Temsirolimus, NSC-683864, CCI-779
西罗莫司脂化物Chemical Name: [1R,9S,12S[1'R(1''R,3''R,4''R)],15R,18R,19R,21R,23S,30S,32S,35R]-1,18-Dihydroxy-12-[2-[4-[3-hydroxy-2-(hydroxymethyl)-2-methylpropionyloxy]-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(E),24(E),26(E),28(E)-tetraene-2,3,10,14,20-pentaone; (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1(R)-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentaone 4'-[2,2-bis(hydroxymethyl)propionate]; Rapamycin 42-[2,2-bis(hydroxymethyl)propionate]
CAS No. 162635-04-3, 343261-52-9
项目整合开发状态: Phase III
项目研究机构: Wyeth Pharmaceuticals (Originator)
合成路线: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.
📌 参考资料/链接：
参考文献标题:Rapamycin hydroxyesters
文献作者:Skotnicki,J.S.; Leone,C.L.; Schiehser,G.A.(American Home Products Corp.)
参考来源:EP 0763039; JP 1997512018; US 5362718; WO 9528406
📄 详细内容
合成路线: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.
参考文献标题:Regioselective synthesis of rapamycin derivs.
文献作者:Noureldin,R.; Fortier,G.; Cheal,G.K.; Shaw,C.-C.; Sellstedt,J.H.(American Home Products Corp.)
参考来源:WO 0123395
合成路线: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.
合成路线: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.
参考文献标题:CCI-779
文献作者:Sorbera,L.A.; del Fresno,M.; Castar,J.
参考来源:Drugs Fut 2002,27(1),7
产品链接: CAS No. 162635-04-3››