(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone -Drug Synthesis Database

【结构式】

【分子编号】11567

【品名】(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone

【CA登记号】

【分子式】C₅₆H₉₇NO₁₂Si₂

【分子量】1032.55672

【元素组成】C 65.14% H 9.47% N 1.36% O 18.59% Si 5.44%

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：(LXVIII)

(LX) is treated successively with H2O2 and LiOH, with triethylsilyl trifluoromethylsulfonate and with water to afford acid (LXI). Cyclization of (LXI) with 2-chloro-N-methylpyridinium iodide and triethylamine in dichloromethane yields the cyclic derivative (LXII), which is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to eliminate the 4-methoxybenzyl protecting group, so yielding alcohol (LXIII). A new partial deprotection of (LXIII) with trifluoroacetic acid affords the glycol (LXIV), which is oxidized with oxalyl chloride in DMSO to the vicinal triketone (LXV). Treatment of (LXV) with HF in acetonitrile gives the epoxy derivative (LXVI) with some free hydroxyl groups which are protected with triethylsilyl chloride, affording the compound (LXVII) with only one free hydroxy group. Oxidation of (LXVII) with Dess-Martin periodinane (DMP) in dichloromethane yields protected FK-506 (LXVIII), which is finally deprotected with HF in acetonitrile.

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	CAS号	分子式	供应商	用于合成
	34696	2-chloro-1-methylpyridinium iodide	14338-32-0	C₆H₇ClIN	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
(LXI)	11560	(2S,3R,4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-6,8-dimethoxy-2-[(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		C₈₈H₁₆₇NO₁₄Si₅	详情	详情
(LXII)	11561	(3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-20-[(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		C₈₈H₁₆₅NO₁₃Si₅	详情	详情
(LXIII)	11562	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-20-hydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-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		C₈₀H₁₅₇NO₁₂Si₅	详情	详情
(LXIV)	11563	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-19,20-dihydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione		C₇₄H₁₄₃NO₁₂Si₄	详情	详情
(LXV)	11564	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[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]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone		C₇₄H₁₃₉NO₁₂Si₄	详情	详情
(LXVI)	11565	(1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione		C₄₄H₇₁NO₁₂	详情	详情
(LXVII)	11566	(1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione		C₅₆H₉₉NO₁₂Si₂	详情	详情
(LXVIII)	11567	(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone		C₅₆H₉₇NO₁₂Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LV)

The macrocyclization of (LI) by means of EDC and DMAP in dichloromethane gives the macrolactone (LII), which is treated with DDQ and oxidized with DMP in dichloromethane to yield the tricarbonyl compound (LIII). The cyclization and desilylation of (LIII) by means of HF in acetonitrile affords the tricyclic macrolactone (LIV), which is treated with Tes-Cl and oxidized with DMP to provide the silylated precursor (LV). Finally, this compound is desilylated with HF in acetonitrile to give the target FK-506.

参考文献中间体

合成目标

【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(LI)	57369	(2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid	C₈₂H₁₅₁NO₁₄Si₄	详情	详情
(LII)	57370	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16-dimethoxy-20-[(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	C₈₂H₁₄₉NO₁₃Si₄	详情	详情
(LIII)	11564	(3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[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]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone	C₇₄H₁₃₉NO₁₂Si₄	详情	详情
(LIV)	11565	(1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione	C₄₄H₇₁NO₁₂	详情	详情
(LV)	11567	(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone	C₅₆H₉₇NO₁₂Si₂	详情	详情

Extended Information