(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 -Drug Synthesis Database

【结构式】

【分子编号】20296

【品名】(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

【CA登记号】53123-88-9

【分子式】C₅₁H₇₉NO₁₃

【分子量】914.1872

【元素组成】C 67.01% H 8.71% N 1.53% O 22.75%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

Alkylation of rapamycin (I) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot toluene gives the silylated target compound (III), which is deprotected by means of 1N HCl in methanol.

参考文献中间体

合成目标

【1】 Castañer, J.; Sorbera, L.A.; Leeson, P.A.; SDZ-RAD. Drugs Fut 1999, 24, 1, 22.
【2】 Cottens, S.; Sedrani, R. (Novartis AG; Novartis Deutschland GmbH); O-Alkylated rapamycin derivs. and their use, particularly as immunosuppressants. EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010 .

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)	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
(II)	20297	2-[[tert-butyl(dimethyl)silyl]oxy]ethyl trifluoromethanesulfonate		C₉H₁₉F₃O₄SSi	详情	详情
(III)	20298	(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-12-[(1R)-2-[(1S,3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethoxy)-3-methoxycyclohexyl]-1-methylethyl]-1,18-dihydroxy-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		C₅₉H₉₇NO₁₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The compound has been obtained biosynthetically by an optimized fermentation process using Streptomyces hygroscopicus mutant RSH 1701 with a complex culture medium were [14C]-labeled (1R,3R,4R)-2,3-dichydroxycyclo-hexanecarboxylic acid (I) and [14C]-labeled (S)-pipecolic acid (II) have been added. This fermentation process yielded [14C]-labeled rapamycin (III), which was finally selectively O-alkylated at the C-40 position with monosilylated ethylene glycol triflate in DMSO/dimethoxyethane.

参考文献中间体

合成目标

【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29.

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)	32019	(1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid		C₇H₁₂O₄	详情	详情
(I)	45302	(1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid		C₇H₁₂O₄	详情	详情
(II)	17380	(2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid	3105-95-1	C₆H₁₁NO₂	详情	详情
(II)	45303	(2S)-2-piperidinecarboxylic acid		C₆H₁₁NO₂	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
(III)	45304	(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		C₅₁H₇₉NO₁₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

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

合成目标

【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4

该中间体在本合成路线中的序号：(III)

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

合成目标

【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