The compounds of formula I wherein R, is chlorine, fluorine or trifluoromethyl; R2 is hydrogen, chlorine, fluorine or trifluoromethyl; R3 is C, alkyl; and R4 is a polyfluoroalkyl Cl group containing at least two fluorine atoms and optionally other halogen atoms selected from chlorine and bromine; and the pharmaceutically acceptable salts thereof, are known as antimycotic and antifungal agents.

The patent application WO 97/31903 (in the Applicant's name) shows a class of compounds where the above compounds of formula I fall, as wide spectrum antimycotics against human and animal pathogenic fungi.

Two preparation processes being a synthetic alternative with respect to the synthetic routes taught by the above said prior art are described in two patent applications filed at the same date of the present one by the Applicant. These two processes use a new intermediate which constitutes the object of the present invention.

Therefore the present invention relates to a compound of formula II

wherein R, is chlorine, fluorine or trifluoromethyl; R2 is hydrogen, chlorine, fluorine or trifluoromethyl ; and R is hydrogen or a protective group for the hydroxy moiety.

The synthesis of the compounds of formula II according to the present invention starts from the iodo-or bromo-benzene derivative of formula III wherein R, and R2 are as defined above, and X is bromine or iodine, which is first turned into the corresponding Grignard reactant according to known methods and then into the corre- sponding phenyl-zinc halide or phenyl-boron acid by treatment with zinc halide, preferably chloride, or with trialkyl borate followed by hydrolysis, which is treated with iodo-or bromo- fumarate, prepared as described in J. Am. Chem. Soc. 1972,94 (12), 4363-4, in the presence of a suitable transition metal (0)-based catalyst. Preferred examples of catalyst are palladium or nickel, optionally supported by ligands such as, for example, triphenylphosphine.

The transition metal (0)-base catalysts may be in case prepared in sitit starting from the cor- responding salts such as, for example, nickel chloride, cobalt chloride, nickel acetylacetonate, ferric chloride, palladium chloride, lithium tetrachlorocuprate, palladium acetate and palla- dium acetylacetonate.

Only for practical reasons palladium tetrakis (triphenylphosphine), nickel tetrakis (triphenyl- phosphine) or palladium on charcoal in the presence of triphenylphosphine are preferred, op- tionally prepared in situ as described, for example, in Org. Synth., 66,67-74,1988.

In this way a diester of formula IV wherein R, and R2 are as defined above, and RI and R are independently a (C, 4) alkyl group, is obtained, which is reduced according to common techniques, for example with diisobutyl- aluminium hydride (DIBAH) to give the compound II wherein R=H.

Another synthetic route for yielding product II starts from the derivative of formula III which, turned into the corresponding Grignard compound and, then, reacted with a diester of oxalic acid, gives the compound of formula V wherein R, and R2 are as defined above, and R"'is a (C, 4) alkyl group, which is reacted in the presence of a base such as, for example, sodium ethylate or methylate, optionally prepared in situ, or sodium hydride, according to the procedures of the so-called Wittig reaction, for e- xample with trialkyl phosphonoacetate.

It is thereby obtained the compound of formula IV which is turned into the compound of for- mula II wherein R=H as already explained above.

It is intended that the product of formula II wherein R is a protective group of the hydroxy moiety may also be obtained by reacting a compound of formula II wherein R is hydrogen with a protective group of the alcoholic function (see, for example, T. W. Greene and P. G. M.

Wuts, Protective groups in organic synthesis, John Wiley & Sons, New York).

Preferred protective groups according to the present invention are those stable in the presence of bases and nucleophilic reactants, in particular silyl ethers, benzyl ether, 2-methoxy-ethoxy- methyl ether, methoxy-methyl ether and tetrahydropyranyl ether.

A further method for yielding the product II entails the reaction of the magnesium derivative of the compound of formula III with the diol of formula VI wherein X'is a halogen atom and R is as defined above or is a MgX'group.

Hereinbelow fulfilment examples of the present invention are provided.

Example 1 Svnthesis of (E)-2-(24-dichlorophenvl)-butendioic acid diethvl ester a) with catalyst prepared in situ from Pd (OAc) 2+PPh3 A suspension of magnesium (1.82 g; 0.075 moles) kept under stirring at 25°C in ethyl

ether (20 ml) was added with ethyl bromide (50 mg). After 15 minutes 1,3-dichloro-4-io- dobenzene (13.65 g; 0.05 moles) in ethyl ether (20 ml) was added in about 1 hour at the temperature of 18-22°C, and at the end of the addition the stirring was kept on at 20°C for further 90 minutes. The metallic magnesium was decanted and the surnatant solution was added in 10 minutes to a suspension of dry zinc chloride (13.6 g; 0.1 mole) in ethyl ether (20 ml). The suspension was stirred at room temperature for 90 minutes, then cooled to 0°C, added with dry DMF (40 ml) then with palladium acetate (168 mg; 0.75 mmoles) and triphenylphosphine (395 mg; 1.5 mmoles) and at last a solution of diethyl iodo-fuma- rate (10.45 g; 0.035 moles), prepared according to J. Am. Chem. Soc. 1972,94 (12), 4363- 4, in DMF (10 ml) was dropped in about 30 minutes. The mixture was stirred at room temperature overnight, then cooled to 0°C. added with IN HCI (80 ml) and twice ex- tracted with hexane (80 ml). The organic phases were anhydrified over Na2SO4 and evaporated to dryness. The residue (13 g) was purified by flash chromatography (Si02; hexane/ethyl ether 95/5) to give 7.82 g of pure (E)-2- (2, 4-dichlorophenyl)-butendioic acid diethyl ester (yield: 70% calculated with respect to the diethyl iodo-fumarate). b) with catalyst prepared in situ from preformed PdCI2 (PPh3) 2 A suspension of magnesium (0.73 g, 0.03 moles) in ethyl ether (20 ml) under nitrogen flow was added with ethyl bromide (50 mg). The solution was stirred for 15 minutes then added with a solution of 1,3-dichloro-4-iodobenzene (5.45 g, 0.02 moles) in ethyl ether (10 ml) in 1 hour keeping the temperature at 18-22°C. At the end of the addition the sus- pension was kept under stirring for 90 minutes at 18-22°C, then decanted and the surna- tant added in 10 minutes to a suspension of dry zinc chloride (5.4 g, 0.04 moles) in ethyl ether (8 ml). At the end of the addition the stirring was kept on at 20°C for further 90 min- utes, then cooled to 0°C. DMF (10 ml) and palladium dichloride triphenylphosphine (351 mg, 0.0005 moles), then a solution of diethyl iodo-fumarate (4.18 g, 0.014 moles) in DMF (4 ml) were added. The mixture was kept under stirring for 15 hours at 25°C and after a work-up similar to the one of point a) 2.1 g of (E)-2- (2, 4-dichlorophenyl)-butendioic acid diethyl ester were yielded (yield: 63% calculated with respect to the iodo-fumarate). lH-NMR (200 MHz, CDC13,6=ppm, J=Hz): 1.10 (t, 3H, J=7.1); 1.25 (t, 3H, J=7.1);

4.05 (q, 2H, J=7.1); 4.24 (q, 2H, J=7.1); 7.09 (s, 1H); 7.07-7.42 (m, 3H).

Example 2 Svnthesis of (2.4-dichloro-phenvl !-oxo-acetic acid ethyl ester A suspension of magnesium (6.7 g; 0.275 moles) in ethyl ether (125 ml) under stirring and ni- trogen flow was added with ethyl bromide (180 mg). A solution of 1,3-dichloro-4-iodobenzene (50 g; 0.183 moles) and ethyl bromide (180 mg) in ethyl ether (100 ml) was dropped in about 1 hour keeping the temperature at 15-20°C. The suspension was stirred for further 2 hours.

After decanting the magnesium in excess, the solution was dropped in about 1 hour in a solu- tion of diethyloxalate (29.32 g; 0.2 moles) in ethyl ether (125 ml) cooled to-70°C. At the end of the addition it was stirred at-70°C for 1 hour, then the temperature was left to rise to 10°C and the stirring was kept on for another hour. The suspension was added with a saturated so- lution of NH4CI (125 ml), the phases were separated and the aqueous one extracted with ethyl acetate (50 ml). The organic phases were washed with a solution of sodium bisulfite and trea- ted with discolouring charcoal. After filtration, the organic solution was distilled under vac- uum to give a crude which was purified by chromatography (Si02; hexane/ethyl ether 9/1) to give 36.2 g of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester (yield 80%) as a colourless oil.

IH-NMR (200 MHz, CDC13, S=ppm, J=Hz): 1.37 (t, 3H, J=7.2); 4.39 (q, 2H, J=7.2); 7.37 (dd, 1H); 7.45 (d, 1H, J=2.0); 7.70 (d, 1H, J=8.4).

Example 3 Svnthesis of (E) 2- (2. 4-dichlorophenyl)-butendioic acid diethvl ester An ethanolic solution of sodium ethylate, obtained from sodium (3.35 g; 0.1457 moles) and dry ethanol (276 ml), kept under stirring ir_ inert atmosphere, was added at 20°C with a solu- tion of (2,4-dichloro-phenyl)-oxo-acetic acid ethyl ester obtained as described in example 2 (36 g; 0.147 moles), and triethyl phosphonoacetate (34.2 g; 0.152 moles) in dry ethanol (70 ml). The reaction mixture was then brought and kept at reflux for 16-20 hours. After cooling to 25°C, the mixture was poured under stirring into a solution of saturated NaCl (500 ml), ethyl ether was added (150 ml) and the phases were separated. The aqueous phase was ex- tracted again with ethyl ether (150 ml). The joined organic phases were washed with water (100 ml), anhydrified over dry Na2SO4, evaporated to dryness. The thus obtained residue was

purified by chromatography (Si02; hexane/ethyl ether 9/1) to give 24.6 g of (E) 2- (2,4-dichlo- rophenyl)-butendioic acid diethyl ester (yield 53%) as a colourless oil.

Example 4 Svnthesis of (E)-2- (2, 4-dichlorophenvl)-buten-1.4-diol A solution of (E)-2- (2, 4-dichlorophenyl)-butendioic acid diethyl ester (3.2 g; 0.01 moles) ob- tained as described in example 1 or 3, in toluene (32 ml) cooled to a-20°C under nitrogen, was added in about 90 minutes with 1.2M DIBAH in toluene (35 ml; 0.042 moles). The mix- ture was stirred at-20°C for 1 hour, then slowly poured into IN HCI (170 ml) while keeping the temperature at 0-5°C. After 15 minutes the stirring was halted and the phases left to sepa- rate. The aqueous one was isolated and extracted again in toluene (30 ml). The organic phases were washed with water (50 ml), anhydrified over dry Na2SO4, dried. The crude was purified by flash chromatography (SiO2; hexane/ethyl acetate/methanol 70/30/2) to give 1.45 g of (E)- 2- (2, 4-dichlorophenyl)-buten-1,4-diol (yield 62%) which was crvstallized from isopropyl ether. m. p. 94-95°C.

IH-NMR (300 MHz, DMSO, 8ppm, J=Hz): 3.66 (dd, 2H, J=6.10, J=5.31); 4.02 (dd, 2H, J=5.62, J=1.41); 4.62 (t, 1H, J=5.31); 5.08 (t, 1H, (tt, 1H, J=6.10, J=1.41); 7.23 (d, 1H, J=8.10); 7.43 (dd, 1H, J=8.10, J=2.00); 7.63 (d, 1H, J=2.00).

Example 5 Svnthesis of (E) (2,4-dichlorophenvl)-2-buten-1, 4-diol A suspension under nitrogen of magnesium (0.8 g; 32.7 mmoles) in ethyl ether (17 ml) kept at 20°C under stirring, was added with ethyl bromide (25 mg). After 15 minutes a solution of 1,3-dichloro-4-iodobenzene (5.95 g; 21.8 mmoles) and ethyl bromide 25 mg) in dry ether (13 ml) was dropwise added (about 1 hour) keeping the temperature at 15-20°C. At the end of the dropping the suspension was kept at 15-20°C for 2 hours more. The magnesium in excess was removed and the obtained solution was dropped, keeping the temperature at 0-5°C, in a second flask containing a suspension formerly prepared. Such suspension was obtained by adding, at 0-5°C, a THF solution of 3M methyl magnesium chloride (9.6 ml; 29 mmoles) to a solution of 2-butin-1,4-diol (1.25 g; 14.5 mmoles) in THF (30 ml). At the end of the addition the suspen- sion was refluxed and stirred at mild reflux for 24 hours. After cooling to 0°C, an aqueous so-

lution of saturated NH4CI was added, the phases were divided and the aqueous one extracted in ether (30 ml). The joined organic phases were washed with water (30 ml), anhydrified over dry Na2SO4, dried. The product was purified by flash chromatography (Si02; petrolatum/ ethyl acetate 60/40) to give 0.24 g of (E) (2,4-dichlorophenyl)-2-buten-1, 4-diol (yield 7,3%).

The 1H-NMR effected on the product is practically the same of the one reported in example 4.