ethyl 2-(trimethylsilyl)acetate -Drug Synthesis Database

【结构式】

【分子编号】49044

【品名】ethyl 2-(trimethylsilyl)acetate

【CA登记号】

【分子式】C₇H₁₆O₂Si

【分子量】160.28834

【元素组成】C 52.45% H 10.06% O 19.96% Si 17.52%

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：(XVIII)

Hydrogenolysis of the isoxazoline ring of (XV) in the presence of Raney-nickel and boric acid generated the (hydroxymethyl)cyclohexanone (XVI). After hydroxyl group protection of (XVI) as the silyl ether (XVII), Peterson olefination of the ketone function of (XVII) with the lithium derivative of ethyl trimethylsilylacetate (XVIII) furnished the unsaturated ester (XIX). Desilylation of (XIX) gave the primary alcohol (XX), which was dehydrated to (XXI) by treatment with methanesulfonyl chloride and pyridine. The 1-(ethoxy)ethoxy protecting group of (XXI) was then replaced by a silyl ether (XXII) by acidic ketal hydrolysis, followed by treatment with tert-butyldiphenylsilyl chloride and imidazole. Subsequent acetonide (XXII) hydrolysis gave diol (XXIII), which was regioselectively mono-silylated providing intermediate (XXIV)

参考文献中间体

合成目标

【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	59863	(3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole	C₁₄H₂₃NO₅	详情	详情
(XVI)	59864	(3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one	C₁₄H₂₄O₆	详情	详情
(XVII)	59865	(3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one	C₂₀H₃₈O₆Si	详情	详情
(XVIII)	49044	ethyl 2-(trimethylsilyl)acetate	C₇H₁₆O₂Si	详情	详情
(XIX)	59867	ethyl 2-[(3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate	C₂₄H₄₄O₇Si	详情	详情
(XX)	59866	ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate	C₁₈H₃₀O₇	详情	详情
(XXI)	59868	ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate	C₁₈H₂₈O₆	详情	详情
(XXII)	59869	ethyl 2-[(3aR,7R,7aS)-7-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate	C₃₀H₃₈O₅Si	详情	详情
(XXIII)	59870	ethyl 2-((3R,4S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)acetate	C₂₇H₃₄O₅Si	详情	详情
(XXIV)	59871	ethyl 2-((3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)acetate	C₄₃H₅₂O₅Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

The hydrogenation of 1,3,5-trihydroxybenzene (X) with H2 over Raney-Ni gives a mixture of the cis-triol (XI) and the trans-triol (XII), which is submitted to a thermal isomerization to obtain a trans-enriched mixture. The acetylation of (XI) + (XII) with acetic anhydride and pyridine affords the mixture of triacetates (XIII) + (XIV), which is submitted to a selective deacetylation by means of Lipase OF (isolated from Candida rugosa) to provide the enantiomerically pure diacetate (XV). The oxidation of (XV) with NaOCl and tempo in dichloromethane/water gives the chiral ketone (XVI), which is condensed with ethyl 2-(trimethylsilyl)acetate (XVII) by means of LDA in THF to yield the cyclohexylideneacetate (XVIII). The deacetylation of (XVIII) by means of K2CO3 in methanol/water affords the chiral dihydroxy compound (XIX), which is protected with Tbdms-Cl and imidazole to provide the bis-silyl ether (XX). The reduction of the ester group of (XX) with Red-Al in toluene furnishes the allyl alcohol (XXI), which is treated with TsCl and n-BuLi to obtain the tosylate (XXII). The reaction of (XXII) with diphenylphosphine and BuLi in THF gives the phosphinoxide (XXIII), which is condensed with the intermediate aldehyde (IX) by means of BuLi in THF to yield the silylated precursor (XXIV). Finally, this compound is desilylated by means of TBAF in THF.

参考文献中间体

合成目标

【1】 Wirz, B.; Hilpert, H.; Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D-3 derivative. Tetrahedron 2001, 57, 4, 681.
【2】 Hilpert, H.; Wirz, B. (F. Hoffmann-La Roche AG); New process for the preparation of retiferol derivs.. EP 1094060 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	49038	(Z)-10,10,10-trifluoro-5,5-dimethyl-9-[(triethylsilyl)oxy]-9-(trifluoromethyl)-7-decenal		C₁₉H₃₂F₆O₂Si	详情	详情
(X)	11799	1,3,5-Benzenetriol; Fluoroglucinol	108-73-6	C₆H₆O₃	详情	详情
(XI)	11800	1,3,5-Cyclohexanetriol; cis,cis-1,3,5-Cyclohexanetriol dihydrate	50409-12-6	C₆H₁₂O₃	详情	详情
(XII)	49039	1,3,5-cyclohexanetriol		C₆H₁₂O₃	详情	详情
(XIII)	49040	3,5-bis(acetoxy)cyclohexyl acetate		C₁₂H₁₈O₆	详情	详情
(XIV)	49041	3,5-bis(acetoxy)cyclohexyl acetate		C₁₂H₁₈O₆	详情	详情
(XV)	49042	(1R,3R)-3-(acetoxy)-5-hydroxycyclohexyl acetate		C₁₀H₁₆O₅	详情	详情
(XVI)	49043	(1S,3S)-3-(acetoxy)-5-oxocyclohexyl acetate		C₁₀H₁₄O₅	详情	详情
(XVII)	49044	ethyl 2-(trimethylsilyl)acetate		C₇H₁₆O₂Si	详情	详情
(XVIII)	49045	ethyl 2-[(3R,5R)-3,5-bis(acetoxy)cyclohexylidene]acetate		C₁₄H₂₀O₆	详情	详情
(XIX)	49046	ethyl 2-[(3R,5R)-3,5-dihydroxycyclohexylidene]acetate		C₁₀H₁₆O₄	详情	详情
(XX)	49047	ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate		C₂₂H₄₄O₄Si₂	详情	详情
(XXI)	49048	2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol		C₂₀H₄₂O₃Si₂	详情	详情
(XXII)	49049	2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl 4-methylbenzenesulfonate		C₂₇H₄₈O₅SSi₂	详情	详情
(XXIII)	30302	[2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide		C₃₂H₅₁O₃PSi₂	详情	详情
(XXIV)	49050	[[(2Z,9E)-11-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-5,5-dimethyl-1,1-bis(trifluoromethyl)-2,9-undecadienyl]oxy](triethyl)silane; (2Z,9E)-11-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-5,5-dimethyl-1,1-bis(trifluoromethyl)-2,9-undecadienyl triethylsilyl ether		C₃₉H₇₂F₆O₃Si₃	详情	详情

Extended Information