A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald-Hartwig Amination and Bruylants Reactions
A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald-Hartwig Amination and Bruylants Reactions
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DOI：
10.1021/op400250s
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发表时间：
2014-01-01
影响因子：
3.4
通讯作者：
Shieh, Wen-Chung
中科院分区：
文献类型：
--
作者：
Liu, Yugang;Prashad, Mahavir;Shieh, Wen-Chung
描述了一种实用的、无色谱合成的趋化因子受体拮抗剂NIBR-1282(1)。这种可规模化合成的亮点包括(1)以(t-Bu)(3)P为配体和5-12摩尔%的水为添加剂的Buchwald-Hartwig胺化反应，得到6，产率提高了2倍以上；(2)通过氨基三氮唑15a而不是传统的氨基腈8合成了α-甲胺10的Bruylants反应的变体；以及(3)开发了结晶诱导的阿托品异构体转化，导致主要产生一个阿托品异构体1。该新方法被用于生产千克量的目标活性药物成分。
A practical, chromatography-free synthesis for a chemokine receptor antagonist NIBR-1282 (1) is described. Highlights of this scalable synthesis include (1) Buchwald-Hartwig amination reaction using (t-Bu)(3)P as the ligand and 5-12 mol % of water as an additive affording 6 with yield increase of more than 2-fold; (2) a variant of the Bruylants reaction for the synthesis of alpha-methyl amine 10 via aminotriazole 15a, instead of classical amino nitrile 8; and (3) development of a crystallization-induced, atropisomer transformation leading to predominantly one atropisomer 1. The new approach was employed for the manufacturing of kilogram quantities of the target active pharmaceutical ingredient.