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【结 构 式】 
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【分子编号】11566 【品名】(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 【CA登记号】 |
【 分 子 式 】C56H99NO12Si2 【 分 子 量 】1034.5726 【元素组成】C 65.01% H 9.65% N 1.35% O 18.56% Si 5.43% |
合成路线1
该中间体在本合成路线中的序号：(LXVII)(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.
| 【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 |