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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

2003; American Chemical Society; Volume: 7; Issue: 5 Linguagem: Inglês

10.1021/op034023k

1520-586X

Richard J. Atkins, Adam Banks, Richard K. Bellingham, Gary F. Breen, John Carey, Stephen K. Etridge, Jerome F. Hayes, Nigel Hussain, David O. Morgan, P. Oxley, Stephen C. Passey, Timothy C. Walsgrove, Andrew S. Wells,

Neuropeptides and Animal Physiology

The process development to the manufacturing route to (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hydrochloride (SB-214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2RS)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2S)-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid. The unreacted (R)-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladium-catalysed aminocarbonylation of the aryl iodide with 4,4'-pyridylpiperidine to give (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.