Process Chemistry: From Millimole to Kilomole

1
Process Chemistry From Millimole to Kilomole

• Kevin P. Schultz
• Nelsen Group
• April 6, 2006

2
Outline

• What is Process Chemistry?
• Drug Development Timeline and Cost
• General Considerations
• Emend
• From Discovery to Scale-Up
• Conclusion

3
What is Process Chemistry?
4
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
• CE News

Henry, C. M. CE News May 26, 2002, pg 53-66.
5
Drug Development Timeline

• Average of 12-15 yrs

Gadamasetti, Kumar G. Process Chemistry in the
Pharmaceutical Industry. Marcel Dekker, Inc. New
York 1999.
6
Total Drug Development Cost

• 400 - 800 million per approved drug

DeMasi, J. A. et al. J. Health Economics 2003,
22, 51185.
7
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
8
Presidential Green Chemistry Challenge Award

• Established in 1995 by the EPA
• For innovations in cleaner, cheaper and smarter
  chemistry

www.epa.gov/greenchemistry/presgcc.html
http//pubs.acs.org/cen/coverstory/8026/8026green
chemistry.html
9
Outline

• What is Process Chemistry?
• Drug Development Timeline and Cost
• General Considerations
• Emend
• From Discovery to Scale-Up
• Conclusion

10
General Considerations for Process Chemistry

• Avoid column chromatography
• Seeding helps crystallization
• Avoid desiccants, use azeotrope
• Avoid solvents with flash point lt 15 ºC
• Ether, hexanes, DCM
• Temperature range -40 to 120 ºC
• Avoid protecting groups
• Impurities of gt 0.1 must be analyzed

11
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

12
Emend - Aprepitant

• 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

1 Hale, J. J. et al J. Med. Chem. 1998, 41,
4607-4614. 2 Rupniak, N. M. et al Eur. J.
Pharmacol. 1997, 326, 201-209. 3
http//www.epa.gov/greenchemistry/past.html
13
Discovery Synthesis Route
Hale, J. J. et al J. Med. Chem. 1998, 41,
4607-4614.
14
Discovery Synthesis Oxazinone

• 40 overall yield

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
15
One-Pot Synthesis of Oxazinone
80 yield
- Washed aminonitrile with 15 wt NaCl
Nelson, T. D. Bhupathy, M. European Patent
1112259, 2001.
16
Dynamic Resolution
Alabaster, R. J. Gibson, A. W. Johnson, S. A.
Edwards, J. S. Cottrell, I. F. Tetrahedron
Asymmetry 1997, 8, 447-450
17
Discovery Synthesis Route
18
Acyl Acetal Formation
strict cryogenic temperatures
Ashwood, M. S. Cottrell, I. F. Davies, A. J.
Tetrahedron Asymmetry 1997, 8, 957.
19
Discovery Synthesis Route
20
Petasis Reagent
gt2 eq of Petasis reagent necessary
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.
21
Sacrificial Ester
Payack, J. F. et al Org. Proc. Res. Develop.
2004, 8, 256.
22
Discovery Synthesis Route
23
Hydrogenation
Nelson, T. D. Synthesis of Aprepitant. Strategies
and Tactics in Organic Synthesis Harmata, M.,
Ed. Elsevier San Diego 2005 pp 321-351.
24
Discovery Synthesis Route
25
Triazolinone Ring
- A single SN2 displacement was envisioned
Hale, J. J. et al J. Med. Chem. 1998, 41,
4607-4614.
26
Facile Addition of Triazolinone Ring
commercially available
Cowden, C. J. et al Tetrahedron Lett. 2000, 41,
8661.
27
1st Generation Synthesis 1993-1999

• 43 overall yield (longest linear sequence)
• Clinical trials
• Larger doses necessary
• Good results for antiemesis
• Possible antidepressant

• Key improvement areas
• Chiral Acid BCSA
• Expensive (1kg NH4 salt 4500)
• Unreacted acid lost
• L-Selectride
• Expensive
• Strict cryogenic temperatures
• Dimethyl titanocene
• Expensive
• Toxic

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.
28
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

29
Logical 3rd Generation Retrosynthesis
Zhao, M. M. et al. J. Org. Chem. 2002, 67,
6743-6747.
30
Cis Acetalization Approach
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.
31
3rd Generation Retrosynthesis
Zhao, M. M. et al. J. Org. Chem. 2002, 67,
6743-6747
32
3rd Generation Synthesis
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
33
3rd Generation Synthesis trans Acetalization
-Difficult to remove CCl3CN -Shifts back to SM
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.
34
3rd Generation Synthesiscis Hydrogenation
Zhao, M. M. et al. J. Org. Chem. 2002, 67,
6743-6747 Cowden, C.J. et al. Tetrahedron Lett.
2000, 41, 8661-8664.
35
Pros/Cons of 3rd Generation Synthesis

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

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

36
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

37
Commercial Scale Retrosynthetic Analysis

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

Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
38
Commercial Scale Synthesis
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
39
Commercial Scale Synthesis Cont.
95 overall yield
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
40
Equilibration Studies
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
41
Crystallization-Induced Asymmetric Transformation
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.
42
Nucleophilic Addition
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.
43
Defluorination

• Catalyst decreased to 3-6wt
• Increase H2 pressure to 20psi
• Gas-liquid mass transfer rate increased
• Defluorinated product becomes lt0.1

Brands, K. M. J. et al. Org. Proc. Res. Dev.
2006, 10, 109-117.
44
Final Step Triazolinone
Cowden, C. J. et al Tetrahedron Lett. 2000, 41,
8661.
45
Presidential Green Chemistry Challenge Award -
2005

• Convergent synthesis
• Overall yield 55 (6 steps)
• Uses 20 of raw materials as original synthesis
• Reduce waste by 85
• 340,000L / metric ton aprepitant

http//www.epa.gov/greenchemistry/past.html CE
News June 27, 2005 pg 40-43
46
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

47
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

48
Conclusion

• Process chemistry is more than just scale-up
• Safe
• Cost effective
• Environmentally friendly
• Timely development

49
Acknowledgements

• Prof. Stephen F. Nelsen
• Nelsen Group Members
• Mike Weaver
• Yun Luo
• Gaoquan Li
• Brian Schuld
• Kim Schultz

• Practice Talk Attendees
• Katie Alfare
• Erik Hadley
• Caroline Pharr
• Will Pomerantz
• Vicki Wilde
• Soo Hyuk Choi

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Crystal Structure of CIAT product (slide 41)
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
52
Crystal Structure of Aprepitant
Brands, K. M. J. et al. J. Am. Chem. Soc. 2003,
125, 2129-2135
53
Modified Strecker Reaction (slide 15)
54
Trizolinone Ring Synthesis (Slide 26)
55
3rd Generation Synthesis of Oxazinone Mechanism
(slide 32)
Agami, C. Couty, F. Prince, B. Venier, O.
Tetrahedron Lett 1993, 34, 7061-7062.
56
Lactam Lactol Synthesis (slide38)