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【结 构 式】 
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【分子编号】51491 【品名】(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate 【CA登记号】 |
【 分 子 式 】C59H91NO16 【 分 子 量 】1070.36868 【元素组成】C 66.21% H 8.57% N 1.31% O 23.92% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of rapamycin (III) with chlorotrimethylsilane and imidazole in AcOEt gives 31,42-bis-O-(trimethylsilyl)rapamycin, which, without isolation, is partially deprotected with sulfuric acid to provide 31-O-(trimethylsilyl)rapamycin (V). Coupling ether (V) with either 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid chloride (VI) by means of DMAP in CH2Cl2/DMF or with carboxylic acid (I) pretreated with 2,4,6-trichlorobenzoyl chloride (II) and DIEA by means of DMAP in CH2Cl2 yields the protected rapamycin 42-ester (VII). Removing the trimethylsilyl group of (VII) by treatment with 0.5N sulfuric acid in acetone affords ester (VIII), which is finally converted into CCI-779 by hydrolysis of the ketal group by means of 2N sulfuric acid in THF.
| 【1】 Sorbera, L.A.; del Fresno, M.; Castaner, J.; CCI-779. Drugs Fut 2002, 27, 1, 7. |
| 【2】 Skotnicki, J.S.; Leone, C.L.; Schiehser, G.A. (American Home Products Corp.); Rapamycin hydroxyesters. EP 0763039; JP 1997512018; US 5362718; WO 9528406 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 51488 | 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid | C8H14O4 | 详情 | 详情 | |
| (II) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (III) | 20296 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | 53123-88-9 | C51H79NO13 | 详情 | 详情 |
| (V) | 51487 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1-hydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-18-[(trimethylsilyl)oxy]-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | C54H87NO13Si | 详情 | 详情 | |
| (VI) | 51489 | 2,2,5-trimethyl-1,3-dioxane-5-carbonyl chloride | C8H13ClO3 | 详情 | 详情 | |
| (VII) | 51490 | (1R,2R,4S)-4-((2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1-hydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-18-[(trimethylsilyl)oxy]-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl)-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C62H99NO16Si | 详情 | 详情 | |
| (VIII) | 51491 | (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C59H91NO16 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2,2-Bis(hydroxymethyl)propionic acid isopropylidene ketal (I) is activated by treatment with 2,4,6-trichlorobenzoyl chloride (II) and triethylamine in anhydrous THF at 0 C. The resulting activated acid is then coupled with rapamycin (III) by means of DMAP in benzene to provide the protected rapamycin derivative (IV). Finally, CCI-779 is obtained by hydrolysis of the ketal group with HCl in THF.
| 【1】 Sorbera, L.A.; del Fresno, M.; Castaner, J.; CCI-779. Drugs Fut 2002, 27, 1, 7. |
| 【2】 Noureldin, R.; Fortier, G.; Cheal, G.K.; Shaw, C.-C.; Sellstedt, J.H. (American Home Products Corp.); Regioselective synthesis of rapamycin derivs.. WO 0123395 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 51488 | 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid | C8H14O4 | 详情 | 详情 | |
| (II) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (III) | 20296 | (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | 53123-88-9 | C51H79NO13 | 详情 | 详情 |
| (IV) | 51491 | (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 2,2,5-trimethyl-1,3-dioxane-5-carboxylate | C59H91NO16 | 详情 | 详情 |