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4-哌啶甲酰胺(4)经氨基保护得N-叔丁氧羰基哌啶-4-甲酰胺(5),经硫代得4-硫代氨甲酰基哌啶-1-甲酸叔丁酯(6),经成环反应得4-(4-氯甲基噻唑-2-基)哌啶-1-甲酸叔丁酯(7),再经醚化、脱保护及取代反应合成MBX-2982(1)。本研究进行如下改进:制备5时,用碳酸钾替代4-二甲胺基吡啶(DMAP)使后处理简便快速;制备6时,用乙醚作析晶溶剂使收率由72%提高至84.5%;制备7时,减少了2种反应试剂(硫酸镁和碳酸镁),降低反应温度(由回流降至室温),反应正常进行。制备1时,采用钯催化剂和膦配体偶联条件使原料反应完全。本研究总收率42%(以4计,文献总收率30.8%)。
4-Piperidinecarboxamide (4) N-tert-Butoxycarbonylpiperidine-4-carboxamide (5) protected by amino group was treated with thio to give tert-butyl 4-thiocarbamoylpiperidine- (6) was synthesized by cyclization reaction of tert-butyl 4- (4-chloromethylthiazol-2-yl) piperidine-1-carboxylate (7), followed by etherification, deprotection and substitution reaction MBX-2982 (1). In this study, the following improvements were made: Preparation of 5, the use of potassium carbonate instead of 4 - dimethylaminopyridine (DMAP) post-processing simple and quick; preparation 6, the use of ether as a crystallization solvent yield increased from 72% to 84.5% ; Preparation 7, reducing the two reaction reagents (magnesium sulfate and magnesium carbonate), reducing the reaction temperature (from reflux to room temperature), the reaction was normal. Preparation 1, the use of palladium catalyst and phosphine ligand coupling conditions so that the reaction of raw materials completely. The total yield of this study was 42% (by 4 terms, the total literature yield was 30.8%).