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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information