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【结 构 式】 
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【药物名称】Risperidone, R-64766, Risperdal M-Tab, Risperdal Consta, Rispolept, Belivon, Risperdal 【化学名称】3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 【CA登记号】106266-06-2 【 分 子 式 】C23H27FN4O2 【 分 子 量 】410.49564 |
【开发单位】Janssen (Originator), Janssen-Kyowa (Licensee), Alkermes (Formulation), Organon (Comarketer) 【药理作用】Antipsychotic Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists |
合成路线1
The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III), which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV). The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V), which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI). Finally, this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.
| 【1】 Kennis, L.E.J.; Vandenberk, J. (Janssen Pharmaceutica NV); Novel 1,2-benzisoxazol-3-yl and 1, 2-benzisothiazo. EP 0196132; ES 8705881; JP 1986221186; US 4804663 . |
| 【2】 Diller, D.; Krochmal, B.; Dolitzky, B.-Z.; Aronhime, J. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Preparation of risperidone. WO 0212200; WO 0214286 . |
| 【3】 Castaner, J.; Prous, J.; Risperidone. Drugs Fut 1988, 13, 12, 1052. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 13700 | 1-Acetyl-4-piperidinecarbonyl chloride | C8H12ClNO2 | 详情 | 详情 | |
| (III) | 23040 | 1-[4-(2,4-difluorobenzoyl)-1-piperidinyl]-1-ethanone | C14H15F2NO2 | 详情 | 详情 | |
| (IV) | 23041 | (2,4-difluorophenyl)(4-piperidinyl)methanone | C12H13F2NO | 详情 | 详情 | |
| (V) | 23042 | (2,4-difluorophenyl)(4-piperidinyl)methanone oxime | C12H14F2N2O | 详情 | 详情 | |
| (VI) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 | |
| (VII) | 23044 | 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | 63234-80-0 | C11H15ClN2O | 详情 | 详情 |
合成路线2
The intermediate 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (IV) has been obtained as follows: The condensation of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (I) with dibenzylamine (II) by means of NaHCO3 in refluxing acetonitrile gives the tertiary amine (III), which is debenzylated by hydrogenation with H2 over Pd/C in warm ethanol to afford the target intermediate (IV).
| 【1】 Huguet-Clotet, J.; Marquillas Olondriz, F.; Caldero Ges, J.M.; Del Castillo Nieto, J.C.; Dalmases Barjoan, P.; Bosch Rovira, A. (Vita-Invest, SA); Process for obtaining 3-2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine-4-one. ES 2074966 . |
| 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) | 23044 | 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | 63234-80-0 | C11H15ClN2O | 详情 | 详情 |
| (II) | 12361 | N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine | 103-49-1 | C14H15N | 详情 | 详情 |
| (III) | 50858 | 3-[2-(dibenzylamino)ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C25H29N3O | 详情 | 详情 | |
| (IV) | 50859 | 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C11H17N3O | 详情 | 详情 |
合成路线3
The condensation of tetrahydropyran-4-carbonyl chloride (V) with refluxing 1,3-difluorobenzene (VI) by means of AlCl3 gives 1-(2,4-difluorophenyl)-1-(tetrahydropyran-4-yl)methanone (VII), which is treated with hydroxylamine hydrochloride and sodium acetate in refluxing ethanol/water to yield the corresponding oxime (VIII). The cyclization of (VIII) by means of KOH in refluxing methanol affords 6-fluoro-3-(tetrahydropyran-4-yl)-1,2-benzisoxazole (IX), which is treated with NaI and Ac-Cl and then with K2CO3 in refluxing acetonitrile to provide the 5-iodopentanol derivative (X). The reaction of the OH group of (X) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XI), which is finally cyclized with the intermediate amine (IV) by means of NaHCO3 in refluxing acetonitrile to yield the target piperidine.
| 【1】 Huguet-Clotet, J.; Marquillas Olondriz, F.; Caldero Ges, J.M.; Del Castillo Nieto, J.C.; Dalmases Barjoan, P.; Bosch Rovira, A. (Vita-Invest, SA); Process for obtaining 3-2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine-4-one. ES 2074966 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 50859 | 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C11H17N3O | 详情 | 详情 | |
| (V) | 50860 | tetrahydro-2H-pyran-4-carbonyl chloride | 40191-32-0 | C6H9ClO2 | 详情 | 详情 |
| (VI) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (VII) | 50861 | (2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanone | C12H12F2O2 | 详情 | 详情 | |
| (VIII) | 50862 | (2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methanone oxime | C12H13F2NO2 | 详情 | 详情 | |
| (IX) | 50863 | 6-fluoro-3-tetrahydro-2H-pyran-4-yl-1,2-benzisoxazole | C12H12FNO2 | 详情 | 详情 | |
| (X) | 50864 | 3-(6-fluoro-1,2-benzisoxazol-3-yl)-5-iodo-1-pentanol | C12H13FINO2 | 详情 | 详情 | |
| (XI) | 50865 | 3-(6-fluoro-1,2-benzisoxazol-3-yl)-5-iodopentyl methanesulfonate | C13H15FINO4S | 详情 | 详情 |
合成路线4
The intermediate 3-(2-chloroethyl)-2-methyl-6, 7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (V) has been obtained as follows: The cyclization of 2-aminopyridine (I) with 3-acetyltetrahydrofuran-2-one (II) by means of polyphosphoric acid (PPA) at 160 C gives 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (III), which is hydrogenated with H2 over Pd/C in ethanol/water to yield the tetrahydro derivative (IV). Finally, the OH group of (IV) is treated with SOCl2 in dichloromethane to afford the target 2-chloroethyl intermediate (V).
| 【1】 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 . |
| 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) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (II) | 24709 | 3-acetyldihydro-2(3H)-furanone | 517-23-7 | C6H8O3 | 详情 | 详情 |
| (III) | 50866 | 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one | C11H12N2O2 | 详情 | 详情 | |
| (IV) | 50867 | 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C11H16N2O2 | 详情 | 详情 | |
| (V) | 23044 | 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | 63234-80-0 | C11H15ClN2O | 详情 | 详情 |
合成路线5
The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII), which is treated with SOCl2 to yield the corresponding acyl chloride (IX). The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI), which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII). The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII), which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV). Finally, this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.
| 【1】 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 23044 | 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | 63234-80-0 | C11H15ClN2O | 详情 | 详情 |
| (VI) | 17402 | 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid | 498-94-2 | C6H11NO2 | 详情 | 详情 |
| (VII) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (VIII) | 50868 | 1-(ethoxycarbonyl)-4-piperidinecarboxylic acid | C9H15NO4 | 详情 | 详情 | |
| (IX) | 50869 | ethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate | C9H14ClNO3 | 详情 | 详情 | |
| (X) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XI) | 50870 | ethyl 4-(2,4-difluorobenzoyl)-1-piperidinecarboxylate | C15H17F2NO3 | 详情 | 详情 | |
| (XII) | 23041 | (2,4-difluorophenyl)(4-piperidinyl)methanone | C12H13F2NO | 详情 | 详情 | |
| (XIII) | 50871 | 3-[2-[4-(2,4-difluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C23H27F2N3O2 | 详情 | 详情 | |
| (XIV) | 50872 | 3-(2-[4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinyl]ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C23H28F2N4O2 | 详情 | 详情 |