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【结 构 式】 
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【分子编号】44337 【品名】(1S)-4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol 【CA登记号】 |
【 分 子 式 】C24H31FN2O3 【 分 子 量 】414.5202232 【元素组成】C 69.54% H 7.54% F 4.58% N 6.76% O 11.58% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII), which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV). The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI), which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII). This compound (XVIII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX), which is submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI). Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII), which is finally treated with POCl3 in refluxing pyridine.
| 【1】 Sorbera, L.A.; Martin, L.; Revel, L.; Castaner, J.; Escitalopram oxalate. Drugs Fut 2001, 26, 2, 115. |
| 【2】 Dall'asta, L.; Casazza, U.; Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0023431 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (XIII) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (XIV) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (XV) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (XVI) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (XVII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XVIII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (XIX) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (XX) | 37599 | 4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (XXI) | 44337 | (1S)-4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol | C24H31FN2O3 | 详情 | 详情 | |
| (XXII) | 44338 | N-[3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine | C24H29FN2O2 | 详情 | 详情 |