Development and manufacture of the inosine monophosphate dehydrogenase inhibitor merimepodib, VX-497

Organic Process Research and Development

Volumn 12, Issue 4, 2008, Pages 666-673

  Looker, Adam R ^a   Littler, Benjamin J ^a,b   Blythe, Todd A ^a,b   Snoonian, John R ^b,c   Ansell, Graham K ^b,d   Jones, Andrew D ^b,e   Nyce, Phil ^a,b   Chen, Minzhang ^a,b   Neubert, Bobbianna J ^a,b  

^a VERTEX PHARMACEUTICALS   (United States)

^b Vertex Pharmaceuticals Inc ^*  (United States)

^c SUNOVION PHARMACEUTICALS INC   (United States)

^d ABBOTT LABORATORIES   (United States)

^e Drug Metabolism and Pharmacokinetics

Author keywords

[No Author keywords available]

Indexed keywords

EID: 58149173769     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800060h     Document Type: Article

References (22)

1. (a) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.; Frank, C. A.; Novak, P. M.; Ronkin, S. M.; Saunders, J. O. (Vertex Pharmaceuticals, Inc.). U.S. Patent 6,344,465, 2002;
2. Chem. Abstr. 2002, 136,151157.
3. (b) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.; Frank, C. A.; Novak, P. M.; Ronkin, S. M.; Saunders, J. O. (Vertex Pharmaceuticals, Inc.). U.S. Patent 6,054,472, 2000;
4. Chem. Abstr. 2000, 132, 28897.
5. (c) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.; Frank, C. A.; Novak, P. M.; Ronkin, S. M.; Saunders, J. O. (Vertex Pharmaceuticals, Inc.). U.S. Patent 5,807,876;
6. Chem. Abstr. 2002, 136, 151157.
7. (a) Sorbera, L. A.; Silvestre, J. S.; Castañer, L. M. Drugs Future 2000, 25, 809.
8. (b) Jain, J.; Almquist, S. J.; Shlyakhter, D.; Harding, M. W. J. Pharm. Sci. 2001, 90, 625.
9. Herr, R. J.; Fairfax, D. J.; Meckler, H.; Wilson, J. D. Org. Process Res. Dev. 2002, 6, 677.
10. Pitt, M. J.; Battle, L. A. Bretherick's Handbook of Reactive Chemical Hazards; Urben, P. G., Ed.; Butterworth-Heinemann: Woburn, MA, 1995; Vol. 1, p 878.
11. Steger, J. L.; Coppedge, E. A.; Johnson, L. D. Proceedings of the EPA/A&WMA International Symposium: Measurement of Toxic and Related Air Pollutants; Research Triangle Park, NC, May, 1996.
12. Greater than 150 kg of 14 was outsourced as the raw material for later campaigns, prepared by the use of triphosgene.
13. It has been shown in laboratory studies that 14 reacts with HCl to give 1 and phosgene to a minor extent, which goes on to react in situ to form 15. Thus, free-basing conditions were required to remove the HCl.
14. (a) Schotten, C. Ber. 1884, 17, 2544.
15. (b) Baumann, E. Ber. 1886, 19, 3218.
16. A phosgene generator utilizing carbon monoxide and chlorine was used to supply scale-up requirements. The phosgene stream was pumped directly into a 630 L glass-lined reactor used for the phosgenation chemistry.
17. For excellent in-depth reading into nitroaromatic hydrogenation chemistry, please see: Augustine, R. L. Heterogeneous Catalysis for the Synthetic Organic Chemist; Marcel Dekker, Inc.: New York, 1996; p 473.
18. Lesce, R. M.; Graziano, L. M.; Cimminiello, G.; Cermola, F.; Parrilli, M,; Scarpati, R. J. Chem. Soc, Perkin Trans. 2 1991, 7, 1085.
19. ICH Harmonized Tripartite Guideline Q3C (R3), revised November 2005, available at http://www.ich.org.
20. Option #1 (530 ppm for NMP) of the ICH Q3C guideline on residual solvents is based on the assumption of a 10 g daily dose. Option #2 (see section 3.3) allows for the calculation based on actual daily dose.
21. (a) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann Ltd.: Oxford, 1993; p 172.
22. (b) Okamoto, M.; Hamano, M.; Igarashi, K.; Ooshima, H. J. Chem. Eng. Jpn. 2004, 37, 1224.