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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information