1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane -Drug Synthesis Database

【结构式】

【分子编号】16517

【品名】1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane

【CA登记号】13411-42-2

【分子式】C₇H₁₆S₂Si

【分子量】192.42154

【元素组成】C 43.69% H 8.38% S 33.33% Si 14.6%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VIII)

The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III). The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX). The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Silvestre, J.S.; SB-207499. Drugs Fut 1998, 23, 6, 607.
【2】 Christensen, S.B.; Forster, C.J.; Guider, A.; et al.; 1,4-Cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma. J Med Chem 1998, 41, 6, 821-35.
【3】 Bordas-Nagy, J.; Gorycki, P.; Webb, K.S. (SmithKline Beecham plc); Cyano cpds. and preparation thereof. JP 1997510213; WO 9524381 .
【4】 Christensen, S.B. IV (SmithKline Beecham plc); Cpds. useful for treating allergic and inflammatory diseases. EP 0633776; EP 0919544; JP 1995508508; US 5552438; US 5602157; WO 9319749 .

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)	16510	3-(cyclopentyloxy)-4-methoxybenzaldehyde		C₁₃H₁₆O₃	详情	详情
(II)	16511	4-(bromomethyl)-2-(cyclopentyloxy)phenyl methyl ether; 4-(bromomethyl)-2-(cyclopentyloxy)-1-methoxybenzene		C₁₃H₁₇BrO₂	详情	详情
(III)	16512	2-[3-(cyclopentyloxy)-4-methoxyphenyl]acetonitrile		C₁₄H₁₇NO₂	详情	详情
(IV)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(V)	16514	dimethyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]heptanedioate		C₂₂H₂₉NO₆	详情	详情
(VI)	16515	methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate		C₂₁H₂₅NO₅	详情	详情
(VII)	16516	1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile		C₁₉H₂₃NO₃	详情	详情
(VIII)	16517	1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane	13411-42-2	C₇H₁₆S₂Si	详情	详情
(IX)	16518	1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-(1,3-dithian-2-ylidene)cyclohexanecarbonitrile		C₂₃H₂₉NO₂S₂	详情	详情
(XII)	16519	methyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate		C₂₁H₂₇NO₄	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 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III), which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV). The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI), which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride, BuLi and TEA in THF giving the acylated thiazolidine (VIII). The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X), which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI). The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII), which is debenzylated by hydrogenation with H2 over Pd/C in methanol.

参考文献中间体

合成目标

【1】 Deal, J.G.; Bender, S.L.; Chong, W.K.M.; et al.; Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's). 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 197.
【2】 Bender, S.L.; Castelhano, A.L.; Chong, W.K.M.; Abreo, M.A.; Billedeau, R.J.; Chen, J.J.; Deal, J.G. (Agouron Pharmaceuticals, Inc.; Syntex (USA), Inc.); Heteroaryl succinamides and their use as metalloproteinase inhibitors. EP 0937042; JP 2000511201; US 6008243; WO 9817643 .

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)	26664	2,5-dimethoxytetrahydro-3-furancarbaldehyde		C₇H₁₂O₄	详情	详情
(II)	16517	1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane	13411-42-2	C₇H₁₆S₂Si	详情	详情
(III)	26665	3-(1,3-dithian-2-ylidenemethyl)-2,5-dimethoxytetrahydrofuran		C₁₁H₁₈O₃S₂	详情	详情
(IV)	26666	methyl 2-(2,5-dimethoxytetrahydro-3-furanyl)acetate		C₉H₁₆O₅	详情	详情
(V)	26667	4'-amino[1,1'-biphenyl]-4-carbonitrile	4854-84-6	C₁₃H₁₀N₂	详情	详情
(VI)	26668	methyl 2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]acetate		C₂₀H₁₆N₂O₂	详情	详情
(VII)	14694	(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone	90719-32-7	C₁₀H₁₁NO₂	详情	详情
(VIII)	26669	4'-(3-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]-1H-pyrrol-1-yl)[1,1'-biphenyl]-4-carbonitrile		C₂₉H₂₃N₃O₃	详情	详情
(IX)	26670	benzyl (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutanoate		C₃₈H₃₁N₃O₅	详情	详情
(X)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(XI)	26671	(2S)-4-(benzyloxy)-2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutyric acid		C₂₈H₂₂N₂O₄	详情	详情
(XII)	26672	(3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone		C₆H₁₁NO₂	详情	详情
(XIII)	26673	benzyl (3S)-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-[[(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl]amino]-4-oxobutanoate		C₃₄H₃₁N₃O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

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).

参考文献中间体

合成目标

【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

Extended Information