An Efficient Process for the Manufacture of Carmegliptin

Abstract

A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

“…The reported synthesis of carmegliptin enlists a Bischler-Napieralski reaction utilising the primary amine 2.76 and methyl formate to yield the initial dihydroquinoline 2.77 as its HCl salt (Scheme 30) [82]. This compound was next treated with 3-oxoglutaric acid mono ethyl ester ( 2.78 ) in the presence of sodium acetate.…”

Hofmann Rearrangement of Carboxamides Mediated by N-Bromo­acetamide

“…All three organohypervalent iodine reagents were tested on hexanamide, dodecanamide and/or 1-benzylpiperidine-4-carboxamide, affording the expected carbamates or free amines, as reported in the literature. [11][12][13][14]…”

“…10 The reaction is usually performed in alcohols, producing carbamates rather than the free amines. Several organohypervalent iodine species have been used extensively, including [bis(trifluoroacetoxy)iodo]benzene (PIFA), 11 (tosylimino)phenyl-λ 3 -iodane (PhINTs), 12 (diacetoxyiodo)benzene (PIDA) 13,14 and others. [15][16][17] Cyclic imides are also useful substrates.…”

Recent Advances and the Prospect of Hypervalent Iodine Chemistry

“…For example, Roche Ltd. by using PIDA-mediated Hofmann rearrangement reaction prepared a precursor of the antidiabetic drug Carmegliptin on hundred-kilogram scale (Scheme 9c). 28 In light of these impressive examples, we think that HIRs would be a promising tool to streamline the total synthesis of challenging molecules and have great potential in industry.…”