Exploratory Process Development of a Novel Diacylglycerol Acyltransferase‑1 (DGAT-1) Inhibitor

A practical large-scale synthesis was developed for 1, a DGAT-1 inhibitor, involving an aza-Michael reaction, amidation, Dieckman cyclization, and conjugate addition of cyanamide followed by cyclization, to form the fused 4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-5-one scaffold. The enabled process...

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Bibliographic Details
Published inOrganic process research & development Vol. 17; no. 12; pp. 1510 - 1516
Main Authors Shavnya, Andrei, Tao, Yong, Lilley, Susan C, Bahnck, Kevin B, Munchhof, Michael J, Nematalla, Asaad, Waldo, Michael, Bill, David R
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 20.12.2013
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
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Summary:A practical large-scale synthesis was developed for 1, a DGAT-1 inhibitor, involving an aza-Michael reaction, amidation, Dieckman cyclization, and conjugate addition of cyanamide followed by cyclization, to form the fused 4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-5-one scaffold. The enabled process presented here substantially improved safety (in particular, due to eliminating a nitration step and optimizing a high-energy intermediate step), reproducibility, and scalability, resulting in delivery of a multikilogram quantity of the API with high purity. The controls of API quality and particle size were also discussed.
ISSN:1083-6160
1520-586X
DOI:10.1021/op400215h