[2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol -Drug Synthesis Database

【结构式】

【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%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

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)

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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

Extended Information