Water soluble prodrugs of azole compounds
a technology of azole compounds and prodrugs, which is applied in the field of water soluble prodrugs of azole compounds, can solve the problems of limited use of this class of compounds
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example 1
[0165] (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(-1H-1,2,4-triazol-1-yl)-2-[[[o-phosphonooxy]benzoyloxy]methoxy]butane 49
[0166] (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1--(1H-1,2,4-triazol-1-yl)-2-[[(o-(benzyloxy)benzoyloxy]methoxy]butane 50
[0167] (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1--(1H-1,2,4-triazol-1-yl)butan-2-ol (1.0 mmol) was added to a suspension of potassium hydride (1.1 mmol) in THF (20 mL) at 0.degree. C. The heterogeneous mixture was stirred for 15 minutes and chloromethyl ester (1.1 mmol) was added. The reaction was allowed to stir at r.t. for 5 h. Excess base was carefully quenched with water, and the crude mixture was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Purification of the crude product via flash chromatography (Hexanes / EtOAc) yielded 200 mg of the subtitled compound as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub...
example 2
[0174] (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1--(1H-1,2,4-triazol-1-yl)-2-[[[p-phosphonooxymethyl]benzoylox]methoxy]butane 54
[0175] (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]2-(2,4-difluorophenvyl)l-(-1H-1 ,2,4-triazol-1-yl)-2-[[[p-dibenzylphosphonooxymethyl]benzoyloxy]metho-xy]butane 55
[0176] The benzyl chloride (made in by the method disclosed in example C) (300 mg, 0.48 mmol), di-benzyl phosphate (270 mg, 0.97 mmol), and silver oxide (115 mg, 0.48 mmol) were disolved in acetonitrile and the rection was allowed to reflux for 7 h. The mixture was cooled, filtered, and the filtrate was diluted with ethyl acetate. This solution was washed with water (2.times.) and brine, dried over Na.sub.2SO.sub.4. Purification of the crude product via flash chromatography (Hexanes / EtOAc) yielded 100 mg of the subtitled compound as a white solid. .sup.1H NMR (CDC13) d 1.31 (d, 3H), 4.13 (q, 1H), 4.97-5.09 (m, 7H), 5.33 (d, 1H), 6.18 (ab, 2H), 6.78 (m, 2H), 7.22-7.46 (m, 17H...
example 3
[0179] (2R,3RZ)-3-[4-(4-cyanopheinvylthiazol-2-yl]-2-(2,4-difluorophenyl)--1-(1H-1,2,4-triazol-1-yl)-2-[[[m-phosphonooxymethyl]]benzoyloxy]methoxy]bu-tane 57
[0180] (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1--(1H-1,2,4-triazol-1-yl)-2-[[[m-chloromethyl]benzoyloxy]methoxy]butane 58
[0181] (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl] -2-(2,4-difluorophenyl)-1--(1H-1,2,4-triazol-1-yl)butan-2-ol (13.9 mmol) was added to a suspension of potassium hydride (15.3 mmol) in THF (100 mL) at 0.degree. C. The heterogeneous mixture was stirred for 15 minutes and the chloromethyl ester (16.8 mmol, prepared by the method disclosed in Houben-Weyl, Methoden Der Organischen Chemie, Band E14a / 3, 85, 1992) was added. The reaction was allowed to stir at 0.degree. C. for 2 h and then warmed to r.t. and stirred for 2 h. Excess base was carefully quenched with water, and the crude reaction was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over Na.s...
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