2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE -Drug Synthesis Database

【结构式】

【分子编号】14534

【品名】2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE

【CA登记号】69097-20-7

【分子式】C₁₁H₂₈O₃Si₃

【分子量】292.59802

【元素组成】C 45.15% H 9.65% O 16.4% Si 28.8%

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：(XIX)

2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.

参考文献中间体

合成目标

【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	13955	(3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide		C₁₄H₂₆N₂O	详情	详情
(XIII)	14528	(3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide		C₂₄H₃₉N₃O₂	详情	详情
(XVIII)	56756	diethyl 2-[(2R)-4-chloro-2-methyl-4-oxobutyl]malonate		C₁₂H₁₉ClO₅	详情	详情
(XIX)	14534	2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE	69097-20-7	C₁₁H₂₈O₃Si₃	详情	详情
(XX)	14535	(4S)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-3-oxo-5-phenylpentanoic acid		C₁₉H₁₅NO₆	详情	详情
(XXI)	14536	2-[(1S)-1-benzyl-3-hydroxy-2-oxopropyl]-1H-isoindole-1,3(2H)-dione		C₁₈H₁₅NO₄	详情	详情
(XXII)	14537	(1R,2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(hydroxymethyl)-3-phenylpropyl methanesulfonate		C₁₉H₁₉NO₆S	详情	详情
(XXIII)	14538	2-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]-1H-isoindole-1,3(2H)-dione		C₁₈H₁₅NO₃	详情	详情
(XXIV)	14539	(3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl]decahydro-3-isoquinolinecarboxamide		C₃₂H₄₁N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(A)

Treatment of phenylacetyl chloride (I) with tris(trimethylsilyloxy)ethylene (A) in the presence of SnCl4 affords 1-hydroxy-3-phenylpropan-2-one (II), which is then condensed with ethyl oxalyl chloride (III) in THF in the presence of Et3N to yield (IV). Phenylhexanoate derivative (IV) is cyclized by means of DBU in DMF to provide valerolactone derivative (V), which is then condensed with 1-methylindole-3-carboxaldehyde (VI) in HOAc to furnish derivative (VII). Finally, the target compound is obtained by treatment of (VII) with NaOMe in MeOH.

参考文献中间体

合成目标

【1】 Liu, K.; Szalkowski, D.; Xu, L.; et al.; Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor. J Med Chem 2000, 43, 19, 3487.
【2】 Wood, H.B.; Jones, A.B.; Zhang, B.; Liu, K. (Merck & Co., Inc.); Antidiabetic agents. EP 1067925; US 6077849; WO 9951225 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	14534	2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE	69097-20-7	C₁₁H₂₈O₃Si₃	详情	详情
(I)	25890	2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride	103-80-0	C₈H₇ClO	详情	详情
(II)	45469	2-phenylethaneperoxoic acid		C₈H₈O₃	详情	详情
(III)	11043	Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride	4755-77-5	C₄H₅ClO₃	详情	详情
(IV)	45470	ethyl 2-oxo-2-[(2-phenylacetyl)peroxy]acetate		C₁₂H₁₂O₆	详情	详情
(V)	45471	3-hydroxy-4-phenyl-2H-pyran-2,5(6H)-dione		C₁₁H₈O₄	详情	详情
(VI)	45472	1-Methylindole-3-carboxaldehyde; 1-Methyl-1H-indole-3-carbaldehyde; 1-Methylindole-3-carbaldehyde	19012-03-4	C₁₀H₉NO	详情	详情
(VII)	45473	3-hydroxy-6-[(Z)-(3-methyl-3H-benzimidazol-1-yl)methylidene]-4-phenyl-2H-pyran-2,5-dione	455-15-2	C₂₀H₁₆N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIII)

The preparation of the hydroxylated adamantane (IV) is shown in Scheme 3. 1-Adamantyl bromide (XXII) is condensed with 1,1,2-tris(trimethylsilyloxy)ethylene (XXIII) by means of ZnCl2 in CH2Cl2 to afford the adamantylglycolic acid (XXIV), which is esterified to (XXV) utilizing a solution of acetyl chloride in MeOH. After Swern oxidation of (XXV) to the corresponding keto ester (XXVI), hydroxylation of the adamantane ring by means of HNO3/H2SO4 provides (XXVII). Alkaline hydrolysis of ester (XXVII) leads to the oxoacetic acid (XXVIII), which is converted to the target (S)-amino acid (IV) by reductive amination with phenylalanine dehydrogenase (3).

参考文献中间体

合成目标

【3】 Politino, M., Cadin, M.M., Skonezny, P.M., Chen, J.G. (Bristol-Myers Squibb Co.). EP 1737970, JP 2007532137, WO 2005106011.

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)	65681	(S)-(3-hydroxyadamantyl)glycine		C₁₂H₁₉NO₃	详情	详情
(XXII)	65698	1-Bromoadamantane; 1-Bromotricyclo[3.3.1.1(3,7)]decane; 1-Adamantyl bromide	768-90-1	C₁₀H₁₅Br	详情	详情
(XXIII)	14534	2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE	69097-20-7	C₁₁H₂₈O₃Si₃	详情	详情
(XXIV)	65699			C₁₂H₁₈O₃	详情	详情
(XXV)	65700			C₁₃H₂₀O₃	详情	详情
(XXVI)	65701			C₁₃H₁₈O₃	详情	详情
(XXVII)	65702	Methyl 2-(3-Hydroxy-1-adamantyl)-2-oxoacetate		C₁₃H₁₈O₄	详情	详情
(XXVIII)	65703	2-(3-Hydroxy-1-adamantyl)-2-oxoacetic acid; 3-Hydroxy-alpha-oxotricyclo[3.3.1.1(3,7)]decane-1-acetic acid;	709031-28-7	C₁₂H₁₆O₄	详情	详情

Extended Information