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
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
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DOI：
10.1021/op034023k
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发表时间：
2003-09-01
影响因子：
3.4
通讯作者：
Wells, AS
中科院分区：
文献类型：
--
作者：
Atkins, RJ;Banks, A;Wells, AS
介绍了(2S)-7-([4，4‘-bipiperidin]-1-ylcarbonyl)-2，3，4，5-tetrahydro-4-methyl-3-oxo-1H-1，4-benzodiazepine-2-acetic酸盐酸盐(SB214857-A，洛曲非班)生产路线的工艺开发。起始点是以前报道的中间体(2RS)-2，3，4，5-tetrahydro-4-methyl-3-oxo-1H-1，4-benzodiazepine-2-acetic酸甲酯。第一阶段是脂肪酶催化将外消旋酯分解为(2S)-2，3，4，5-tetrahydro-4-methyl-3-oxo-1H-1，4-benzodiazepine-2-acetic酸，然后使用吡啶碘一氯络合物进行碘化反应得到(2S)-2，3，4，5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1，4-benzodiazepine-2-acetic酸。通过甲醇钠处理，回收起始酯的未反应的(R)-对映体，并循环到外消旋体。下一阶段描述了钯催化的芳基碘化物与4，4‘-吡啶基哌啶的氨甲酰化反应，得到(2S)-2，3，4，5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1，4-benzodiazepine-2-acetic酸二水合物。第三步是以钯为催化剂，将吡啶亚基在木炭上进行加氢反应，得到两性离子(2S)-7-([4，4‘-bipiperidin]-1-ylcarbonyl)-2，3，4，5-tetrahydro-4-methyl-3-oxo-1H-1，4-benzodiazepine-2-acetic酸。最后一个阶段是盐酸盐的形成，以提供药物物质。
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.