Stereoselective synthesis of a MCHr1 antagonist

被引：22

作者：

Andersen, Denise ^{[1
]}

Storz, Thomas

Liu, Pingli

Wang, Xin

Li, Leping

Fan, Pingchen

Chen, Xiaoqi

Allgeier, Alan

Burgos, Alain

Tedrow, Jason

Baum, Jean

Chen, Ying

Crockett, Rich

Huang, Liang

Syed, Rashid

Larsen, Robert D.

Martinelli, Mike

机构：

[1] Amgen Inc, Chem Proc Res & Dev, Thousand Oaks, CA USA

[2] Amgen SF, Med Chem, San Francisco, CA 94080 USA

[3] Incycle Corp, Proc Chem, Wilmington, DE 19880 USA

[4] Pharmaceut Prod PPG Sipsy, ZI Croix Cadeau, F-49242 Avrille, France

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2007年 / 72卷 / 25期

关键词：

D O I：

10.1021/jo701894v

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

[GRAPHICS] 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.

引用

页码：9648 / 9655

页数：8

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