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【结 构 式】 
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【分子编号】30994 【品名】3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane 【CA登记号】 |
【 分 子 式 】C9H21BrOSi 【 分 子 量 】253.25464 【元素组成】C 42.68% H 8.36% Br 31.55% O 6.32% Si 11.09% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(II)The reaction of 3-bromopropanol (I) with TBDMS-Cl, DIEA and DMAP in dichloromethane gives the silyl ether (II), which is treated with PPh3 in refluxing acetonitrile yielding the phosphonium salt (III). The Wittig reaction of (III) with 3-cholestanone (IV) by means of BuLi in DME affords 3-[3-(tert-butyldimethylsilyloxy)propylidene]cholestane (V), which is reduced with H2 over PtO2 in ethyl acetate giving 3beta-[3-(tert-butyldimethylsilyloxy)propyl]cholestane (VI). The reaction of (VI) with TBAF in THF gives the 3-hydroxypropyl derivative (VII), which is treated with CBr4 and PPh3 in dichloromethane yielding the 3-bromopropyl derivative (VIII). The reaction of (VIII) with PPh3 in refluxing chlorobenzene affords the phosphonium salt (IX), which is submitted to a Wittig condensation with 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) by means of NaN(SiMe3)2 in THF giving the expected condensation intermediate (XI). The intermediate 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) has been obtained as follows: The dimerization of 3-chloro-2-hydroxybenzoic acid (XII) with H2CO and H2SO4 in methanol gives 5,5'-methylenebis(3-chloro-2-hydroxybenzoic acid) (XIII), which is fully methylated with SO4Me2 or CO3Me2 and K2CO3 yielding 5,5'-methylenebis(3-chloro-2-methoxybenzoic acid methyl ester) (XIV). Finally, this compound is oxidized with CrO3 in acetic anhydride to afford the desired intermediate (X).
| 【1】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739. |
| 【2】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040. |
| 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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 30994 | 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane | C9H21BrOSi | 详情 | 详情 | |
| (III) | 30995 | (3-[[tert-butyl(dimethyl)silyl]oxy]propyl)(triphenyl)phosphonium bromide | C27H36BrOPSi | 详情 | 详情 | |
| (IV) | 30996 | (10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | 15600-08-5 | C27H46O | 详情 | 详情 |
| (V) | 30997 | tert-butyl(3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propyl ether | C36H66OSi | 详情 | 详情 | |
| (VI) | 30998 | tert-butyl(dimethyl)silyl 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl ether; tert-butyl(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propoxy)dimethylsilane | C36H68OSi | 详情 | 详情 | |
| (VII) | 30999 | 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-propanol | C30H54O | 详情 | 详情 | |
| (VIII) | 31000 | (3R,10S,13R,17R)-3-(3-bromopropyl)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene | C30H53Br | 详情 | 详情 | |
| (IX) | 31001 | (3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl)(trimethyl)phosphonium bromide | C33H62BrP | 详情 | 详情 | |
| (X) | 26176 | methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzoyl]-2-methoxybenzoate | C19H16Cl2O7 | 详情 | 详情 | |
| (XI) | 31002 | methyl 3-chloro-5-(1-[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-2-methoxybenzoate | C49H68Cl2O6 | 详情 | 详情 | |
| (XII) | 31003 | 3-chloro-2-hydroxybenzoic acid | C7H5ClO3 | 详情 | 详情 | |
| (XIII) | 31004 | 5-(3-carboxy-5-chloro-4-hydroxybenzyl)-3-chloro-2-hydroxybenzoic acid | C15H10Cl2O6 | 详情 | 详情 | |
| (XIV) | 31005 | methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate | C19H18Cl2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 3-bromopropanol (I) with TBDMS-Cl, DIEA and DMAP in dichloromethane gives the silyl ether (II), which is treated with PPh3 in refluxing acetonitrile yielding the phosphonium salt (III). The Wittig reaction of (III) with 3-cholestanone (IV) by means of BuLi in DME affords 3-[3-(tert-butyldimethylsilyloxy)propylidene]cholestane (V), which is reduced with H2 over PtO2 in ethyl acetate giving 3beta-[3-(tert-butyldimethylsilyloxy)propyl]cholestane (VI). The reaction of (VI) with TBAF in THF gives the 3-hydroxypropyl derivative (VII), which is treated with CBr4 and PPh3 in dichloromethane yielding the 3-bromopropyl derivative (VIII). The reaction of (VIII) with PPh3 in refluxing chlorobenzene affords the phosphonium salt (IX), which is submitted to a Wittig condensation with 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) by means of NaN(SiMe3)2 in THF giving the expected condensation intermediate (XI). The intermediate 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) has been obtained as follows: The dimerization of 3-chloro-2-hydroxybenzoic acid (XII) with H2CO and H2SO4 in methanol gives 5,5'-methylenebis(3-chloro-2-hydroxybenzoic acid) (XIII), which is fully methylated with SO4Me2 or CO3Me2 and K2CO3 yielding 5,5'-methylenebis(3-chloro-2-methoxy-benzoic acid methyl ester) (XIV). Finally, this compound is oxidized with CrO3 in acetic anhydride to afford the desired intermediate (X).
| 【1】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040. |
| 【2】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739. |
| 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) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (II) | 30994 | 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane | C9H21BrOSi | 详情 | 详情 | |
| (III) | 30995 | (3-[[tert-butyl(dimethyl)silyl]oxy]propyl)(triphenyl)phosphonium bromide | C27H36BrOPSi | 详情 | 详情 | |
| (IV) | 30996 | (10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | 15600-08-5 | C27H46O | 详情 | 详情 |
| (V) | 30997 | tert-butyl(3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propyl ether | C36H66OSi | 详情 | 详情 | |
| (VI) | 30998 | tert-butyl(dimethyl)silyl 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl ether; tert-butyl(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propoxy)dimethylsilane | C36H68OSi | 详情 | 详情 | |
| (VII) | 30999 | 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-propanol | C30H54O | 详情 | 详情 | |
| (VIII) | 31000 | (3R,10S,13R,17R)-3-(3-bromopropyl)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene | C30H53Br | 详情 | 详情 | |
| (IX) | 31001 | (3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl)(trimethyl)phosphonium bromide | C33H62BrP | 详情 | 详情 | |
| (X) | 26176 | methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzoyl]-2-methoxybenzoate | C19H16Cl2O7 | 详情 | 详情 | |
| (XI) | 31002 | methyl 3-chloro-5-(1-[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-2-methoxybenzoate | C49H68Cl2O6 | 详情 | 详情 | |
| (XII) | 31003 | 3-chloro-2-hydroxybenzoic acid | C7H5ClO3 | 详情 | 详情 | |
| (XIII) | 31004 | 5-(3-carboxy-5-chloro-4-hydroxybenzyl)-3-chloro-2-hydroxybenzoic acid | C15H10Cl2O6 | 详情 | 详情 | |
| (XIV) | 31005 | methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate | C19H18Cl2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)An alternative procedure for the synthesis of indolylpropanol (VII) is depicted as follows: alkylation of 2-trimethylsilyl-1,3-dithiane (IX) with bromide (X) employing n-butyllithium in cold THF afforded (XI). Subsequent hydrolysis of the thioacetal group of (XI) by means of HgO/HgCl2 provided acylsilane (XII). Iodoaniline (XIII) was prepared by iodination of p-triazolylaniline (IV) with iodine monochloride. Condensation of iodoaniline (XIII) with acylsilane (XII) in the presence of Pd(OAc)2 produced the silylated indole (XIV). Then acid treatment of (XIV) removed both silyl groups to give (VII).
| 【1】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
| 【2】 Chen, C.-Y.; Larsen, R.D. (Merck & Co., Inc.); Palladium catalyzed indolization. US 5808064; WO 9806725 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 36537 | 4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline | C8H8N4 | 详情 | 详情 | |
| (VII) | 36538 | 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]-1-propanol | C13H14N4O | 详情 | 详情 | |
| (IX) | 16517 | 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane | 13411-42-2 | C7H16S2Si | 详情 | 详情 |
| (X) | 30994 | 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane | C9H21BrOSi | 详情 | 详情 | |
| (XI) | 36540 | tert-butyl(dimethyl)[3-[2-(trimethylsilyl)-1,3-dithian-2-yl]propoxy]silane; tert-butyl(dimethyl)silyl 3-[2-(trimethylsilyl)-1,3-dithian-2-yl]propyl ether | C16H36OS2Si2 | 详情 | 详情 | |
| (XII) | 36541 | 4-[[tert-butyl(dimethyl)silyl]oxy]-1-(trimethylsilyl)-1-butanone | C13H30O2Si2 | 详情 | 详情 | |
| (XIII) | 36542 | 2-iodo-4-(4H-1,2,4-triazol-4-yl)aniline; 2-iodo-4-(4H-1,2,4-triazol-4-yl)phenylamine | C8H7IN4 | 详情 | 详情 | |
| (XIV) | 36543 | 3-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-5-(4H-1,2,4-triazol-4-yl)-2-(trimethylsilyl)-1H-indole; tert-butyl(dimethyl)silyl 3-[5-(4H-1,2,4-triazol-4-yl)-2-(trimethylsilyl)-1H-indol-3-yl]propyl ether | C22H36N4OSi2 | 详情 | 详情 |