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【结 构 式】 
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【分子编号】49155 【品名】[2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol 【CA登记号】 |
【 分 子 式 】C19H30Cl2O2S2Si 【 分 子 量 】453.5689 【元素组成】C 50.31% H 6.67% Cl 15.63% O 7.05% S 14.14% Si 6.19% |
合成路线1
该中间体在本合成路线中的序号：(I)In a different strategy, the racemic intermediate aldehyde (IX) has been obtained as follows: Swern oxidation of the known racemic alcohol (I) yields aldehyde (II), which is further reductively aminated with methylamine to produce the secondary amine (III). Acylation of amine (III) with 3,5-dichlorobenzoyl chloride (IV) leads to amide (V). Subsequent desilylation of (V) with HF in acetonitrile provides alcohol (VI). The thioketal group of (VI) is then removed by treatment with HgClO4 and CaCO3, yielding ketone (VII). Treatment of (VII) with O-methyl hydroxylamine, followed by separation of the resultant E-/Z- mixture of isomers furnishes the desired O-methyl oxime (VIII). The primary alcohol function of (VIII) is then oxidized under Swern conditions to provide aldehyde (IX)
| 【1】 Ting, P.C.; Lee, J.F.; Shih, N.-Y.; et al.; Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]- 2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist. Bioog. Med. Chem. Lett. 2002, 12, 16, 2125. |
| 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) | 49155 | [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol | C19H30Cl2O2S2Si | 详情 | 详情 | |
| (II) | 61355 | 2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolane-2-carbaldehyde | C19H28Cl2O2S2Si | 详情 | 详情 | |
| (III) | 61356 | N-({2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}methyl)-N-methylamine; {2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}-N-methylmethanamine | C20H33Cl2NOS2Si | 详情 | 详情 | |
| (IV) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (V) | 61357 | N-({2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}methyl)-3,5-dichloro-N-methylbenzamide | C27H35Cl4NO2S2Si | 详情 | 详情 | |
| (VI) | 61358 | 3,5-dichloro-N-({2-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-1,3-dithiolan-2-yl}methyl)-N-methylbenzamide | C21H21Cl4NO2S2 | 详情 | 详情 | |
| (VII) | 61359 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-5-hydroxy-2-oxopentyl]-N-methylbenzamide | C19H17Cl4NO3 | 详情 | 详情 | |
| (VIII) | 61360 | 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-5-hydroxy-2-(methoxyimino)pentyl]-N-methylbenzamide | C20H20Cl4N2O3 | 详情 | 详情 | |
| (IX) | 44276 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide | C20H18Cl4N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Conjugate addition of the lithium enolate of ethyl 1,3-dithiolane-2-carboxylate (II) to methyl 3,4-dichlorocinnamate (I) afforded the diester adduct (III). Reduction of (III) with LiAlH4 gave diol (IV), which was selectively monosilylated with tert-butyldimethylsilyl chloride, yielding (V). Condensation of the potassium alkoxide of (V) with 3,5-bis(trifluoromethyl)benzyl bromide (VI) provided ether (VII). After desilylation of (VII) with HF in acetonitrile to alcohol (VIII), the hydrolysis of its thioketal function with mercuric perchlorate and CaCO3 furnished ketone (IX). Treatment of (IX) with methoxyamine gave rise to a mixture of (E)- and (Z)-oximes from which the desired (Z)-isomer (X) was isolated by flash chromatography. Swern oxidation of the alcohol functionality of (X) produced the corresponding aldehyde, which was reductively condensed with piperidinyl pyrrolidone (XI) in the presence of NaBH3CN to afford the title compound.
| 【1】 Anthes, J.C.; Lee, J.F.; Piwinski, J.J.; Shih, N.-Y.; Ting, P.C.; Synthesis of substituted 4(Z)-(methoxyimino)penthyl-1-piperidines as dual NK1/NK2 inhibitors. Bioorg Med Chem Lett 2001, 11, 4, 491. |
| 【2】 Shankar, B.B. (Schering Corp.); Substd. oximes, hydrazones and olefins useful as neurokinin antagonists. EP 0823896; EP 0937064; JP 1998506923; JP 2000504341; US 5688960; US 5696267; WO 9634857; WO 9818785 . |
| 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) | 49151 | methyl (E)-3-(3,4-dichlorophenyl)-2-propenoate | C10H8Cl2O2 | 详情 | 详情 | |
| (II) | 49152 | 2-Carboethoxy-1,3-dithiolane; Ethyl glyoxylate ethylene thioacetal; 1,3-Dithiolane-2-carboxylic acid ethyl ester; 2-Ethoxycarbonyl-1,3-dithiolane; Glyoxylic acid ethyl ester ethylene mercaptal; Ethyl 1,3-dithiolane-2-carboxylate | 20461-99-8 | C6H10O2S2 | 详情 | 详情 |
| (III) | 49153 | ethyl 2-[1-(3,4-dichlorophenyl)-3-methoxy-3-oxopropyl]-1,3-dithiolane-2-carboxylate | C16H18Cl2O4S2 | 详情 | 详情 | |
| (IV) | 49154 | 3-(3,4-dichlorophenyl)-3-[2-(hydroxymethyl)-1,3-dithiolan-2-yl]-1-propanol | C13H16Cl2O2S2 | 详情 | 详情 | |
| (V) | 49155 | [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol | C19H30Cl2O2S2Si | 详情 | 详情 | |
| (VI) | 27677 | 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene | 32247-96-4 | C9H5BrF6 | 详情 | 详情 |
| (VII) | 49156 | 3,5-bis(trifluoromethyl)benzyl [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methyl ether; [3-[2-([[3,5-bis(trifluoromethyl)benzyl]oxy]methyl)-1,3-dithiolan-2-yl]-3-(3,4-dichlorophenyl)propoxy](tert-butyl)dimethylsilane | C28H34Cl2F6O2S2Si | 详情 | 详情 | |
| (VIII) | 49157 | 3-[2-([[3,5-bis(trifluoromethyl)benzyl]oxy]methyl)-1,3-dithiolan-2-yl]-3-(3,4-dichlorophenyl)-1-propanol | C22H20Cl2F6O2S2 | 详情 | 详情 | |
| (IX) | 49158 | 1-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-(3,4-dichlorophenyl)-5-hydroxy-2-pentanone | C20H16Cl2F6O3 | 详情 | 详情 | |
| (X) | 49159 | 1-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-(3,4-dichlorophenyl)-5-hydroxy-2-pentanone O-methyloxime | C21H19Cl2F6NO3 | 详情 | 详情 | |
| (XI) | 49160 | 1-(4-piperidinyl)-2-pyrrolidinone | C9H16N2O | 详情 | 详情 |