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【结 构 式】 
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【分子编号】37605 【品名】5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine 【CA登记号】 |
【 分 子 式 】C19H21BrFNO 【 分 子 量 】378.2842832 【元素组成】C 60.33% H 5.6% Br 21.12% F 5.02% N 3.7% O 4.23% |
合成路线1
该中间体在本合成路线中的序号：(IV)Two new methods for the preparation of citalopram have been developed: 1) The Grignard condensation of 5-bromoisobenzofuran-1(3H)-one (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethyiamino)propylmagnesium bromide (III) in THF yields N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (IV). Finally, this compound is treated with Zn(CN) and Pd(PPh3)4 with or without NaCN in refluxing THF. 2) The Grignard condensation of 5-hydroxyisobenzofuran-1(3H)-one (V) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (III) in THF yields N-[3-[5-hydroxy-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (VI). The sulfonation of the hydroxy group of (VI) with trifluromethanesulfonyl chloride affords the triflate (VII), which is finally treated with NaCN, Cul and Pd(PPh3)4 in refluxing acetonitrile.
| 【1】 Rock, M.H.; Petersen, H.; Svane, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0013648 . |
| 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) | 33229 | 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one | 64169-34-2 | C8H5BrO2 | 详情 | 详情 |
| (II) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (III) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
| (IV) | 37605 | 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine | C19H21BrFNO | 详情 | 详情 | |
| (V) | 37606 | 5-hydroxy-2-benzofuran-1(3H)-one | C8H6O3 | 详情 | 详情 | |
| (VI) | 37607 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-ol | C19H22FNO2 | 详情 | 详情 | |
| (VII) | 37608 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl trifluoromethanesulfonate | C20H21F4NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Racemic 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (I) is submitted to optical resolution by chiral chromatography to give the corresponding (S)-isomer (II), which is treated with Zn(CN)2 and Pd(PPh3)4 to afford the target Escitalopram.
| 【1】 Pedersen, H.; Petersen, H.; Lee, J.; Bech Sommer, M.; Nielsen, O.; Ahmadian, H.; Broesen, P.; Geiser, F.; Cox, G.; Dapremont, O.; Suteu, C.; Assenza, S.P.; Hariharan, S.; Nair, U. (H. Lundbeck A/S); Method for the preparation of escitalopram. WO 0306449 . |
| 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) | 37605 | 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine | C19H21BrFNO | 详情 | 详情 | |
| (II) | 60650 | 3-[(1R)-5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine; N-{3-[(1R)-5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl}-N,N-dimethylamine | C19H21BrFNO | 详情 | 详情 |