FI79703B - TRIAZOLDERIVAT. - Google Patents

Description

1 79703

triazole derivatives

The invention relates to novel triazole derivatives of the formula

F X

^ I II

N N-C— C

10 \ / li »

10 V N R1 R

wherein Ron is phenyl substituted with 1 to 3 substituents each of which is independently F, Cl or Br, R is H, CH 8 or F and X is O or salts thereof.

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

• 20 1

OH R

N-CH0-C - C-N ^ N (I)

Un l I n ^ / 25 where R and R1 have the same meaning as above.

R is preferably phenyl substituted with 1-2 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-chloro-phenyl, 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-difluorophenyl.

2 79703 R is preferably H or F.

In a preferred embodiment, R is 2,4-difluorophenyl and R 1 is H.

The compounds of formula (I) may be prepared in a conventional manner according to the following reaction scheme: F 1, 2, 4-triazole, preferably in the presence of a base, such as in the presence of N, N-NC-C-CH 2, or , 2,4-triazole \ / II Iin basic salt 10 il k -> (II)

F OH

15 “C-C-if ^ N

w I: '. = /: (i) In a typical reaction, the epoxide (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. The product (I) can then be isolated and purified in a conventional manner.

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

The starting materials of the formula (II) in which R 2 = H 2 O or CH 2 are conventionally obtained, e.g.

3 79703

i) NaH

F

ii) C103F j

N-CH-C-R N ^ N-C-C-R

= N R 0 1 = N R 0 5 (HI) (IV) (R 2 = H or CH 2) Dimethylsulfoxonium methylide

V

10

F 0 K

N * C-C-CH 2 to 2 L = -N 11

15 R R

(HA)

It is not necessary to isolate and purify compound 20 (IIA), 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.

Ketones (III) are either known compounds (see for example EP patent application 0044605 or GB patent application 2,099,818A) or can be prepared analogously by known methods.

An alternative route for the preparation of ketones (IV) (R 2 = H); is as follows:

30 F

r R.COCH2F + SO2Cl2 — ► R.COCH.C1 1,2,4-Triazole / K2CCO> 3 -> Compound (IV) 4 79703

The compounds of formula (I) have at least one chiral center.

When R1 is H or ΟΗβ, the compounds exist as two stereoisomeric pairs. A typical complete separation of such a compound of formula 5 (I) into two diastereoisomeric pairs is described in Example 2, and a partial separation in Example 1 (B).

Starting materials of formula (II) where = F can be prepared as follows:

F

N 2 - (CH-C-R j) NaH n'j ^ Nnn-cfO-c-r K - 2 s

ii) C103F

(V) (IV) (R * = H) Dimethyloxosulfonium methylide

O

20 f r <CH3) 2S = CH27

V

N-CF _-C-CH0 1/2 and 2

l = r N R

(HB) 30

Again, it is not necessary to isolate the intermediate (IIB). Another route to prepare oxiranes (II) where RA is: H, CH3 or F is as follows: 5 79703 ^ F F CH0 I k, CO-, I 2

N N-C-COR 2 3_ ^ N ^ N-C— C— R

^ = - N r1 CH3Ah3Brö, V = -N {^ 1 5 (IV) reflux,

dioxane / I ^ O

m-chloroperbenzoic acid, radical inhibitor, reflux, 1,2-dichloroethane

V

F .0.

15 N'ä!? VsN-C- C-CH ~ \ I 11 I 2 (II)

V - = .N R R

The preferred free radical inhibitor is 3,3'-di-t-butyl-4,4'-dihydroxy-5,5'-dimethyldiphenyl sulfide having the formula: fcBu fcBu

25 H ° / ^ ~~ S— ^ ° H

: CH3 CH3

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. by mixing solutions containing the free base and the volatile acid, and the resulting salt is recovered by filtration, if insoluble, or by evaporation of the solvent.

6 79703

The compounds of formula (I) and their pharmaceutically acceptable salts are antifungal agents useful in the fight against fungal infections in animals, including humans.

5 For example, they are useful in the treatment of local fungal infections in humans caused by Candida, Trichophyton, Microsporum or Epidermophyton species, among other organisms, or by yeast infections caused by Candida albicans 10 (e.g., thrush and vaginal candidiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidiosis, Paracoccidioides, Histoplasma or Blastomyces.

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

The acetophenones and propiophenones 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. All temperatures are in degrees Celsius.

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

3 0 F F

(i) AlCl 3 COCH 2 F

[Ojl ^ (ii) C1COCH2F *

F

7 79703 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 by volume). Fractions containing product were collected. The title compound crystallized on evaporation of these fractions and was dried in a vacuum desiccator to give a colorless crystalline solid (1.12 g; 36%), m.p. 57-58 ° C.

Analysis%:

Found: C 55.0; H 2.8: Calculated for C 8 H 5 F 3 O: C 55.2; H 2,9 ^ (ii) 2,21,41-trifluoro-2-chloroacetophenone

; F

L ^ F

X-Ny- COCH2F f COCH

A solution of 2,2 ', 4'-trifluoroacetophenone (1.60 g; 9.2 mM) in sulfuryl chloride (4 mL) was heated at 75 ° C for 18 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, and then dried over magnesium sulfate. Evaporation gave the desired product as a colorless, highly tearful liquid (2.0 g; 100%).

8 79703 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, δ 1H, J = 51); IR (KBr), -C- at 1710 cm-1.

O

(iii) 2- (1H-1,2,4-triazol-1-yl) -2,2 ', 41-trifluoroacetophenone 10 pp

X. COCH

M * Q ^ 15

F

N— N —CH-CO- ^ Q> F

A mixture of 1,2,4-triazole (1.25 g; 18 mM) and anhydrous potassium carbonate (2.0 g; 14.5 mM) in anhydrous tetrahydrofurar (20 ml) was stirred at reflux. A solution of 2,21,41-trifluoro-2-chloroacetophenone (1.5 g; 7.19 mM) in tetrahydrofuran (10 mL) was added over ten minutes. The mixture was refluxed 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, after evaporation of the appropriate fractions, the desired product as a gum (130 mg; 7.5%). NMR confirmed the desired structure.

9 79703

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

5 Analysis%:

Found: C, 39.1; H 3.0; N 12.4

Calculated for c 10 H 6 F 3 N 3 O · CH 4 O 3 S: C, 39.2; II 3.0; N 12.5.

Example 2 10 / —v f (i) NaH \ r- \

N — NCH2CO- ^ Q ^ - f + ^ (ii) c1o3f - »N- ~ JI-CH-CO-toy“ F

F

15

Sodium hydride (285 mg of a 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-tri-20-azol-1-yl) acetophenone (1.115 g; 5 mM) ( see GB Application Publication 2,099,818A) in parts over 5 minutes.

The resulting brown solution was stirred under a mixture of perchloryl fluorine until the theoretical amount was absorbed. 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 by NMR and TLC to be the same as the product of Example 1 (iii), in the form of the free base, with a purity of about 80%.

10 79703

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 perchloroyl fluoride:

^ F

N N-C-CO-R

\ / K

'—N R1

Eg. Analysis% No. R R1 Sp. ° C (or NMR) (theoretical)

C H N

3 H, 98-100 NMR (cdc13: δ = 7.2 (m), 2H;

] 7.3 (d), 1H, J

48Hz; 8.1 (m),

3H; 8.5 (s), 1H

4 H 137 '138 50'3 3' ° 17/5 (50.2 2.9 17.6)

Cl

Arcl ~ 5 I il H 64 - 66 43.9 2.2 15.4 (43.9 2.2 15.4)

Cl JL F NMR (CDCl 3): δ IL-CH 3 oil δ = 2.25 (d), 3H, J 19Hz; 6.9 T (m), 2 H; 7.8 (m), F 1H? 8.0 (s), 1 H;

8.45 (s), 1 H

,, 79703

Example 7 Method (A) 1,3-Bis (1H, 1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol (mixture of two pairs of diastereomers) )

F

N-N-CHCO - {() V-F Y

Ky 10 N /

F

F 04 i / N-CH-C-CH- (A). ”V φτ; F \ 20

F OH

_ M _

NN-CH-C-CH-NM

Q $

F

. A mixture of sodium hydride (21 mg of a 60% dispersion in oil, 0.54 nM sodium hydride) and trimethylsulfoxonium iodide 30 (143 mg; 0.65 mM) was stirred under a nitrogen atmosphere and anhydrous dimethyl sulfoxide (4 ml) was added. After forty minutes, anhydrous tetrahydrofuran (4 ml) was added to the solution, and the mixture was cooled to -40 ° C. A solution of 2- (1H-1,2,4-triazol-1-yl) -2,2 *, 4'-trifluoro-12,7703 riacetophenone (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 were added 1,2,4-triazole (112 mg; 1.62 mM), anhydrous potassium carbonate (223 mg; 1.62 mM) and anhydrous dimethylformamide (4 ml), and the mixture was stirred and heated to 70 ° C. At 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 give the title compound as a colorless solid (72 mg; 41%), m.p. after crystallization from a mixture of ethyl acetate and cyclohexane, it was 142-145 ° C. The compound was a mixture of two pairs of diastereoisomers in a ratio of about 4: 1.

Analysis%:

Found: C, 48.3; H, 3.5; N, 25.6 Calculated for C 13 H 11 LF 3 N 6 O: C, 48.2; H, 3.4; N, 25.9.

Method (B) Partial 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 : A mixture of sodium hydride (406 mg of 60% dispersion in oil, 10.17 mM sodium hydride) and trimethylsulfoxonium 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 13,770,703 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 rise to 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 MgSO 4 and evaporated to give the intermediate epoxide (A) (1.89 g) as a semicrystalline solid. To this was added 1,2,4-triazole (3.51 g, 50.85 mM), anhydrous potassium carbonate (7.0 g; 50.85 mM) and anhydrous dimethylformamide (40 mL), and the mixture was stirred and heated to 70 ° C: in 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 chloride extracts with xylene after drying over 15 mg of MgSO 4 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 20 eluted in an 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 (688 mg), m.p. 149-150 ° C.

3 ° Analysis S:

Calcd for C 13 H 13 P 3 N 9 O C, 48.2; H, 3.4; N, 25.9 Found: C, 48.0; H, 3.4; N, 25.9.

14 79703

Concentration of the crystallization solutions gave a second crop of crystals (88 mg), m.p. 117-123 ° C. HPLC showed that this was a mixture of two pairs of diastereomers in a ratio of about 1: 5.

5 Analysis%:

Calcd for C 18 H 18 F 3 O 3 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 di-1O astereomers in a ratio of about 1: 1.

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 15 L 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1-fluoropropan-2-ol [10 mg, mixture of diastereoisomeric pairs in a ratio of about 1 : 1 from Example 1 of Method (B) J was dissolved in methylene chloride (1 mL) and then absorbed onto a column (2 x 30 cm) containing Merck • 20 (trademark) silica (230-400 mesh) prepared in hexane, to a mixture of isopropanol and acetic acid (60/40/2).

Elution with 500 ml of the same solvent under moderate pressure of 3.45x10 4 Pa (5 psi) gave complete separation of the diastereoisomeric pairs. Evaporation of the solvents gave the isomers as colorless solids (ethyl acetate was successfully used as eluent in repeating this procedure).

: Diastereoisomer pair 1 (eluted first): 80 mg was crystallized from ethyl acetate / hexane to give; 30 crystalline substance, m.p. 148-150 ° C.

Analysis%: Calculated for C 18 H 19 F 3 O 3: C 48.2: H 3.4; N 25.9

Found: C, 48.0; H 3.4; N 25.9.

The diastereoisomer pair 2: 70 mg was crystallized from ethyl acetate / hexane to give a crystalline material, m.p. 137-139 ° C.

15 79703

Analysis%:

Calcd for C 18 H 18 F 3 O 3 O: C, 48.2; H 3.4; N 25.9

Found: C, 48.4; H 3.5; N 25.7.

Examples 9-12 The following compounds were prepared by the same procedure as from the appropriate starting materials of the method (A) of Example 7 using methylene chloride containing 2% by volume of isopropyl alcohol and 0.2% ammonia (SG 0.880) for chromatography and crystallizing the product. of a mixture of ethyl acetate and petroleum ether (boiling point 60 to 80 ° C): ie 79703

F OH

I I / * 5.

N N-C-C —CH „—N N

l = -N J, 1 I K = J

Analysis,%

Eg Ώ „1 c o_ (theoretical)

R R Sp. C

n: o C H N

9 H 3 H 136 - 136 48.3 3.7 25.8 ^ (48.4 3.7 26.0)

Cl

Γ X

10 I | J H 74 - 76 50.6 4.1 26.7 T (50.9 3.9 27.4)

F

Cl (a) 11,200 - 202 43.7 3.1 22.9 H (43.7 3.1 23.5) i

Cl-- (b) 180 - 184 44.1 3.2 23.4: (43.7 3.1 23.5) 12 Π j CH3 138 - 145 49.2 3.8 24.6 (49.6 3.9 24.8)

F

----- i7 79703

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 eluted first and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C), m.p. 200 ...

5,202 ° 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 ', 41-tetrafluoroacetophenone N, N-CHF-CO (l) NaH 4 -FC -C (> ^ "" Uf

UN '(ϋ) C103F W

"2- (1H-1,2,4-triazol-1-yl) -2,2 ', 4'-trifluoroacetophenone (160 mg) was treated with ether washed sodium hydride (25 mg) in dry tetrahydrofuran 20 (5 ml). This solution was placed in an atmosphere of perchloryl fluoride, whereupon rapid absorption of this chemical caused the formation of a pale yellow suspension.Tetrahydrofuran was removed under reduced pressure, the residue partitioned between water (10 ml) and ethyl acetate (10 ml), the organic layer dried ( MgSO 4) and evaporated to give the title compound as an oil, 127 mg.

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

18 79703 (ii) 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -1,1-difluoropropan-2-ol p 9 5 ^ .c ^ co ^ y,, ch3, ^ ch2,

io ^ / ° \? H

N N ~ CF ~ C - "CH0 * / V

V / 2] 2 N N —FF-C ”CH0-N2N

W ^ \ / Γκ2αθ3 \ _ / 2 I 2 l _ /

L jj n ^ -n rrF

! \ = - n u y

t 15 F

F

(B)

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 25-40 ° C. Crude 2- (1H-1,2,4-triazol-1-yl) -2,2,2 ', 41-tetrafluoroacetophenone (0.52 g) was added in dry tetrahydrofuran (5 ml). 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) for 3q and extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate extracts were washed with brine (2 x 10 ml), dried (MgSO 4) and evaporated to give oxirane 79703 (B) as an oil 240 mg. This oil was heated in dimethylformamide (5 mL) at 50 ° C for three 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 (MgSO 4) and evaporated to an oil (235 mg).

Flash chromatography of this oil on silica as eluent of methylene chloride containing isopropanol (10% v / v) and 0.880 (SG) ammonium hydroxide (1% v / v) gave 53 mg of a material with an Rf value of 0.3 (in the same 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%: Calculated for C 13 H 10 F 4 N 6 O C 45.7; H 2.9; N 24.6

Found: C, 45.6; H 3.0; N 24.3; 2 H NMR (CDCl 3) δ = 4.77 (d), 1H, J = 14 Hz; 5.39 (d), 1H, J = 14 Hz; 6.1 (6s), 1 H; 6.75 (m), 2 H; 7.44 (dd), 1H, 14Hz, 7Hz; 7.73 (s), 1 H; 7.82 (s), 1 H; 7.10 (s), 1 H; 8.32 (s), 1 H. m / e 343 (M + 1).

Method (b) 25 This is an alternative to route (a). Oxirane (B) is not isolated in this route.

Dimethyloxosulfonium methylide was prepared from trimethylsulfoxonium iodide (1.2 g) and sodium hydride (0.3 g of a 50% dispersion in oil) in dimethylsulfoxy (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) -2,2,21,4'-tetrafluoroacetophenone (1.3 g) was added in tetrahydrofuran (5 ml) and the mixture was stirred at -30 ° C. minutes, the temperature was allowed to rise to 35-10 ° C over 15 minutes, the mixture was stirred at -10 ° C for 20 minutes, and then 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 5, 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 (MgSO 4), evaporated to an oil (1.6 g) and flash chromatographed on silica, eluting with methylene chloride / -10 isopropanol / ammonia (0.880) (90: 10: 1 v / v) to give the appropriate fractions by evaporation of the crystalline solid. substance, 447 mg. Recrystallization of this material from cyclohexane / ethyl acetate gave colorless crystals, m.p. 132-133 ° C, identical to the product of method (a).

: * 15 Example 14 1,3-bis (1H-1,2,4-triazol-1-yl) -2- (2,4-dichlorophenyl) -1,1-difluoropropan-2-ol. mp. 155-6 ° C, was prepared according to the procedure of Example 13 (b) from the appropriate starting materials.

20% analysis:

Found: C, 41.8; II 2.7; N 22.5

Calculated ^ 3 ^ 10 ^ 2 ^^ 6 ^ 1: ^ ^ 2.7; N 22.4.

The starting ketone, 2 ', 41-dichloro-2,2-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone, was prepared according to Example 13 (i). It was oil. NMR

*: (CDCl 3): δ = 7.3 (m), 3H; 7.55 (s), 1 H; 7.8 (s), 1 H.

Example 15 * '(i) 2- (2,4-Difluorophenyl) -3-fluoro-3- (1H-1,2,4-triazol-1-yl) -prop-1-ene 30 F CH2 1 1 · vv.

I mf \ „K, CO, N N-CH-C-r> F

N N-CH-CO-f 'VF 2,3-xl> = / 35 2- (1H-1,2,4-triazol-1-yl) -2,2', 4'-trifluoroacetophenone 2i 79703 (10 g), anhydrous potassium carbonate (7.3 g) and methyl triphenylphosphonium bromide (15.5 g) were heated under reflux for 16 hours in 1,4-dioxane (250 ml) to which water (1.0 g) had been added. Methyl triphenylphosphonium bromide (0.74 g) was further adjusted and heating was continued for a further 1 hour at which time TLC (silica, ether as eluent) indicated that no starting material remained. 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), ether as eluent. 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, 2H 2; 6.03 (d), 1H, J 2 Hz; 7.0, (m), 4 H; 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 2 F 0 25 N -CH —C — fi \ -F MCPBA ^ N ^^ N — CH - (/ —- CH2 V = _N radical-V = .ip F inhibitor

30 F

1 / 2,4-triazole, k2co3, ψ 70 °

F OH

^ I 1

N 2 N -CH -C-CH 2 -N N

\ _ / I '/' -N I τρ N '=='

F

22 79703 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-4,41-dihydroxy-5,5'-dimethyldiphenylsulf-5 dia (0.11 g) were heated to reflux cooling 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 bisulfate 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 saturated sodium chloride solution (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, m.p. 138-35 140 ° C. This material was confirmed to be spectroscopically identical to the latter pair of di-astereoisomers isolated in Example 8.

Claims (2)

23 79703 Claim Triazole derivatives of the formula ^ F X I il 5. N-C 1 -C 1 'R wherein R is phenyl substituted with 1 to 3 substituents each of which is independently F, Cl 10 or Br; is H, CH 2 or F; and X is O or CH 2, and salts thereof. 15 Triazole derivatives of the formula 20 F X N N-C — C \ = V U 'R R 25 color R is phenyl substituted with 1-3 substituents, optionally substituted with a variety of F, Cl and Br; R is H, CH3 or F; and X is O or CH2, the same salt is added.