Microsoft powerpoint - dgs-flow chemistry-ncl-20dec'11.ppt [read-only]

Transition from batch processes to continuous flow!!? • Indian Generic Company• Annual sales of about 1000 Cr• Business includes APIs, FDFs for • R&D and Corporate office at Jogeshwari, • API Plants at Roha and Indore• FDF plants at Goa, Gaziabad and Sikkim – Small molecules: mw 400-600– Macromolecules: Scerolimus, Tacrolimus– Peptides, nucleosides, nucleotides – Carbohydrates: Levonox– Polymers: Sevelamer – General: Diabetese, Cardiovascular, CNS etc– Oncology: Anticancers– Steroids– Antiinfectives: Antibiotics, Antivirals, • Markets: US, EU, Japan, ROW• Strategy – API selection– Growth: New Products, New Customers, New Markets– Operation: Supply Chain, Continuous Development– PIV or PIII entry • Chemistry: Chiral, Organometallic etc• Technology: TFF, SMB etc • Is Micro Tubular Reactor an enabling technology – Waste management– Safety issues– Supply chain – Intense competition from other generic players– Complicated IPR scenario: PIII, PIV– Regulatory issues: ICH Guideline– The window of opportunity is short lived • Single step to Multistep Synthesis• Multi component reactions• Batch Processes• Batch sizes ranging from Multigram to • Pressures ranging from Atmospheric to • Biphasic reactions• Telescopic reactions – Hydrazoic acid, Diborane, EO– Nitration, Azidation – Low yields– Time consuming reactions– Dilute reactions • Where does it fit in?• Which chemistries can it handle?• Is it a laboratory technique?• Are the standard protocols available?• Are the prototype equipments available?• Can it be scaled up?• Is there a technology barrier?• Can it be patented?• Can it be validated? • C-C Bond formation: Grignard, Wittig, Evans Auxillary• Oxidation/Reduction: Swern Oxidation, Hydride • Heterocyclic ring formations: Pyrrols, Pyridones, • Condensation reactions: Amide, Ester synthesis• Fluorination• Nitration• Diazotization• Polymerization • C-C bond formation: Heck, Suzuki, Kumada• Oxidation/Reductions• Organocatalysis: CBS Catalysts• Enzymatic • Oxazolidone Chiral Auxillary• Batch Reaction: • 31% Yield, 85:15 de, >10% Byproduct• >50% Byproduct at higher temperature • 19% Product, 72% Byproducts• Cryogenic conditions • Highly exothermic and explosive• Significant decarboxylated byproduct formation• Longer reaction time >12 Hrs • >73% Product formation, in 35 min residence time• No byproduct formation – Eli Lilly potent NK1 Antagonists 2 & 3 1 Azidomethyl 3,5 trifluoromethyl benzene • Longer reaction time ~48 hrs• Side reaction• Hydrazoic acid vapor formation in the head • SS 316 coil placed in GC oven with T joint • Temperatures 50, 70 and 90oC• Residence time 60 min• Back pressure 200 psig• Only 64% conversion • Temperature 60oC• Residence time 20 min • Back pressure 200 psig• Conversion >99%, Purity 98.5% • Reacts with metals and forms metal azides which • Liberates low boiling hydrozoic acid in contact with • Converting Alkyl Halides or Tosylate/Mesylates to Amines – Valsartan, Irbesartan, Olmesartan, Losartan etc • Converting Alkynes to Triazoles : Click Chemistry• Converting Carboxylic Acids to Amines: Curtius • Angeotensin II receptor antagonists• Clinically used as anti hypertensives• Doses are in the range of 40-400 mg • Tetrazole formation is the last step in the • It is a time consuming reaction• Energy demanding• Generally high yielding• Generates toxic and explosive hydrazoic acid • Peptide Homopolymers and Copolymers• L-Lysine, L-Alanine, L-Leucine, L-Glutamic • Low PDI in the range of 1.19-1.32• Molecular wt distrebution is tunable• Function of residence time, monomer ratios, • It is a $3bn molecule invented by TEVA• Clinically used for the treatment of RRMS• It’s a “complex” copolymer of L-Lysine, L-Alanine, L-Tyrosine, • Average MW is in the range of 5-9KDa• Its PDI is about 1.6• It’s a 2 stage process: • Copolymerization to 40 Kda• Cutting down to desired MW range of 5-9 KDa • Final step is TFF purification to remove low molecular wt • Batch size is limited by TFF capacity, and TFF systems are • It has to make a commercial sense• To debottleneck API processes• To free capacity for new products• If it is a technology barrier• If it can be exclusive • Chem. Rev. 2007, 107, 2300-2318• Organic Process Research &


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