Process Chemistry: From Millimole to Kilomole

Kevin P. Schultz Nelsen Group April 6, 2006

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
From

Discovery to Scale-Up

Conclusion
2

What is Process Chemistry?

Safe Environmentally friendly

Cl N

Efficient Economical ($ and atom)

CO2 CF3

HO HN

HCl

HO

N F N O N Cl Cl O O H N O HN N H N CF3 F

Emend Merck

Zoloft Pfizer

Claritin Schering-Plough

Lipitor Pfizer
3

Process Chemistry

Process Chemistry is usually equated with scale-up, but characterizing process chemistry simply as the scale-up of a synthetic route does a grave disservice to the organic chemists who have chosen to focus their creative efforts in this field.
- Celia M. Henry, Senior Editor C&E News

Henry, C. M. C&E News May 26, 2002, pg 53-66.

Drug Development Timeline

Target Screen(s) Hit

Average of 12-15 yrs

Lead Candidate
CLINICAL
P A T E N T

Launch

Patent Expiration

D I S C O V E R Y SAFETY/PHARMACEUTICAL STUDIES

P R O C E S S 4.5 yrs 200-300 gms 2 yrs

R E S E A R C H 8.2 years < 100 kg

100-2000 kg

Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Marcel Dekker, Inc. New York: 1999.

Total Drug Development Cost

$400 - $800 million per approved drug

DeMasi, J. A. et al. J. Health Economics 2003, 22, 51185.

Need For Efficient Process Chemistry

Patent protection for 20 years

Generic drug application: Abbreviated New Drug Application (ANDA)

http://www.fda.gov/cder/index.html

Presidential Green Chemistry Challenge Award

Established in 1995 by the EPA For innovations in cleaner, cheaper and smarter chemistry
O HN H2N N N
O O

HN

HCl
CF3

N
N

O HO

OH Cl Cl
O

H N N

CF3 F

HN

Cytovene 2000 Roche Corp. Reduced liquid waste: 1120 metric tons / year Reduced solid waste: 25 metric tons / year

Zoloft 2002 Pfizer, Inc. Reduced waste: HCl (conc): 150 metric tons / year TiO2: 440 metric tons / year

Emend 2005 Merck Reduced waste: 340,000 L / metric ton

www.epa.gov/greenchemistry/presgcc.html http://pubs.acs.org/cen/coverstory/8026/8026greenchemistry.html

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
From

Discovery to Scale-Up

Conclusion
9

General Considerations for Process Chemistry

Avoid column chromatography Seeding helps crystallization Avoid desiccants, use azeotrope Avoid solvents with flash point < 15 C

Ether, hexanes, DCM

Temperature range -40 to 120 C Avoid protecting groups Impurities of > 0.1% must be analyzed
10

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
Discovery

Synthesis Refined Process Chemistry Route 2nd Generation Synthesis Commercial Synthesis

Conclusion
11

Emend - Aprepitant
N HN NH O

O 2

CF3

N 3

CF3 F

hNK1 receptor antagonist (IC50 = 0.09 nM)1 Treatment of chemotherapy-induced emesis2 FDA approval in 2003 2005 Presidential Green Chemistry Challenge Award3 Entered preclinical trials in 19931
2

1 3

Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614. http://www.epa.gov/greenchemistry/past.html

Rupniak, N. M. et al; Eur. J. Pharmacol. 1997, 326, 201-209.

12

Discovery Synthesis Route

CF3 CF3 CF3 Me CF3 O O O Me CF3 O O Me CF3 O

N H N O HN N F H2N O

N H F Cl N O N H CF3 Ph

N F

CF3

O O O O N N Ph F Ph F Ph O CF3

H2C O O

CF3

N F

Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.

13

Discovery Synthesis: Oxazinone

HO O O NH Ph F Ph O O N O

1) KHMDS
O

O N

O O

2)

O S

N3 O

Ph

N3

83%

67% 92% de 1) LiOH 2) HCl 3) H2, Pd/C

Br O O

1) Br (i-Pr)2NEt DMF

HO

PhCHO NaOH NaBH4

HO

HN

2) HCl
Ph F Ph F

H2N F

74% (two steps) 92% ee

40% overall yield

14

Hale, J. J. et al. J. Med. Chem. 1996, 39, 1760-1762. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030

One-Pot Synthesis of Oxazinone

O H

1) Na2S2O5, NaCN H2O, MeOH 2)

F NH Ph OH

HO CN

NH

HCl(g)
N Ph F Ph N

HCl

in i-PrOAc 1.2 eq H2O

O O O O

KHCO3
N Ph F Ph N

HCl

racemate 80% yield

> 1.2 eq H2O

HO HO O

- Washed aminonitrile with 15 wt % NaCl

Ph

N F

Nelson, T. D.; Bhupathy, M. European Patent 1112259, 2001.

15

Dynamic Resolution
SO3H Br O O
(S)

O
(S)

1.2 eq O
N Ph F

BCSA

(-) - BCSA i-PrOAc, reflux

Ph

NH3 toluene

O
(S)

N F

N Ph F

99% de 90% yield

O
(R)

i-PrOAc, HCl

BSCA

NH4

N Ph F

Alabaster, R. J.; Gibson, A. W.; Johnson, S. A.; Edwards, J. S.; Cottrell, I. F. Tetrahedron: Asymmetry 1997, 8, 447-450

16

Discovery Synthesis Route

CF3 CF3 CF3 Me CF3 O O O Me CF3 O O Me CF3 O

N H N O HN N F H2N O

N H F Cl N O N H CF3 Ph

N F

CF3

O O O O N N Ph F Ph F Ph O CF3

H2C O O

CF3

N F

17

Acyl Acetal Formation

O O CF3 O Ph F Cl CF3 O O
(S) (S) (S)

CF3

O CF3 O

L-Selectride THF/toluene > -60 oC

O

N Ph F

N Ph F Ph

N CF3 F CF3 O Cl CF3 O N O

(R) (S)

L-Selectride THF/toluene < -60 oC

> -60 oC
O O

CF3 O

strict cryogenic temperatures

< -60 oC
Ph F Ph

N F

99% de 82% yield

Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron: Asymmetry 1997, 8, 957. 18

Discovery Synthesis Route

CF3 CF3 CF3 Me CF3 O O O Me CF3 O O Me CF3 O

N H N O HN N F H2N O

N H F Cl N O N H CF3 Ph

N F

CF3

O O O O N N Ph F Ph F Ph O CF3

H2C O O

CF3

N F

19

Petasis Reagent
Petasis Reagent
Cl Ti Cl Ti

Me Me

MeMgCl -5 to -10 C
o

Me Ti Me

heat -CH4
Ti

CH2

energetic decomposition

decomposes in solid state

excess
Ti

titanium carbene reactive and unstable

O

CH2

R' CH2 R' R O Cp Ti O Cp R O

undesired products

excess

Me Ti Me

R' O
Ti

O
Ti Ti

HCl recycle
Ti

Cl Cl

>2 eq of Petasis reagent necessary

major byproduct

Hughes, D. L.; Payack, J. F.; Cai, D.; Verhoeven, T. R.; Reider, P. J. Organometallics 1996, 15, 663. Payack, J. F. et al Org. Proc. Res. Develop. 2004, 8, 256.

20

Sacrificial Ester
O Ph O Ph O
(R)

O O
(S)

CF3

<
N

CF3 F
CF3
Me Ti Me

CF3 Cp Cp CF3 Ti O O O
(R) (S)

CF3 H2C O
(R) (S)

CF3 O

80 C THF/ toluene
N

CF3

O
(R) (S)

N Ph F O F

N Ph
O

92%

Ph

0.75 eq
O

Ph

Ti

Ti

Payack, J. F. et al Org. Proc. Res. Develop. 2004, 8, 256.

21

Discovery Synthesis Route

CF3 CF3 CF3 Me CF3 O O O Me CF3 O O Me CF3 O

N H N O HN N F H2N O

N H F Cl N O N H CF3 Ph

N F

CF3

O O O O N N Ph F Ph F Ph O CF3

H2C O O

CF3

N F

22

Hydrogenation
CF3 CF3 CF3 H2C O
(R) (S)

CF3 O

Pd/Al2O3, H2

Me
(R)

CF3

Me
(S)

CF3

O
(R) (S)

O
(R) (S)

N Ph F

EtOH:EtOAc O 1:1
Ph

N F Ph

N F

91

9 Pd/Al2O3, TsOH, H2

CF3

CF3

CF3

Me

CF3 O
(R) (S)

(R)

CF3 O

Me
(S)

CF3

O
(R) (S)

O
(R) (S)

TsOH

TsOH
N H F

TsOH

86% yield 99% de F

N H

Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.

23

Discovery Synthesis Route

CF3 CF3 CF3 Me CF3 O O O Me CF3 O O Me CF3 O

N H N O HN N F H2N O

N H F Cl N O N H CF3 Ph

N F

CF3

O O O O N N Ph F Ph F Ph O CF3

H2C O O

CF3

N F

24

Triazolinone Ring
CF3 H2N O Me
(R)

Cl

CF3

CF3

Me N
(R)

CF3

N H

CF3

Me
(R)

O
(R) (S)

O
(R) (S)

CF3

K2CO3, toluene, DMSO

H2N O N O N H

xylenes 140oC

O
(R) (S)

N H F

N N F O HN N H N

aprepitant 85%

- Charcoal treatment - A single SN2 displacement was envisioned

Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614.
25

Facile Addition of Triazolinone Ring

H2N O H N NH2 O O O

MeOH, 20oC
O

H N N H N

Cl

HCl

3 days
Cl

commercially available
CF3 H N Me
(R)

90%
CF3

Me Cl N O
(R) (S) (R)

CF
3

O CF3 O N H

O
(R) (S)

N H F

K2CO3, DMF, 1hr, RT

O

N H N HN N F

aprepitant 98%
Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.
26

1st Generation Synthesis: 1993-1999

43% overall yield (longest linear sequence) Clinical trials

Key improvement areas

Chiral Acid BCSA

Expensive (1kg NH4 salt= $4500) Unreacted acid lost Expensive Strict cryogenic temperatures Expensive Toxic

Larger doses necessary Good results for antiemesis Possible antidepressant

L-Selectride

Dimethyl titanocene

NO NEW IMPURITIES
Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.
27

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
Discovery

Synthesis Refined Process Chemistry Route 3rd Generation Synthesis Commercial Synthesis

Conclusion

28

Logical 3rd Generation Retrosynthesis

CF3 CF3 CF3

CF3 O O

CF3 O O OH N CF3

N H N O N H N O F

P F H N N H N Cl

LG

N P F

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747.

29

Cis Acetalization Approach

O OH F3C N

N
Ph O O F Me CF3

Ph
OH

DIBALH
N Ph F O OR

Lewis Acid

CF3

1) base
N

CF3 O
F

2) RCl
Ph

R= C(O)CH3 C(O)CF3 C(NH)CCl3

N Ph F

-trans acetalization and elimination products

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747. Ashwood, M. S.; Cottrell, I. F.; Davies, A. J. Tetrahedron: Asymmetry 1997, 8, 957-963.
30

3rd Generation Retrosynthesis

CF3 CF3 CF3 CF3 O O O N H N O N H N F N H N N H F N F H N Cl O O CF3 O O CF3

O NH OH O OH F N OH Ph N H Ph F Ph N F OH CF3 O O O CCl3 CF3

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747

31

rd 3
OH
O

Generation Synthesis
O O O O O
(R)

HCl

AcOH / i-PrOAc
F Ph N
(R)

HCl i-PrOAc 70 oC
Ph

NH
(R)

N
(R)

Ph

2:1 (3S) : (3R)

90% 98% de

F OH HO O O

N
(R)

N Ph

Ph

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747 Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062

32

3rd Generation Synthesis:

trans Acetalization
O
(R)

NH O OH
(S) (R)

DIBALH toluene/THF -20oC

F Ph N

CCl3CN K2CO3
F Ph

CCl3

N Ph

N F

trans / cis 8/1

-Difficult to remove CCl3CN -Shifts back to SM

CF3

BF3 Et2O HO

CF3

1) H2, 5% Pd / C TsOH H2O, toluene/EtOH 2) NCS, DMF, K2CO3, 0oC, 0.5hrs 3) DBU
N N

CF3 CF3

N CF3 Ph F

N CF3 F

85% (three steps) trans / cis 96 / 4

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747 Nelson, T. D. Synthesis of Aprepitant. Strategies and Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier: San Diego; 2005: pp 321-351.

33

3rd Generation Synthesis:

cis Hydrogenation
CF3 H N HN N H CF3 F N N H N O N H N F Cl O O CF3

CF3

CF3

H2
N CF3 F

5% Pd / C

K2CO3 / DMF

81% (four steps) >99% cis

Aprepitant 98%

Zhao, M. M. et al. J. Org. Chem. 2002, 67, 6743-6747 Cowden, C.J. et al. Tetrahedron Lett. 2000, 41, 8661-8664.

34

Pros/Cons of 3rd Generation Synthesis

Pros:

Cons:

52% yield (longest linear sequence) Cheap, available starting materials No cryogenic temperatures

Removal of trichloroacetonitrile Inversion of C3 stereocenter Operationally lengthy synthesis (12 steps)

35

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
Discovery

Synthesis Refined Process Chemistry Route 3rd Generation Synthesis Commercial Synthesis

Conclusion

36

Commercial Scale Retrosynthetic Analysis

CF3 CF3 CF3 CF3 O O O O O N H F N O H N N H N O O O CF3 CF3 Cl F Ph O CF3 CF3

N H N O N H

Solve deprotonation problem with adjacent sp2 center (C3) Dynamic Resolution

3
N Ph O OH CF3

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135

37

Commercial Scale Synthesis

OH O

2.3 eq
NH Ph O OH

THF/H2O

O COOH N Ph

heat

OH

N Ph

76%

OH O N OH Ph

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135

38

Commercial Scale Synthesis Cont.

O O OH F3C O O CF3 F3C O O O HO
(R)

1) 0.5 eq BF3 Et2O

N Ph O F3C CF3

N Ph

CH3CN

CH3CN 2) NaOH

CF3

CF3

(R)

CF3 O
(S)

(R)

CF3

O
(R)

95% overall yield

N Ph

O Ph

55

45
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135
39

Equilibration Studies

CF3

CF3

(R)

CF3 O
(S)

(R)

CF3

O
(R)

N Ph

O Ph

65

35
40

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135

Crystallization-Induced Asymmetric Transformation

CF3

1) , -CH3CN +heptane 2) 0.9 eq

CF3 OH

CF3

CF3 O O
(R)

3) -10 to -5 oC, seed with R diastereomer

N O-K+ Ph

N Ph

4) 0.3 eq 55 : 45 R:S 5 hours

84% yield > 99% de

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135. Anderson, N. G. Org. Proc. Res. Dev. 2005, 9, 800-813.

41

Nucleophilic Addition
CF3

CF3

CF3
Me CF3

MgBr Me

THF
O O OMgBr F N Ph F

CF3

Me CF3 O O

O Ph

N H

0.5%

-Unacceptable levels of defluorinated product

CF3 CF3

1) MeOH 2) Pd/C, H2, 1.5eq TsOH

CF3

Me CF3 O O O

Me CF3 O O

Me CF3 O

TsOH
N H F

91% >300 : 1 cis : trans

N H F

N F

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135. Brands, K. M. J. et al. Org. Proc. Res. Dev. 2006, 10, 109-117.

42

Defluorination
CF3 CF3 Me CF3 O O Me Me CF3 O O O

CF3

Pd*

CF3 O

N F

N Pd F

N H

H2
CF3

H2

Me CF3 O O

N H F

Catalyst decreased to 3-6wt% Increase H2 pressure to 20psi Gas-liquid mass transfer rate increased Defluorinated product becomes <0.1%

CF3

Me CF3 O O

N H H

Brands, K. M. J. et al. Org. Proc. Res. Dev. 2006, 10, 109-117.

43

Final Step: Triazolinone

CF3 CF3 Cl CF3 O O O N H H N N N H N F O N H N F CF3

K2CO3 DMF / H2O

N H

Aprepitant 98%

Cowden, C. J. et al Tetrahedron Lett. 2000, 41, 8661.

44

Presidential Green Chemistry Challenge Award - 2005

O OH N O

CF3

CF3

Convergent synthesis
Overall

Ph N

OH Cl NH BrMg

yield 55% (6 steps) Uses 20% of raw materials as original synthesis

Reduce

HN

CF3

waste by 85%
CF3 O O N N HN NH O F

340,000L / metric ton aprepitant

http://www.epa.gov/greenchemistry/past.html C&E News June 27, 2005 pg 40-43

45

Outline

What is Process Chemistry? Drug Development Timeline and Cost General Considerations Emend
Discovery

Synthesis Refined Process Chemistry Route 3rd Generation Synthesis Commercial Synthesis

Conclusions

46

Emend Process Research

10 years of process research 4 synthetic generations Increased yield from 12% to 55% Eliminated toxic chemicals Reduced waste Developed prior to drug launch

47

Conclusion

Process chemistry is more than just scale-up

Safe Cost

effective friendly development

Environmentally Timely

48

Acknowledgements

Prof. Stephen F. Nelsen Nelsen Group Members

Practice Talk Attendees

Mike Weaver Yun Luo Gaoquan Li Brian Schuld

Katie Alfare Erik Hadley Caroline Pharr Will Pomerantz Vicki Wilde
Soo Hyuk Choi

Kim Schultz

49

50

Crystal Structure of CIAT product (slide 41)

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135

51

Crystal Structure of Aprepitant

F 3C CF3
(R)

O O H
(R) (S)

F R

F3C O O
(R) (R) (S)

N H

F 3C

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003, 125, 2129-2135

52

Modified Strecker Reaction (slide 15)

O H F OH CN

Na2S2O5 H2O
NaO3S F

CNHO F OH

NH

N F

1) HCl(g) H 2O 2) KHCO3

OH CN N F

53

Trizolinone Ring Synthesis (Slide 26)

H2N O H N NH2 O O O H H2N H N O N H O O H Cl H2N O H N N O H Cl

1 2
Cl

H N O N H N

Cl H2N O H N N

Cl

90% Decomposition:
H O O O H

Cl

Cl

Me

H O

O O O

O Cl

Cl

Cl

54

3rd Generation Synthesis of Oxazinone Mechanism (slide 32)

2
O

F OH O O O

OH

NH
(R)

N
F
(R)

N
(R)

Ph

Ph

Ph

Agami, C.; Couty, F.; Prince, B.; Venier, O. Tetrahedron Lett 1993, 34, 7061-7062.

55

Lactam Lactol Synthesis (slide38)

OH HO HO O N O Ph OH2 Ph Ph HO O HO HO O O N N H O OH NH Ph

H O H O OH O O OH N Ph O N H O N H O H H

56