO2

I /

L

LR2Cu

L

L

Fe

PCy2Ph2P

=

CuPCy2Ph2P

NOMg

Br

H

R2

O

TS,

R1

R (major)

I

(S)(Rp)

Catalytic Cycle and Mechanistic Consideration

32


Life Research Hope

33

Medium Size: Regioselective Methylation

Life Research Hope

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

NH

NN

NR R

R1R1

CF3SO3H

O CCl3

NH

34


Life Research Hope

NH

NN

N

1 2

O2N O2N

N-2 product

NN

O2N

N-1 product3

2H-indazole 1H-indazole

"Mesource" +

Different Methods

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

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

35


Life Research Hope

Generality of the Methods

N

HN

NN

R R

N-2 productR= NO2, CO2Me, Cl, I, H, OMeR1= H,Me

NN

O2N NN

NO2

NN

O2N

NN

O2NN

N

NO2N

NMeO2C

NN

Cl NN

IN

N

NN

MeO

NN

MeO

87% 96% 97%

95% 94% 87%

85% 83% 79%

90% 78%

5a 5b 5c

5d 5e 5f

5g 5h 5i

5j 5k

1.0 eq. CF3SO3H

5 (a-k)

2.5 eq.CCl3CNHOMe

7 (a-k)

R1 R1

NN

O2N

N

N

NH

N NN

SNH2

O OHCl

4 5a

NH

NO2N

6

This reagent is suitable to both EWG and EDG containing substrates

36

Process Innovation: Grignard Reaction

Life Research Hope

ONC

F

N

HBr

1

NC

F

OH

OHN

HBr

2

OBr

O F

MgBrBr

F

OHO

Cl NCH3

CH3

Br

F

OHOH

Br

F

ONC

F

O

LiAlH4 or NaBH4

H3PO4 or TsOH orH2SO4

DMF,140°CNaH, DMSO

+

3 4 5 6

78

9

1

100 °C

10°C to 25°C

Ether, THF

Cu2(CN)2

First reported synthesis of Citalopram 1

37


Life Research Hope

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

38


Life Research Hope

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

NCO

O F

MgBrNC

F

OMgBr

O

F Br

+

ClMg N Cl N. HCl

NC

F

OH

OHN

NC

F

N HBr

Crude Citalopram HBr

HBr

Diol HBr2

10 4

11

12

13 9

Step 1.1

Step 1.2

Step 1.4Step 1.3

Step 2

O

Step 31

39


Life Research Hope

Role of Solvents and Inherent KF

40


Life Research Hope

Temperature Profile

41


Life Research Hope

DoE: Full Factorial

1.Pre DoE experiments 2.Based on domain knowledge, deciding on the

variable and response factors 3.Use of software e.g. Design Expert 4.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

42


Life Research Hope

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

43


Life Research Hope

Design space obtained for BFB and CPA Grignard reactions

44


Life Research Hope

Optimized Conditions

Diol HBr2

Step 1.4

Step 2

Step 3

1

Water, 98% H2SO495 °C, 6h, toluene

10% NaOH, silicagelIPA, 47% aq. HBr

aq. IPA

10 12

13 9

Step 1.2

Step 1.3

1.3 mol Mg0.04 mol iodine THF, 65 °C, 2h

1.0 mol

4, DCM-5 °C, 40 min

2.2 mol

3.0 mol Mg0.06 mol iodinetoluene, THF

90 °C, 3h

13, 0 °C, 1htoluene

CrudeCitalopram HBr

Over all yields

Over all E-factor

44%

53

411

Step 1.11.3 mol

68% (Step 1)

70%

93%

5% NH4Cl47% aq. HBr

45


Life Research Hope

Work up Simplification

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Life Research Hope

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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Life Research Hope

Safety Consideration

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

48


Life Research Hope

Michael E Kopach <[email protected]> 05/10/2013 04:45 AM To "[email protected]" <[email protected]> Cc Subject Citalopram Paper Dear 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

49

Technology Based Innovation: Biocatalysis

Life Research Hope

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

N

O NH2

O

N

HO

O NH2

NADP+NADPH

Glucose Gluconic acid

30oC, 150 rpm

10-oxo-10,11-dihydro-5H-dibenzo[b,f ]azepine-5-carboxamide

(S)-10-hydroxy-10,11-dihydro-5H-dibenzo[b,f ]azepine-5-carboxamide

1 2

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

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Life Research Hope

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

95

96

97

98

99

100

0

20

40

60

80

100

0 12 24 36 48 60

Enan

tiom

eric

exc

ess (

ee%

)

Conv

ersi

on (%

)

Time (h)

Conversion (%) ee (%)

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Life Research Hope

Effect of Substrate Concentration

0

20

40

60

80

100

3 6 12 24

Conv

ersi

on (%

)

Time (h)

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

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Life Research Hope

Effect of Cell Concentration

0102030405060708090

100

50100

150200

250

Conv

ersi

on (%

)

Cell concentration (gL-1)

Conversion (%)

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Life Research Hope

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

54

Technology Based Innovation: Flow Chemistry

Life Research Hope

Application of Flow Technology in the Process Development of Prazoles

55


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Synthesis of Prazoles

56


Life Research Hope

Continuous Flow Micromixing Reactor Set up

57


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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)

60

Major Innovation: Diastereoselective Reduction

Life Research Hope

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

FF

F

NH2

NON

NN

CF3

FF

F

HN

NON

NN

CF3

R

R= H (OR)CONH2Ph

Rh(COD)2OTf (5 mol%)tBu JOSHIPHOS(10 mol%)

H2 (90 psi), MeOH, 50 0C

H2/PtO2

Resolution

FF

F

HN

NON

NN

CF3

R

FF

F

NH2

NON

NN

CF3

racemic

Precedented Approaches

Recently Developed Asymmetric Reduction Involving Biocatalysis is More Prefered

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Life Research Hope

Innovative Approaches

Strategy I Strategy II

FF

F

HN

NON

NN

CF3

NaBH4, MsOHNaBH4, MsOH

FF

F

HN

NON

NN

CF3

Yield ??; dr ??

FF

F

HN

NON

NN

CF3

NN

OOH

10 mol%

HSiCl3

FF

F

HN

NON

NN

CF3

Yield ??; dr ??

F

FF

N N

O

N

NN

CF3

Si

Cl

ClClN N

OHO H

HN

BO OMsMsO

H

OMsNN

NNF3CFF

F

H NBO OMs

MsO

H

OMsNN

NNF3CFF

F

Hor

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Life Research Hope

Evolution of Concept

dr : 83:17 undesired isomer

FF

F

HN

NON

NN

CF3

FF

F

HN

NON

NN

CF3

FF

F

NH2

NON

NN

CF3

NaBH4, MsOHDME:IPA

RT, overnight

Pd(OH)2/CHCO2H, H2O

MeOH, THF (1:1)

FF

F

HN

NON

NN

CF3

NaBH4, MsOHDME:IPA

RT, overnight

FF

F

HN

NON

NN

CF3

FF

F

NH2

NON

NN

CF3

Pd(OH)2/CHCO2H, H2O

MeOH, THF (1:1)

dr: 85:15 desired isomer

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Life Research Hope

FF

F

HN

NON

NN

CF3

NaBH4, MsOH

DME:IPA(20:7)

-40 0C, 12h

FF

F

HN

NON

NN

CF3

yield 85%; dr = 85:15

Required diastereomer crystallized with dr>99%

Pd(OH)2/C/HCO2H, H2O MeOH, THF

or Pd/C/H2

FF

F

NH2

NON

NN

CF3

H3PO4, IPA60-650C

FF

F

NH2

NON

NN

CF3

H3PO4 H2ONBO OMs

MsO

H

OMsNN

NNF3CFF

F

H

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

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

7000 vs 700 USD

64

Major Innovation: Amino Acid

Life Research Hope

H2ON2

NH3

COCH4

H H

O

NH

CO2HCH3CO2H

HCO2H

NH

NH2

O

H2N NH2

O

Aminoacids

CO2 HCO2H Amino acids

HCN Amino acidsNH3

CO2 Amino acids

O

O

HO

Citric and

Glyoxylate cycles

1

starting point

prebiotic high energyinduced

NH3

Miller-Urey

Calvin

Karat

Our work

Different conceived approaches towards the synthesis of amino acids

Discovery of Redox System Enabling C-N-C Bonds Formation: Indicator of Prebiotic Synthesis of Amino Acid

65


Life Research Hope

EtO

ONH2

EtO

OOH

O

reduced

oxidized

HO

O

O

O

OH

OH

O

OH

1

2

3

4

5

6

NH3

Redox chemistry on ethyl glyoxylate and Cannizzaro reaction

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Life Research Hope

EtOHN

OEt

O

O

O

EtO

O

O

NH4OAc

THFEtO

O

NH1 7

9

OHHO

NH2

O

2

EtON

OEt

O

OH

O

8

EtO

O

O

HO

OOH

O3

+

no metal-H2 source [(e.g. Ru or Ir or Pd or Cu or Fe etc.)-H2]

no hydride source

Synthesis of glycine 2

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Life Research Hope

EtON

OEt

O

OH

OH

EtOHN

OEt

O

O

O

7 8H H

H

EtON

OEt

O

O

O

H2

H1

7

H

EtON

OEt

O

O

O

H2H

H1

EtON

OEt

O

O

O

H

H2H1

EtON

OEt

O

O

O

H2

H1

H

EtON

OEt

O

O

O

H2H

EtON

OEt

O

O

O

H

H1H2

8

H1

path a path b

step

1st

ep 2

Two different reaction pathways (a and b)

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Life Research Hope

IS -50

257 267

136

-142

228

FS

0

Ener

gy, k

J/m

ol

Reaction coordinate

TS1 TS2

TS3 InS1

InS2

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Life Research Hope

IS

FS

-39

220

-142

42

Ener

gy, k

J/m

ol

0

Reaction coordinate

InS

TS1

TS2

Bandichhor et al. Chem. Com. 2014 under revision

70

Major Innovation: Synthesis of Eribulin

Life Research Hope

O

Me

O

OO

O

OO

H

H

O

HO

OMe

H2N

OH

Eribulin19 stereocenters

Target 64 to 20 Steps

Late Stage Breast Cancer (Two Chemotherapies and Treated With Anthramycin 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).

71

Major Innovation: Synthesis of Eribulin

Life Research Hope

OO O

O

O

MeOHO

H2N

O

O

H

H

H

OO

BA

C

Sulfone addition

Nozaki-Hiyama-Kishi (NHK) reaction

Ketal formation

NHK reaction /Cross metathesisOlefination

72

Inspiration

Life Research Hope

“A chain is as strong as its weakest link”

Reading Materials: 1. Scalable Green Chemistry: Case Studies from the Pharmaceutical Industry 2. Green Chemistry in the Pharmaceutical Industry Apart from Leading Journals 1. OPRD 2. Journal of Chemical Education

73

Recognition

Life Research Hope

Green Innovation Award-2013 in the Large MNC Category

Life Research Hope

Amit Biswas Vilas Dhahanukar Apurba Bhattacharya Dhileep K. Krishnamurthy P. Pratap Reddy Arnab Amar Namrata Dinesh Gade Srinivas David (Clinton Foundation) Nagaraju Udai Sudhakar Kiran Prasanth Pallavi ERR Gangula Chirotech team Srinivas (DRILS) All 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

IPDOChemistry Engineering

Formulation API R

&D&A

R&D

P ack eg i ngC

oll ab o rati o ns

Inte

llect

ual P

ro per t y

Reg ulatory

Oliver (Regensburg) Marisa (Upenn) Burgess (College Station) Greg Fu (MIT) Mike Kirsche (UT Austin) G. Mehta (DRILS) J. Iqbal (DRILS) V.K.Tandon (LU) Hajela (CDRI) S.N.Rastogi (CDRI)

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

75

Thank You

Life Research Hope

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