(3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone -Drug Synthesis Database

【结构式】

【分子编号】11499

【品名】(3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone

【CA登记号】

【分子式】C₆₈H₁₂₃NO₁₂Si₃

【分子量】1230.98066

【元素组成】C 66.35% H 10.07% N 1.14% O 15.6% Si 6.84%

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：(LX)

The cyclization of (LVI) by means of N-methyl-2-chloropyridinium iodide and triethylamine yields the macrocyclic lactam (LVII), which is selectively deprotected with trifluoroacetic acid in THF - water and oxidized with DMP in dichloromethane affording the beta-keto lactam (LVIII). Selective deprotection of (LVIII) with DDQ in dichloromethane - tert-butyl alcohol gives the diol (LIX), which is then oxidized with DMP in dichloromethane yielding the silylated FK-506 (LX). Finally, this compound is deprotected by treatment with HF in acetonitrile.

参考文献中间体

合成目标

【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(LVI)	11495	(4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid	C₉₁H₁₆₃NO₁₆Si₄	详情	详情
(LVII)	11496	(3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione	C₉₁H₁₆₁NO₁₅Si₄	详情	详情
(LVIII)	11497	(3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione	C₈₅H₁₄₅NO₁₅Si₃	详情	详情
(LIX)	11498	(3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-7,20-dihydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione	C₆₈H₁₂₇NO₁₂Si₃	详情	详情
(LX)	11499	(3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone	C₆₈H₁₂₃NO₁₂Si₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LIII)

The condensation of carbaldehyde (XLVIII) with the chiral intermediate phosphonamide (XXXII), by means of BuLi, gives the adduct (XLIX), which is treated with phenyliodonium trifluoroacetate and AcOH to cleave the 1,3-dithiane ring and yield the carbaldehyde (L). The cyclocondensation of (L) with 2-(2,4-dimethoxybenzyloxy)acetic acid methyl ester (LI) by means of LDA, LiOH, TesOTf and 2-chloro-1-methylpyridinium iodide (CMPI) affords the macrolactone (LII), which is submitted to a sequence of deprotection (DDQ), oxidation (DMP), deprotection (TFA) and oxidation (DMP) to provide the tricarbonyl compound (LIII). A similar sequence (TFA, DMP, DDQ, and DMP) can also be used to obtain the tricarbonyl compound (LIII). Finally this compound is fully desilylated by means of HF in acetonitrile to provide the target FK-506.

参考文献中间体

合成目标

【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXXII)	11491	(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide	C₂₈H₆₁N₂O₄PS₂Si	详情	详情
(XLVIII)	57271	1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate	C₅₈H₁₀₁NO₁₀Si₂	详情	详情
(XLIX)	57272	2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10-trimet	C₈₂H₁₄₉NO₁₂S₂Si₃	详情	详情
(L)	57273	2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(tr	C₇₉H₁₄₃NO₁₃Si₃	详情	详情
(LI)	57274	methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate	C₁₂H₁₆O₅	详情	详情
(LII)	57275	(3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-15-{[tert-butyl(dimethyl)silyl]oxy}-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione	C₉₁H₁₆₁NO₁₅Si₄	详情	详情
(LIII)	11499	(3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone	C₆₈H₁₂₃NO₁₂Si₃	详情	详情

Extended Information