(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol -Drug Synthesis Database

【结构式】

【分子编号】60160

【品名】(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol

【CA登记号】

【分子式】C₃₅H₆₂O₅Si

【分子量】590.95978

【元素组成】C 71.14% H 10.57% O 13.54% Si 4.75%

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：(XXXV)

Synthesis of the target cholestane glycoside. The reaction of 3-beta-hydroxy-5-androsten-17-one (XXV) with Tbdms-Cl gives the silyl ether (XXVI), which is condensed with phosphorane (XXVII), yielding the ethylidene derivative (XXVIII). The oxidation of (XXVIII) by means of SeO2 and tert-butyl hydroperoxide affords the alcohol (XXIX), which is submitted to a Swern oxidation to provide the enone (XXX). The condensation of (XXX) with the intermediate vinyl bromide (XXIV) by means of CuCN, LiCl and Tms-Cl gives the non isolated intermediate (XXXI), which is treated with acetyl chloride to yield the enol acetate (XXXII). The reaction of (XXXII) with ethyleneglycol and PPTS in dichloromethane affords the ethylene ketal (XXXIII), which is submitted to a stereoselective oxidation with Davis reagent and t-BuOK to provide the hydroxy ketone (XXXIV). The stereoselective reduction of (XXXIV) by means of LiAlH4 in dichloromethane leads to the dihydroxy compound (XXXV).

参考文献中间体

合成目标

【1】 Yu, W.; Jin, Z.; Total synthesis of the anticancer natural product OSW-1. J Am Chem Soc 2002, 124, 23, 6576.

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)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(XXIV)	48956	(E)-1-bromo-4-methyl-1-pentenyl cyclohexyl ether; 1-[[(E)-1-bromo-4-methyl-1-pentenyl]oxy]cyclohexane		C₁₂H₂₁BrO	详情	详情
(XXV)	11713	Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one	53-43-0	C₁₉H₂₈O₂	详情	详情
(XXVI)	16818	(3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one		C₂₅H₄₂O₂Si	详情	详情
(XXVII)	60152	ethylidene(triphenyl)phosphorane		C₂₀H₁₉P	详情	详情
(XXVIII)	60153	tert-butyl(dimethyl)silyl (3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane		C₂₇H₄₆OSi	详情	详情
(XXIX)	60154	(3S,8R,9S,10R,13S,14S,16R)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-ol		C₂₇H₄₆O₂Si	详情	详情
(XXX)	60155	(3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one		C₂₇H₄₄O₂Si	详情	详情
(XXXI)	60156	tert-butyl(dimethyl)silyl (3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane		C₄₂H₇₄O₃Si₂	详情	详情
(XXXII)	60157	(3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate		C₄₁H₆₈O₄Si	详情	详情
(XXXIII)	60158	(3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate		C₃₇H₆₂O₅Si	详情	详情
(XXXIV)	60159	(3S,8R,9S,10R,13S,14S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one		C₃₅H₆₀O₅Si	详情	详情
(XXXV)	60160	(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol		C₃₅H₆₂O₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXXV)

Coupling of the steroid aglycon (XXXV) with the intermediate disaccharide (XX) by means of Tms-OTf in dichloromethane gives the glycoside (XXXVI), which is finally deprotected by reaction sequentially with DDQ and with Pd(CH3CN)2Cl2 to yield the target cholestane glycoside

参考文献中间体

合成目标

【1】 Yu, W.; Jin, Z.; Total synthesis of the anticancer natural product OSW-1. J Am Chem Soc 2002, 124, 23, 6576.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XX)	60151	(2S,3R,4S,5R)-2-({(2S,3R,4R,5S)-3-(acetyloxy)-2-[(2,2,2-trichloroethanimidoyl)oxy]-5-[(triethylsilyl)oxy]tetrahydro-2H-pyran-4-yl}oxy)-4,5-bis[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3-yl 4-methoxybenzoate	C₄₄H₅₆Cl₃NO₁₄Si	详情	详情
(XXXV)	60160	(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol	C₃₅H₆₂O₅Si	详情	详情
(XXXVI)	60161	(2S,3R,4S,5R)-2-({(2S,3R,4R,5S)-3-(acetyloxy)-2-({(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cycl	C₇₇H₁₁₆O₁₈Si₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The reduction of 2-chloroacetylamino-3-(o-chlorobenzoyl)thiophene (I) with NaBH4 in DMF gives 2-chloroacetylamino-3-[(o-chlorophenyl)hydroxymethyl]thiophene (II), which is cyclized by means of sodium isopropoxide in refluxing isopropanol to afford 5-(o-chlorophenyl)thieno[2,3-e]-4,1-oxazepin-2-one (III). The bromination of (III) with Br2 in CHCl3 - pyridine yields 7-bromo-5-(o-chlorophenyl)thieno[2,3-e]-4,1-oxazepin-2-one (IV), which by reaction with P2S5 and NaHCO3 in hot diglyme is converted into 7-bromo-5-(o-chlorophenyl)thieno[2,3-e]-4,1-oxazepin-2-thione (V) (1). The cyclization of (V) with cyclohexanecarboxyl hydrazide (A) in THF gives 7-bromo-5-(o-chlorophenyl)-1-cyclohexylthieno[2,3-e]triazolo[3,4-c]-4,1-oxazepin-2-one (VI). The ring opening of (VI) by treatment with concentrated HBr yields 3-cyclohexyl-4-[3-(o-chlorophenylbromomethyl)-5-bromo-2-thienyl]-5-hydroxymethyl-1,2,4-triazole (VII), which by reaction with SOCl2 is converted into 3-cyclohexyl-4-[3-(o-chlorophenyl-bromomethyl)-5-bromo-2-thienyl]-5-chloromethyl-1,2,4-triazole (VIII). The cyclization of (VIII) with NH3 in methanol a 100 C in a pressure vessel yields 8-bromo-6-(o-chlorophenyl)-1-cyclohexyl-4H-s-triazolo[3,4-c]thieno[2,3-e]-5,6-dihydro-1,4-diazepine (IX), which is finally dehydrogenated by treatment with KMnO4 in refluxing acetone

参考文献中间体

合成目标

【1】 Weber, K.H.; et al. (C.H. Boehringer Sohn); BE 844170; CA 1077475; DD 126744; DE 2531677; DE 2531678; DE 2531679; DE 2533924; FR 2318165; GB 1550679; GB 1550680; JP 7712189; JP 7712193; JP 7714800; JP 7717496; NL 7607871; NL 7607872; US 4201712; ZA 7604212 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Owen, R.T.; Ciclotizolam. Drugs Fut 1981, 6, 6, 342.
【3】 Imvamune IND receives approval. Justus Liebigs Ann Chem. 1978, 1257.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(A)	61061	cyclohexanecarbohydrazide	C₇H₁₄N₂O	详情	详情
(I)	61056	2-chloro-N-[3-(2-chlorobenzoyl)-2-thienyl]acetamide	C₁₃H₉Cl₂NO₂S	详情	详情
(II)	61057	2-chloro-N-{3-[(2-chlorophenyl)(hydroxy)methyl]-2-thienyl}acetamide	C₁₃H₁₁Cl₂NO₂S	详情	详情
(III)	61058	5-(2-chlorophenyl)-1,5-dihydrothieno[2,3-e][1,4]oxazepin-2(3H)-one	C₁₃H₁₀ClNO₂S	详情	详情
(IV)	61059	7-bromo-5-(2-chlorophenyl)-1,5-dihydrothieno[2,3-e][1,4]oxazepin-2(3H)-one	C₁₃H₉BrClNO₂S	详情	详情
(V)	60160	(3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol	C₃₅H₆₂O₅Si	详情	详情
(VI)	61062	2-bromo-4-(2-chlorophenyl)-9-cyclohexyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine	C₂₀H₁₉BrClN₃OS	详情	详情
(VII)	60163	4-fluorobenzaldehyde	C₇H₅FO	详情	详情
(VIII)	61064	4-{5-bromo-3-[bromo(2-chlorophenyl)methyl]-2-thienyl}-3-(chloromethyl)-5-cyclohexyl-4H-1,2,4-triazole	C₂₀H₁₉Br₂Cl₂N₃S	详情	详情
(IX)	61065	2-bromo-4-(2-chlorophenyl)-9-cyclohexyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine	C₂₀H₂₀BrClN₄S	详情	详情

Extended Information