An Alternative Scalable Process for the Synthesis of the Key Intermediate of Omarigliptin

Abstract

An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The asymmetric synthesis relies on the initial diastereoselective alkylation and subsequent aluminum-catalyzed substrate-controlled Meerwein−Ponndorf−Verley reduction. A highly regioselective 5-exo-dig iodocyclization followed to afford 11b, which was then subjected to ring-opening cycloetherification to give product 1 with >99:1 dr and >99% ee in 31.2% overall yield in nine steps. This synthetic strategy has been successfully applied for multikilogram scale production.

Reductive Decarboxylative Alkynylation of N‐Hydroxyphthalimide Esters with Bromoalkynes

“…Propargylglycine, obtainable from 3g by routine deprotection, has been made on large scale to support pharmaceutical synthesis. [20] Our route, from aspartic acid, is an attractive alternative to the chiral auxiliary approach that was recently reported. [21] Linoleic acid was coupled to form 3i in high yield without isomerization of the Z -olefins.…”

“…Propargylglycine, obtainable from 3g by routine deprotection, has been made on large scale to support pharmaceutical synthesis. [20] Our route,f rom aspartic acid, is an attractive alternative to the chiral auxiliary approach that has recently been reported. [21] Linoleic acid was coupled to form 3i in high yield without isomerization of the Z olefins.Although these reactions were set up in ag lovebox for convenience,t he reaction could be run on preparative scale (5 mmol NHP ester) on the benchtop without the need for strict exclusion of moisture and air.…”

Reductive Decarboxylative Alkynylation of N‐Hydroxyphthalimide Esters with Bromoalkynes

“…Another advantage of the NHP esters is that readily available amino acids can be easily converted into useful alkynyl amino acids ( 3 g ) and alkynyl amines ( 3 k and 3 m ). Propargylglycine, obtainable from 3 g by routine deprotection, has been made on large scale to support pharmaceutical synthesis . Our route, from aspartic acid, is an attractive alternative to the chiral auxiliary approach that has recently been reported .…”

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

“…Reducing this approach to practice would result in a more cost-effective and sustainable approach to 4 . Herein, we describe a highly efficient alternative pyranol 4 synthesis that features a highly stereoselective Henry reaction and a unique and effective nitro-Michael–lactolization–dehydration sequence …”