【结 构 式】 |
【分子编号】62897 【品名】methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetate 【CA登记号】 |
【 分 子 式 】C22H23ClN4O4S 【 分 子 量 】474.96788 【元素组成】C 55.63% H 4.88% Cl 7.46% N 11.8% O 13.47% S 6.75% |
合成路线1
该中间体在本合成路线中的序号:(XI)The nitration of 2,5-dichlorotoluene (I) with HNO3 in H2SO4/AcOH gives 2,5-dichloro-4-methylnitrobenzene (II), which is treated with t-butoxybis(dimethylamino)methane (III) in refluxing THF to yield 2,5-dichloro-4-[2-(dimethylamino)vinyl]nitrobenzene (IV). The condensation of (IV) with 1-(1,2-benzoisothiazol-3-yl)piperazine (V) in AcOH affords the disubstituted piperazine (VI), whose double bond is reduced by means of NaBH(OAc)3 in dichloroethane/AcOH to provide the saturated compound (VII). The condensation of (VII) with dimethyl malonate (VIII) by means of KOH in NMP gives the alkylated malonic ester (IX), which is hydrolyzed and monodecarboxylated with refluxing 3N HCl to yield the phenylacetic acid (X). The esterification of (X) with SOCl2 and methanol affords the methyl ester (XI), which is finally cyclized to the target indolone by reduction of its nitro group with sodium hydrosulfite in refluxing THF/ethanol. Alternatively, compound (VII) can be condensed with methyl cyanacetate (XII) by means of KOH in NMP to give the alkylated cyanacetic ester (XIII), which is hydrolyzed with refluxing 3N HCl to afford the already reported phenylacetic acid (X).
【1】 Urban, F.J.; et al.; A novel synthesis of the antipsychotic agent ziprasidone. Synth Commun 1996, 26, 8, 1629. |
【2】 Urban, F.J. (Pfizer Inc.); Processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one. WO 9500510 . |
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) | 62890 | 1,4-dichloro-2-methylbenzene | C7H6Cl2 | 详情 | 详情 | |
(II) | 62891 | 1,4-dichloro-2-methyl-5-nitrobenzene | C7H5Cl2NO2 | 详情 | 详情 | |
(III) | 21487 | N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine | C9H22N2O | 详情 | 详情 | |
(IV) | 62892 | (E)-2-(2,5-dichloro-4-nitrophenyl)-N,N-dimethyl-1-ethenamine; N-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-N,N-dimethylamine | C10H10Cl2N2O2 | 详情 | 详情 | |
(V) | 16280 | 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) | 87691-87-0 | C11H13N3S | 详情 | 详情 |
(VI) | 62893 | 3-{4-[(E)-2-(2,5-dichloro-4-nitrophenyl)ethenyl]-1-piperazinyl}-1,2-benzisothiazole | C19H16Cl2N4O2S | 详情 | 详情 | |
(VII) | 62894 | 3-[4-(2,5-dichloro-4-nitrophenethyl)-1-piperazinyl]-1,2-benzisothiazole | C19H18Cl2N4O2S | 详情 | 详情 | |
(VIII) | 19373 | dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
(IX) | 62895 | dimethyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)malonate | C24H25ClN4O6S | 详情 | 详情 | |
(X) | 62896 | 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetic acid | C21H21ClN4O4S | 详情 | 详情 | |
(XI) | 62897 | methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)acetate | C22H23ClN4O4S | 详情 | 详情 | |
(XII) | 34458 | Cyanoacetic acid methyl ester; methyl 2-cyanoacetate | 105-34-0 | C4H5NO2 | 详情 | 详情 |
(XIII) | 62898 | methyl 2-(5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-4-chloro-2-nitrophenyl)-2-cyanoacetate | C23H22ClN5O4S | 详情 | 详情 |