氯氮平的合成

Synthesis of Clozapine

用2,5-二氯硝基苯与邻氨基苯甲酸在DMF中以碳酸钾催化直接进行乌尔曼缩合反应得2-(4-氯-2-硝基苯胺基)苯甲酸,然后经水合肼/三氯化铁还原生成2-(2-氨基-4-氯苯胺基)苯甲酸,再在二甲苯中以多聚磷酸催化环合得8-氯-5,10-二氢-11H-二苯并[b,e][1,4]二氮-11-酮,最后在四氯化钛作用下与N-甲基哌嗪缩合得氯氮平,总收率以2,5-二氯硝基苯计为43%。

2,5-Dichloronitrobenzene and anthranilic acid were reacted in the presence of potassium carbonate with DMF as solvent to produce 2-（4-chloro-2-nitroanilino）benzoic acid, which was reduced to 2-（2-amino-4- chloroanilino） benzoic acid （5） by hydrazine hydrate and FeC13·6H2O. Catalyzed by polyphosphoric acid in xylene, 5 was cyclized into 8-chloro-5,10-dihydro- 11H-dibenzo [b,e] [ 1,4] diazepin- I 1-one. The later was coupled with N-methylpiperazine in the presence of titanium tetrachloride to give clozapine. The overall yield was 43 %, based on 2,5- dichloronitrobenzene.