DEVELOPMENT OF ROBUST, ENVIRONMENTALLY RESPONSIBLE … · 2018. 3. 26. · Developed a robust,...

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