Synthesis Of Technical Improvement Of DGAT Inhibitor Intermediates

Diacylglyceryl transferase(DGAT)inhibitor is used primarily to treat obesity and type?diabetes.Over the years,The number of obesity and type?diabetic patients is increasing,It is urgent to develop effective and low toxicity therapeutic drugs.2-(4-bromobenzoyl)cyclopentanecarboxylic acid is an important intermediate for synthesis of diacylglyceryl transferase inhibitors.Synthesis of pure chiral intermediate 2-(4-bromobenzoyl)cyclopentane carboxylic acid is also the focus of this study.The contents of the study consist of two parts:(1)Synthesis of Methyl 2-(4-bromobenzoyl)cyclopentane carboxylate 2-(4-bromobenzoyl)cyclopentane carboxylic acid:Using ethyl acetate cyclohexanone as the raw material.By electrophilic substitution,Favorskii rearrangement,ester hydrolysis,carboxylic acid intramolecular dehydration form anhydride,anhydride alcoholysis,Carboxylic acid forms acyl chloride,The Friedel-Crafts reaction,ester hydrolysis reaction in eight steps to synthesize Methyl 2-(4-bromobenzoyl)cyclopentanecarboxylat.The reaction mechanism of partial synthesis and influencing factors(Such as reaction temperature,solvent,time)were analyzed and screened in this paper.On this basis,the synthetic route is improved and optimized.(2)Chiral resolution of 2-(4-bromobenzoyl)cyclopentane carboxylic acid:It was separated by photoactive resolution.Finally,the optical active pure diacylglyceryl transferase inhibitor intermediate(1R,2R)-2-(4-bromobenzoyl)cyclopentane carboxylic acid and(1S,2S)-2-(4-bromobenzoyl)cyclopentane carboxylic acid were prepared by strong acid treatment.The selection of the splitting agent was analyzed,and the best resolution agent was selected.The product was determined by nuclear magnetic resonance,and the EE value was up to 97%by SFC.The products were confirmed by ~1H NMR spectrum.Through the exploration of the conditions,a series of improvements were made,and finally the optically active pure(1R,2R)-2-(4-bromobenzoyl)cyclopentane carboxylic acid and(1S,2S)-2-(4-bromobenzoyl)cyclopentane carboxylic acid were obtained.