巴多昔芬的合成工艺及其晶型A的制备研究

目的改进巴多昔芬的合成工艺并制备晶型A。方法以对苄氧基溴代苯丙酮为起始原料,经Bischler吲哚成环制得母核;以对羟基苯甲醇为起始原料,经缩合、氯代两步反应制得侧链;母核与侧链经缩合、氢解、成盐、转晶得到晶型A。结果与结论目标化合物的结构经1H-NMR、MS、IR谱等确证,晶型经X-RD衍射确证。新合成路线操作简便,反应条件温和,适合工业化生产,总收率为38.7%。HPLC法检测纯度达99.88%,单个杂质含量小于千分之一,符合中国药典标准。

Preparation of bazedoxifene acetate and its polymorphic form A

Bazedoxifene acetate is a new-generation selective estrogen receptor modulator having a significant therapeutic effect for the treatment of osteoporosis in postmenopausal w omen. An improved method w as designed to prepare the target compound and its polymorphic form A in this paper. Bazedoxifene acetate w as synthesized through 6 steps. The side chain w as got by condensation and chlorination starting from 4-（ hydroxymethyl）-phenol. The parent nucleus was synthesized by condensation taking 1-4-（ benzyloxy）phenyl]-2-bromopropan-1-one as starting material. The synthesized parent nucleus and side chain w ere condensed and further reacted by hydrogenation and acidification to get the objective compound,finally to obtain its polymorphic form A via crystal transformation. The bazedoxifene acetate and its polymorphic form w ere identified by1H-NM R,IR,M S and X-RD diffraction. The improved process w as facile w ith relatively convenient operation procedures and suitable for industrial production.