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

Abstract

The process development to the manufacturing route to (2 S )-7-([4,4‘-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid hydrochloride (SB-214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2 RS )-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2 S )-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2 S )-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1 H -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 (2 S )-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1 H -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 (2 S )-7-([4,4‘-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.