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Scalable Green Chemistry Practices Scalable Green Chemistry Practices Rakeshwar Bandichhor Ph.D. Director, API-R&D, Innovation Plaza IPDO, Dr. Reddy’s Laboratories, Hyderabad India ICGW-2013 6-8 December, 2013 Renaissance Hotel Mumbai, India 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 2 Life Research Hope Significance of Chemistry 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 prevention of waste in any activity around us by design. 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, 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 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 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 Life Research Hope 13 Innovation Types of Innovation 1. Incremental 2. Medium Size 3. Process 4. Technology based a. Biocatalysis b. Continuous 5. Major 14 Life Research Hope Incremental: Reductive Amination Kumar, U. Tetrahedron Lett. 2012, 53, 4354-4356 15 Life Research Hope Incremental: Reductive Amination Mechanistic Considerations 16 Life Research Hope Incremental: Reductive Amination Generality of the Method 17 Life Research Hope Incremental: Acylation Kumar, U. Tetrahedron Lett. 2013, in print 18 Life Research Hope Incremental: Acylation Generality of the Method 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 Tetrahedron Lett. 2013, 54, 4908-4913. (Featured in R&D Highlights Published in Org.Proc.Res.&Dev. 2013, ASAP and being tracked in Article Usage Dashboard) 21 Life Research Hope Incremental: Amide Reduction Mechanistic Considerations 22 Life Research Hope Incremental: Amide Reduction Generality of the Method 23 Life Research Hope Incremental: Amide Reduction Generality of the Method 24 Life Research Hope Incremental: Amide Reduction 25 Life Research Hope Medium Size: Enantioselective Grignard addition to Nitroolefin Prashanth Reddy, G. Tetrahedron Lett., 2013, 54, 3911-3915 26 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin Potential Application 27 Life Research Hope Medium Size: Enantioselective Grignard Addition to Nitroolefin Screening er (R/S) S.No. Catalyst R1/R2/X °C Yield (%) (HPLC) 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
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