抗精神病新药阿立哌唑的合成

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)-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%。

Synthesis of antipsychotic aripiprazole

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 was reacted with potassium carbonate and 1,4-dibromobutane via etherification to give 2. And then 2 was reacted with potassium carbonate and 1-(2,3-dichloropheny1) piperazine hydrochloride under the catalysis of potassium 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 m.p.(139-140℃) of product 1 is consistent with the that （139.0-140.0℃） reported in the literature. Conclusion Compare with the previous methods in the literatures, this synthesis process was improved by changing the reaction solvent from DMF to acetone to increase the purity of 2, Compound 1 could be obtained by recrystallization once instead of separation on columns. The changes can reduce the costs and simplify the experimental operations. Besides, through improving the procedure is of intermediate 2, the overall yield is superior 5% and the yield of intermediate 2 is superior 10% to the literature, respectively.