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【结 构 式】

【药物名称】26-Fluoroepothilone, CGP-85715

【化学名称】(1S,3S,7S,10R,11S,12S,16R)-16-(Fluoromethyl)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1(E)-methyl-2-(2-methylthiazol-4-yl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

【CA登记号】201137-02-2

【 分 子 式 】C27H40FNO6S

【 分 子 量 】525.68535

【开发单位】Novartis (Originator), Scripps Research Institute (Originator)

【药理作用】Oncolytic Drugs, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

合成路线1

The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II), which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV). The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI), which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4, NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is protected with trityl chloride and DMAP to provide the trityl ether (XII). The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII), which is treated with I2 and PPh3 to yield the iodo compound (XIV). The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI), which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII). The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).

1 Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127.
2 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.
3 He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 .
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) 44454 ethyl 2-methyl-1,3-thiazole-4-carboxylate 6436-59-5 C7H9NO2S 详情 详情
(II) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(III) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(IV) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(VI) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(VII) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(VIII) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(IX) 46110 methyl 2-(triphenylphosphoranylidene)-4-pentenoate C24H23O2P 详情 详情
(X) 46111 methyl (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate C22H35NO3SSi 详情 详情
(XI) 46112 (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C21H35NO2SSi 详情 详情
(XII) 54771 (2E,5S,6E)-2-allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienyl trityl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-6-[(trityloxy)methyl]-1,5,8-nonatrienyl}-2-methyl-1,3-thiazole C40H49NO2SSi 详情 详情
(XIII) 54772 (4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-methyl-9-(2-methyl-1,3-thiazol-4-yl)-4-[(trityloxy)methyl]-4,8-nonadien-1-ol C40H51NO3SSi 详情 详情
(XIV) 54773 tert-butyl(dimethyl)silyl (1S,3E)-7-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole C40H50INO2SSi 详情 详情
(XV) 44460 N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine C8H16N2O 详情 详情
(XVI) 54774 (2R)-N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-2-methoxy-1-pyrrolidinamine; N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-N-[(2R)-2-methoxypyrrolidinyl]amine C48H65N3O3SSi 详情 详情
(XVII) 54775 (2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienenitrile C43H54N2O2SSi 详情 详情
(XVIII) 54776 (2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal C43H55NO3SSi 详情 详情

合成路线2

The condensation of aldehyde (XVIII) with the chiral 3-heptanone derivative (XIX) by means of LDA in THF gives the heptadecadien-7-ol derivative (XX), which is silylated with Tbdms-OTf to yield the fully silylated compound (XXI). The selective desilylation of the primary OH group with HF and pyridine in THF affords the heptadecadien-1-ol derivative (XXII), which is submitted to a Swern oxidation followed by a treatment with NaClO2 to provide the carboxylic acid (XXIII). The selective desilylation of the 15-hydroxyl of (XXII) by means of TBAF in THF gives the hydroxyacid (XXIV), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the macrolactone (XXV). The fully deprotection of (XXV) with HF and pyridine affords the hydroxymethyl macrolactone (XXVI), which is epoxidated with Ti(O-iPr)4, diethyl-L-tartrate and tBu-OOH to provide the epoxidated precursor (XXVII). Finally, this compound is treated with diethylaminosulfurtrifluoride (DAST) in dichloromethane to furnish the target fluorinated epothilone.

1 Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127.
2 He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 54776 (2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal C43H55NO3SSi 详情 详情
(XIX) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(XX) 54777 (7S,10R,11S,12S,16E,19S)-7-{[tert-butyl(dimethyl)silyl]oxy}-11-hydroxy-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C64H101NO6SSi3 详情 详情
(XXI) 54778 (7S,10R,11S,12S,16E,19S)-7,11-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,3,3,8,8,10,12,21,21,22,22-dodecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-16-[(trityloxy)methyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C70H115NO6SSi4 详情 详情
(XXII) 54779 (5S,8R,9S,10S,14E,17S)-9-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,19,19,20,20-dodecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-14-[(trityloxy)methyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one C64H101NO6SSi3 详情 详情
(XXIII) 54780 (3S,6R,7S,8S,12E,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-[(trityloxy)methyl]-12,16-heptadecadienoic acid C64H99NO7SSi3 详情 详情
(XXIV) 54781 (3S,6R,7S,8S,12E,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-[(trityloxy)methyl]-12,16-heptadecadienoic acid C58H85NO7SSi2 详情 详情
(XXV) 54782 (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]-13-[(trityloxy)methyl]oxa-13-cyclohexadecene-2,6-dione C58H83NO6SSi2 详情 详情
(XXVI) 54783 (4S,7R,8S,9S,16S)-4,8-dihydroxy-13-(hydroxymethyl)-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO6S 详情 详情
(XXVII) 54784 (1R,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-16-(hydroxymethyl)-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C27H41NO7S 详情 详情
Extended Information