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【结 构 式】 
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【分子编号】37598 【品名】[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone 【CA登记号】 |
【 分 子 式 】C19H18FNO3 【 分 子 量 】327.3552632 【元素组成】C 69.71% H 5.54% F 5.8% N 4.28% O 14.66% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II), which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV). The cyclization of (IV) by means of SOCl2 affords the oxazoline (V), which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII). This compound (VII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent, providing the cabinol (IX), which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X). Finally, this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (II) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (V) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (VI) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (VII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (VIII) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 37600 | N-[3-[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-[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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II), which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III). The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V), which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI). The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII), which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X). Finally, this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram. Alternatively, the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI), which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII). The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII), which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.
| 【1】 Greenwood, A.K.; McHattie, D.; Rechka, J.A.; Hedger, P.C.M.; Gamble, M.P. (Resolution Chemicals Ltd.); Process for the preparation of citalopram. WO 0166536 . |
| 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) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (II) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (III) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (VI) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (VII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (VIII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (IX) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
| (X) | 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 | |
| (XI) | 55284 | sodium 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxylate | C20H21FNNaO3 | 详情 | 详情 | |
| (XII) | 55285 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C20H21ClFNO2 | 详情 | 详情 | |
| (XIII) | 55286 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxamide | C20H23FN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)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 |