The development of a manufacturing route for the GPIIb/IIIs receptor antagonist SB-214857-A. Part 2: Conversion of the key intermediate SB-235349 to SB-214857-A

被引：27

作者：

Atkins, RJ ^{[1
]}

Banks, A ^{[1
]}

Bellingham, RK ^{[1
]}

Breen, GF ^{[1
]}

Carey, JS ^{[1
]}

Etridge, SK ^{[1
]}

Hayes, JF ^{[1
]}

Hussain, N ^{[1
]}

Morgan, DO ^{[1
]}

Oxley, P ^{[1
]}

Passey, SC ^{[1
]}

Walsgrove, TC ^{[1
]}

Wells, AS ^{[1
]}

机构：

[1] GlaxoSmithKline, Synthet Chem, Tonbridge TN11 9AN, Kent, England

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2003年 / 7卷 / 05期

关键词：

D O I：

10.1021/op034023k

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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 (SB214857-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.

引用

页码：663 / 675

页数：13

共 24 条

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