Stereoselective synthesis of a MCHr1 antagonist.
Stereoselective synthesis of a MCHr1 antagonist.
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MCHr1 拮抗剂的立体选择性合成。
DOI：
10.1021/jo701894v
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
M. Martinelli
中科院分区：
文献类型：
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作者：
Denise Andersen;T. Storz;Pingli Liu;Xin Wang;Leping Li;P. Fan;Xiaoqi Chen;A. Allgeier;A. Burgos;J. Tedrow;Jean Baum;Ying Chen;Richard D. Crockett;Liang Huang;R. Syed;R. Larsen;M. Martinelli
黑色素浓集激素（MCH）与哺乳动物的摄食行为有关，是控制人类暴饮暴食的潜在靶点。化合物1（AMG 076）已被鉴定为用于治疗肥胖症的有效MCHr 1拮抗剂。开发了一种适合大规模制备该先导候选药物的合成方法，以支持临床前研究。苄基哌啶酮的罗宾逊环化和所需的烯酮从非对映异构体的混合物中的拆分在立体选择性氢化后提供关键中间体6。随后用肼5进行Fischer吲哚合成，然后提供高级中间体吲哚2。采用醛3或内半缩醛4的两种互补的还原胺化策略导致标题化合物1的合成。
Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.