盐酸鲁拉西酮的合成工艺研究

Study on Process of Lurasidone Hydrochloride

合成了抗精神分裂药物盐酸鲁拉西酮。以苯并异噻唑-3(2H)-酮为原料,经氯代、与无水哌嗪缩合得3-(哌嗪-1-基)苯并异噻唑,其和(1R,2R)-环己-1,2-二甲醇二甲磺酸酯反应得反式-3aR,7aR-八氢异吲哚啉-2-螺-1'-[4'-(1,2-苯并异噻唑-3-基)哌嗪]甲磺酸盐,再和顺-降冰片烷-外-2,3-二甲酰亚胺反应得鲁拉西酮,最后经成盐得盐酸鲁拉西酮。目标化合物经光谱确证,三步收率为42%(以苯并异噻唑-3(2H)-酮计)。反应条件温和、操作简便,各步原料价格低廉,采用的工艺操作简便易行。

The synthetic process of Lurasidone Hydrochloride,an atypical antipsychotics which had high affinity with5-HT2 A receptor and the dopamine D2 receptor,was studied. The key intermediate 3-（ piperidin-1-yl） benzisothiazole was synthesized from benzisothiazole-3（ 2H）-one as raw matercial via chlorinated reaction,condensation reaction with anhydrous piperazine. The intermediate trans-3aR,7aR-octahydro-isoindol-2-spiro-1＇-[4＇-（ 1,2-benzisothiazol-oxadia-zol-3-yl） piperazine]methanesulfonate was synthesized from 3-（ piperidin-1-yl） benzisothiazole and（ 1R,2R）-cyclohex-1,2-dimethanol dimethyl sulfonic acid ester by condensation reaction. The free base,lurasidone,was obtained from trans-3aR,7aR-octa-hydroisoindol-2-spiro-1＇-[4＇-（ 1,2-benzisothiazol-oxadia-zol-3-yl） piperazine]methanesulfonate and cis-norbornane-exo-2,3-dicarboxylic amide by condensation reaction. The target compound,lurasidone hydrochloride,was obtained by salification. Results whowed that the total yield of three steps was 42%,and the structure of final compoud was confirmed by the spectrum. The process was simple and easy for industrial production.