dr. dhananjay sathe vice president-crd - nclwcip.ncl.res.in/uploads/presentation/flow...
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API PROCESS DEVELOPMENT: Transition from batch processes to continuous flow!!?
Dr. Dhananjay Sathe
Vice President-CRD
20 December 2011 1CONFIDENTIAL
UNICHEM
• Indian Generic Company
• Annual sales of about 1000 Cr
• Business includes APIs, FDFs for domestic as well as export markets
• R&D and Corporate office at Jogeshwari, Mumbai
• API Plants at Roha and Indore
• FDF plants at Goa, Gaziabad and Sikkim
20 December 2011 2CONFIDENTIAL
API
• Active pharmaceutical ingredients
– Small molecules: mw 400-600
– Macromolecules: Scerolimus, Tacrolimus
– Peptides, nucleosides, nucleotides
• Glatiramer Acetate
• Eptifibatide
– Carbohydrates: Levonox
– Polymers: Sevelamer
20 December 2011 3CONFIDENTIAL
API
• Categories
– General: Diabetese, Cardiovascular, CNS etc
– Oncology: Anticancers
– Steroids
– Antiinfectives: Antibiotics, Antivirals, Antifungals
– Natural or semi synthetic
20 December 2011 4CONFIDENTIAL
API Business
• Markets: US, EU, Japan, ROW• Strategy
– API selection– Growth: New Products, New Customers, New Markets– Operation: Supply Chain, Continuous Development– PIV or PIII entry
• Commoditized– Entry barrier
• Chemistry: Chiral, Organometallic etc• Technology: TFF, SMB etc
• Is Micro Tubular Reactor an enabling technology which can create entry barrier?
20 December 2011 5CONFIDENTIAL
Challenges
• Local
– Waste management
– Safety issues
– Supply chain
• Global
– Intense competition from other generic players
– Complicated IPR scenario: PIII, PIV
– Regulatory issues: ICH Guideline
– The window of opportunity is short lived
20 December 2011 6CONFIDENTIAL
API Processes
• Encompass entire range of Synthetic Organic Chemistry
• Single step to Multistep Synthesis
• Multi component reactions
• Batch Processes
• Batch sizes ranging from Multigram to Multiton
• Homogenous or Heterogenous
20 December 2011 7CONFIDENTIAL
API Processes
• Temperatures ranging from -70oC to +200oC
• Pressures ranging from Atmospheric to 100 bar
• Biphasic reactions
• Telescopic reactions
20 December 2011 8CONFIDENTIAL
Bottlenecks
• Hazardous reactions/reagents– Hydrazoic acid, Diborane, EO
– Nitration, Azidation
• Cryogenic reactions– Swern Oxidation, Butyl Lithium
• Lower batch sizes– Low yields
– Time consuming reactions
– Dilute reactions
20 December 2011 9CONFIDENTIAL
Flow Chemistry
• 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?
20 December 2011 10CONFIDENTIAL
Prior Art
• Stoicheometric Reactions• C-C Bond formation: Grignard, Wittig, Evans Auxillary
• Oxidation/Reduction: Swern Oxidation, Hydride Reductions
• Heterocyclic ring formations: Pyrrols, Pyridones, Indoles?
• Condensation reactions: Amide, Ester synthesis
• Fluorination
• Nitration
• Diazotization
• Polymerization
20 December 2011 11CONFIDENTIAL
Prior Art
• Catalytic Reactions• C-C bond formation: Heck, Suzuki, Kumada
• Oxidation/Reductions
• Organocatalysis: CBS Catalysts
• Enzymatic
20 December 2011 12CONFIDENTIAL
C-C Bond Formation
• Oxazolidone Chiral Auxillary
• Batch Reaction:• 31% Yield, 85:15 de, >10% Byproduct
• >50% Byproduct at higher temperature
• Flow Reaction• 41% Yield, 91:9 de, No Byproduct
20 December 2011 13
N O
CH3
OO
CH3N O
CH3
OO
CH3
N O
CH3
OO
CH3+NaHMDS, THF, -100
oC
Br
+
N O
CH3
O
Ph
CONFIDENTIAL
Aliskiren Building Blocks
20 December 2011 14
NH NH2
O
CH3CH3
O
OHCH3 CH3
NH2
CH3CH3O
CH3
OOCH3
CH3CH3O
CH3
OOCH3
O
OHN O
O
Ph
O
CH3 CH3
Cl
O
CH3
OR
+
N O
O
Ph
O
CH3 CH3
OH
O
CH3 CH3
ClClCl +
CONFIDENTIAL
Swern Oxidation
• Batch Process:• 19% Product, 72% Byproducts
• Cryogenic conditions
• Microreactor Process• 88% Product
• RT
20 December 2011 15
OH O O
S
CH3
O
O
FF
F
+ +DMSO/TFAA
TEA/-200C
CONFIDENTIAL
API Building Blocks
20 December 2011 16
NO
OCH3
CH3
O
N
O
N
OH
Swern Oxidation
Donepezil
O O
O
OROH
O O
O
ORO
Swern Oxidation
CONFIDENTIAL
Nitration
• Batch Process• Highly exothermic and explosive• Significant decarboxylated byproduct formation• Longer reaction time >12 Hrs
• Microreactor• >73% Product formation, in 35 min residence time• No byproduct formation
20 December 2011 17
NH
N
SN
N
N
N
CH3
O
CH3
O
OO
CH3
CH3
O2N
N
N
CH3
CH3
O2N
N
N
CH3
CH3
O
OH
N
N
CH3
CH3
O
OH
+HNO3/H2SO4
90-100
oC
CONFIDENTIAL
Condensation Reaction
– Eli Lilly potent NK1 Antagonists 2 & 3
20 December 2011 18
N
N N
N
FF
F
F
F
F
Cl
O
CH3 N N
N
N
O
FF
F
F
F
F
O
N
O
CH3
Cl
FF
F
F
F
F
N
N+
N-
23
NK1 Antagonists
1-Azidomethyl
-3,5
-trifluoromethyl benzene
CONFIDENTIAL
Batch Process
• DMSO/Water/NaN3/RT
• Longer reaction time ~48 hrs
• Side reaction
• Hydrazoic acid vapor formation in the head space
• Explosive
20 December 2011 19
FF
F
F
F
F
N
N+
N-
FF
F
F
F
F
Cl
NaN3
FF
F
F
F
F
OH
+
CONFIDENTIAL
Flow Process
• SS 316 coil placed in GC oven with T joint outside oven for injecting reagents– Dia 2.16mm
• Temperatures 50, 70 and 90oC• Residence time 60 min• Back pressure 200 psig• Only 64% conversion
– Dia 1 mm• Temperature 60oC• Residence time 20 min • Back pressure 200 psig• Conversion >99%, Purity 98.5%
20 December 2011 20CONFIDENTIAL
Azide Chemistry
• Reacts with metals and forms metal azides which can detonate
• Liberates low boiling hydrozoic acid in contact with water which lowers BP and is explosive
• Wide application in API industry• Converting Alkyl Halides or Tosylate/Mesylates to Amines
– Linezolid– Aliskiren
• Converting Nitriles to Tetrazoles– Valsartan, Irbesartan, Olmesartan, Losartan etc
• Converting Alkynes to Triazoles : Click Chemistry• Converting Carboxylic Acids to Amines: Curtius
Rearrangement
20 December 2011 21CONFIDENTIAL
Sartans
• Angeotensin II receptor antagonists• Clinically used as anti hypertensives• Doses are in the range of 40-400 mg
20 December 2011 22
N NH
N N
R
R=
CH3
N
O OH
CH3
CH3O
Valsartan
N
N
O
CH3
Irbesartan
N
N
CH3
O
OO
O
CH3
O
OH
CH3
CH3
Olmesartan modoxamil
N
N
CH3
OH
Cl
Losartan
CONFIDENTIAL
Sartans
• Tetrazole formation is the last step in the sartan synthesis
• It is a time consuming reaction• Energy demanding• Generally high yielding• Generates toxic and explosive hydrazoic acid
during the work up
20 December 2011 23
N NH
N N
RR
N
NaN3/TEA.HCl
Xylene/140oC
24-48Hrs
CONFIDENTIAL
Sartans
• Losartan sales are $3.6 bn, Kilo consumption is ~500 MT
• Irbesartan sales are $3 bn, Kilo consumption is ~700 MT
• Valsartan sales are $8.9 bn, Kilo consumption is ~1000 MT
• Olmesartan sales are $3.9 bn, Kilo consumption is ~75 MT
20 December 2011 24CONFIDENTIAL
Polymerization
• Peptide Homopolymers and Copolymers
• L-Lysine, L-Alanine, L-Leucine, L-Glutamic acid
• Low PDI in the range of 1.19-1.32
• Molecular wt distrebution is tunable
• Function of residence time, monomer ratios, monomer/base ratios
20 December 2011 25
NH
O
O
O
R
N-
O
O
O
R
NH
O
O
O
R
+N
O
O
O
R
O
R
NH2
NCA
Base
Active Monomer NCA Peptide
Chain Reaction
CONFIDENTIAL
Copaxone
• 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,
L-Glutamic acid• 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 fractions.
• Batch size is limited by TFF capacity, and TFF systems are very expensive
20 December 2011 26CONFIDENTIAL
Conclusion
• 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
20 December 2011 27CONFIDENTIAL
Bibliography
• Chem. Rev. 2007, 107, 2300-2318
• Organic Process Research & Development 2009, 13, 152-160
• References therein
20 December 2011 28CONFIDENTIAL