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Synthesis 2014; 46(22): 3047-3058
DOI: 10.1055/s-0034-1378653
paper
© Georg Thieme Verlag Stuttgart · New York

A Practical Synthesis of a Potent and Selective Diacylglycerol Acyltransferase-1 (DGAT-1) Inhibitor

Youngsook Shin
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Philippe Bergeron
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Brian M. Fox
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Frank Kayser
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Lawrence R. McGee
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Sharon McKendry
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Dustin L. McMinn
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Marc Labelle
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
,
Timothy D. Cushing*
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA   Fax: +1(650)8379369   eMail: tcushing@amgen.com
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Publikationsverlauf

Received: 12. Juni 2014

Accepted: 21. Juli 2014

Publikationsdatum:
25. August 2014 (online)

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Abstract

A practical synthesis of a potent, selective, and orally efficacious diacylglycerol acyltransferase-1 (DGAT-1) inhibitor, is described. This synthesis is suitable for multi-kilogram scale with high regioselectivity and stereoselectivity. The synthesis involves a Knoevenagel condensation with Meldrum’s acid followed by the stereoselective addition of phenyl cuprate, regioselective Friedel–Crafts acylation, cyclization, and a regioselective reduction through an enol triflate with catalytic platinum oxide to provide the desired compound in 5.2% yield over 12 steps.

Key words

diacylglycerol acyltransferase-1 - hydrogenation - Knoevenagel­ condensation - Friedel–Crafts acylation - Friedel–Crafts alkylation - stereoselectivity - regioselectivitiy
 

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