Studies On Synthesis And Technique Of Raloxifien: A Selective Estrogen Receptor Modulator

In order to reduce the cost and facilitate the steps, the reaction condition was optimized and the craft of raloxifene, hydrochloride, was researched during the synthesis of it. Reloxifene, [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, hydrochloride, was synthesized with 6-methoxy-2-(4-methoxyphenyl)bnzo[b]thiophene and 4-(2-piperidinoethoxy)benzo-ic acid, hydrochloride. As part of studies with reloxifene, m-methoxy benzenethiol was synthesized with 3-nitroanisole as the raw material, and followed by esterified with sodium ethyl xanthate and hydrolyzed in sodium hydroxide solution, and then acidification. The key intermediate 6-methoxy-2-(4-methoxyphenyl)bnzo[b]thio-phene was prepared by the cyclization rearrangenent induced by polyphosphoric acid (PPA). 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, was prepared by hexahydropyridine. During the synthesis of m-methoxybenzenethiol, m-methoxy-aniline was firstly synthesized with cheap and easily obatained 3-nitroanisole, then drawed the appropriate reaction condition: the reaction temperature is 105℃, the reaction time is 5 hours, and obtained 75% yield. For the process of synthesizing m-methoxyphenethiol from m-methoxyaniline the hydrolyzing reaction condition was optimized, the appropriate reaction temperature is 75℃, the reaction time is 2 hours, and obtained 61% yield. In particular, we added toluene as solvents to serve the m-methoxy benzenexanthate. During the synthesis of 4-methoxy-α-[(3-methoxy-phenyl)thio]acetophenone, the reaction was optimized: the appropriate reaction temperature is 60℃, the reaction time is 3 hours, the mol ratio of m-methoxy benzenexanthate and 4-methoxy-α-[(3-methoxyphenyl)thio]acetophenone is 0.7, the volume ratio of ethanol and water is 2.5, and obtained 84% yield. During the synthesis of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, the reaction was optimized: suitable amount of polyphosphoric acid (PPA) is 6 grammes per 4-methoxy-α-[(3-methoxyphenyl)thio]acetophenone, and obtained 71% yield. During the synthesis of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperi-dinoethoxy)benzoyl]-benzo[b]thiophene, hydrochloride, a mixture of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, and phosphorus pentachloride was heated. The product of crude raloxifene was recrystallized by methanol and water, the steps of purfication were reduced.