3-氨基吡咯烷及其N-衍生物的合成

Synthesis of 3-Aminopyrrolidine and its N-alkylating Derivatives

3-氨基吡咯烷的二盐酸盐和乙酰化物是合成托氟沙星和其它喹诺酮类抗菌药的关键中间体。以苄胺和丙烯酸乙酯为原料经加成反应制得3-苄胺基丙酸乙酯;再与氯乙酸甲酯进行N-烷基化反应制得3-[N-(甲氧羰基亚甲基)苄胺基]丙酸乙酯;然后经狄克曼缩合、脱羧而得1-苄基-3-吡咯烷酮;再经肟化、还原而得中间体3-氨基-1-苄基吡咯烷,并由它进而制得目标化合物的路线因原料价廉易得而具有很大的工业化价值。但原有方法存在产率低,操作烦琐等缺点。经过研究,将原来的N-烷基化反应收率从62.4%提高到95%以上,并对其它一些反应操作进行了相应改进;从而得到一条原料价廉易得,操作方便,成本低的适于工业化的制备目标产物的工艺路线。

The target compounds——3-aminopyrrolidine dihydrochloride and its acetate are the key intermediates of tosufloxacin and other quinolone antibiotics. One of the synthetic routes of the target compounds is from benzylamine and ethylacrylate, which lead to 3-benzylaminopropionate by additional reaction, then affords 3-[N-(methoxycarbonylmethene)benzylamino]propionate through N-alkylation with methyl chloroacetate, further by Dieckmann cyclization, decarboxylation to obtain 1-benzyl-3-pyrrolidine, then oximate and hydrogenate it to gain the intermediate 3-amino-1-benzy1-pyrrolidone, which can be changed to target compounds easily. This route is much of industrial value because of the cheap and easily gained materials. But the original method presents many weakness such as low overall yield and troublesome operate process. We carried out our research work to improve the above method and got an obvious increase of N-alkylation yield from 62.4% to more than 95%, and also some improvement in some reaction process. Thus we succeed in getting an industrial route characterized by cheap and easily gained materials, convenient operate process and low cost.