Efficient Synthesis of 4-Amino-2-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-5-ones: Practical Access to a Novel Chemotype in the Development of DGAT-1 Inhibitors

Abstract

A practical access to an unprecedented, fused bicyclic 4-amino-2-alkoxy-7, 8-dihydropyrido[4,3-d]pyrimidin-5-one scaffold is developed. The synthesis of the potent inhibitor, 2-{4-[4-amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}-2-methylpropanamide is detailed, with particular emphasis placed on synthetic efficiency and scalability. With the isolation of solid intermediates, the routes described offer clear elements of practicality and facilitate production of the target compound on large scale (>10 g) without chromatography.

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

“…It has recently emerged as an attractive target for therapeutic intervention in the treatment of Type II diabetes and obesity . As part of the program aimed at finding an orally active API, a series of highly potent and selective DGAT-1 inhibitors was recently discovered carrying a novel 4-amino-7,8-dihydropyrido[4,3- d ]pyrimidin-5-one scaffold . Compound A (Figure ) was first identified as a promising lead to inhibit the DGAT-1-mediated pathway.…”