CZ20002088A3 - Process for preparing triazole derivatives - Google Patents

Abstract

A process for the preparation of a compound of formula VII wherein R 1 is Cl, F or CF3; R 2 is H, Cl, F or CF 3 and R 3 is C 1-4 alkyl; where olefin is epoxidizing to give an oxirane which is converted by treatment alkylmagnesium halide to triol, which is converted to triol an epoxide which is then treated with 1,2,4-triazole. Compounds VII are useful for the preparation of azole derivatives useful as antifungal agents.

Description

Process for the preparation of triazole derivatives

Technical field

The present invention relates to a process for the preparation of azotic compounds having antifungal effects.

BACKGROUND OF THE INVENTION

Compounds of formula I

wherein is chlorine, fluorine or trifluoromethyl;

R ₂ is hydrogen, chlorine, fluorine or trifluoromethyl;

R ₃ is C 1-4 alkyl; and

R ₄ is a C 1-5 polyfluoroalkyl group having at least two fluorine atoms and optionally other halogen atoms selected from chloro and bromo;

and salts thereof with pharmaceutically acceptable acids are known as antifungal and antifungal agents.

WO 97/31903 of the Applicants discloses a class of compounds to which the compounds of formula I above belong as broad-spectrum antifungal agents against pathogenic fungi of humans and animals. These compounds are obtained from the intermediate of formula (VII)

- 2 9 9 9 9

9 · 9999 9999

wherein R 1, R ₂ and R ₃ are as defined above, which is reacted with a suitable polyfluoroalkyl derivative to provide the desired compound of formula I.

We have now found a novel process for the preparation of compounds of formula VII which is an alternative to the synthetic methods described in the above-mentioned prior art.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a process for the preparation of compounds 15 of formula VII as follows.

The synthesis of the compounds I according to the invention starts from olefins of the formula II

(Π) wherein R 1 and R ₂ are as defined above, and R is a hydrogen atom or a hydroxyl protecting group. This compound is described and claimed as such in a related patent application filed by the applicant on the same day. This compound is epoxidized, for example, as described in EP-0 046 033 (Stanford University), using titanium alcoholate in the presence of a suitable acid derivative. · · · · · · · · · ·

- 3 tartaric and organic hydroperoxide, for example tert-butyl or cumyl hydroperoxide, or according to the procedure described in Synthesis, 1986, p. 89. This provides an oxirane of formula IIIa.

wherein R, R 1 and R ₂ are as defined above, by reacting with a (C 1-4) alkylmagnesium halide in the presence of copper (I) iodide produced as described in Organocopper Reagents: a practical approach, p. 39, ed. RIK Tayior, provides the triol of formula IV

wherein R, R 1, R ₂ and R 3 are as defined above.

The triol of formula IV is treated with a sulfonic acid chloride such as 20 for example methanesulfonyl chloride or tosyl chloride, or a halogenating agent such as phosphorus tribromide, thionyl chloride or phosphorus pentachloride and then a strong base such as NaOH to give a compound of formula V

5-2 (A)

- 4 wherein R I, R ₂ and R ₃ are as defined above, and Lg is halogen or a group OSO ₂ ^{R V} wherein R ^IV is a (C _1.4) alkyf or phenyl optionally substituted by methyl, which for Reaction 5 aimed at substituting the leaving group Lg by known methods yields a compound of formula VI

wherein R _{1 t} R ₂ and R ₃ are as defined above. This compound is treated with 1,2,4-triazole in basic medium to give the desired compound of formula VII.

The following are examples of some embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis of (E) - (2R, 3R) -2- (2,4-dichlorophenyl) -2,3-dihydroxymethyloxirane

A suspension of the pre-ground 4A molecular sieves (2.4 g) and (-) - diethyl tartrate (3.4 g; 16.3 mmol) in methylene chloride (150 mL) was cooled to -20 ° C under nitrogen, then mixed with titanium isopropylate (3.9 g; 13.6 mmol) and (E) -2- (2,4-dichlorophenyl) 2-butene-1,4-diol (3.2 g; 13.6 mmol). The temperature was maintained at

-20 ° C and 2M tert-butyl hydroperoxide in methylene chloride (13.5 mL; 27 mmol) was slowly added over 30 min and the mixture was stirred at -20 ° C for an additional 20 hours. Then 10% sulphite was added. 9 9 9 9

Sodium (35 mL; 28 mmol), the phases were separated and the aqueous phase was extracted with methylene chloride (30 mL). The combined organic phases were filtered through a pad of celite and concentrated to half volume. The solution was cooled to 0 ° C and 30% sodium hydroxide solution (20 mL) saturated with NaCl was added. Stirring was continued for 1 h. The mixture was acidified with 50% H 2 SO 4 and the organic phase was dried to give 2.9 g of raw material. After purification by flash chromatography (SiO ₂ ; hexane / ethyl acetate / methanol 70/30/2), 2.63 g of (E) - (2R, 3R) -2- (2,4-dichlorophenyl) -2,3-dihydroxymethyloxirane was obtained (yield 78%;

enantiomeric excess: 97.8%).

Synthesis of (E) - (2R, 3R) -2- (2,4-dichlorophenyl) -2,3-dihydroxymethyloxirane

The procedure described in Example 1 was repeated using 1 g (4.18 mmol) of (E) -2- (2,4-dichlorophenyl) -butene-1,4-diol but using (-) diethyl tartrate and titanium isopropylate in catalytic amounts relative to (E) -2- (2,4-dichlorophenyl) -butene-1,4-diol in concentrations of 6% and 5%, respectively, and with a longer reaction time (about 70 hours), 800 mg (E) were obtained. - (2R, 3R) -2- (2,4-dichlorophenyl) -2,3-dihydroxymethyloxirane (yield 76.2%; enantiomeric excess)

68%) after purification by flash column chromatography (SiO ₂ ;

ethyl acetate: petrolatum 1: 1).

¹ H-NMR (300 MHz, DMSO, d = 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, J H, J = 12.2, J = 2.5, J = 5.6); 3.88 (dd, 1 H,

J = 12.6, J = 6.5); 4.89 (t, 1H, J = 5.6); 5.06 (t, 1H, J = 6.5); 7.38 (d, 1 H,

J = 8.3); 7.45 (dd, 1H, J = 8.3, J = 2.0); 7.6 (d, 1H, J = 2.0).

Μ 99 ·· ·· ··

9

999 99 99 · ·

- 6 Example 3

Synthesis of (2R, 3S) -2- (2,4-dichlorophenyl) -3-methyl-1,2,4-trihydroxybutane

To a suspension of copper (I) iodide (2.75 g; 14.45 mmol) in dry THF (360 mL) cooled to -10 ° C was added a solution of 3 M methylmagnesium chloride in THF (48.2 mL; 144.5 mmol), and then a solution of (E) - (2R, 3R) -2- (2,4-dichlorophenyl) -2,3-dihydroxymethyloxirane obtained as described in Example 1 or 2 (6 g; 24.1) was added dropwise over 1 hour mmoi) maintaining the temperature at -10 ° C. The temperature was allowed to rise to + 5 ° C and stirring was continued for 120 hours. The mixture was poured into saturated ammonium chloride solution (350 mL), the phases were separated and the aqueous phase was extracted with ether (100 mL). The organic phases were washed with saturated NaCl solution (200 mL), dried over Na ₂ SO ₄ and evaporated. The crude was purified by flash chromatography (SiO ₂ ; n-heptane / ethyl acetate 60/40) to give

3.75 g of (2R, 3R) -2- (2,4-dichlorophenyl) -3-methyl-1,2,4-trihydroxybutane (yield 58%; enantiomeric excess: 97%).

¹ H-NMR (300 MHz, DMSO, δ = 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, 1 H,

J = 6.23, J = 4.39); 4.70 (dd, 1H, J = 4.84, J = 4.76); 5.00 (s, 1 H); 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 ₂ 5 Synthesis of (2R) -2- (2R) -2- (2,4-dichlorophenyl) -oxiranyne-1-propylmethanesulfonate

To a solution of (2R, 3S) -2- (2,4-dichlorophenyl) -3-methyl-1,2,4-trihydroxybutane obtained as in Example 3 (1 g; 3.77 mmol) in pyridine (20 mL) was added methanesulfonyl chloride (0.91 g; 7.92 mmol) was added with stirring over approximately 30 min at 15 ° C, then

9 9 9 9 9 9 9 9 9

The mixture was stirred for 20 hours while maintaining the temperature at 15 ° C. To the reaction mixture was added 10 N sodium hydroxide solution (2 mL; 20 mmol). The mixture was poured into ice (about 80 g), acidified with 50% H 2 SO 4 (about 35 mL) and extracted twice with methylene chloride (30 mL). The combined organic phases were dried. The crude (1.23 g) was purified by flash chromatography (SiO 2; n-heptane / ethyl acetate 85/15) to give 0.96 g of (2R) -2 - [(2R) -2- (2,4-dichlorophenyl) - oxiranyl] -1-propyl methanesulfonate (78% yield).

¹ H-NMR (300 MHz, DMSO, δ = 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 (m, 3H); 7.66 (d, 1H, J = 1.65).

Example 5

Synthesis of (2R) -2- (2R) -2- (2,4-dichlorophenyl) -oxiranine-1-propanol |

To a solution of (2R) -2 - [(2R) -2- (2,4-dichlorophenyl) -oxiranyl] -1-propyl methanesulfonate obtained as described in Example 4 (0.9 g; 2.77 mmol) in DMF (12 mL) was added potassium acetate (710 mg; 7.25 mmol) and tetrabutylammonium iodide (45 mg; 0.14 mmol) and the mixture was heated to 75 ° C for 4 h. An additional portion of tetrabutylammonium iodide (45 mg; 0) was added. , 14 mmol) and the mixture was stirred at 75 ° C for 18 h. After cooling to 20 ° C, water (1 mL) and 30% NaOH (0.4 mL; 4 mmol) were added and the mixture was stirred while maintaining the temperature at The mixture was diluted with water (50 mL) and extracted with ether (20 mL). After separation, the phases were dehydrated over dry Na 2 SO 4 and dried. The crude (0.7 g) was purified by flash chromatography (SiO 2; hexane / ethyl acetate 85/15) to give 0.57 g of (2R) -2 - [(2R) -2- (2,4-dichlorophenyl) -oxiranyl] -1-propanol (83% yield).

¹ H-NMR (300 MHz, DMSO, δ = ppm, J = Hz): 0.83 (dm 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 • 99,999,999

999 9 9 99 9 · · »

99,999 9,999 9

-8 (ddd 1H, J = 11.00, J = 6.60, J = 5.30); 3.22 (d, 1H, J = 4.70); 2.38 (ddd, 1H, J = 11.00, J = 6.10, J = 5.30); 4.8 (t, 1H, J = 5.30); 7.43 (s, 2 H); 7.61 (s, 1 H).

Example 6

Synthesis of (2R, 3S) -2- (2,4-dichlorophenyl) -3-methyl-1- (1H-1,2,4-triazol-1-yl) 2,4-butanediol

To a solution of 1,2,4-triazole (0.65 g; 9.4 mmol) in DMF (7 mL) was added portionwise at 15-20 ° C 60% NaH (370 mg; 9.4 mmol). At the end of the addition, stirring was continued until complete 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 mmol) was added. in DMF (2.5 mL) and the mixture was heated at 125 ° C for 2 h. The mixture was cooled, diluted with water (50 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were washed with water (30 ml), dehydrated over dry Na ₂ SO ₄ , then dried. The crude (0.7 g) was purified by flash chromatography (SiO ₂ ; hexane / ethyl acetate / methanol 70/30/10) to give 0.57 g of (2R, 3S) -2- (2,4-dichlorophenyl) -3- methyl 1- (1H-1,2,4-triazol-1-yl) -2,4-butanediol (77% yield), which was crystallized from isopropyl ether / toluene 8/2. Mp 115 116 ° C; enantiomeric excess: 97%.

¹ H-NMR (300 MHz, DMSO, δ = 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, IH).

J = 4.60); 5.05 (t, 1H, J = 5.00); 5.2 (d, 1H, J = 4.60); 5.63 (s, 1 H); 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, 1 H); 8.25 (s, 1 H).

Claims (3)

PATENT CLAIMS A process for the preparation of triazole derivatives of the formula VII wherein (VII) R 1 is chloro, fluoro or trifluoromethyl; R ₂ is hydrogen, chlorine, fluorine or trifluoromethyl group; R ₃ is C ₁ _ ₄ alkyl; characterized in that an olefin of formula II (Π) is epoxidized wherein R 1 and R ₂ are as defined above and R is a hydrogen atom or a hydroxyl protecting group to give oxirane III (ΠΙ) Wherein R, R 1 and R ₂ are as defined above, which by treatment of (C _1-4 ) alkylimagnesium halide in the presence of cuprous iodide affords the triol of formula IV wherein R, R 1, R ₂ and R ₃ are as defined above; and the triol of formula IV is reacted with sulfonic acid chloride or a halogenating agent and then with a strong base to give a compound of formula V wherein R 1, R ₂ and R ₃ are as defined above and Lg is halogen or OSO ₂ R ^IV wherein R ^IV is a (C _1-4 ) alkyl group or an optionally methyl-substituted phenyl group, which compound is subjected to a reaction to replace the leaving group Lg to give a compound of formula VI (VI). - 11 10 99 99 9 9 9 9 9 9 9 99 99 99 99 99 · 9 · Wherein R 1, R 2 and R 3 are as defined above treated with 1,2,4-triazole in a basic medium to obtain a triazole compound of formula VII. A process for the preparation of triazole derivatives of formula I (I) wherein R 1 is chloro, fluoro or trifluoromethyl; R ₂ is hydrogen, chlorine, fluorine or trifluoromethyl group; R ₃ is C _1-4 alkyl; and R ₄ is a C 1-5 polyfluoroalkyl group containing at least 2 fluorine atoms and optionally other halogen atoms selected from chlorine and bromine; and a salt thereof with a pharmaceutically acceptable acid, characterized in that an olefin of formula II is epoxidized wherein R 1 and R ₂ are as defined in claim 1 and R is a hydrogen atom or a hydroxyl protecting group to provide oxirane IIIa. 4 »9 99 9 9 9 9 (III) wherein R, R 1 and R ₂ are as defined in claim 1, which treatment of (C _1-4 ) alkylmagnesium halide in the presence of cuprous iodide affords a triol of formula IV wherein R, R 1, R 2 and R 3 are as defined in claim 1 ; and the triol of formula IV is reacted with sulfonic acid chloride or a halogenating agent and then with a strong base to give a compound of formula V wherein R 1, R 2 and R 3 are as defined in claim 1 and Lg is halogen or OSO ₂ R ^IV , wherein R ^1v is a (C 1-4) alkyl group or an optionally methyl-substituted phenyl group, which compound is subjected to a reaction for substitution of a leaving group Lg to give a compound of the formula VI . ΦΦΦΦ t t t t t t Φ ·· ΦΦΦΦ «ΦΦΦ (VI) wherein R 1, R 2 and R 3 are as defined in claim 1, treated with 1,2,4-triazole in a basic medium to obtain a triazole compound of formula VII (VII) wherein R 1, R 2 and R 3 are as defined in claim 1 which is reacted with a suitable polyfluoroalkyl derivative.