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【结 构 式】 
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【分子编号】21487 【品名】N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine 【CA登记号】 |
【 分 子 式 】C9H22N2O 【 分 子 量 】174.28656 【元素组成】C 62.02% H 12.72% N 16.07% O 9.18% |
合成路线1
该中间体在本合成路线中的序号：(B)The acetylation of 5-aminoindane (I) with acetic anhydride gives N-(5-indanyl)acetamide (II), which is nitrated with HNO3 in glacial acetic acid yielding N-(6-nitro-5-indanyl)acetamide (III) and a small amount of the isomer (IV). The product (III) is hydrolyzed with HCl to 6-nitro-5-indanylamine (V). This nitroamine can also be obtained by nitration of 5-aminoindane (I). The Sandmeyer reaction of 6-nitro-5-indanylamine (V) with HNO2 and CuBr/NaBr in HBr leads to 6-nitro-5-bromoindane (VI), which reacts with 2,4-difluorophenol in the presence of KOC(CH3)3/CuCl in tert-butanol to yield 6-nitro-5-(2,4-difluorophenoxy)indane (VII). Starting from (VII), CGP-28238 can be prepared by two different routes: a) Condensation of (VII) with tert-butoxy-bis(dimethylamino)methane followed by ozonolysis of the enamine (VIII), and reduction of the nitro group using Raney-Ni and hydrazine hydrate yields 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X). In the last step the intermediate (X) is mesylated with mesylchloride to give CGP-28238. b) Reduction of (VII) using Raney-Ni and hydrazine hydrate gives 5-amino-6-(2,4-difluorophenoxy)indane (XI), which is acetylated with acetic anhydride and oxidized with CrO3 to yield a mixture of indanone (XII) and (XIII). Chromatographic separation and hydrolysis of (XII) with HCl in ethanol gives 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X), which can be mesylated, as before, to CGP-28238.
| 【1】 Schroder, E.; Rufer, C.; Bottcher, I.; Kapp, J.-F. (Schering AG); Novel indanyl derivs., their preparation and use. EP 0056956; US 4375479 . |
| 【2】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80. |
| 【3】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42. |
| 【4】 Wiesenberg, I.; Ferrini, P.G.; CGP-28238. Drugs Fut 1989, 14, 11, 1035. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 21486 | 2,4-difluorophenol | 367-27-1 | C6H4F2O | 详情 | 详情 |
| (B) | 21487 | N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine | C9H22N2O | 详情 | 详情 | |
| (I) | 21473 | 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine | 24425-40-9 | C9H11N | 详情 | 详情 |
| (II) | 21474 | N-(2,3-dihydro-1H-inden-5-yl)acetamide | C11H13NO | 详情 | 详情 | |
| (III) | 21475 | N-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide | C11H12N2O3 | 详情 | 详情 | |
| (IV) | 21476 | N-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide | C11H12N2O3 | 详情 | 详情 | |
| (V) | 21477 | 6-nitro-2,3-dihydro-1H-inden-5-ylamine; 6-nitro-5-indanamine | C9H10N2O2 | 详情 | 详情 | |
| (VI) | 21478 | 5-bromo-6-nitroindane | C9H8BrNO2 | 详情 | 详情 | |
| (VII) | 21479 | 5-(2,4-difluorophenoxy)-6-nitroindane | C15H11F2NO3 | 详情 | 详情 | |
| (VIII) | 21480 | N-[[6-(2,4-difluorophenoxy)-5-nitro-2,3-dihydro-1H-inden-1-ylidene]methyl]-N,N-dimethylamine | C18H16F2N2O3 | 详情 | 详情 | |
| (IX) | 21481 | 6-(2,4-difluorophenoxy)-5-nitro-1-indanone | C15H9F2NO4 | 详情 | 详情 | |
| (X) | 21482 | 5-amino-6-(2,4-difluorophenoxy)-1-indanone | C15H11F2NO2 | 详情 | 详情 | |
| (XI) | 21483 | 6-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-ylamine | C15H13F2NO | 详情 | 详情 | |
| (XII) | 21484 | N-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydro-1H-inden-5-yl]acetamide | C17H13F2NO3 | 详情 | 详情 | |
| (XIII) | 21485 | N-[6-(2,4-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-5-yl]acetamide | C17H13F2NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)1) Condensation of (VII) with tert-butoxybis(dimethylamino)methane followed by ozonolysis of the enamine (VIII) and reduction of the nitro group using Raney Ni yields 5-amino-6-phenoxy-1-indanone (X). In the last step the intermediate (X) is mesylated with mesyl chloride to give CGP 28237.
| 【1】 Ferrini, P.G.; Bottcher, I.; CGP-28237. Drugs Fut 1987, 12, 1, 9. |
| 【2】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42. |
| 【3】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 21487 | N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine | C9H22N2O | 详情 | 详情 | |
| (VII) | 23070 | 6-nitro-2,3-dihydro-1H-inden-5-yl phenyl ether; 5-nitro-6-phenoxyindane | C15H13NO3 | 详情 | 详情 | |
| (VIII) | 23071 | N,N-dimethyl-N-[(5-nitro-6-phenoxy-2,3-dihydro-1H-inden-1-ylidene)methyl]amine; N,N-dimethyl(5-nitro-6-phenoxy-2,3-dihydro-1H-inden-1-ylidene)methanamine | C18H18N2O3 | 详情 | 详情 | |
| (IX) | 23072 | 5-nitro-6-phenoxy-1-indanone | C15H11NO4 | 详情 | 详情 | |
| (X) | 23073 | 5-amino-6-phenoxy-1-indanone | C15H13NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |