丙酸氟替卡松杂质K(EP)的合成  

Synthesis of Impurity K(EP)of Fluticasone Propionate

作　　者：高雨 张国宁[1] 王玉成[1] GAO Yu;ZHANG Guoning;WANG Yucheng(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Perking Union Medical College,Beijing 100050)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所,北京100050

出　　处：《中国医药工业杂志》2024年第6期783-788,共6页Chinese Journal of Pharmaceuticals

摘　　要：为控制丙酸氟替卡松原料药的质量,合成了丙酸氟替卡松欧洲药典(EP)杂质K(1)。以经济、易得的地塞米松(2)为起始物,经酰化、氯代、水解脱酰基得6α-氯-9α-氟-11β,17α,21-三羟基-16α-甲基雄甾-1,4-二烯-3,20-二酮(5);5经高碘酸氧化,并与丙酰氯发生取代反应,得6α-氯-9α-氟-11β-羟基-16α-甲基-17α-丙酰氧基-3-氧代雄甾-1,4-二烯-17β-羧酸(7);7与N,N-二甲基硫代甲酰氯进行重排酰化反应后在碱性条件下水解,得6α-氯-9α-氟-11β-羟基-16α-甲基-17α-丙酰氧基-3-氧代雄甾-1,4-二烯-17β-硫代羧酸(9);9与氟溴甲烷在碱性条件下经亲核取代反应,得目标产物1。总收率约48.34%(以2计),纯度大于99%。该路线为1的首次合成报道,同时对丙酸氟替卡松的合成具有一定的参考意义。In order to control the quality of fluticasone propionate,the synthesis route of impurity K(1)in EP of fluticasone propionate was designed.An economical and available starting material,dexamethasone(2),was acylated,chlorinated,hydrolyzed and deacetylated to obtain 6a-chloro-9a-fluoro-11,17a,21-trihydroxy-16a-methyl-androstane-1,4-diene-3,20-dione(5).Then 5 was oxidized by periodic acid followed by the substitution with propionyl chloride to obtain 6α-chloro-9α-fluoro-11β-hydroxy-16a-methyl-17a-propoyloxy-3-oxandrostane-1,4-diene-17β-carboxylic acid(7).Then 7 underwent the rearrangement acylation reaction with N,N-dimethylthioformyl chloride,and then was hydrolyzed under alkaline conditions to obtain 6α-chloro-9a-fluoro-11β-hydroxy-16α-methyl-17α-propoyloxy-3-oxandrostane-1,4-diene-17β-carbothioic acid(9).Finally,the target product 1 was obtained by substituting 9 with bromofluoromethane under alkaline conditions.The total yield was about 48.34%(based on 2)with the purity more than 99%.This synthetic route of1 was reported at the first time,which had certain reference significance for the synthesis of fluticasone propionate.

关 键 词：丙酸氟替卡松杂质K 丙酸氟替卡松 合成工艺 质量控制 

分 类 号：TQ460.6[化学工程—制药化工] R974.3[医药卫生—药品]