盐酸绿卡色林半水合物的合成工艺及有关物质研究  

Study on synthetic process and impurity of lorcaserin hydrochloride hemihydrate

作　　者：孟涛 刘丹 赫畅 刘晨芳 王钝[1] MENG Tao;LIU Dan;HE Chang;LIU Chen-fang;WANG Dun(School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;Northeast Pharmaceutical Group Co. , Ltd. , Shenyang 110027, China)

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]东北制药集团股份有限公司,辽宁沈阳110027

出　　处：《中国药物化学杂志》2018年第2期128-133,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的优化合成工艺,制备高光学纯度的减肥药盐酸绿卡色林半水合物(lorcaserin hydrochloride hemihydrate)及有关物质。方法以4-氯苯乙酸为起始原料,经过酯化、还原、溴代、胺化、氯代、傅克烃化、拆分、游离、成盐共9步反应得到盐酸绿卡色林半水合物,同时合成一种异构体杂质,分离出一种中间体杂质,并对其进行LC-MS初步结构确证。结果与结论改进后的合成路线总收率为17.8%(4-氯苯乙酸计),含量为99.5%(滴定法)。目标化合物的结构经氢谱、碳谱及质谱确证。该路线原料廉价易得,溶剂可回收套用,收率有大幅度提高,产品化学和光学纯度高,反应操作简便稳定,适合工业化生产。Lorcaserin hydrochloride hemihydrate,an agonist of 5-HT2Creceptor,is indicated for use in the treatment of obesity. An improved synthetic method to synthesize the target structure was reported in this paper. Total nine steps include esterification,reduction,substitution reaction,amination reaction,chlorination reaction,Friedel-Crafts alkylation,enantiomer resolution,free reaction,and salt formation reaction which was started from 4-chlorophenylacetic acid. One intermediate impurity was separated and confirmd preliminaryly by LC-MS,another isomer impurity was synthesized. The overall yield was 17. 8%（based on 4-chlorophenylacetic acid）. The final structure was confirmed by 1H-NMR,13C-NMR and MS. The route has the following advantages： 1） Four-chlorophenylacetic acid as the starting material,the reaction reagents in each step were easy to get,the solvent can be recycled to apply,so the production costs were reduced. 2） The improved synthesis process has higher yield than reported literature,and the product has high chemical purity and optical purity. 3） Each step has the advantages such as simple operation,short time consuming,stable operation.Therefore,the route was very suitable for industrial production.

关 键 词：减肥药 半水合物 绿卡色林 工艺研究 有关物质 

分 类 号：R914[医药卫生—药物化学]