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【结 构 式】 
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【药物名称】Lurasidone Hydrochloride, MK-3756, SM-13496, SMP-13496 【化学名称】(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-1H-4,7-methanoisoindole-1,3-dione hydrochloride 【CA登记号】367514-88-3 【 分 子 式 】C28H37ClN4O2S 【 分 子 量 】529.1378 |
【开发单位】Dainippon Sumitomo Pharma Co., Ltd. (JP). 【药理作用】Dopamine D2/5-HT2A Antagonist, Treatment of Schizophrenia |
合成路线1
Lurasidone hydrochloride can be synthesized as follows. The condensation of 1-(1,2-benzoisothiazol-3-yl)piperazine (I) with (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane (II) in the presence of potassium carbonate and tetrabutylammonium bisulfate in boiling toluene gives the spiropiperazinium salt (III) (1-3), which is further reacted with bicyclo[2.2.1]heptane-2,3-dicarboximide (IV) by means of potassium carbonate in hot xylene or toluene to yield lurasidone (1-4). Lurasidone base is finally converted to the corresponding hydrochloride salt by treatment with HCl in acetone (5). Scheme 1.
| 【1】 Yujiro, K., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Sumitomo Pharm. Co., Ltd.). Production method of imido derivative. JP 2003160583. |
| 【2】 Nobuyuki, A., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.). Method for producing quaternary ammonium salt. JP 2006169154. |
| 【3】 Nobuyuki, A., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.). Method for producing quaternary ammonium salt. JP 2006169155. |
| 【4】 Saji, I., Muto, M., Tanno, N., Yoshigi, M. (Dainippon Sumitomo Pharma Co., Ltd.). Imide derivatives and their production and use. EP 0464846, JP 5017440, US 5532372, US 5780632. |
| 【5】 Kakiya, Y., Oda, M. (Sumitomo Pharm. Co., Ltd.). Process for producing imide compound. WO 2005009999. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16280 | 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) | 87691-87-0 | C11H13N3S | 详情 | 详情 |
| (II) | 65627 | (R,R)-1,2-Bis(methanesulfonyloxymethyl)cyclohexane; (1R-trans)-1,2-Cyclohexanedimethanol dimethanesulfonate,; (1R,2R)-1,2-Bis(methanesulfonyloxymethyl)cyclohexane | 186204-35-3 | C10H20O6S2 | 详情 | 详情 |
| (III) | 65628 | (3aR,7aR)-4'-(1,2-Benzisothiazol-3-yl)octahydrospiro[2H-isoindole-2,1'-piperazinium] methanesulfonate | 186204-37-5 | C19H26N3S.CH3O3S | 详情 | 详情 |
| (IV) | 11173 | (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C9H11NO2 | 详情 | 详情 |