The compound of formula I wherein Rl is chlorine, fluorine or trifluoromethyl; R2 is hydrogen, chlorine, fluorine or trifluoromethyl; R3 is C, alkyl; and <BR> <BR> R4 is a Cri-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 VII wherein R1, R2 and R3 are as defined above, which reacted with the suitable polyfluoroalkyl derivative provides the desired compound of formula I.

It has been now found a new method for preparing the compound of formula VII 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 VII as

illustrated hereinbelow.

The synthesis of the compound I according to the invention starts from the olefin of formula II wherein R, and R2 are as defined above, and R is hydrogen or a protecting group for the hy- droxy moiety. This compound is described and claimed per se in the co-pending patent appli- cation filed in the same date of the present one by the Applicant. It is epoxidized, for example according to what described in the patent EP-0 046 033 (in the name of Standford University) which uses titanium alcoholate in the presence of a suitable derivative of tartaric acid and of an organic hydroperoxide, for example tert. butyl- or cumyl-hydroperoxide, or according to what taught in Synthesis, 1986, page 89. It is thus obtained the oxirane of formula III wherein R, R, and R2 are as defined above, which, treated with (CI-4) alkyl-magnesium halide in the presence of copper (I) iodide, prepared according to what described in Organocopper Reagents: a practical approach, page 39, ed. R. I. K Taylor, provides the thiol of formula IV wherein R, Rl, R2 and R3 are as defined above.

The triol of formula IV is treated with a sulfonic acid chloride, such as, for example methan- sulfonyl-chloride or tosyl chloride, or with a halogenating agent such as, for example, phos- phorous tribromide, thionyl chloride or phosphorous pentachloride and, sequentially, with a strong base, for example NaOH, to give the compound of formula V

wherein Rl, R2 and R3 are as defined above, and Lg is halogen or a OSO2RIV group wherein Wu is a (Cl4) alkyl or an optionally methyl-substituted phenyl group, which subdued to a reac tion for substituting the leaving group Lg according to knout methods gives the compound of formula VI wherein R1, R2 and R3 are as defined above. This is treated with 1,2,4-triazole in basic me- dium to give the desired compound of formula VII.

Hereinbelow fulfilment examples of the present invention are provided.

Example 1 Synthesis of (E)-f2R3R)-2- (2. 4-dichlorophen)-2. 3-dihvdroxvmethvl-oxirane A suspension of previously ground 4Å molecular sieves (2.4 g) and (-)-diethyl tartrate (3.4 g; 16.3 mmoles) in methylene chloride (150 ml) was cooled to-20°C under nitrogen, then treated with titanium isopropylate (3.9 g; 13.6 mmoles) and (E)-2- (2,4-dichlorophenyl)-buten-1,4-diol (3. 2 g; 13.6 mmoles). Keeping the temperature at-20°C 2M tert.-butyl hydroperoxide in methylene chloride (13.5 ml; 27 mmoles) was slowly added in about 30 minutes and it was stirred at-20°C for further 20 hours. Then 10% sodium sulfite (35 ml; 28 mmoles) was ad- ded, the phases were separated and the aqueous one extracted with methylene chloride (30 ml).

The joined organic phases were filtered on celite cake and concentrated to half the volume. It was cooled to 0°C, a 30% solution of sodium hydroxide (20 ml) saturated with NaCI was ad- ded. The stirring was kept on for 1 hour. The mixture was acidifie with 50% H2SO4, and the organic phase was dried to give 2.9 g of crude. After purification by flash chromatography (Si02; hexane/ethyl acetate/methanol 70/30/2) 2.63 g of (E)- (2R, 3R)-2- (2,4-dichlorophenyl)- 2,3-dihydroxymethyl-oxirane were obtained (yield 78%; enantiomeric excess: 97.8%).

Exemple 2 Synthesis of (E)-(2R,3R)-2-(2,4-dichlorophenyl)-2,3-dihydroxymethyl-oxira ne Starting from 1 g (4.18 moles) of (E)-2-(2, 4-dichlorophenyl)-buten-1,4-diol and operating as described in example 1, but using (-) diethyl tartrate and titanium isopropylate in catalytic amounts with respect to (E)-2- (2,4-dichlorophenyl)-buten-1,4-diol, respectively 6% and 5% molar, and with a longer rection time (about 70 hours), 800 mg of (E)- (2F, 3R)-2- (2,4-di- chlorophenyl)-2, 3-dihydroxymethyl-oxirane were obtained (yield 76.2%; enantiomeric excess 68%) after purification by column chromatography (Si02; ethyl acetate: petrolatum 1: 1).

1H-NMR (300 MHz, DMSO, 8=ppm, J=Hz): 2.74 (ddd, 1H, J=12.2, J=7.6, J=5.6); 3.45 (dd, 1H, J=7.6, J=2.5); 3.54 (dd, 1H, J=12.6, J=6.5); 3.58 (ddd, 1H, J=12.2, J=2.5, J=5.6); 3.88 (dd, IH, J=12.6, J=6.5); 4.89 (t, 1H, J=5. 6); 5.06 (t, 1H, J=6.5); 7. 38 (d, IH, J=8.3); 7.45 (dd, 1H, J=8.3, J=2.0); 7.6 (d, 1H, J=2.0).

Example 3 Svnthesis of (2R3S)-2- (2. 4-dichlorophenyl-3-methvl-1, 2, 4-trihvdroxy-butane A suspension of copper (I) iodide (2. 75 g; 14.45 immoles) in dry THF (360 ml) and cooled to -10°C was added with a solution of 3M methyl-magnesium chloride in THF (48.2 ml; 144.5 mmoles) then dropwise added, in about 1 hour, with a solution of (E)-(2R, 3R)-2-(2,4-dichlo- rophenyl)-2, 3-dihydroxymethyl-oxirane obtained as described in example 1 or 2 (6 g; 24.1 mmoles) keeping the temperature at -10°C. The temperature was left to raise up to +S°C and it was stirred for 120 hours. The mixture was poured into a saturated solution of ammonium chloride (350 mol), the phases were separated and the aqueous one extracted with ether (100 ml). The organic phases were washed with a saturated solution of NaCI (200 ml), dried over dry Na2SO4 and evaporated. The crude was purifie by flash chromatography (Si02; n-hep- tane/ethyl acetate 60/40) to give 3.75 g of (2R, 3S)-2- (2,4-dichlorophenyl)-3-methyl-1,2,4-tri- hydroxy-butane (yield 58%; enantiomeric excess: 97%).

IH-NMR (300 MHz, DMSO, #=ppm, J=Hz): 0.55 (d, 3H, J=7.00); 2.47 (ddq, 1H, J=6.30, J=4.80, J=7.00); 3.38 (ddd, 1H, J=11.00, J=4.84, J=6.30); 3.68 (ddd, 1H, J=11.00, J=4.80, J=4.76); 3.86 (dd, 1H, J=11.35, J=4.39); 4.18 (dd, 1H, J=11.35, J=6.23); 4. 58 (dd, 1H, J=6.23, J=4.39); 4.70 (dd, 1H, J=4.84, J=4.76); 5.00 (s, IM; 7.38 (dd, 1H, J=8.80, J=2.20);

7.47 (d, 1H, J=2.20); 7.76 (d, 1H, J=8.80).

Example 4 Svnthesis of (2R)-2-[(2R)-2-(2,4-dichlorophenyl)-oxiranyl]-1-propyl methansulfonate A solution of (2R, 3S)-2-(2,4-dichlorophenyl)-3-methyl-1,2, 4-trihydroxy-butane obtained as in example 3 (1 g; 3.77 mmoles) in pyridine (20 ml) was added, under stirring in about 30 min- utes at a temperature of 15°C, with methansulfonyl chloride (0.91 g; 7.92 mmoles), then the stirring was kept on at 15°C for 20 hours. The rection mixture was added with a ION solu- tion of sodium hydroxide (2 ml; 20 mmoles), and the whole was heated to 35°C under stirring for I hour. Then it was poured into ice (about 80 g), acidifie with 50% H2SO4 (about 35 ml) and twice extracted with methylene chloride (30 mol). The joined organic phases were dried.

The crude (1.23 g) was purifie by flash chromatography (SiO2 ; n-heptane/ethyl acetate 85/15) to give 0.96 g of (2R)-2- [ (2R)-2- (2, 4-dichlorophenyl)-oxlranyl]-l-propyl methansul- fonate (yield 78%).

1H-NMR (300 MHz, DMSO, 6=ppm, J=Hz): 0.94 (d, 3H, J=7.03); 2.50 (ddq, 1H, J=6.40, J=6.10, J=7.00); 2.82 (d, 1H, J=4.40); 3.19 (s, 3H); 3.24 (d, 1H, J=4.40); 4.1 (dd, 1H, J=10.25, J=6.10); 4.12 (dd, 1H, J=10.25, J=6.40); 7.46 (ion, 3H); 7.66 (d, 1H, J=1.65).

Example 5 Synthesis of (2R)-2-[(2R)-2-(2,4-dichlorophenyl)-oxiranyl]-1-propanol A solution of (2R)-2- [ (2R)-2- (2, 4-dichlorophenyl)-oiranyl]-1-propyl methansulfonate ob- tained as described in example 4 (0.9 g; 2.77 moles) in DMF (12 ml) was added with potas- sium acetate (710 mg; 7.25 mmoles) and tetrabutylammonium iodide (45 mg; 0.14 immoles) then heated to 75°C for 4 hours. Another purtion of tetrabutylammonium iodide (45 mg; 0.14 mmoles) was added and it was stirred at 75°C for total 18 hours. After cooling to 20°C, water (1 ml) and 30% NaOH (0.4 ml; 4 moles) were added and the stirring was kept on at 20°C for 1 hour. It was diluted with water (50 ml) and extracted with ether (20 ml). After separa- tion of the phases it was anhydrified over dry Na2SO4 and dried. The crude (0.7 g) was puri- fied by flash chromatography (Si02; hexane/ethyl acetate 85/15) to give 0.57 g of (2R)-2- [ (2R)-2- (2, 4-dichlorophenyl)-oxiranyl]-l-propanol (yield 83%).

IH-NMR (300 MHz, DMSO, #=ppm, J=Hz): 0.83 (d, 3H, J=6.80); 2.15 (ddq, 1H, J=6.60, J=

6.10, J=6.80); 2.72 (d, 1H, J=4.70); 3.17 (ddd 1H, J=11. 00, J=6.60, J=5.30); 3.22 (d, 1H, J= 4.70); 3.38 (ddd, 1H, J=11. 00, J=6.10, J=5.30); 4.8 (t, 1H, J=5.30); 7.43 (s, 2H); 7.61 (s, 1H).

Example 6 Svnthesis of (2R,3S)-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol- 1-yl)-2, 4-butan- diol A solution of 1,2,4-triazole (0.65 g; 9.4 mmoles) in DMF (7 ml) was portionwise added, at 15-20°C, with 60% NaH (370 mg; 9.4 mmoles). At the end of the addition, the stirring was kept on until total dissolution. A solution of (2R)-2-[(2R)-2-(2, 4-dichlorophenyl)-oxiranyl]-1- propanol obtained as described in example 5 (0.62 g; 2.34 mmoles) in DMF (2.5 ml) was ad- ded and heated to 125°C for 2 hours. The mixture was cooled, diluted with water (50 ml) and twice extracted with ethyl acetate (30 ml). The organic phases were washed with water (30 ml), anhydrified over dry Na2SO4, then dried. The crude (0.7 g) was purifie by flash chroma- tography (Si02; hexane/ethyl acetate/methanol 70/30/10) to give 0.57 g of (2R, 3S)-2-(2,4-di- chlorophenyl)-3-methyl-1-(1H-1, 2,4-triazol-1-yl)-2,4-butandiol (yield 77%), then crystallized from isopropyl ether/toluene 8/2. m. p. 115-116°C; enantiomeric excess: 97%.

1H-NMR (300 MHz, DMSO, #=ppm, J=Hz): 0.56 (d, 3H, J=7.00); 2.86 (ddq, 1H, 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); 7.2 (dd, 1H, J=8.60, J=2.20); 7.36 (d, 1H, J=8.60); 7.47 (d, 1H, J=2.20); 7.7 (s, 1H); 8.25 (s, 1H).