GeMigliptin

Description

Gemigliptin is a prolyl-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26) inhibitor approved for the treatment of type 2 diabetes mellitus by the Korean Food and Drug Administration in 2012. Gemigliptin was discovered and developed by LG Life Sciences and is now the sixth DPP-4 inhibitor approved for the treatment of type 2 diabetes. At the time this review was prepared, there were no publications describing the discovery strategy and preclinical data that led to the advancement of gemigliptin to the clinic.

The Uses of GeMigliptin

Gemigliptin Hydrochloride is used in biological studies as a novel dipeptidyl peptidase IV (DPP-IV) inhibitors and potential antidiabetic drug.

Definition

ChEBI: Gemigliptin is an organonitrogen compound and an organooxygen compound. It is functionally related to a beta-amino acid.

Synthesis

Commercial N-Boc-3-piperidone (71) was treated with LHMDS followed by ethyl trifluoroacetate to effect a Claisen condensation, producing diketone 72 in 81% yield. Cyclization of 72 with 2,2,2-trifluoroacetamide (73) gave bis-trifluoromethyl dihydropyridopyrimidine 74 in 23% yield. Removal of the Boc protecting group efficiently provided amine 75 in 96% yield.
1,4-Addition of ethyl bromodifluoroacetate (76) to ethyl acrylate (77) in the presence of copper powder and tetramethylethylenediamine (TMEDA) gave diester 78, which was selectively reduced with sodium borohydride (NaBH4) to give alcohol 79 in 90% overall yield for the two-step procedure. Alcohol 79 was then treated with perfluorobutanesulfonyl chloride and triethylamine to give activated alcohol 80 in 75% yield. Boc-L-aspartic acid 4-tert-butyl ester (81) was treated with ammonium bicarbonate and pyridine in the presence of di-tert-butyl dicarbonate to give formamide 82. Dehydration of 82 to give nitrile 83 was accomplished through reaction with cyanuric chloride in 95% overall yield for the two-step sequence. Hydrogenation of 83 in the presence of Pearlman?ˉs catalyst provided butyl amine 84. Alkylation of 84 with activated alcohol 80 in triethylamine followed by cyclization in acetic acid afforded difluoropyridone 85. Acidic hydrolysis of the ester proceeded with concomitant removal of the Boc protecting group, and was followed by reprotection of the amine with di-tert-butyl dicarbonate to give acid 86 in 84% overall yield for the three-step procedure in >97% ee. Coupling of 86 with fragment 75 in the presence of 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) gave amide 87 in 51% yield. Removal of the Boc group with thionyl chloride in ethanol followed by neutralization with aqueous sodium hydroxide and salt formation with L-tartaric acid provided gemigliptin L-tartrate hydrate (X) in 97.5% yield.