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DEVELOPMENT OF ROBUST,
ENVIRONMENTALLY RESPONSIBLE
PROCESSES FOR NEW CHEMICAL ENTITIES
Rajappa Vaidyanathan
BRISTOL-MYERS SQUIBB
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
REPRESENTATIVE RESPONSE: PSORIASIS
Baseline Day 14
RETROSYNTHETIC STRATEGY
5
RETROSYNTHETIC STRATEGY
6
RETROSYNTHETIC STRATEGY
7
OUTLINE
Approaches to “Head-Piece”
Choice and Synthesis of “Coupling Partner”
Development of “End-Game”
Lessons Learned
8
HEAD-PIECE
9
ORIGINAL ROUTE TO HEAD-PIECE
10
ORIGINAL ROUTE TO HEAD-PIECE
11
ORIGINAL ROUTE TO HEAD-PIECE
12
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
13
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
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
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
PYRIDINE REDUCTION ROUTE
17
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
18
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
19
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
20
PYRIDINE REDUCTION ROUTE
21
PYRIDINE REDUCTION ROUTE
Overall yield: 32.5% (65% of theory)
22
CHOICE OF COUPLING PARTNER
23
4-CHLOROPYRROLOPYRIMIDINE
24
COUPLING: FIRST GENERATION APPROACH
Slow coupling reaction: four days to achieve reasonable
conversion
Excess 4-chloropyrrolopyrimidine required
25
INVESTIGATION OF COUPLING STEP
26
INVESTIGATION OF COUPLING STEP
27
INVESTIGATION OF COUPLING STEP
28
INVESTIGATION OF COUPLING STEP
29
INVESTIGATION OF COUPLING STEP
30
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
31
COUPLING: SECOND GENERATION
32
COUPLING: SECOND GENERATION
33
COUPLING: SECOND GENERATION
34
COUPLING: SECOND GENERATION
Issue:
Protection-deprotection
sequence wasteful
35
ALTERNATIVE ACTIVATION STRATEGY
36
ALTERNATIVE ACTIVATION STRATEGY
37
ALTERNATIVE ACTIVATION STRATEGY
38
2,4-DICHLOROPYRROLOPYRIMIDINE
Brit. Pat. 812,366 (April 22, 1959)
39
COUPLING STRATEGY BREAKTHROUGH
40
COUPLING STRATEGY BREAKTHROUGH
41
COUPLING STRATEGY BREAKTHROUGH
42
THE REDUCTION
43
DEBENZYLATION/DECHLORINATION
44
DEBENZYLATION/DECHLORINATION
45
DEBENZYLATION/DECHLORINATION
46
THE AMIDATION STEP
47
FIRST GENERATION AMIDATION
Step-wise amidation from isolated amine
Residues from amide coupling agents contaminated final product
Modest yields
48
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
49
AMIDATION ATTEMPTS
Issues:
Use of CH2Cl2 undesirable
Presence of impurities necessitated multiple reworks
Activation/amidation perhaps wasteful
Still modest yields
50
BEST CONDITIONS THUS FAR
51
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
AMIDATION CONSIDERATIONS
1-Butanol emerged as extraction solvent of choice from screening
Excellent azeotrope with water (43% water; bp of azeotrope = 93 °C)
53
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
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
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
56
BASE SCREEN IN PROPYLENE GLYCOL
N
N
(DBU)
N
Me
NN
i-Pr2NEt Et3N
(TMEDA)
O
N
N
N
EtBu
57
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)
58
FINAL AMIDATION CONDITIONS
59
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
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
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
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
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
EXAMPLES
65
EXAMPLES
66
EXAMPLES
67
EXAMPLES
68
EXAMPLES
69
END-GAME
70
END-GAME
71
END-GAME
72
END-GAME
73
END-GAME
74
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
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