氯氮平的合成工艺改进

Improved Synthetic Process of Clozapine

本研究基于绿色制药理念对氯氮平(1)的合成工艺进行改进。邻氨基苯甲酸(2)和2,5-二氯硝基苯(3)经偶联反应得2-(4-氯-2-硝基苯基)氨基苯甲酸钾(4),该反应用N-甲基吡咯烷酮(NMP)代替N,N-二甲基甲酰胺(DMF)作溶剂,革除了因DMF引入的二甲胺取代杂质2-硝基-4-氯-N,N-二甲基苯胺(7)。用连二亚硫酸钠/氢氧化钠代替水合肼/三氯化铁,还原4得2-(2-氨基-4-氯苯基)氨基苯甲酸(5),并将上述2步“一锅法”反应。用10%硫酸代替多聚磷酸/二甲苯脱水缩合得8-氯-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂䓬-11-酮(6),收率90%。6再在四氯化钛(TiCl4)作用下,与N-甲基哌嗪反应得到1。优化后的工艺操作简便,过程质量强度(PMI)降低约50%,总收率41%(以3计),产品纯度99.93%,更适合工业化生产。

The synthetic process of clozapine(1)was improved based on green chemistry in pharmaceutical industry.2,5-Dichloronitrobenzene(3)coupled with o-aminobenzoic acid(2)to give potassium 2-(4-chloro-2-nitrophenyl)aminobenzoate(4).In the reaction,N-methyl pyrrolidone(NMP)instead of N,N-dimethylformamide(DMF)was used as solvent to avoid the formation of dimethylamine-substituted impurity(4-chloro-N,N-dimethyl-2-nitroaniline,7).Sodium dithionite/sodium hydroxide was used to replace hydrazine hydrate/FeCl3 to give 2-[(2-amino4-chlorobenzyl)amino]benzoic acid(5)by reduction of 4,and the above two steps were merged into one-pot operation.8-Chloro-5,10-dihydro-11H-dibenzodiazepine[b,e][1,4]diazotre-11-one(6)was obtained by dehydration condensation from compound 5 in 10%sulfuric acid instead of polyphosphoric acid/xylene,with the yield of 90%.Compound 6 reacted with N-methyl piperazine in the presence of titanium tetrachloride(TiCl4)to obtain 1 in a purity of 99.93%and a total yield of 41%(based on 3).This improved process was easy to operate and the process mass intensity(PMI)was reduced by half,which was more suitable for industrial production.