拉洛西芬製程研究

本研究是以間-甲氧基苯硫酚經一系列反應合成具有苯併噻吩之拉洛西芬，並以高壓液相層析方法探討製程。拉洛西芬的合成開發是以間-甲氧基苯硫酚與2-溴-4-甲氧基苯乙酮反應，來合成2-(間-甲氧基苯硫基)-4-甲氧基苯乙酮)，經環化後，得到6-甲氧基-2-(4-甲氧基苯基) 苯併噻吩。另外將4-羥基-苯甲酸甲酯與1-(2-氯乙氧基) 哌吡啶鹽酸鹽合成得到4-(2-哌吡啶基乙氧基)-苯甲酸鹽酸鹽，並進一步醯化後與6-甲氧基-2-(4-甲氧基苯基) 苯併噻吩合成6-羥基-2-(4-羥基苯基)-3-[4-(2-哌吡啶基乙氧基)苯甲基] 苯併噻吩鹽酸鹽。另外利用雙-(N,N-三甲基矽基)尿素 (BSU )，進行6-甲氧基-2-(4-甲氧基苯基)苯併噻吩保護基置換，修改反應途徑，得到6-三甲基矽氧基-2-(4-三甲基矽氧基苯基) 苯併噻吩，再與4-(2-哌吡啶基乙氧基)-苯甲酸鹽酸鹽進行Friedel craft 反應，在去甲基保護時，更易於脫去，並解決了空氣污染的環保問題。

關鍵字

拉洛西芬；苯併噻吩

並列摘要

3-methoxybenzenethiol is used as the starting material to yield Raloxifene. α-(3-methoxyphenylthio)-4-methoxyacetophenoe was prepared from the reaction of 3-methoxybenzenethiol with 2-bromo-4-methoxy acetophenone. The key intermediate 6-methoxy-2-(4-methoxyphenyl) benzo[b]thiophene was prepared by the cyclization rearrangement induced by polyphosphoric acid (PPA). The intermediate 4-(2-piperidinoethoxy)benzoic acid hydrochloride was prepared from the reaction of methyl-4-hydroxybenzoate with 1-(2-chloroethyl) piperidine hydrochloride. They reacted with 6-methoxy-2-(4-methoxyphenyl) benzo[b]thiophene to yield 6-hydroxy-2-(4-hydroxypheneyl)-3-[4-(2- piperidinoethoxyl)benzyl]benzo[b]thiophene hydrochloride (Raloxifene). The compoud 6-trimethylsiloxy-2-(4-trimethylsiloxyphenyl)benzo[b] thiophene 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene was prepared from Bis-(N,N-trimethylsilyl)-urea (BSU ). It reacted with 4- (2-piperidinoethoxy)benzoic acid hydrochloride to yield Raloxifene. The latter method gave more efficient demethylation and environmental problems .

並列關鍵字

demethylation ； Friedel craft ； Raloxifene ； polyphosphoric acid

參考文獻

1.Charles D.Jones,Mary G.Jevnikar,Andrew J.Pike, Mary K.Peters,Larry

J.Black,Allen R. Thompson, Julie F.Falcone,and James A. Clemens. J.Med.

chem.,27,1057-1066. (1984)

2.Charles D.Jones,U.S.Patent.4418068, 1983.

5.C. David Jones;Tulio Suarez ,U.S.Patent.4133814, 1979 .

國際替代計量

拉洛西芬製程研究

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