【结 构 式】 |
【分子编号】55302 【品名】3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl methanesulfonate 【CA登记号】 |
【 分 子 式 】C19H18FNO4S 【 分 子 量 】375.4206632 【元素组成】C 60.79% H 4.83% F 5.06% N 3.73% O 17.05% S 8.54% |
合成路线1
该中间体在本合成路线中的序号:(X)The intermediate 1-(4-fluorophenyl)-1-(3-hydroxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (IV) has been obtained by three related ways: 1. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(tert-butyldimethylsilyloxy)propyl bromide (II) by means of LDA in THF gives 1-[3-(tert-butyldimethylsilyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (III), which is deprotected with HCl in methanol to yield the hydroxypropyl intermediate (IV). 2. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(benzyloxy)propyl bromide (V) by means of LDA in THF gives 1-[3-(benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (VI), which is deprotected by treatment with 1,4-cyclohexadiene over Pd/C in ethanol to yield the hydroxypropyl intermediate (IV). 3. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(tetrahydropyranyloxy)propyl bromide (VII) by means of LDA in THF gives 1-(4-fluorophenyl)-1-[3-(tetrahydropyranyloxy)propyl]-1,3-dihydroisobenzofuran-5-carbonitrile (VIII), which is deprotected with Ts-OH in methanol to yield the hydroxypropyl intermediate (IV). The reaction of the intermediate (IV) with Ts-Cl and TEA in toluene gives the corresponding tosylate (IX), which is finally treated with dimethylamine in hot DMF to afford the target citalopram. The reaction of the intermediate (IV) with Ms-Cl and TEA in THF gives the corresponding mesylate (X), which is finally treated with dimethylamine in hot ethanol/THF to afford the target citalopram. Alternatively, the reaction of mesylate (X) with NaN3 in hot DMF gives the corresponding azido compound (XI), which is hydrogenated with H2 over Pd/C in EtOH to yield the 3-aminopropyl derivative (XII). Finally, this compound is methylated by means of formaldehyde and NaCNBH3 in methanol to provide the target citalopram.
【1】 Petersen, H.; Rock, M.H.; Ahmadian, H. (H. Lundbeck A/S); Method for the preparation of citalopram. US 6420574 . |
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) | 33233 | 1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C15H10FNO | 详情 | 详情 | |
(II) | 30994 | 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane | C9H21BrOSi | 详情 | 详情 | |
(III) | 55297 | 1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C24H30FNO2Si | 详情 | 详情 | |
(IV) | 55298 | 1-(4-fluorophenyl)-1-(3-hydroxypropyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C18H16FNO2 | 详情 | 详情 | |
(V) | 28080 | 1-[(3-bromopropoxy)methyl]benzene | C10H13BrO | 详情 | 详情 | |
(VI) | 55299 | 1-[3-(benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C25H22FNO2 | 详情 | 详情 | |
(VII) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
(VIII) | 55300 | 1-(4-fluorophenyl)-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1,3-dihydro-2-benzofuran-5-carbonitrile | C23H24FNO3 | 详情 | 详情 | |
(IX) | 55301 | 3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl 4-methylbenzenesulfonate | C25H22FNO4S | 详情 | 详情 | |
(X) | 55302 | 3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl methanesulfonate | C19H18FNO4S | 详情 | 详情 | |
(XI) | 55303 | 1-(3-azidopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C18H15FN4O | 详情 | 详情 | |
(XII) | 55304 | 1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C18H17FN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)This compound has been obtained by several related ways. 1.- The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (I) with 3-chloropropyl tosylate (II) by means of LDA in THF gives 1-(4-fluorophenyl)-1-(3-tosyloxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (III), which is then condensed with dimethylamine in hot DMF to yield the target citalopram. 2.- The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (I) with 3-chloropropyl mesylate (IV) by means of LDA in THF gives 1-(4-fluorophenyl)-1-(3-mesyloxypropyl)-1,3-dihydroisobenzofuran-5- carbonitrile (V), which is then condensed with sodium azide in hot DMF to yield the corresponding azido derivative (VI). The reduction of (VI) with H2 over Pd/C in ethanol affords the 3-aminopropyl derivative (VII), which is finally reductively methylated with formaldehyde and NaBH3CN in methanol to provide the target citalopram. 3.- The reaction of mesylate (V) with methylamine in THF gives the corresponding methylaminopropyl derivative (VIII), which is finally methylated by means of HCHO in refluxing HCOOH to yield the target citalopram. 4.- The direct condensation of mesylate (V) with dimethylamine in hot ethanol/THF also gives the target citalopram.
【1】 Rock, M.H.; Ahmadian, H. (H. Lundbeck A/S); Method for the preparation of citalopram. CA 2401374; EP 1263750; FR 2805814; JP 2003519692; US 2003092761; WO 0151478 . |
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) | 33233 | 1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C15H10FNO | 详情 | 详情 | |
(II) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
(III) | 55301 | 3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl 4-methylbenzenesulfonate | C25H22FNO4S | 详情 | 详情 | |
(IV) | 64194 | 3-chloropropyl methanesulfonate | C4H9ClO3S | 详情 | 详情 | |
(V) | 55302 | 3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl methanesulfonate | C19H18FNO4S | 详情 | 详情 | |
(VI) | 55303 | 1-(3-azidopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C18H15FN4O | 详情 | 详情 | |
(VII) | 55304 | 1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile | C18H17FN2O | 详情 | 详情 | |
(VIII) | 64195 | 1-(4-fluorophenyl)-1-[3-(methylamino)propyl]-1,3-dihydro-2-benzofuran-5-carbonitrile | C19H19FN2O | 详情 | 详情 |