(2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal -Drug Synthesis Database

【结构式】

【分子编号】11550

【品名】(2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal

【CA登记号】

【分子式】C₅₁H₁₀₄O₆Si₄

【分子量】925.72516

【元素组成】C 66.17% H 11.32% O 10.37% Si 12.14%

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：(LI)

(XLIII) is silylated with TIPS-SO3CF3 to the protected ester (XLIV). The reduction of (XLIV) with diisobutylaluminum hydride yields the primary alcohol (XLV), which is oxidized with the complex pyridine - SO3 to the aldehyde (XLVI). The condensation of (XLVI) with the boron enolate of the oxazolidone (XLVII) affords the oxazolidone derivative (XLVIII), which is treated with methylchloroaluminum N-methoxy-N-methylamide as before to give the methoxyamide (XLIX). Silylation of (XLIX) with TBS-SO3CF3 as usual yields the protected amide (L), which is finally reduced with diisobutylaluminum hydride to the second building group, the aldehyde (LI).

参考文献中间体

合成目标

【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	63306		C₃H₉AlClNO	详情	详情
(IL)	11548	(2S,3S,5S,6S,7S,8E)-2-Allyl-3-hydroxy-N-methoxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,6,8-trimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenamide	C₄₇H₉₅NO₇Si₃	详情	详情
(XLIII)	11542	methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate	C₃₂H₆₄O₆Si₂	详情	详情
(XLIV)	11543	methyl (3S,4S,5S,6E)-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-heptenoate	C₄₁H₈₄O₆Si₃	详情	详情
(XLV)	11544	(3S,4S,5S,6E)-7-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-hepten-1-ol	C₄₀H₈₄O₅Si₃	详情	详情
(XLVI)	11545	(3S,4S,5S,6E)-7-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-heptenal	C₄₀H₈₂O₅Si₃	详情	详情
(XLVII)	11546	(4S)-4-Isopropyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one	C₁₁H₁₇NO₃	详情	详情
(XLVIII)	11547	(4S)-3-[(2S,3S,5S,6S,7S,8E)-2-Allyl-3-hydroxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenoyl]-4-isopropyl-1,3-oxazolidin-2-one	C₅₁H₉₉NO₈Si₃	详情	详情
(L)	11549	(2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,6,8-trimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenamide	C₅₃H₁₀₉NO₇Si₄	详情	详情
(LI)	11550	(2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal	C₅₁H₁₀₄O₆Si₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LI)

3) Coupling and cyclization process.- The condensation of the diphenylphosphine derivative (XXIV) with aldehyde (LI) by means of butyllithium in THF gives the hydroxy phosphine derivative (LII), which is treated with potassium hexamethyldisylazane (KHMDS) to afford dithiane (LIII). Partial desilylation of (LIII) with THF - water - trifluoroacetic acid gives alcohol (LIV), which is condensed with N-tert-butoxycarbonylpiperidine-2(S)-carboxylic acid (LV) by means of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine in dichloromethane to yield the ester (LVI). Elimination of the dithiane ring of (LVI) with N-chlorosuccinimide and silver nitrate in anhydrous methanol affords the dimethyl acetal (LVII), which is hydrolyzed to the corresponding aldehyde (LVIII) with acetic acid. The condensation of (LVIII) with 4(S)-benzyl-3-[2-(4-methoxybenzyloxy)acetyl]oxazolidin-2-one (LIX) by means of dibutylboron trifluoromethylsulfonate in toluene gives the oxazolidone derivative (LX).

参考文献中间体

合成目标

【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIV)	11523	(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl(diphenyl)phosphine oxide; [(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl](oxo)diphenylphosphorane	C₃₆H₅₉O₄PS₂Si	详情	详情
(LI)	11550	(2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal	C₅₁H₁₀₄O₆Si₄	详情	详情
(LII)	11553	(1E,3S,4S,5S,7S,8R,9E,12S,14S,15R,16S,18R)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-18-(1,3-dithian-2-yl)-14,16-dimethoxy-1-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4,10,12-tetramethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol	C₆₉H₁₃₈O₈S₂Si₄	详情	详情
(LIII)	11552	(5R,6S,8S,10E,12R,13S,15S,16S,17S)-12-Allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,2,3,3,8,10,16-heptamethyl-15-[(triisopropylsilyl)oxy]-4,18-dioxa-3,19-disila-10-henicosene; (1S,3S,4R,5E,8S,10S,11R,12S,14R)-4-Allyl-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-14-(1,3-dithian-2-yl)-10,12-dimethoxy-1-[(1S,2S,3E)-4-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-6,8-dimethyl-5-pentadecenyl triisopropylsilyl ether	C₇₅H₁₅₂O₈S₂Si₅	详情	详情
(LIV)	11551	(5R,6S,8R,12R,13S,15S,16S,17S)-12-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-9-(diphenylphosphoryl)-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methyl	C₈₇H₁₆₃O₁₀PS₂Si₅	详情	详情
(LV)	11487	(2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid	C₁₁H₁₉NO₄	详情	详情
(LVI)	11555	2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-16-(1,3-dithian-2-yl)-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate	C₈₀H₁₅₅NO₁₁S₂Si₄	详情	详情
(LVII)	11556	2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14,17,17-tetramethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate	C₇₉H₁₅₅NO₁₃Si₄	详情	详情
(LVIII)	11557	2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate	C₇₇H₁₄₉NO₁₂Si₄	详情	详情
(LIX)	11558	(4S)-4-Benzyl-3-[3-(4-methoxyphenyl)propanoyl]-1,3-oxazolidin-2-one	C₂₀H₂₁NO₄	详情	详情
(LX)	11559	2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R,17R)-6-allyl-19-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-12,14-dimethoxy-18-[(4-methoxybenzyl)oxy]-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate	C₉₇H₁₇₀N₂O₁₇Si₄	详情	详情

Extended Information