曲安奈德的合成新方法  

A Novel Synthetic Process of Triamcinolone Acetonide

作　　者：张金峰[1] 张天杰 郭晔堃[1] 钟静芬[1] ZHANG Jinfeng;ZHANG Tianjie;GUO Yekun;ZHONG Jingfen(Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203)

机构地区：[1]中国医药工业研究总院上海医药工业研究院,上海201203

出　　处：《中国医药工业杂志》2018年第6期737-741,共5页Chinese Journal of Pharmaceuticals

摘　　要：本研究报道了一条合成曲安奈德的新路线。泼尼松龙(2)经21-位羟基乙酰化,在五氯化磷作用下消除11-位羟基、与二氧化硫/N-氯代丁二酰亚胺反应消除17-位羟基得21-羟基孕甾-1,4,9(11),16-四烯-3,20-二酮-21-乙酸酯(5),再经高锰酸钾氧化、亲核加成、21-位酯基水解得16α,17-[(1-甲基亚乙基)双(氧)]孕甾-1,4,9(11)-三烯-21-羟基-3,20-二酮(8),8在二噁烷/水中与二溴海因反应引入9α-位溴和11β-位羟基,最后经9,11-位环氧化、氟代共9步反应合成曲安奈德,总收率为24.2%(以2计),纯度99.9%。其中由化合物2制备5的方法未见文献报道。A novel synthetic route for triamcinolone acetonide was reported. Pregna-1,4,9（11）,16-tetraen-21-hydroxyl-3,20-dione-21-acetate（5） was obtained from prednisolone（2） via acetylation of 21-hydroxy, elimination of 11-hydroxy with phosphorus pentachloride and elimination of 17-hydroxy with N-chlorosuccinimide/SO2 sequentially. Then 5 was subjected to oxidition by potassium permanganate, nucleophilic addition and hydrolysis of 21-ester to give pregna-1,4,9（11）-triene-16α,17-[（1-methylethylidene）bis（oxy）]-21-hydroxyl-3,20-dione（8）. Then 8 reacted with dibromohydantoin in dioxane/water to introduce 9α-bromine and 11β-hydroxy, which was followed by epoxidation and substitution with hydrogen fluoride to give the target compound with an overall yield of 24.2%（based on 2） and a purity of 99.9%. The method for preparing 5 from 2 has not yet been reported in literature.

关 键 词：曲安奈德 糖皮质激素受体激动药 甾体 合成 

分 类 号：R977.1[医药卫生—药品] R914.5[医药卫生—药学]