(3R,4R)-4-叠氮基-3-哌啶醇的合成

Synthesis of (3R,4R)-4-azido-3-piperidinol

研究了以吡啶和苄氯为起始原料,经五步反应得到抗癌药BMS-690514的关键中间体(3R,4R)-4-叠氮基-3-哌啶醇.反应首先得到N-苄基-1,2,3,6-四氢吡啶,进一步通过氯甲酸乙酯取代、环氧化反应得到7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸乙酯,然后发生叠氮化反应得到构型不同的混合产物,通过手性制备得到(3R,4R)-4-叠氮基-3-羟基-1-哌啶甲酸乙酯,水解该中间产物得到最终产物(3R,4R)-4-叠氮基-3-哌啶醇.该方法使用苄氯反应得到更易离去的苄基离去基团,使产物的收率提高了14.2%;采用与已有手性制备(3R,4R)-4-叠氮基-3-羟基-1-哌啶甲酸乙酯的不同方法,使产物的收率提高了20.2%.所用原材料廉价易得,可有效降低成本.

The acquirement of key intermediate (3R, 4R)-4-azido-3-piperidinol of anticancer drug BMS-690514, through five-step reaction is investigated by taking pyridine and benzyl chloride as raw materials. In the reaction, N- benzyl -1,2,3,6- four hydrogen pyridine is obtained. First, Further, 7 - oxa - 3 - azabicyclo[4.1.0]heptane-3-ethyl formate is obtained by substitution of ethyl chloroformate and reaction of epoxidation. Then, the mixed resultants with different types of configuration will be gotten after azide reaction,(3R, 4R)-4-azido base-3-hydroxy-1-piperidine ethyl formate will be obtained by chiral preparation, and final resultant (3R, 4R)-4-azido-3-piperidinol will be gotten to get by hydrolysis of the intermediate resultant. In this method, the benzyl chloride react is used to get a easily departing benzyl-base leaving group, which will increase the yield of the resultant by 14.2%;employment of preparation method of (3R,4R)-ethyl 4-azido-3-hydroxypiperidine-1-carboxylate different from available chiral preparation one will be able to increase the yield of the resultant by 20.2%. Raw materials are cheap and easy to get, and the cost will be effectively reduced.