Green Chemistry Innovation in the Synthesis of Medicines Rakeshwar Bandichhor Ph.D. Director, API-R&D, Innovation Plaza IPDO, Dr. Reddy’s Laboratories, Hyderabad India 198th OMICS Group Conference International Summit on Past and Present Research Systems of Green Chemistry August 25-27, 2014 Hilton Philadelphia Airport, USA http://www.drreddys.com/products/green-chemistry.html (Green Chemistry Website) Nature Medicine 2013, 19, 1200-1203 (Finding Right Chemistry)
1 Life Research Hope Significance of Chemistry
•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.
Green Tea Coffee Cigarette
>200 >1000 >7000 Chemicals Evolving Path of Chemistry H N H O H H N N N N H N O H N N H N H O H Resource Value O UnderstandingH of life N H H H N added N processes and stressed planet N N H N chemicalO matter at products N H H N from nature molecular level O H N H O H N H H N N H N N H N O H N N N H O H H Utility Science Core and Integrative Science Sustainability Science 2 Life Research Hope Significance of Chemistry
-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.
Chemistry Signifies Love and Hate Relationship -can’t live without it but can’t accept everything that it has
3 Life Research Hope Green Chemistry
•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.
CHALLENGES
OPPORTUNITIES SKILL GREEN CHEMISTRY SETS ???
EDUCATION ENVIRONMENT
ENERGY
4 Life Research Hope Industry Sectors
Energy alternatives
Textile, printing, agro and construction
Electronics and semiconductors
Pharmaceutical, medical and biotech
Cosmetics
Retail and everyday commodity
5 Life Research Hope Complexity
Abacavir, Acefylline, Acrivastine, Alendronate sodium, Alfuzosin, Almotriptan, Altretamine, Alvimopan, Amifostine, Amlodipine, Amprenavir, Anastrozole, Angiotensinamide, AprepitantMe , Arformoterol, AripiprazoleMe , Atorvastatin calcium, Azacitidine, Azelastine, Bamifylline, Benazepril, Betaine hydrate, BicalutamideH , BifonazoleH , BromfenacH sodium, Bupheniode, Buprenorphine, Cafedrine, O O O Calcitonin, Candesartan cilexetil, CapecitabineH , Caroxazone, Carvedilol, Cefpodoxime Proxetil, Celecoxib, Cetalkonium chloride, Cetirizine, Chlorobutanol, Choline salicylateO, Choline theophyllinate, Ciclopirox, Cimetidine, Cinmetacin,H Ciprofloxacin, Citalopram, H Clomifene, Clomipramine, Clopidogrel hydrogensulfate, Danazol, Dantrolene, DapoxetineO , ODarifenacin, Darunavir, Decitabine, HO O O O O Degarelix, Desloratadine, Desvenlafaxine, DexamethasoneH valerateH , HDexrazoxane, DextromethorphanH , Dezocine, Diazepam, O H Diethylstilbestrol, DimestrolHO , Diprophylline, Domperidone, Donepezil hydrochlorideO , Doxazosin, Doxofylline, Doxylamine, H O Dronedarone, Duloxetine oxalate, DutasterideMe , Elcatonin, Enalapril, Enalaprilat, Escitalopram oxalateO , Esomeprazole, Eszopiclone, Ethinamate, Etofylline, HOEtravirine, Everolimus, Exemestane, Exenatide, Ezetimibe, FamotidineMe , FebuprolO , Felodipine, Fenclofenac, Fenetylline, Fexofenadine hydrochloride, FinasterideHalichondrin, Flecainide, Fleroxacin B , FluconazoleO , 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, MontelukastOMe sodium, Moxifloxacin hydrochloride, Naproxen, Naratriptan, Nateglinide, Nebivolol, Nicardipine, Nisoldipine, OHNizatidine, Nomifensine, Olanzapine, Olmesartan medoxomil, Ondansetron, Oxaprozin, Oxcarbazepine, Oxitriptan, Paliperidone, Palonosetron, Pamidronic acid, PantoprazoleH sodium, Parecoxib H2N sodium, Paroxetine, Perindopril, Phenytoin, Pimefylline, Pimeprofen, Pioglitazone, OPiproxenO , Pitavastatin, Prednival acetate, O O Pregabalin, Primidone, Proxyphylline, Pyridofylline, Quetiapine fumarate, Quinapril hydrochlorideH , RabeprazoleH sodium, Raloxifene hydrochloride, Ramipril, Ranitidine, Ranolazine, Rasagiline, Repaglinide, RetapamulinO , Riluzole, Risedronate sodium, Risperidone, O Ritonavir, Rivastigmine, Rizatriptan benzoate, Rocuronium bromide, Ropinirole, Rosiglitazone, RosuvastatinO calcium, Rupatadine, Salmeterol, Saxagliptin, Sertaconazole, Sertraline, SildenafilEribulin, Simvastatin, Sitagliptin phosphateMe , SolifenacinO , Sulindac, Sulpiride, Sumatriptan, Tacrolimus, Tadalafil, Talaporfin, Tamsulosin hydrochloride, Tapentadol, Telcagepant, Telmisartan, Tenoxicam, O Terbinafine, Teriparatide, Thalidomide, Tipranavir19 stereocenters, 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 6 Life Research Hope Higher E Factor α Degree of Complexity ?
Material Demand in Tonnage E-Factor in Kg 12,00,00,000 120
100000000 100 10,00,00,000 100
8,00,00,000 80
60 6,00,00,000 50
40 4,00,00,000
20 2,00,00,000 5 0.1 1000 10000 1000000 0 0 1 2 3 4 1 2 3 4
1. Pharma; 2. Fine; 3. Bulk; 4. Oil
7 Life Research Hope Net E-Factor
Net E-Factor in Kg 12000000
10000000 10000000
8000000
6000000 5000000
4000000
2000000
500000 100000 0 1 2 3 4 1. Pharma; 2. Fine; 3. Bulk; 4. Oil 8 Life Research Hope Approaches
Understanding the Pivotal Role of Organic Chemistry in Addressing the Challenges
Consistent Eco-friendly Quality
IP Speed of Challenges Development (IP-free) Low Cost
of Application Scalable recent Organic of trends i.e. Synthesis Chemistry Genric API OC, OM, BC etc Safe Scalable Process Solvents & Engineering Reagents Challengs
Consistent in Control of Polymorphic Impurites forms
9 Life Research Hope Approaches
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
1 Life Research Hope 0
Approaches: Flow Technology
BATCH FLOW MICROREACTION TECHNOLOGY (space-resolved process) (time-resolved process)
• Conventional method • Emerging Technology • Several Disadvantages • Advantages over batch process - Time and labor intensive - High surface area, precisely - A number of unit processes controlled conditions - Needs extensive optimization - Rapid screening of reaction conditions - “Scale-out” instead of “Scale-up” - Safety 1 Life Research Hope 1
Approaches: Biocatalysis
Screening Optimization CPP Production
Microbe, enzyme Production Shake Flask Lab Fermenter Seed Fermenter collection Fermenter
Life Research Hope 12 Innovative Research Since 2007
S H HN N AcO N N NC N O O O OH HN O OH HN O
N N HN HN O O O NH2 S HBr N F O O Citalopram Esclicarzepine Ritonavir Lopinavir
Org.Proc.Res.&Dev. 2013, 17, 798-805 Catal. Sci. Technol., 2012, 2, 1602-1605 Tetrahedron Lett. 2011, 52, 6968-6970 O
O OCH2CF3 O N O HN H O N O EtO C 2 H S NH2 Bn N N N N N H H O O CO2H O Ramipril Dexlansoprazole Levetiracetam Amtolmetin
Synthetic Commun. 2011, 41, 1186-1191 Tetrahedron Lett., 2011, 52, 5464-5468 Green Chem. Lett. Rev. 2010, 3, 225-230 Org.Proc.Res.&Dev., 2010, 40, 362-368 H O N HN O N N O N O N CF3 N N O N H N Cl N O N Et S N CF3 N NH H O Cl F Cl
Rizatriptan Pioglitazone Rimonabant Aprepitant
Org.Proc.Res.&Dev. 2009, 13, 683-689 Org.Proc.Res.&Dev., 2009, 13, 1190-1194 Monatsh. Chem., 2008, 139, 1091-1094 Tetrahedron Lett., 2007, 48, 8001-8004 Life Research Hope 13 Innovation Types of Innovation 1. Incremental 2. Medium Size 3. Process BIG 4. Technology based IMPACT a. Biocatalysis b. Continuous 5. Major
14 Life Research Hope Incremental: Reductive Amination
Direct H catalyst O NHR1 R reagent R
catalyst H reagent NR1 R Indirect Kumar, U. Tetrahedron Lett. 2012, 53, 4354-4356
15 Life Research Hope Incremental: Reductive Amination Mechanistic Considerations LA OLA O O R H H R H 1 R Fe(OTf)3 R N H H NH2 R1 H H (TfO)3Fe O OLA R H R H NaBH4 R H N 1 NH R1 N R1 R H H2O Class 1 (toxic) Class 2 (less toxic) Class 3 (non-toxic) Pt, Pd, Ir, Rh, Ru, Os Cu, Mn, Ti, Sc Zn, Fe Mo, Ni, Cr, V 16 Life Research Hope Incremental: Reductive Amination
Generality of the Method 1 O 1 mol% Fe(OTf)3 NR 1 H2NR R 1 eq. NaBH4 R 1 2 3 1 (a-t) R, R = alkyl,aryl or heterocyclic
Ph NHPh NHPh N N H N Ph H H Ph N Cl CF3 H 3a 90% 3b 90% 3c 92% 3d 90% 3e 80% 3f 88%
NHPh NHPh NHPh NHPh H3CO O EtO N F OCH3 H C2H5O 3g 90% 3h 90% 3i 82% 3j 87% 3k 88%
N Ph N Ph N H N Ph Ph N Ph H H H H H3CO C H O NO2 Cl O N 2 5 2 OCH3 3l 89% 3m 92% 3n 89% 3o 90% 3p 90% O H O N O N N Ph CF 2 N Ph H 3 O O H HN OH O CF3 Ph 3q 90% 3r 89% 3s Cinacalcet 80% 3t Aliskiren intermediate 88%
17 Life Research Hope Incremental: Acylation
Conventional Ac2O, DMAP Less Toxic Pyridine 0-5 °C LA O O low cost, Acetylation H3C O CH3 Acylation ROH LessROAc High yield Zn(OTf)2 stable H O R Ac2O than Zn(OTf)2, 25 °C aRapid recation time Catalytical minute Superfast
Kumar, U. Tetrahedron Lett. 2013, in print
18 Life Research Hope Incremental: Acylation
Generality of the Method 0.1 mol% Zn(OTf)2 R XH Ac2O R XAc 0 Neat or CH2Cl2, 25 C 1 2 3 (a-i)
R = alkyl, benzyl, phenyl; X=O, S OAc OAc OAc OAc OAc O2N Br 3a 98% 3b 95% 3c 98% 3d 93% 3e 94%
O OAc F C OAc 3 SAc OAc O AcO CF3 3f 97% 3g 98% 3h 95% 3i 98% 3j 92%
OAc O AcO O OAc N O F N
H2N O 3k 98% 3l 90% 3m 85%
19 Life Research Hope Incremental: Acylation
Pyridine (Py)/AC2O Mediated vs Zn(OTf)2 Catalyzed Acylation
Yield Substrate Reagent/catalyst Conditions Time (%)
cat. DMAP, Py/Ac2O CH2Cl2, Reflux 2 h 90 2l Zn(OTf) (0.1 mol%) 2 25-25 °C 60s 90 /Ac2O
Py/Ac2O 25-25 °C 3 h 87 2j Zn(OTf) (0.1 mol%) 2 25-25 °C 30s 92 /Ac2O
20 Life Research Hope Incremental: Amide Reduction
O H TMSCl H R2 LAH R2 N R3 N R3 R1 DCM R1 0-10 oC, 30 min
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) 21 Life Research Hope Incremental: Amide Reduction Mechanistic Considerations
O OTMS AlH TMSCl LA 3 R2 ( ) R2 LAH OTMS N R3 N R3 Cl R2 R1 R1 N R3 R1 H H H LAH R2 R2 N R3 N R3 1 1 R TMSOAlH3 R
22 Life Research Hope Incremental: Amide Reduction
Generality of the Method
O N N Cl N N
O N Cl
1b, 85% 2b, 78% 3b, 79% 4b, 77% 5b, 81% Cl
O CF3 O HN O N F C O N H N 3 O
Cl
6 75% 7b, 77% 8b, 81% b, 9b, 74% O O CF3 CF 3 O
N H N
10b, 84% 11b, 79% 23 Life Research Hope Incremental: Amide Reduction
Generality of the Method O O H H N S N S Cl NH H Cl H 2 NH2 H H N N N N
1b', 85%, 99% de 1b'', 79%, 99% de 12b, 77%, 98.5% ee 13b, 72%, 98.5% ee Cl Cl
O O NH NH O O NH NH
Cl Cl
14b, 81%, 99% ee 15b, 79%, 99% ee 16b, 82%, 98.5% ee 17b, 79%, 98.5% ee
24 Life Research Hope Incremental: Amide Reduction
25 Life Research Hope Medium Size: Enantioselective Grignard addition to Nitroolefin
6 mol% L3 R2 5 mol% Cu(I) 1 NO2 R 2 NO 1.2 eq of R MgX R1 2
MTBE, 3 h upto 97% ee
Prashanth Reddy, G. Tetrahedron Lett., 2013, 54, 3911-3915
26 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
Potential Application CHO NO Nitromethane 2
O NH4OAc, AcOH O 97%
MeMgCl Toluene NO2 Naproxen NH Cl 4 O H2O 80%
Mg NO2 THF 5 °C,1h
Br
O
27 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
Screening R2 NO 20 mol% catalyst R1 2 NO 1.2 of R2 1 2 eq MgX R O O THF, 8 h N N er (R/S) S.No. Catalyst R1/R2/X °C Yield (%) (HPLC) : 1 CuTC/L 6Mn/Me/Br -60 49.5/50.5 75 L1 (SS)-isopropyl 1 bisoxazoline 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 PPh2 PPh 5 Zn(OTf)2/L1 6Mn/Me/Br -60 49.5/50.5 70 2 6 Zn(OTf)2/L1 6Mn/Me/Br -20 49.5/50.5 70 7 CuTC/L2 6Mn/Me/Br -60 49/51 75 L2: (R)-BINAP 8 CuTC/L2 6Mn/Me/Br -20 49.5/50.5 75 9 CuI/L 6Mn/Me/Br -60 49.3/50.7 70 Ph2P 2 PCy2 Fe 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 L3: [(S)-1-[(Rp)- 13 CuTC/L1 6Mn/Me/Cl -70 49.2/50.8 70 2-(Dicyclohexyl- phosphino)- 14 CuTC/L1 6Mn/Me/Cl -20 49.3/50.7 70 15 CuTC/L 6Mn/Me/Cl -35 48/52 72 ferrocenylethyl]di 1 phenylphosphine] 28 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
Screening
O O R2 20 mol% catalyst 1 NO2 N N R 2 NO 1.2 eq of R MgX R1 2 MTBE, 8 h L1: (SS)-isopropyl bisoxazoline
er (R/S) PPh2 S.No. Catalyst R1/R2/X °C Yield % PPh (HPLC) 2
1 CuTC/L1 6Mn/Me/Cl -40 48.7/51.3 70 2 CuTC/L1 6Mn/Et/Cl -40 49/51 69 L2: (R)-BINAP i 3 CuTC/L1 6Mn/ Pr/Cl -40 51/49 67 t Ph2P 4 CuTC/L1 6Mn/ Bu/Cl -40 72/28 68 PCy2 t Fe 5 CuTC/L1 6Mn/ Bu/Cl -70 77/23 69
L3: [(S)-1-[(Rp)- 2-(Dicyclohexyl- phosphino)- ferrocenylethyl]di phenylphosphine] 29 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
Screening R2 20 mol% catalyst 1 NO2 R 2 NO O O 1.2 eq of R MgX R1 2 MTBE, 8 h N N
S.No. Catalyst R1/R2/X °C er (R/S) (HPLC) Yield % L1: (SS)-isopropyl 1 CuI/L3 6Mn/Me/Cl -70 49.2/50.8 68 bisoxazoline 2 CuI/L3 6Mn/Et/Cl -70 49.5/50.5 64 i 3 CuI/L3 6Mn/ Pr/Cl -70 51.97/48.03 64 t PPh2 4 CuTC/L3 6Mn/ Bu/Cl -70 61/39 62 t PPh2 5 CuI/L3 6Mn/ Bu/Cl -70 98.5/1.5 62 t 6 CuI/L3 6Mn/ Bu/Cl -70 97.9/2.1 64 t 7 CuI/L3 6Mn/ Bu/Cl -70 97.9/2.1 65 L2: (R)-BINAP t 8 CuI/L3 6Mn/ Bu/Cl -70 97.8/2.2 63 i Ph2P 9 CuI/L Bu/6Mn/Br -70 25/75 75 PCy2 3 Fe 10 CuTC/L3 6Mn/Ph/Cl -70 50.56/49.44 62 11 CuTC/L3 6Mn/Benzyl/Cl -70 49.49/50.51 66 t L : S 12 CuI/L3 Ph/ Bu/Cl -70 39.5/60.5 60 3 [( )-1-[(Rp)- t 2-(Dicyclohexyl- 13 CuI/L3 p-EtO-Ph/ Bu/Cl -70 23/77 65 t phosphino)- 14 CuI/L3 p-F-Ph/ Bu/Cl -70 4/96 60 ferrocenylethyl]di phenylphosphine] 30 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
2 R MgX Catalytic Cycle and Mechanistic Consideration
L L 2 CuI/TC R Cu L L
O N O R2 NO R1 2 R1
PCy Ph2P 2 H Cu 2O 2 OMgBr R r 1 B 2 R Mg S R O L N N Ph2P ( ) Mg Rp PCy2 2 O H O O ( ) N R Cu = Fe R1 O I , L R1 TS I / CO2 Br S R (major)
31 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin
32 Life Research Hope Medium Size: Regioselective Methylation
1 NH R R1
O CCl3 R N R N N H CF3SO3H N
Sudhakar, Tetrahedron Lett., 2013, 54, 1661-1663
33 Life Research Hope Medium Size: Regioselective Methylation
Different Methods "Me N N source" N + N O N N N O2N 2 H O2N 1 2 3 N-2 product N-1 product 2H-indazole 1H-indazole
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
34 Life Research Hope Medium Size: Regioselective Methylation
Generality of the Methods H N N 2.5 eq.CCl3CNHOMe R N R N N 1.0 eq. CF3SO3H 1 R1 R N N N-2 product N R= NO2, CO2Me, Cl, I, H, OMe 1 5 a-k 7 (a-k) R = H,Me ( ) N N O2N
N O2N N NH2 N N N N S N N H O2N O O NO2 87% 96% 97% HCl 5a 5b 5c 4 5a NO2 O2N N MeO2C N N N N N N 95% 94% 87% 5d 5e 5f O N N 2 H Cl I N N N N N N 6
85% 83% 79% 5g 5h 5i N MeO N This reagent is suitable to both EWG and N N MeO EDG containing substrates 90% 78% 5j 5k 35 Life Research Hope Process Innovation: Grignard Reaction
First reported synthesis of Citalopram 1
MgBr Br Br LiAlH4 Br Ether, THF OH or NaBH OH O + 4 10°C to 25°C O OH O F
OH NC NC F F O OH N 3 4 5 6 N
r r H3PO4 or HB HB TsOH or 100 °C F F 1 2 H2SO4 NC Br 9 CH3 Cl N O O CH 3 Cu2(CN)2 1 NaH, DMSO DMF,140°C
F F 8 7
36 Life Research Hope Process Innovation: Grignard Reaction
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
37 Life Research Hope Process Innovation: Grignard Reaction
Outline Towards Realizing the Strategies : One Pot Synthesis of Diol HBr
OM Br MgBr g NC NC O + O Step 1.2 O F 10 4
12 F Step 1.1
Step 1.3 . F Br HCl Step 1.4 Cl N ClMg N 11 13 9
OH NC NC O HBr OH HBr N N 1 Step 2 Step 3
F F Diol HBr Crude Citalopram HBr 2
38 Life Research Hope Process Innovation: Grignard Reaction
Role of Solvents and Inherent KF
39 Life Research Hope Process Innovation: Grignard Reaction
Temperature Profile
40 Life Research Hope Process Innovation: Grignard Reaction
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
41 Life Research Hope Process Innovation: Grignard Reaction
Operable ranges for DoE based on pre-DoE experiments
process variables low high process variables low high BFB CPA 1.2 1.5 1.8 3.0 (mol equiv.) (mol equiv.) Mg Mg 1.2 1.5 2.0 4.0 (mol equiv.) (mol equiv.) Iodine Iodine 1 10 1 10 (% w/w) (% w/w)
Response Factors >75% yield and >98% purity
42 Life Research Hope Process Innovation: Grignard Reaction
Design space obtained for BFB and CPA Grignard reactions
43 Life Research Hope Process Innovation: Grignard Reaction
Optimized Conditions
1.3 mol Mg 3.0 mol Mg 0.04 mol iodine 0.06 mol iodine THF, 65 °C, 2h toluene, THF 11 4 90 °C, 3h 13 9 1.3 mol . mo Step 1.1 Step 1.3 2 2 l
4, DCM 13, 0 °C, 1h -5 °C, 40 min toluene 10 12 Diol HBr 5% NH Cl 2 1.0 mol 4 47% aq. HBr 68% (Step 1) Step 1.2 Step 1.4
Water, 98% H2SO4 70% 95 °C, 6h, toluene a s ca e Step 2 10% N OH, ili g l IPA, 47% aq. HBr
aq. IPA 1 Crude 93% Citalopram HBr Step 3
Over all yields 44%
Over all E-factor 53
44 Life Research Hope Process Innovation: Grignard Reaction
Work up Simplification
45 Life Research Hope Process Innovation: Grignard Reaction
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
46 Life Research Hope Process Innovation: Grignard Reaction
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 47 Life Research Hope Process Innovation: Grignard Reaction
Appreciation
Michael E Kopach
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
Org.Proc.Res.&Dev. 2013, 17, 798-805.
48 Life Research Hope Technology Based Innovation: Biocatalysis
Asymmetric Reduction of a Key Intermediate of Esclicarbazepine Acetate Using Whole Cell
Glucose Gluconic acid
O HO NADPH NADP+
N N 30oC, 150 rpm O NH2 O NH2 1 2
10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5- (S)-10-hydroxy-10,11-dihydro-5H- carboxamide dibenzo[b,f]azepine-5-carboxamide
Catalysis Science & Technology 2012, 2, 1602-1605. (One of the Hot Articles).
49 Life Research Hope Technology Based Innovation: Biocatalysis
Bioreduction of Ketone 1 by P. methanolica whole-cells in biphasic system at 30°C
Conversion (%) ee (%)
100 100
80 99
60 98
40 97 Conversion (%) Conversion 20 96 Enantiomeric excess (ee%) excess Enantiomeric 0 95 0 12 24 36 48 60
Time (h)
50 Life Research Hope Technology Based Innovation: Biocatalysis
Effect of Substrate Concentration
0.5g/l 1.0g/l 1.5g/l 2.0g/l 2.5g/l 3.0g/l
100
(%)
80
60
Conversion 40
20
0 3 6 12 24
Time (h)
51 Life Research Hope Technology Based Innovation: Biocatalysis
Effect of Cell Concentration
Conversion (%)
100 90 80 70 60 50 40 30 20
Conversion (%) Conversion 10 0 50 100 150 200 250 Cell concentration (gL-1)
52 Life Research Hope Technology Based Innovation: Biocatalysis
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
53 Life Research Hope Technology Based Innovation: Flow Chemistry
Application of Flow Technology in the Process Development of Prazoles
54 Life Research Hope Technology Based Innovation: Flow Chemistry
Synthesis of Prazoles
55 Life Research Hope Technology Based Innovation: Flow Chemistry
Continuous Flow Micromixing Reactor Set up
56 Life Research Hope Technology Based Innovation: Flow Chemistry
Effect of Flow Rate on Conversion
57 Life Research Hope Technology Based Innovation: Flow Chemistry
Batch vs Flow
58 Life Research Hope Technology Based Innovation: Flow Chemistry
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)
59 Life Research Hope Major Innovation: Diastereoselective Reduction
Precedented Approaches F F R HN
H /PtO F 2 2 O N N N N
CF3 F F F R F HN 0 NH2 H2 (90 psi), MeOH, 50 C
F N Rh(COD)2OTf (5 mol%) F O N O N N R= H (OR) N tBu JOSHIPHOS(10 mol%) N N N Ph CONH2 CF3 CF3
F F Resolution NH2
F O N N N racemic N
CF3 Recently Developed Asymmetric Reduction Involving Biocatalysis is More Prefered 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 60 Life Research Hope Major Innovation: Diastereoselective Reduction
Innovative Approaches
Strategy I Strategy II
F F F N HN F N F F O NaBH4, MsOH F F HN HN OH HN
F 10 mol% O N N F N F N F N O N N N O N O N N N N N HSiCl N N CF3 3 CF3 CF3 CF 3 Yield ??; dr ?? Yield ??; dr ??
N N N F N F F C N F F C N F 3 F 3 F Cl CF N N H N N 3 N MsO OMs N MsO OMs H O N O B OMs O B OMs H O Si Cl H H H H FN N or N N Cl O F F
61 Life Research Hope Major Innovation: Diastereoselective Reduction
Evolution of Concept
F F F F F F HN NH2 HN Pd(OH)2/C NaBH4, MsOH HCO2H, H2O F DME:IPA THF F O N N F N MeOH, O N N RT, overnight O N N N (1:1) N N N N
CF3 CF3 CF3 dr : 83:17
undesired isomer
F F F F F F NH2 HN HN Pd(OH)2/C NaBH4, MsOH HCO2H, H2O DME:IPA F N THF O N F N RT, overnight F N MeOH, O N O N N N N (1:1) N N N CF3 CF3 CF3 dr: 85:15 desired isomer
62 Life Research Hope Major Innovation: Diastereoselective Reduction
F F F F F F HN NH2 HN Pd(OH)2/C/ HCO2H, H2O MeOH, THF NaBH4, MsOH F N F N F N O N O N O N DME:IPA N or N N N N N (20:7) Pd/C/H2 0 -40 C, 12h CF3 CF CF 3 3 yield 85%; dr = 85:15 Required diastereomer crystallized with
dr>99% H3PO4, IPA 60-650C
N F F C N F 3 N F F N MsO OMs F O B OMs NH2 H N H H3PO4 H2O F O N N N -90 0C: dr=93:07, Yield= >90% N CF3 7000 vs 700 USD Bandichhor, R.; et al. WO 2011025932 A2 20110303
63 Life Research Hope Major Innovation: Amino Acid
Discovery of Redox System Enabling C-N-C Bonds Formation: Indicator of Prebiotic Synthesis of Amino Acid
Miller-Urey CO2H H H2O CH3CO2 HCO H N O 2 2 O NH Amino 3 H H acids CO N NH2 H N H O CH4
H2N NH2 Calvin Our work CO HCO H 2 2 Amino acids prebiotic high energy induced Karat NH3 HCN Amino acids Citric and O NH Glyoxylate cycles HO 3 CO2 Amino acids O 1 Different conceived approaches towards the synthesis of amino acids starting point 64 Life Research Hope Major Innovation: Amino Acid
OH O
NH2 EtO O O reduced NH3 2 OH 5 HO O O O OH OH EtO 4 O 1 oxidized 6 3
Redox chemistry on ethyl glyoxylate and Cannizzaro reaction
65 Life Research Hope Major Innovation: Amino Acid
O O O EtO EtO NH4OAc EtO O O THF NH 1 7 no metal-H2 source [(e.g. Ru or Ir or Pd or Cu or Fe etc.)-H2]
O O O O H N N EtO OEt EtO OEt OH O 8 9 no hydride source O O OH NH + OH HO 2 HO O 2 3 Synthesis of glycine 2
66 Life Research Hope Major Innovation: Amino Acid
O O O O H H H N N EtO OEt EtO OEt H OH H O 7 7 8 O O O O H1 H N N 1 EtO OEt EtO OEt H O H O H2 H 1 2 O O O H O H1 1 step N N EtO OEt EtO OEt H O H H O 2 H2 O H2 O 2 H O H1 O 1 N H2 EtO OEt N
step EtO OEt H O H O 8 path a path b
Two different reaction pathways (a and b)
67 Life Research Hope Major Innovation: Amino Acid
267 257
TS2 TS1
228 136 TS3
Energy, kJ/mol Energy, InS1 IS 0 Reaction coordinate -50 InS2 -142 FS
68 Life Research Hope Major Innovation: Amino Acid
220 TS1
42 TS2 Energy, kJ/mol Energy, IS 0 -39 InS
Reaction coordinate -142 FS
Bandichhor et al. Chem. Com. 2014 under revision
69 Life Research Hope Major Innovation: Synthesis of Eribulin
Target 64 to 20 Steps
OMe HALAVEN is a clear, OH colorless, sterile H solution for intravenous H2N O O administration. Each O O vial contains 1 mg of H H O eribulin mesylate as a O 0.5 mg/mL solution in O ethanol: water (5:95). Eribulin Me O 19 stereocenters O
Late Stage Breast Cancer (Two Chemotherapies and Treated With Anthramycin and Taxane Class of Medicine) 70 Life Research Hope Major Innovation: Synthesis of Eribulin
Sulfone addition B MeO A HO H O O H2N O O H Nozaki-Hiyama- O O O Kishi (NHK) reaction O H O NHK reaction / Olefination Cross metathesis Ketal formation C
71 Life Research Hope Inspiration
“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
72 Life Research Hope Recognition
Green Innovation Award-2013 in the Large MNC Category
73 Life Research Hope Acknowledgement
Amit Biswas Oliver (Regensburg) Vilas Dhahanukar Marisa (Upenn) Apurba Bhattacharya Burgess (College Station)
C
o Dhileep K. Krishnamurthy
l
l
a Greg Fu (MIT) b P. Pratap Reddy
o D
r & Mike Kirsche (UT Austin) F a o R t A Arnab r i m o &
u n D G. Mehta (DRILS)
la s & Amar t R io n PI Namrata J. Iqbal (DRILS) A Dinesh V.K.Tandon (LU) Gade Srinivas Chemistry IPDO Engineering Hajela (CDRI) David (Clinton Foundation) S.N.Rastogi (CDRI) R t y e Nagaraju r g e P u p a la Udai o c r to P k r l e y
a g Sudhakar
u i
t n c e g Kiran ll e t In Prasanth Pallavi ERR Department of Science and Technology 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 Life Research Hope Thank You
75 Life Research Hope