FI82244B - 1H-1,2,4-Triazolyloxyranes - Google Patents

Description

x 82244 1H-1,2,4-triazolyloxiranes

The invention relates to novel 1H-1,2,4-triazolyloxy

to sirans of formula II

r1 o

^ t / ° N

N NCC-CH 9 (II) \ III i 10 \ = - N \ 1 wherein R is phenyl substituted with 1 to 3 substituents each of which is independently F, Cl or Br 15 and R 1 is H, CH 3 or F, as well as their salts.

These compounds can be used as intermediates in the preparation of the bis-triazole derivatives of formula I described in the parent application.

OH R1 20 ^ I I ^ N f-CH2-C-C-N N (I) I I N = y wherein R and R1 are as defined above.

R is preferably phenyl substituted with 1 to 2 substituents each of which is independently F, Cl or Br. Preferred individual groups represented by R are 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4 -chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl and 4-bromo-2,5-difluorophenyl. The most preferred groups represented by R are 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-fluorophenyl and 4-chlorophenyl. The most preferred group represented by R is 2,4-35 difluorophenyl.

R 1 is preferably H or F.

2 82244

In the most preferred compound, R is 2,4-difluorophenyl and R 1 is H.

Compounds of formula I may be prepared in a conventional manner according to the following reaction scheme: R 1 I 1,2,4-triazole, preferably in the presence of a base N NCC-CH 2 such as K 2 CO, or a basic salt of NFR 1,2,4-triazole 10 "~

(ID

OH R1

I I

15 N N-CH -C-C-N N

In a typical such reaction, the epoxide of formula II, 1,2,4-triazole and anhydrous potassium carbonate are heated together, for example at 40 to 120 ° C, in a suitable solvent, e.g. anhydrous dimethylformamide, until the reaction is complete. at the end. The product (I) can then be isolated and purified in a conventional manner.

If a basic salt of 1,2,4-triazole is used in the reaction, this is preferably an alkali metal salt, and very preferably a sodium or potassium salt.

Compounds of formula II in which R 1 is H or CH 3 are conventionally obtained, e.g. as follows:

II

3 82244

F

i

N N-CH-C-R. . „“ N N-C - C-R

X) L II x) NaIi LJ I i Il 5 N R1 o ii) C103F '-N R1 o -► (III) (IV) (R1 = H or CH3) 10 Dimethyloxosulfonium methyldi v

15 ^ I

N N-C — C -CH, \ _ 1 I I 2 '1 \

R R

(HA) 20

The compound of formula IIA does not need to be isolated and purified, but can be converted in situ to the desired product.

Trimethylsulfoxonium iodide and sodium hydride in dimethyl sulfoxide are generally used to form dimethyloxosulfonium methylide in situ.

The ketones of the formula III are either known compounds (see e.g. patent applications EP-0044605 and GB 2 099 818A) or can be prepared analogously to known methods.

Alternatively, the route for the preparation of ketones of formula IV (R 1 is H) is as follows:

F

35 R-COCH2F + SO2Cl2 R-COCH-C1 1,2,4-triazole / K2CO3 -► —-fr- _fr Compound (IV) 4 82244

The intermediates of the invention wherein R 1 is F in formula II can be prepared as follows:

F

5 N N-CH-C-R i) NaH N 'N-CF - C-R

\ I »\ l II

(Ii) C103F \ -No -► (IV) (V) 10 (R1 is H)

Dimethyloxosulfonium methylide 0 t 15 [(CH3) 2S = CH2] ▼ N N-CF--C-CH- \ I 2 I 2

i - = - N R

20 (HB)

It is not necessary to isolate a compound of formula IIB. Another way to prepare oxiranes of formula II wherein R 1 is H, CH 3 or F is as follows:

II

5 82244 _ F CH „I K2co3>»

N ^ N-C-COR - fr *? C_R

- N ^ 1 C ^ I ^ PhjBr0, V == N r1 5 reflux, dioxane / H2O (IV) m-chloroperbenzoic acid, radical) inhibitor, reflux, 1,2-dichloroethane ψ

F

15 I / N \ N N-C-C-CHO

Wi I

R R

(II) A preferred free radical inhibitor is 3,3'-di-tert-butyl-4,4'-dihydroxy-5,5'-dimethyldiphenyl sulfide of the formula fcBu. S— \ y — oh CH3 ^ CH3

The compounds of formula I have at least one chiral center. When R 1 is H or CH 3, the compounds exist as two stereoisomeric pairs. A typical complete separation of such a compound of formula I into two diastereoisomeric pairs is described in Example 8 and a partial separation in Example 7 (B).

The pharmaceutically acceptable acid addition salts of the compounds of formula I are those formed from strong acids which form non-toxic acid addition salts such as hydrochloric, hydrobromic, sulfuric, oxalic and methanesulfonic acids.

The salts are obtained by conventional methods, e.g.

5 by mixing solutions containing approximately equimolar amounts of the free base and the desired acid, and the resulting salt is recovered by filtration, if insoluble, or by evaporation of the solvent.

The compounds of formula I and their pharmaceutically acceptable salts are antifungal agents useful in the fight against fungal infections in animals, including man. For example, they are useful in the treatment of local fungal infections in humans caused by infections such as Candida, Trichophyton, Microsporum or

Epidermophyton species; or yeast infections caused by Candida albicans (e.g., thrush and vaginal candidiasis). They can also be used to treat systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

The compounds of formula I and their salts also have activity against a variety of plant pathogenic fungi, including, for example, various rust, mildew and mold fungi, and the compounds are thus useful in treating plants and seeds to eradicate or prevent such diseases.

The acetophenones and propiophenones 30 used as starting materials were prepared analogously to the method described in GB application 2,099,818A to prepare 2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone.

The following examples illustrate the invention.

Il 7 82244

Example 1 i) 2,2 *, 4'-trifluoroacetophenone

5 F F

i) A1C13 COCH2F

(QL + iU cicoch2f * (O

F F

1,3-Difluorobenzene (2.02 g; 17.7 mM) and anhydrous aluminum chloride (2.60 g; 19.47 mM) were mixed together in a dry nitrogen atmosphere at room temperature. A solution of fluoroacetyl chloride (1.71 g; 17.7 mM) in anhydrous methylene chloride (2 mL) was added over 30 minutes. The mixture was then heated at about 50 ° C for 3 hours. On cooling, methylene chloride (40 ml) was added and the mixture was poured onto ice. The methylene chloride layer was separated, dried over magnesium sulfate and evaporated to give a white solid. This material was chromatographed on a silica column eluting with a mixture of hexane and methylene chloride (65:35, v / v). Fractions containing product were collected. The title compound crystallized on evaporation of these fractions and was dried in a hot desiccator to give a colorless crystalline solid (1.12 g, 36%); mp. 57-58 ° C.

Analysis calculated for C 9 H 5 F 3 O: C 55.2 H 2.9 Found: C 55.0 H 2.8.

8 82244 ii) 2,21,41-trifluoro-2-chloroacetophenone

F F F

JL COCH2F I COCH

5 jgf o '«

F F

A solution of 2,2 ', 4'-trifluoroacetophenone (1.60 g; 9.2 mM) in sulfuryl chloride (4 mL) was heated at 75 ° C for 8 h. The mixture was then cooled and ice-water (40 ml) was added. The product was extracted with ether (80 ml), which was washed with water and aqueous sodium bicarbonate solution and then dried over magnesium sulfate.

Evaporation gave the desired product as a colorless, highly tearful liquid (2.0 g, 100%).

The NMR and IR spectra of this liquid confirmed the desired structure, and the liquid was used directly in the next step.

NMR (CDCl 3) δ = 8.05 (m, 1H), 6.95 (m, 2H), 6.87 (d, 1H, J = 51).

IR (KBr), -C- 1710 cm -1.

:: il

O

111) 2-1H-1,2,4-trazol-1-yl) -2,2 ', 4'-25 trifluoroacetophenone

f / F

COCH ..__ .. u

Λ-o, --- \ N NH

O "· 30 ^

F F

N-N-CH-CO -7 [] \ - F

II

9 82244 A mixture of 1,2,4-triazole (1.25 g, 18 mM) and anhydrous potassium carbonate (2.0 g 14 14.5 mM) in anhydrous tetrahydrofuran (20 mL) was stirred at reflux. A solution of 2,2 ', 4'-trifluoro-2-chloroacetophenone 5 (1.5 g; 7.19 mM) in tetrahydrofuran (10 ml) was added over 10 minutes. The mixture was heated at reflux for 2 hours and then allowed to stand overnight at room temperature. Water (50 ml) was added and the mixture was extracted with methylene chloride (2 x 100 ml). The combined organic extracts were dried over magnesium sulfate and evaporated to give a gum. Chromatography on a silica column eluting with a mixture of ethyl acetate, hexane and diethylamine (70: 30: 3 by volume) gave the desired product as a gum (130 mg; 7.5%) after evaporation of the appropriate fractions. NMR confirmed the desired structure.

The compound was characterized as the methanesulfonic acid salt (m.p. 158-160 ° C) prepared by mixing the free base as a solution in ether / acetone and the acid in ether / acetone and recovering the precipitated salt.

Analysis cxQHgF ^ O. Calculated for CH 4 q 3 S: C 39.2 H 3.0 N 12.5 Found: C 39.1 H 3.0 N 12.4.

Example 2 25 "

N-NCH 2 CO- / qV- F i) NaH

'+ ii) C103F

F

30

F

^ n — n-ch-co (oVf ^) -7

F

10 82244

Sodium hydride (285 mg; 50% dispersion in oil, 5.94 mM sodium hydride) was washed with ether and dried under nitrogen. Anhydrous tetrahydrofuran (15 mL) was added first, followed by 2 ', 4'-difluoro-2- (1H-1,2,4-5 triazol-1-yl) acetophenone (1.115 g; 5 mM) (see .GB application publication 2,099,818 Λ) in parts in 5 minutes. The resulting brown solution was stirred under an atmosphere of perchloryl fluoride until the theoretical amount was adsorbed. The pale yellow suspension was evaporated and partitioned between water (25 ml) and ethyl acetate (50 ml). The ethyl acetate phase was separated, washed with water, dried over magnesium sulphate and evaporated to give an oil which crystallized (1.21 g). The product was found to be the same as the product of Preparation 1 (iii) by NMR and TLC; 15 in base form; about 80% purity.

Examples 3-6

The following ketones were prepared in the same manner as in the procedure of Example 2 starting from the appropriate acetophenone or propiophenone, sodium hydride and perchloro-20-fluoryl fluoride: li 11 82244

F

'O I N N-C-CO-R

W 1 'I

'-N R1

Analysis% (or NMR) 1 M.p. (theoretical in parentheses) R Rx

Example (° C) C H N

NMR (CDCl 3): δ = 3 | H 98-100 1> 2 (m, 2H), 7.3 (d, 1 H, J = 48 Hz), 8.1 F (m, 3H), 8.5 (s, 1H) 4 | H 137 - 50.3 3.0 17.5 138 (50.2 2.9 17.6)

Cl J ^ Cl 5 l if H 64 - 66 43.9 2.2 15.4 (43.9 2.2 15.4)

Cl NMR (CDCl 3) β = 6 Y || CH 3 oil 2.25 (d, 3H, J = 19 Hz) N / 6.9 (m, 2H), 7.8 (m, 1H) 1 L 8.0 (s, 1H), 8.45 (s , 1H)

F

12 82244

Example 7

Method (a) 1,3-bis (1H-1,2,4-triazol-1 H -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol) (mixture of two pairs of diastereomers) 0 i / ^ λ _x__i / \ NN-CHCO - / () VF -> f ~~ N-CH-C-CH, S. 'Γ K' 'Ar' "/ Of

F OH kf X

I I _

H tf-CH-C-CH.-N H

</ I 's. / Ψ ’

F

A mixture of sodium hydride (21 mg; 60% dispersion in oil; 0.54 mM sodium hydride) and trimethylsulfoxynium iodide (143 mg; 0.65 mM) was stirred under a nitrogen atmosphere and anhydrous dimethyl sulfoxide (4 ml) was added. After 40 minutes, anhydrous tetrahydrofuran (4 ml) was added to the solution, and the mixture was cooled to -40 ° C. A solution of 2- (1H-23 1,2,4-triazol-1-yl) -2,2 ', 41-trifluoroacetophenone (130 mg; 0.54 mM) in tetrahydrofuran (3 ml) was added and the temperature was allowed to slowly rise to room temperature. . Water (10 ml) and ether (50 ml) were then added. The ether layer was separated, dried over magnesium sulfate and evaporated to give the intermediate epoxide (A) as a gum. To this was added 1,2,4-triazole (112 mg; 1.62 mM), anhydrous potassium carbonate (223 mg; 1.62 mM) and anhydrous dimethylformamide.

II

i3 82244 (4 ml), and the mixture was stirred and heated at 70 ° C for 2 hours. The mixture was cooled, water was added (50 ml) and the mixture was extracted with methylene chloride (2 x 50 ml). Evaporation of the combined methylene chloride extracts together with xylene gave a gum containing the crude product as a mixture of two pairs of diastereomers. The gum was chromatographed on a silica column eluting with a mixture of 4% (v / v) methanol in methylene chloride. The product-containing fractions were collected and evaporated to dryness to give the title compound as a colorless solid (72 mg; 41%), m.p. after crystallization from a mixture of ethyl acetate and cyclohexane was 142-145 ° C. The compound was a mixture of two pairs of diastereoisomers in a ratio of about 4: 1. Analysis calculated for C 48 H 19 N 2 O 3: C 48.2 H 3.4 N 25.9 Found: C 48.3 H 3.5 N 25.6.

Method B

Partial separation of two diastereo-20 isomer pairs of 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol

A mixture of sodium hydride (406 mg; 60% dispersion in oil, 10.17 mM sodium hydride) and trimethylsulfoxynium iodide (2.68 mg; 12.20 mM) was stirred under a nitrogen atmosphere and anhydrous dimethyl sulfoxide (40 ml) was added. After 30 minutes, anhydrous tetrahydrofuran (40 ml) was added to the solution, and the mixture was cooled to -30 ° C. A solution of 2- (1H-1,2,4-triazol-1-yl) -2,2 ', 4'-trifluoroacetophenone (2.45 g; 10.17 mM) in tetrahydrofuran (30 ml) was added and the temperature was allowed to rise slowly. 0 ° C. Water (50 ml) was added and the mixture was extracted with three portions (60 ml) of ether. The combined ether layers were dried over magnesium sulfate and evaporated to give the intermediate epoxide (A) (1.89 g) as a semi-solid. To this were added 1,2,4-triazole (3.51 g? 50.85 mM), 35 anhydrous potassium carbonate (7.0 g; 50.85 mM) and anhydrous dimethylformamide (40 ml), and the mixture was stirred and stirred. heated at 70 ° C for 18 hours. The mixture was cooled, water (100 ml) was added and the mixture was extracted with methylene chloride (3 x 60 ml). Evaporation of the combined methylene-5 nichloride extracts with xylene after drying over magnesium sulfate gave a gum. This gum was chromatographed on a silica column eluting with a mixture of 3% (v / v) methanol in methylene chloride and then with a mixture of 4% methanol in methylene chloride. Two pairs of diastereoisomers eluted in inseparable form. The product-containing fractions were collected and evaporated to give the title compound as a colorless solid (1.1 g; 33%). High performance liquid chromatography (HPLC) showed that the product was a mixture of two diastereomeric pairs in a ratio of about 4: 1 ·

Crystallization of this mixture of isomers from a mixture of ethyl acetate (20 ml) and hexane (30 ml) gave a pure pair of diastereoisomers 1 as a colorless solid 20 (688 mg); mp. 149-150 ° C.

Analysis calculated for C 48 H 19 N 3 O 2: C 48.2 H 3.4 N 25.9 Found: C 48.0 H 3.4 N 25.9.

Concentration of the crystallization solutions gave another 25 batches of crystals (88 mg); mp. 117-123 ° C. HPLC showed that this was a mixture of two pairs of diastereoisomers in a ratio of about 1: 5.

Analysis calculated for C 13 H 11 F 3 N 6 O C 48.2 H 3.4 N 25.9 Found: C 48.0 H 3.5 N 26.0.

Evaporation of the remaining crystallization solutions gave a gum (170 mg) which was shown by HPLC to be a mixture of two pairs of diastereomers in a ratio of about 1: 1.

It is 82244

Example 8 Complete separation of two pairs of diastereoisomers of 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol 5 L 1,3-bis (1H-1,2,4-triazol-1-yl) -1- (2,4-difluorophenyl) -1-fluoropropan-2-ol (170 mg, mixture of diastereoisomeric pairs in a ratio of about 1 : 1 from Method B of Example 1 was dissolved in methylene chloride (1 mL) and then absorbed onto a column (2 x 30 cm) containing Merck (ta-10 trademark) silica (230-400 mesh) prepared from hexane, isopropanol and to a mixture of acetic acid (60: 40: 2). Elution with 500 ml of the same solvent under moderate pressure (34 kPa) gave complete separation of the diastereoisomeric pairs. Evaporation of the solvents gave the isomers as colorless solids (ethyl acetate was used successfully in repeating this procedure).

Diastereoisomer pair 1 (eluted first): 80 mg, crystallized from ethyl acetate / hexane to give 20 crystals, m.p. 148-150 ° C.

Analysis: Calculated: C 48.2 H 3.4 N 25.9 ·: Found: C 48.0 H 3.4 N 25.9.

Diastereoisomer pair 2: 70 mg, crystallized from ethyl acetate / hexane to give a crystalline material; : sp. 137-139 ° C.

; : Analysis: Calculated: C 48.2 H 3.4 N 25.9 Found: C 48.4 H 3.5 N 25.7.

30 Examples 9-12

The following compounds were prepared by the same procedure as in Example 7, Method A from the appropriate starting materials, chromatographed using methylene chloride containing 2% by volume of isopropyl alcohol and 0.2% of am-35 polyacia (m.p. 0.880) and crystallizing the products from ethyl acetate and petroleum ether (b.p. 60 - 80 ° C) of the mixture.

82244 BC

F OH

N '^^ N - C - C - C H „- N

\ / 'i 1 2 \ I

V = ^ N R R N

! Analysis (k)

Eg m.p.

1 r (theoretical su- n: ° R R (° C) in bones)

C H N

- 9 II) H 134-136 48.3 3.7 25.8 (48.4 3.7 26.0)

Cl 10 H 74-76 50.6 4.1 26.7 (50.9 3.9 27.4)

F

λ ^ 11 Cl H 200-202 43.7 3.1 22.9 _ (43.7 3.1 23.5)

Cl b) 180-184 44.1 3.2 23.4 _ (43.7 3.1 23.5) · 12 I ^ F CH3 138 "145 49.2 3.8 24.6 (f ^ J ( 49.6 3.9 24.8)

F

----- 17 82244

In Examples 9, 10 and 12, no separation of diastereomers was achieved. In Example 11, chromatography resulted in partial separation. One pure diastereomer ("a") was first eluted and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C); mp. 200-202 ° C.

The mixture of diastereomers was then eluted in a ratio of about 1: 1 ("b") and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C); mp. 180-184 ° C. Example 13 i) 2- (1H-1,2,4-triazol-1-yl) -2,2,2 ', 4'-tetrafluoroacetophenone FV i) NaH Syl-

15 fl-CHF-CO - ^^ - F ii) C1Q3F N N ~ CF2 ~ C0 \ .J / ~ F

U = .N 2 = Ν 2- (1H-1,2,4-triazol-1-yl) -2,2 ', 4'-trifluoro-20-acetophenone (160 mg) was treated with ether washed sodium hydride (25 mg) in dry in tetrahydrofuran (5 ml) to give an orange solution. This solution was placed in a perchloryl fluoride atmosphere, whereupon rapid absorption of this chemical resulted in the formation of a pale yellow suspension. The tetrahydrofuran was removed under reduced pressure, the residue partitioned between water (10 ml) and ethyl acetate (10 ml), the organic layer dried over magnesium sulphate and evaporated to give the title compound as an oil; 127 mg.

NMR (CDCl 3) δ = 6.95 (m, 2H), 8.0 (s, 1H), 8.2 (m, 1H) and 8.69 (s, 1H).

, 8 82244 (ii) 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1,1-difluoropropan-2-ol

F

5 N, N-CF -CO- / y-F (CH) S = CH

w ^

0 K 2 CO 3, OH

N ^ 'n-CFj-C-CH2 - = ► N ^' N-CF -c-cn -N ^ H

io ^ == n c ^ yF \ ^? / Nn

r F

(B) 15 Method (a)

Dimethyloxosulfonium methylide was prepared from trimethylsulfoxonium iodide (0.44 g) and sodium hydride (0.12 g; 50% suspension in oil) in dry dimethyl sulfoxide (10 mL) at 50 ° C. Dry tetrahydrofuran (<10 mL) was added and the mixture was cooled to -40 ° C. Crude 2- (1H-1,2,4-triazol-1-yl) -2,2,2 ', 4'-tetrafluoroacetophenone (0.52 g) in dry tetrahydrofuran (5 ml) was added. The mixture was stirred at -40 ° C for 10 minutes, then allowed to warm to -10 ° C over 15 minutes, then poured onto ice (100 g) and extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate extracts were washed with brine (2 x 10 mL), dried over magnesium sulfate and evaporated to give oxirane (B) as an oil; 30 240 mg. This oil was heated in dimethylformamide (5 mL) at 50 ° C for 3 hours along with potassium carbonate (200 mg) and 1,2,4-triazole (200 mg). The reaction mixture was then allowed to cool, after which it was poured into water (30 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with brine (2 x 5 mL), dried over magnesium sulfate and evaporated to an oil; 235 mg.

19 82244

Flash chromatography of this oil on silica eluting with methylene chloride containing isopropanol (10% v / v) and 0.880 (om.p.) ammonium hydroxide (1% v / v) gave 53 mg of material with an Rf value of 0. 3 (sa-5 mass in a solvent system) which was solidified by trituration with ether. Crystallization of this solid from cyclohexane / ethyl acetate gave the title compound as colorless crystals, m.p. 132-133 ° C.

Analysis for C 18 H 28 F 2 N 2 O 2 ° calculated: C 45.7 H 2.9 N 24.6 Found: C 45.6 H 3.0 N 24.3.

NMR (CDCl 3) δ = 4.77 (d, 1H, J = 14 Hz), 5.39 (d, 1H, J = 14 Hz), 6.1 (6s, 1H) 6.75 (m, 2H) , 7.44 (dd, 1H, J = 14 Hz, 7 Hz), 7.73 (s, 1H), 7.82 (s, 1H), 7.10 (s, 1H), 8.32 ( s, 1H). m / e 343 (M + 1).

Method (b)

Alternative to route (a); in this route oxirane (B) is not isolated.

Dimethyloxosulfonium methylide was prepared from tri-methylsulfoxonium iodide (1.2 g) and sodium hydride (0.3 g; 50% dispersion in oil) in dimethyl sulfoxide (20 ml). Dry tetrahydrofuran (30 ml) was then added and the mixture was cooled to -35 ° C. 2- (1H-1,2,4-triazol-1-yl) -2,2,2 ', 4'-tetrafluoroacetophenone (1.3 g) in tetrahydrofuran (5 ml) was added and the mixture was stirred at -30 ° C: at 15 minutes, the temperature was allowed to rise to -10 ° C over 15 minutes, and the mixture was stirred at -10 ° C for 30 minutes. The temperature was allowed to rise to 10 ° C over 15 minutes. At this point, 1,2,4-triazole (1.0 g) and anhydrous potassium carbonate (1.0 g) were added and the mixture was heated at 70 ° C for 3 hours and then stirred at room temperature overnight. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried over magnesium sulphate, evaporated to an oil (1.6 g) and chromatographed on silica, eluting with methylene chloride / isopropanol / ammonia (m.p. 0.880) (90: 10: 1, v / v) to give the appropriate fractions by evaporation of crystalline crystals. substance; 447 mg. Recrystallization of this material from cyclohexane / ethyl acetate gave colorless crystals; mp.

132-133 ° C; identical to the product of method (a).

Example 14 1,3-Bis (1H-1,2,4-triazol-1-yl) -2- (2,4-dichlorophenyl) -1,1-difluoropropan-2-ol Melting point 155-156 ° C; was prepared according to method (b) of Example 13 from the appropriate starting materials.

Analysis: Calculated: C 41.6 H 2.7 N 22.4 Found: C 41.8 H 2.7 N 22.5 Ketone starting material, 2 ', 4'-dichloro-2 , 2-Difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone, was prepared according to Example 13, part (i). It was oil.

NMR (CDCl 3) δ = 7.3 (m, 3H), 7.55 (s, 1H), 7.8 (s, 1H). Example 15 i) 2- (2,4-Difluorophenyl) -3-fluoro-3- (1H-1,2,4-triazol-1-yl) -prop-1-ene 20 A-L / Vr · ^

\ ^ l CH3P®Ph3Br © V = / fW

V 25 2- (1H-1,2,4-triazol-1-yl) -2,2 ', 4'-trifluoroacetophenone (10 g), anhydrous potassium carbonate (7.3 g) and methyltriphenylphosphonium bromide (15.5 g). g) was heated at reflux for 16 hours in 1,4-dioxane (250 ml) to which water (1.0 g) had been added. Methyltriphenylphosphonium bromide (0.74 g) was further added and heating was continued for a further 1 hour, at which time TLC (silica, ether as eluent) showed no starting material 35 remaining. The dioxane was then removed under reduced pressure and the dark brown residue was triturated with ether (150 ml) to give a precipitate of inorganic material and triphenylphosphine oxide. The ether solution was decanted from the precipitate, the precipitate was washed with ether (100 ml) and the ether solutions were added to the decanted ether solution. The combined ether solutions were evaporated to a dark brown oil; 20.0 g. This oil was chromatographed on silica (150 g) eluting with ether. Fractions containing product (detected by TLC) were combined and evaporated to give the title compound as an amber oil; 9.6 g.

NMR (CDCl 3) δ = 5.78 (dd, 1H, J = 4 Hz, 2Hz), 6.03 (d, 1H, 10 J = 2 Hz), 7.0 (m, 4H), 7.9 ( s, 1H), 8.25 (s, 1H).

ii) 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol F CH,

15 1 II f / ~ \ f A

M N-CH-C— (f \ f / \ \ / \ / MCPBA M-CH-C-> CH, V = N A —Γ \ / I 2 radical- JL p inhibitor II j

V

20 F

1,2,4-triazole K 2 CO 3, 70 ° C

25 Ψ

F OH

\ / i 2 \ _7

30 V = N V

F

22 82244 2- (2,4-Difluorophenyl) -3-fluoro-3- (1H-1,2,4-triazol-1-yl) prop-1-ene (5.0 g), m-chloroperbenzoic acid acid (10.8 g) (MCPBA) and a radical inhibitor, 3,3'-di-t-butyl-4,4'-dihydroxy-5,5'-dimethyldiphenylsulf-5 dia (0.11 g) were heated at reflux in 1,2-dichloroethane (75 ml) for 3 hours. The sampled NMR spectrum showed some starting material remaining, so additional m-chloroperbenzoic acid (3.5 g) was added and the reaction mixture was heated for an additional 1 hour.

The reaction mixture was cooled and filtered to remove m-chloroperbenzoic acid, then diluted with methylene chloride (150 mL), washed with 10% sodium sulfate solution (2 x 100 mL). The organic layer was then washed with brine (2 x 50 ml), dried (MgSO 4) and evaporated to a yellow oil, 7.7 g. the NMR spectrum of the oil showed that it contained epoxide as a 3: 2 mixture of two pairs of diastereomers, together with other organic residues. The total epoxide yield was estimated to be about 50%. This crude reaction product was reacted with 1,2,4-triazole (7.5 g) and potassium carbonate (7.5 g) in dimethylformamide (100 ml) at 70 ° C overnight. The reaction mixture was then cooled, diluted to 300 mL with water, and extracted with ethyl acetate (3 x 100 mL). The organic extract was washed with brine (2 x 50 ml), dried (MgSO 4) and evaporated to a dark brown oil (4.8 g). This oil was chromatographed on silica (200 g), eluting first with ethyl acetate, 1.5 liters, and then with ethyl acetate containing isopropanol, which gradually increased from 5% to 20% (v / v). Subsequent fractions were found by TLC to contain the desired product and these fractions were evaporated to a white solid (1.4 g) which was triturated with ether to give a white solid, 1.15 g; mp. 138-35 140 ° C. This material was confirmed spectroscopically identical to the latter pair of diastereoisomers isolated in Example 8.

Claims (3)

23 82244 Claim Oxirane of formula II 5 R 1 is N-C-C-CH-U 2 I 2 (II) FR 10 wherein R is phenyl substituted with 1 to 3 substituents each of which is independently F, Cl or Br; R 1 is H, CH 3 or F; and its salts. 15 20 Oxiran with formula II N N-C-C-CH? 25 '11 (II) "F R color R is phenyl, wherein the substituents are 1-3 substituents, a single addition of a variant F, Cl or Br; Rx is H, 30 CH3 or F;