抗精神病新药阿立哌唑的合成

Synthesis of antipsychotic aripiprazole

目的合成阿立哌唑并考察优化中间体合成工艺。方法采用7-羟基-3，4-二氢-2（1H）-喹诺酮为起始原料，在碳酸钾存在下，与1，4-二溴丁烷发生醚化生成中间体7-（4-溴丁氧基）-3，4-二氢-2（1H）一喹诺酮（2），在KI和TBAB催化下，继续与N-（2，3-二氯苯基）哌嗪盐酸盐反应，制得目标产物阿立哌唑（1）。在此基础上，对中间体2的合成工艺进行考察，确立了最佳反应条件。结果中间体2和目标产物的结构均已由1H-NMR和MS确证，总收率为67．6％，熔点：139～140℃，与文献报道（139．0～140．0℃）相符。结论和文献报道方法相比，本工艺采用丙酮作为溶剂，代替了文献中采用的DMF溶剂，使合成成本大为降低；采用重结晶的方法进行中间体和目标化合物的纯化，取代了文献中采用的柱层析方法，使操作大为简化，合成工艺更适合于放大合成及工业化。此外，中间体2的合成工艺得到优化后，收率比文献提高了近10％；总收率比文献提高5％．

Objective To prepare aripiprazole（ 1 ） and optimize the synthetic process for the intermediate 7- （4-bromobutoxy） -3,4-dihydro-2 （1H） -quinolone （2）. Methods 7-Hydroxy-3,4-dihydro-2 （1H） -quinolone reacted with potassium carbonate and 1,4-dibromobutane via etherification to give 2. And then 2 reacted with potassium carbonate and 1- （2,3-dichlorophenyl） piperazine hydrochloride under the catalysis of potas- sium iodide and TBAB to give the target product 1. The synthetic process was researched and the reaction conditions were optimized. Results The structures of intermediate 2 and target 1 had been characterized by IR and 1H-NMR. The overall yield was 67.6%. The mp（ 139- 140 ℃ ） of product 1 is consistent with the that （139.0-140.0℃ ）reported in the literature. Conclusions Compare with the previous methods in the lit- eratures,this synthesis process was improved by changing the reaction solvent from DMF to acetone to in- crease the purity of 2. Compound 1 could be obtained by recrystallization once instead of separation on col- umns. The changes can reduce the costs and simplify the experimental operations. Besides, through impro- ving the procedureis of intermediate 2, the overall yield is superior 5 % and the yield of intermediate 2 is su- perior 10% to the literatures＇s,respectively.