The compound of formula I wherein Rl is chlorine, fluorine or trifluoromethyl; R2 is hydrogen, chlorine, fluorine or trifluoromethyl; R3 is C 1-4 alkyl; and R4 is a C, 5 polyfluoroalkyl group containing at least two fluorine atoms and optionally other halogen atoms selected from chlorine and bromine; and their salts with pharmaceutically acceptable acids, are known as antimycotic and antifun- gal agents.

The patent application WO 97/31903 (in the Applicant's name) shows a class of compound which those of formula I above fall within, as broad spectrum antimycotics against human and animal pathogenic fungi. Such compound are obtained from the intermediate of formula VIII wherein RI, R2 and R3 are as defined above, which reacted with the suitable polyfluoroalkyl derivative provides the desired compound of formula 1.

It has been now found a new method for preparing the compound of formula VIII constituting an alternative to the synthetic routes described in the above cited prior art.

Therefore the present invention refers to a method for preparing compound of formula VIII as illustrated hereinbelow.

The synthesis of the compound of formula VIII according to the present invention starts from

the triol of formula II wherein Rl, R2 and R3 are as defined above. This is treated with a suitable ketone or aldehyde in acidic medium, for example in p-toluensulfonic acid, to selectively protect the two OH groups in a-position each other. For avoiding the formation of a further stereogenic centre it is preferred to use a symmetric ketone such as, for example, acetone or cyclohexanone. It is thus obtained the dioxolane of formula III wherein RI, R2 and R3 are as defined above, and RI and RII are depending on the aldehyde or ketone employed, which is duly protected on the free hydroxy moiety with an easily removable group, whereas resistant in acidic or weakly basic medium. Preferred examples of such groups are aryl-methyl such as benzyl or furfuryl-methyl optionally substituted which may be re- moved by hydrogenation. The protection rection is effected, for example with an arylmethyl halite in the presence of an alkali metal hydride, for example sodium hybride, and provides the compound of formula IV wherein Rl, R2, R3, RI and RII are as defined above, and Ar is an optionally substituted aryl group. This is hydrolyse in strong acidic medium according to common methods, preferably in alcool, for example ethanol, to give the compound of formula V

wherein Rl, R2, R3 and Ar are as defined above, which is functionalized on the primary hydro- xy group by a leaving group Lg through rection with a sulfonic acid chloride, such as meth- ansulfonyl-chloride or tosyl chloride, or with a halogenating agent such as, for example, phos- phorous tribromide, thionyl chloride or phosphorous pentachloride, thus obtaining the com- pound of formula VI wherein Rl, R2, R3 and Ar are as defined above, Lg is halogen or a OSO2Rlv group wherein Rlv is a (C ») alkyl or an optionally methyl-substituted phenyl group. The compound of formu- la VI is treated with a salt of 1,2,4-triazole prepared previously or in situ, for example, with 1, 2,4-triazole in the presence of sodium hydride and gives the compound of formula VII wherein Rl, R2, R3 and Ar are as defined above. Then the clearing of the protected hydroxy group is effected by common techniques (see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York), thus yielding the desired compound of formula VISU. The intermediates V and VI are known (patent application EP 667346 in the name of Eisai).

In particular, intermediate V is said to be obtained from one of the following compound

wherein Xs are halogen atoms, Pr is a protecting group, R is a lower alkyl group, R3 is methyl or a lower alkoxy group and R2 is a lower alkyl group. The intermediate of formula VI is obtained from the intermediate of formula V.

The substrate of formula 11 is known too and may be obtained both via literature methods and using a synthetic route claimed in a co-pending patent application filed in the same date of the present one by the Applicant, starting from a new compound claimed in another co-pending patent application filed in the same date of the present one by the Applicant.

Hereinbelow fulfilment examples of the present invention are provided.

Example 1 Synthesis of (2S,4R)-2,2-dimethyl-4-(2,4-dichlorophenyl)-4-(2-methyl-3-hy droxypropyl)-1,3- dioxolane A solution of (2R, 3S)-2-(2,4-dichlorophenyl)-3-methyl-1,2,4-trihvdroxy-butane (2.65 g; 10 mmoles; enantiomeric excess: 97. 8%) and p-toluensolfonic acid monohydrate (0.19 g; 1 mmole) in acetone (25 ml) was refluxed for 60 minutes, then cooled to 20°C, poured into water (100 ml) and extracted with toluene (25 mol a 3). The joined organic phases were washed with water (50 mol), anhydrified on dry Na2S04, dried. 3.05 g Of (2S, 4R)-2,2-dimethyl-4- (2,4- dichlorophenyl)-4- (2-methyl-3-hydroxypropyl)-1,3-dioxolane were obtained as a viscous oil.

1H-NMR (300MHz, DMSO, #=ppm, J=Hz) : 0.55 (d, 3H, J=6.90); 1.10 (s, 3H); 1.40 (s, 3H); 2.23 (ddq, 1H, J=8.30, J=6.90, J=3.95); 3.17 (ddt, 1H, J=11.20, J=8.30, J=5.30); 3.77 (ddt, 1H, J=11.20, J=3.95, J=5.30); 4.06 (d, 1H, J=9.29); 4.50 (t, 1H, J=5.30); 4.72 (d, 1H, J=9.20); 7.43 (dd, 1H, J=8.50, J=2.16); 7.59 (d, 1H, J=2.16); 7.63 (d, 1H, J=8.50).

Example 2

Svnthesis of (2S 4R)-2 2-dimethvl-4-24-dichlorophenyl)-4- (2-methyl-3-phenvlmethoxy)-pro- pyl-1,3-dioxolane A solution of crude (2S, 4R)-2, 2-dimethyl-4-(2,4-dichlorophenyl)-4-(2-methyl-3-hydroxypro- pyl)-1, 3-dioxolane obtained in exemple 1 (3.05 g; 10 mmoles) in DMF (20 ml) cooled to 15°C under nitrogen was portionwise added with 60% NaH (0.5 g; 12.5 mmoles). The suspension was stirred for 30 minutes, then slowly added, in about 1 hour, with benzyl chloride (1.58 g; 12.5 mmoles) diluted in DMF (5 ml) and the mixture was kept under stirring at 15°C under nitrogen for further 20 hours, then poured into water (150 ml) and extracted with toluene (30 ml x 3). The organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purifie by flash chromatography (Si02; n-heptane/ethyl acetate 90/10) to give 3.82 g of (2S, 4R)-2, 2-dimethyl-4-(2,4-dichlorophenyl)-4-(2-methyl-3-phenylmethox y)- propyl-1, 3-dioxolane (yield 97/o) as a colourless oil.

IH-NMR (300 MHz, DMSO, 6=ppm, J=Hz): 0.59 (d, 3H, J=6.85); 1.05 (s, 3H); 1.41 (s, 3H); 2.55 (ddq, 1H, J=7.60, J=4.70, J=6.85); 3.26 (dd, 1H, J=9.50, J=7.60); 3.76 (dd, 1H, J=9.50, J=4.70); 4.05 (d, 1H, J=9.20); 4.46 (d, 1H, J=11. 90); 4.52 (d, 1H, J=11.90) ; 4.75 (d, 1H, J=9.20); 7.25-7.40 (m, 5H); 7.44 (dd, 1H, J=8.50, J=2.20); 7.62 (d, 1H, J=2.20); 7.64 (d, 1H, J=8.50).

Example 3 (2R,3S)-1-(2,4-dichlorophenyl)-1-[(2-phenylmethoxy-1-methyl) -ethyl]-ethandiolSynthesisof A solution of (2S, 4R)-2, 2-dimethyl-4-(2,4-dichlorophenyl)-4-(2-methyl-3-phenylmethox y)- propyl-1,3-dioxolane obtained in example 2 (3.75 g; 9.5 mmoles), 37% HCI (3.75 ml) and water (3.75 ml) in ethanol (37.5 ml) was refluxed for 24 hours, then cooled to room tempera- ture, poured into water (150 ml) and extracted with toluene (30 ml x 3). The organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purifie by flash chromatography (Si02; n-heptane/ethyl acetate 75/25) to give 2.32 g of (2R, 3S)-1- (2, 4-dichlorophenyl)-1-[(2-phenylmethoxy-1-methyl)-ethyl]-ethan diol (yield 73%) as a colour- less oil.

IH-NMR (300MHz, DMSO, #=ppm, J=Hz): 0.58 (d, 3H, J=7.00); 2.65 (ddq, 1H, J=6.90, J=5.20, J=7.00); 3.32 (dd, 1H, J=9.70, J=6.90); 3.76 (dd, 1H, J=9.70, J=5.20); 3.80 (dd, 1H, J=11.80, J=5.13); 4.25 (dd, 1H, J=11.80, J=5.50); 4.47 (t, 2H, J=14.10); 4.52 (dd, 1H,

J=5.49, J=5.10); 5.00 (s, IH); 7.25-7.5 (ion, 7H); 7.76 (d, 1H, J=8.70).

Example 4 Synthesis of (2R,3S)-1-(2,4-dichlorophenyl)-[(2-phenylmethoxy-1-methyl)-e thyl]-ethandiol-2- p-toluensulfonate A solution of (2R, 3S)-1- (2, 4-dichlorophenyl)-1- [ (2-phenylmethoxy-1-methyl)-ethyl]-ethandiol obtained in example 3 (2.15 g; 6.05 moles) in pyridine (15 ml) cooled to 15-17°C under ni- trogen was portionwise added in about 30 minutes with p-toluensulfonyl chloride (1.32 g; 6.9 mmoles) and the solution was stirred at 15°C under nitrogen for further 16 hours, then poured into water (100 mol), acidifie to pH#2 with 50% H2SO4 and extracted with toluene (30 ml x 3). The joined organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purifie by flash chromatography (Si02; n-heptane/ethyl acetate 85/15) to give 2.80 g of (2R, 3S)-1- (2, 4-dichlorophenyl)- [ (2-phenylmethoxy-1-methyl)-ethyl]-ethan- diol-2-p-toluensulfonate (yield 91%).

1H-NMR (300MHz, DMSO, 5=ppm, J=Hz): 0.45 (d, 3H, J=7.00); 2.40 (s, 3H); 2.67 (ddq, 1H, J=9.50, J=4.10, J=7.00); 3.26 (dd, 1H, J=9.90, J=4.10); 3.72 (dd, 1H, J=9.90, J=9.50) ; 4.42 (s, 2H); 4.44 (d, 1H, J=10.50); 4.85 (d, IH, J=10.50); 5.85 (bs, 1H); 7.20-7.70 (ion, 12H).

Example 5 Synthesis of (2R,3S)-2-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-1-(1,2,4-t riazol-1-yl)-4-ben- zyloxy-butane A solution of 1,2,4-triazole (0.56 g; 8.1 mmoles) in DMF (6 ml) cooled to 16°C was portion- wise added, under nitrogen, with 60% NaH (0.32 g; 8 moles) keeping the temperature at 15- 20°C. The mixture was stirred at room temperature until the end of the gas generation, then heated to 125°C, slowly added in 30 minutes with a solution of (2R,3S)-1-(2, 4-dichlorophen- yl)-[(2-phenylmethoxy-1-methyl)-ethyl]-ethandiol-2-p-toluens ulfonate[(2-phenylmethoxy-1-methyl)-ethyl]-ethandiol-2-p-tol uensulfonate obtained in example 4 (1.02 g; 2 immoles) in DMF (2 ml), then kept under stirring at 125°C for further 90 minutes.

The mixture was then poured into water (40 ml) and extracted with methylene chloride (20 ml x 3). The joined organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purifie by flash chromatography (Si02; hexane/ethyl aceta- te/methanol 80/20/5) to give 0.66 g of (2R, 3S)-2- (2, 4-dichlorophenyl)-2-hydroxy-3-methyl-1-

(1,2,4-triazol-1-yl)-4-benzyloxy-butane (yield 82%).

1H-NMR (300MHz, DMSO, 5=ppm, J=Hz): 0.69 (d, 3H, J=7.00); 3.07 (ddq, 1H, J=6.60, J=5.50, J=7.00); 3.45 (dd, 1H, J=9.50, J=5.50); 3.90 (dd, 1H, J=9.50, J=6.60); 4.53 (d, 1H, J=12.00); 4.60 (d, 1H, J=12.00); 4.74 (d, 1H, J=14.60); 5.18 (d, 1H, J=14.60); 5.65 (s, IH); 7.18-7.50 (m, 9H); 7.60 (s, 1H) ; 8.22 (s, 1H).

Exemple 6 Synthesis of (2R,3S)-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol- 1-yl)-2,4-butan- diol A solution of (2R,3S)-2-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-1-(1,2,4-t riazol-1-yl)-4- benzyloxy-butane obtained in example 5 (0.66 g; 1.64 mmoles) in 37% HCl (10 ml) was heated to 125°C for 30 minutes. After cooling to room temperature, the mixture was poured into ice (20 g), alkalinized to pH#10 by 30% NaOH and extracted with methylene chloride (15 ml x 3). The joined organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purifie by flash chromatography (Si02; hexane/ethyl acetate/ methanol 70/30/10) to give 0.44 g of (2R, 3S)-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1, 2,4- 86%;enantiomericexcess:97%).triazol-1-yl)-2,4-butandiol(yiel d 1H-NMR (300MHz, DMSO, 5=ppm, J=Hz): 0.56 (d, 3H, J=7.00); 2.86 (ddq, IH, J=5.60, J=5.30, J=7.00); 3. 58 (ddd, 1H, J=11.00, J=5.30, J=5.00); 3.83 (ddd, 1H, J=11.00, J=5.60, J=5.00); 4.78 (d, 1H, J=4.60); 5.05 (t, 1H, J=5.00); 5.2 (d, 1H, J=4.60); 5.63 (s, 1H); 7.20 (dd, 1H, J=8.60, J=2.20); 7.36 (d, 1H, J=8.60); 7.47 (d, 1H, J=2.20); 7.70 (s, 1H); 8.25 s, 1H).