Preparation of Saxagliptin, a Novel DPP-IV Inhibitor

Abstract

The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (1), is described from the two unnatural amino acid derivatives 2 and 3. After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.

The many faces of the adamantyl group in drug design

“…The adamantyl group in 6 and 7 serves a dual role in terms of directing inter-and intra-molecular interactions in the DPP-IV binding site and in reducing the propensity towards intramolecular cyclisation reactions. The production of the inactive cyclic amidine form of 7 has been observed during process-scale production [24].…”

“…The adamantyl-based derivative of pindolol, adamanolol (24), was shown to repress the expression of the Her2 oncogene, which is overexpressed in 30% of patients with breast cancer [112]. The interaction between the activation domain of an epithelialspecific transcription factor, ESX, and the Sur-2 coactivator was inhibited by 24, which lead to repressed Her2 gene expression in cells and a decrease in the viability of Her2-positive breast cancer cell lines [112].…”

Synthetic approaches to the 2009 new drugs

“…The preparation of nalfurafine hydrochloride started with naltrexone benzoate (76) which is available commercially from Aldrich. 62-64 76 was treated with benzylmethylamine (77) in refluxing THF in the presence of molecular sieves (4 Å) to form the intermediate imine which was subsequently reduced in situ using sodium cyanoborohydride to provide benzylmethyl amine 78 in 88% yield (Scheme 13). Removal of the benzyl group in 78 via catalytic hydrogenation and salting the resulting amine with phthalic acid (79) gave secondary amine 80 in 54% yield.…”

Biocatalytic cascade reactions for asymmetric synthesis of aliphatic amino acids in a biphasic reaction system

“…For example, L-3-hydroxyadamantylglycine (L-Hag) and L-tertleucine (L-Tle), which are unnatural amino acids carrying branched-chain aliphatic groups, are essential components of a type-2 diabetes drug (i.e. saxagliptin) [3] and a HIV-protease inhibitor [4], respectively. In addition, L-norvaline carrying a linear aliphatic side chain is a key intermediate of Perindopril (i.e.…”