Stereoselective synthesis of a MCHr1 antagonist |
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Authors: | Andersen Denise 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 |
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Institution: | Chemistry Process Research and Development, Amgen Inc., Thousand Oaks, California 19320, USA. danders555@yahoo.com |
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Abstract: | 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. |
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