Yaozh News Star Club Edu BBS TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】43177

【品名】3-methyl-3-(trifluoromethyl)-1,2-dioxirane

【CA登记号】

【 分 子 式 】C3H3F3O2

【 分 子 量 】128.0508296

【元素组成】C 28.14% H 2.36% F 44.51% O 24.99%
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：(XIV)

Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). The desilylation of (XII) by means of TFA in dichloromethane gives the precursor (XIII), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (XI) to yield the target epothilone A.

参考文献 中间体
合成目标
【1】 Park, K.-H.; Kurth, M.J.; Cyclo-elimination release strategies applied to solid-phase organic synthesis in drug discovery. Drugs Fut 2000, 25, 12, 1265.
【2】 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXa) 43167 (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid C27H52O6Si 详情 详情
(IXb) 43168 (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid C27H52O6Si 详情 详情
(IXc) 43169 (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid C27H52O6Si 详情 详情
(IXd) 43170 (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid C27H52O6Si 详情 详情
(XIa) 43172 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate C38H65NO6SSi 详情 详情
(XIb) 43173 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate C38H65NO6SSi 详情 详情
(XIc) 43174 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate C38H65NO6SSi 详情 详情
(XId) 43175 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate C38H65NO6SSi 详情 详情
(II) 43160 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol 110-63-4 C4H10O2 详情 详情
(III) 43161 (4-methoxybutyl)(triphenyl)phosphonium iodide C23H26IOP 详情 详情
(IV) 43162 (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether C23H25OP 详情 详情
(V) 43163 (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal C13H28O2Si 详情 详情
(VI) 43164 tert-butyl(dimethyl)silyl (2S,6Z)-10-methoxy-2-methyl-6-decenyl ether; tert-butyl[[(2S,6Z)-10-methoxy-2-methyl-6-decenyl]oxy]dimethylsilane C18H38O2Si 详情 详情
(VII) 43165 (2S,6Z)-10-methoxy-2-methyl-6-decenal C12H22O2 详情 详情
(VIII) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(X) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XII) 43176 (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C32H53NO5SSi 详情 详情
(XIII) 44447 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C26H39NO5S 详情 详情
(XIV) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXIII). Finally, the double bond of (XXXIII) is epoxidated with methyl(trifluoromethyl)dioxirane (A) in acetonitrile.

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 详情 详情
(XXVIII) 44470 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情
(XXIX) 44471 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C50H97NO6SSi4 详情 详情
(XXX) 44472 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C44H83NO6SSi3 详情 详情
(XXXI) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C38H69NO6SSi2 详情 详情
(XXXII) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXXIII) 44467 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether C29H55NO2SSi2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXX)

Compound (XXVIII) is deprotected with TFA in CH2Cl2 to provide the dihydroxymacrolactone (XXIX). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (XXX) or MCPBA to furnish the target epothilone B.

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXIX) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXX) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXXVI)

The fully silylation of (XXX) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXXI). The stepwise desilylation first with K2CO3 in methanol to yield the carboxylic acid (XXXII), and then with TBAF in THF, affords the hydroxyacid (XXXIII). The macrolactonization of (XXXIII) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXIV), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXV). Finally, the double bond of (XXXV) is epoxidated with methyl(trifluoromethyl)dioxirane (XXXVI) in acetonitrile to provide the target epothilone B.

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXI) 46119 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C51H99NO6SSi4 详情 详情
(XXXII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXXIII) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXIV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXXV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXXVI) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 详情 详情
Extended Information