In this exercise, you will contrast the medicinal chemistry and manufacturing routes to Lotrafiban and critically assess why the early route is suitable for medicinal chemistry but unsuitable for manufacturing. Details of the medicinal chemistry route and the manufacturing route are given in these briefing sheets:
In order to answer the questions fully, the following literature references should be read and analysed beforehand.
Medicinal Chemistry route:
- W. H. Miller, T. W. Ku, F. E. Ali, W. E. Bondinell, R. R. Calvo, L. D. Davis, K. F. Erhard, L. B. Hall, W. F. Huffman, R. M. Keenan, C. Kwon, K. A. Newlander, S. T. Ross, J. M. Samanen, D. T. Takata and C. – K. Yuan, Enantiospecific synthesis of SB 214857, a potent, orally active, nonpeptide fibrinogen receptor antagonist, Tetrahedron Lett., 1995, 36, 9433-9436.
Manufacturing route (split into two parts):
- I. P. Andrews, R. J. Atkins, G. F. Breen, J. S. Carey, M. A. Forth, D. O. Morgan, A. Shamji, A. C. Share, S. A. C. Smith, T. C. Walsgrove and A. S. Wells, The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 1: Synthesis of the Key Intermediate 2,3,4,5-Tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic Acid Methyl Ester, SB-235349, Org. Process Res. Dev., 2003, 7, 655-662.
- R. J. Atkins, A. Banks, R. K. Bellingham, G. F. Breen, J. S. Carey, S. K. Etridge, J. F. Hayes, N. Hussain, D. O. Morgan, P. Oxley, S. C. Passey, T. C. Walsgrove and A. S. Wells, The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2: Conversion of the Key Intermediate SB-235349 to SB-214857-A, Org. Process Res. Dev., 2003, 7, 663-675.
