Temsirolimus, NSC-683864, CCI-779, -Drug Synthesis Database

【结构式】

【药物名称】Temsirolimus, NSC-683864, CCI-779

【化学名称】[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

【CA登记号】162635-04-3, 343261-52-9

【分子式】C₅₆H₈₇NO₁₆

【分子量】1030.31489

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】Breast Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, Inhibitors of Signal Transduction Pathways, mTOR Inhibitors

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(2)