DEVELOPMENT OF ROBUST, ENVIRONMENTALLY RESPONSIBLE … · 2018. 3. 26. · Developed a robust,...
Transcript of DEVELOPMENT OF ROBUST, ENVIRONMENTALLY RESPONSIBLE … · 2018. 3. 26. · Developed a robust,...
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DEVELOPMENT OF ROBUST,
ENVIRONMENTALLY RESPONSIBLE
PROCESSES FOR NEW CHEMICAL ENTITIES
Rajappa Vaidyanathan
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BRISTOL-MYERS SQUIBB
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TOFACITINIB CITRATE
Orally active, potent, selective, reversible inhibitor of Janus
kinase discovered and developed by Pfizer Inc
Potent immunosuppressant/immunomodulator recently
approved in the US for the treatment of rheumatoid arthritis
Also under development for the treatment of:
Psoriasis
Dry eye
Crohn’s disease
Ulcerative colitis
Transplant rejection
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REPRESENTATIVE RESPONSE: PSORIASIS
Baseline Day 14
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RETROSYNTHETIC STRATEGY
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RETROSYNTHETIC STRATEGY
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RETROSYNTHETIC STRATEGY
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OUTLINE
Approaches to “Head-Piece”
Choice and Synthesis of “Coupling Partner”
Development of “End-Game”
Lessons Learned
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HEAD-PIECE
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ORIGINAL ROUTE TO HEAD-PIECE
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ORIGINAL ROUTE TO HEAD-PIECE
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ORIGINAL ROUTE TO HEAD-PIECE
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ORIGINAL ROUTE TO HEAD-PIECE
Ripin, D. H. B.; Abele, S.; Cai, W.; Blumenkopf, T.; Casavant, J. M.; Doty, J. L.;Flanagan, M.;
Koecher, C.; Laue, K. W.; McCarthy, K.; Meltz, C.; Munchhoff, M.; Pouwer, K.; Shah, B.; Sun, J.;
Teixeira, J.; Vries, T.; Whipple, D. A.; Wilcox, G. Org. Process Res. Dev. 2003, 7, 115–120.
6.6% overall yield
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PYRIDINE REDUCTION ROUTE
Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.;
Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.;
White, T. D. Org. Process Res. Dev. 2005, 9, 51–56.14
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PYRIDINE REDUCTION ROUTE
Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.;
Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.;
White, T. D. Org. Process Res. Dev. 2005, 9, 51–56.15
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PYRIDINE REDUCTION ROUTE
Cai, W.; Colony, J. L.; Frost, H.; Hudspeth, J. P.; Kendall, P. M.; Krishnan, A. M.;
Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.;
White, T. D. Org. Process Res. Dev. 2005, 9, 51–56.16
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PYRIDINE REDUCTION ROUTE
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FLOW HYDROGENATION
H2 gas Substrate
Product
Solution of
substrate
trickles over
catalyst
exposed to H2
HEL FlowCat
prototype
Good review: S. T. Sie and R. Krishna “Process Development and Scale Up: III. Scale-up and scale-
down of trickle bed processes” Reviews in Chemical Engineering 1998, 14, 203.
HEL FlowCat
commercial unit
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FLOW HYDROGENATION
100 g hydrogenated with 1 g of catalyst which was still active
Longer flow time = lower catalyst loading
1% loading in flow performs as well as 3% batch loading
Loading important because Rh is a major cost contributor
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FLOW HYDROGENATION
Gre
ate
r e
ffe
ctive
ca
taly
st lo
ad
ing
Substrate
flow rate
(mL/min)
0.5 0.75 1.0
10
15
20
Volumes
MeOH
(mL/g)
56:1, 100%
132:1, 100%
86:1, 100%
86:1, 100%
58:1, 100% 26:1, 100%
Mo
re c
on
ce
ntr
ate
d
Greater effective
Catalyst loading
Higher throughput
49:1, 86% 24:1, 50%
26:1, 86%
Cis / trans ratio, Conversion
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PYRIDINE REDUCTION ROUTE
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PYRIDINE REDUCTION ROUTE
Overall yield: 32.5% (65% of theory)
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CHOICE OF COUPLING PARTNER
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4-CHLOROPYRROLOPYRIMIDINE
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COUPLING: FIRST GENERATION APPROACH
Slow coupling reaction: four days to achieve reasonable
conversion
Excess 4-chloropyrrolopyrimidine required
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INVESTIGATION OF COUPLING STEP
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INVESTIGATION OF COUPLING STEP
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INVESTIGATION OF COUPLING STEP
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INVESTIGATION OF COUPLING STEP
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INVESTIGATION OF COUPLING STEP
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INVESTIGATION OF COUPLING STEP
Amine deactivated due to
inductive effect of b-amino
substituent
Increasing nucleophilicity
of amine might be
challenging
Increase electrophilicity of
coupling partner
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COUPLING: SECOND GENERATION
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COUPLING: SECOND GENERATION
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COUPLING: SECOND GENERATION
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COUPLING: SECOND GENERATION
Issue:
Protection-deprotection
sequence wasteful
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ALTERNATIVE ACTIVATION STRATEGY
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ALTERNATIVE ACTIVATION STRATEGY
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ALTERNATIVE ACTIVATION STRATEGY
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2,4-DICHLOROPYRROLOPYRIMIDINE
Brit. Pat. 812,366 (April 22, 1959)
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COUPLING STRATEGY BREAKTHROUGH
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COUPLING STRATEGY BREAKTHROUGH
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COUPLING STRATEGY BREAKTHROUGH
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THE REDUCTION
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DEBENZYLATION/DECHLORINATION
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DEBENZYLATION/DECHLORINATION
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DEBENZYLATION/DECHLORINATION
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THE AMIDATION STEP
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FIRST GENERATION AMIDATION
Step-wise amidation from isolated amine
Residues from amide coupling agents contaminated final product
Modest yields
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AMIDATION ATTEMPTS
Screened a variety of common activation/amidation conditions
CDI, SOCl2, (COCl)2, EDCI/HOBt etc.
Most resulted in slow reactions, incomplete conversions, multiple by-products
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AMIDATION ATTEMPTS
Issues:
Use of CH2Cl2 undesirable
Presence of impurities necessitated multiple reworks
Activation/amidation perhaps wasteful
Still modest yields
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BEST CONDITIONS THUS FAR
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AMIDATION CONSIDERATIONS
Need amidation conditions that generate innocuous by-products
Prefer a single solvent for HCl salt-break and amidation reaction
Water immiscible polar organic solvent52
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AMIDATION CONSIDERATIONS
1-Butanol emerged as extraction solvent of choice from screening
Excellent azeotrope with water (43% water; bp of azeotrope = 93 °C)
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AMIDATIONS USING THE ESTER
Reaction stalled at ~80% conversion
Required prolonged heating for complete conversion
Significant by-product formation
~70% yield
Ashford, S. W.; Henegar, K. E.; Anderson, A. M.; Wuts, P. G. M. J. Org. Chem 2002, 67, 7147-7150 54
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AMIDATIONS USING THE ESTER
Reaction stalled at ~80% conversion
Required prolonged heating for complete conversion
Significant by-product formation
~70% yield
Amine: base or nucleophile?
Ashford, S. W.; Henegar, K. E.; Anderson, A. M.; Wuts, P. G. M. J. Org. Chem 2002, 67, 7147-7150 55
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BASE SCREEN IN PROPYLENE GLYCOL
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 5 10 15 20 25 30
Time (h)
Con
vers
ion
N
N
(DBU)
N
Me
NN
i-Pr2NEt Et3N
(TMEDA)
O
N
N
N
EtBu
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BASE SCREEN IN PROPYLENE GLYCOL
N
N
(DBU)
N
Me
NN
i-Pr2NEt Et3N
(TMEDA)
O
N
N
N
EtBu
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BASE SCREEN IN 1-BUTANOL
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 5 10 15 20
Time (h)
Co
nve
rsio
n
N
N
(DBU)
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FINAL AMIDATION CONDITIONS
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PROPOSED PATHWAY
Price, K. E.; Larrivée-Aboussafy, C.; Lillie, B. M.; McLaughlin, R. W.; Hettenbach, K. W.;
Mustakis, J.; Hawkins, J. M.; Vaidyanathan, R. Org. Lett. 2009, 11, 2003–200660
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PROPOSED PATHWAY
Price, K. E.; Larrivée-Aboussafy, C.; Lillie, B. M.; McLaughlin, R. W.; Hettenbach, K. W.;
Mustakis, J.; Hawkins, J. M.; Vaidyanathan, R. Org. Lett. 2009, 11, 2003–200661
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AMIDINES AS NUCLEOPHILIC CATALYSTS
Aggarwal, V. K.; Mereu, A.
Chem. Commun. 1999, 2311–2312
Shieh, W. C.; Dell, S.; Repic, O.
J. Org. Chem. 2002, 67, 2188–2191
Kiesewetter, M. K.; Schloten, M. D.; Kirn, N.; Weber, R. L.; Hedrick,
J. L.; Waymouth, R. M. J. Org. Chem. 2009, 74, 9490–949662
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AMIDINES AS NUCLEOPHILIC CATALYSTS
Aggarwal, V. K.; Mereu, A.
Chem. Commun. 1999, 2311–2312
Shieh, W. C.; Dell, S.; Repic, O.
J. Org. Chem. 2002, 67, 2188–2191
Kiesewetter, M. K.; Schloten, M. D.; Kirn, N.; Weber, R. L.; Hedrick,
J. L.; Waymouth, R. M. J. Org. Chem. 2009, 74, 9490–949663
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AMIDINES AS NUCLEOPHILIC CATALYSTS
Aggarwal, V. K.; Mereu, A.
Chem. Commun. 1999, 2311–2312
Shieh, W. C.; Dell, S.; Repic, O.
J. Org. Chem. 2002, 67, 2188–2191
Kiesewetter, M. K.; Schloten, M. D.; Kirn, N.; Weber, R. L.; Hedrick,
J. L.; Waymouth, R. M. J. Org. Chem. 2009, 74, 9490–949664
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EXAMPLES
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EXAMPLES
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EXAMPLES
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EXAMPLES
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EXAMPLES
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END-GAME
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END-GAME
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END-GAME
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END-GAME
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END-GAME
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CONCLUSIONS
Developed a robust, sustainable process for the manufacture
of tofacitinib citrate
First two steps in water
Second and third steps telescoped
Minimized waste
Atom economical process (Major by-products: KHCO3,
KCl, HCl, toluene, ethanol, DBU-citrate)
Direct drop isolation of API (>99.5% pure)
Discovered that DBU catalyzes amidations of cyanoacetates
Mild and efficient conditions75
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ACKNOWLEDGMENTS
Pre-PoC Approaches
Sally Gut Ruggeri
David H. B. Ripin
Timothy D. White
Darrell Fox
Heather Frost
Clifford Meltz
James Phillips
Barbara Sitter
Frank Urban
Stanley Walinsky
“Head-piece”
Frank R. Busch
Jian Jin
Dennis E. Bourassa
“Coupling partner”
Timothy N. Norris
Marcus Ewing
Stephen E. Hubbs
Material Sciences
George Quallich
Peter Rose
Brian P. Chekal
Phillip Johnson
Analytical
Kevin M. Doyle
Philip Dietrich
Todd S. Smith
Hong Jiang
Sourcing/Supply Chain
Andrew Anderson
Carol Rose
James Long
Management
Juan Colberg
Stéphane Caron
End-game
Brett M. Lillie
Robert W. McLaughlin
Robert W. Dugger
New Approaches
Nathan D. Ide
Daniel Parker
Engineering Technologies
Jason Mustakis
Kevin W. Hettenbach
Chemical Technologies
Joel M. Hawkins
Kristin E. Price
Teresa Makowski
John Lucas
Jennifer Rutherford
Process Safety
David Bill
76