DD232043A5 - PROCESS FOR THE PREPARATION OF TRIAZOL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of triazole derivatives which are useful as fungicides.

Description

  O-

or -N N-R

in which R ^{4 is} H, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkanoyl or (C ₁ -C ₄ -alkoxylcarbonyl, characterized in that a compound of the formula

0-C-O

^ X I I 5

N is N-CH-C -C-R (A)

/ ²

'Ν R R

wherein R, R ⁵ and R ^{6 are} as defined above, with an amine of the formula R ² R ³ NH, wherein R ² and R ^{3 are} as defined above, is reacted.

2. The method according to item 1, characterized in that the reaction is carried out in methanol at about room temperature.

3. The method according to item 1 or 2, characterized in that a lactone (A), wherein R 2,4-dichlorophenyl and R ⁵ and R ^{6 are} both H, is reacted with ammonia.

A process according to any one of the preceding claims, characterized in that the reaction product is converted to a pharmaceutically or agriculturally acceptable acid addition salt by reaction with a suitable acid.

Field of application of the invention

The invention relates to a process for the preparation of novel triazole derivatives having antifungal activity, useful in the treatment of fungal infections in animals, humans included, and as agricultural fungicides.

Aim and presentation of the essence of the invention

According to the invention, compounds of the formula

OH R ⁵ N ^^ N-CH.-CC-CONR ² R ³ (D.

provided wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, I, CF _3, C ₁ -C ₄ -alkyl and C _r C ₄ alkoxy, or R is a 5 Chloropyrid-2-yl group; (a) R ^{2 is} H or C ₁ -C ₆ -alkyl and R ^{3 is} H, C ₁ -C ₆ -alkyl, benzyl, phenethyl, phenyl, -CH ₂ CF ₃ , adamantyl, pyridylmethyl, C ₃ -C ₇ -cycloalkyl , Carbamoylmethyl, (C ₂ -C ₄ -alkenyimethyl, 2-hydroxyethyl, 2- (dimethylamino) ethyl, 2- (methylthio) ethyl, 2- (methylsulfinyl (ethyl, 2- (methylsulfonyl) ethyl or 2-phenoxyethyl ; wherein the benzyl, phenethyl, phenyl and phenoxy groups being optionally ring-substituted by 1 or 2 substituents each independently selected from Ci-C ₄ alkyl, C ₁ -C ₄ -AJkOXy, F, Cl, Br, I and CF ₃ , or (b) R ² and R ³ together with the nitrogen atom to which they are attached form a group of the formula

vi

-N I, -N, -N), -N Ο or

wherein R ⁴ is H, C ₁ -C ₄ -alkyl, Cr-C ₄ alkanoyl or (Cr-Q-Alkoxyjcarbonyl;

R ^{5 is} H or CH ₃ and R ^{6 is} H or CH ₃ , as well as their pharmaceutically and agriculturally acceptable salts.

The invention further provides an agricultural agent comprising a compound of formula (I) or an agriculturally acceptable salt thereof together with an agriculturally acceptable diluent or carrier.

The invention also provides a method of treating a plant or seed with a fungal infection in which the plant or seed or locus of the plant is brought into contact with an antifungal amount of the compound of formula (I) or an agriculturally acceptable salt thereof ,

In one aspect, R is preferably phenyl substituted by 1 to 3 substituents, more preferably by 1 or 2 substituents, each independently selected from F, Cl, Br, J and CF ₃ .

R is preferably 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2-fluoro-4 -chlorophenyl, 2-chloro-4- (fluorophenyl), 2,4,6-trifluorophenyl and 4-bromo-2,5-difluorophenyl.

R is more preferably 2,4-dichlorophenyl, 4-chlorophenyl or 2,4-difluorophenyl.

R is most preferably 2,4-dichlorophenyl or 2,4-difluorophenyl.

Preferably, either

(a) R ^{2 is} H, CH ₃ or C ₂ H ₅ and R ^{3 is} H, C ₁ -C ₆ -alkyl, p-chlorobenzyl, p-chlorophenethyl, p -methylphenethyl, -CH ₂ CF ₃ , 1-adamantyl, 4 Pyridylmethyl, cyclopropyl, carbamoylmethyl, -CH ₂ .CH = CH ₂ , 2-hydroxyethyl, 2- (dimethylamino) ethyl, 2- (methylthio) ethyl, 2- (methylsulfinylethyl), 2- (methylsulfonylethyl), p-chlorophenyl, or 2- (p-chlorophenoxy) ethyl; or mean it

(b) R ² and R ^{3 taken} together with the nitrogen atom to which they are attached form a group of the formula

-N 0, -N N-COCH. , -N N-COOC.H,, "NM ^he -N

The group-CONR ² R ³ is more preferably-CONH ₂ or-CONH (C 1 -C ₄ -alkyl), most preferably-CONH ₂ , -CONHCH ₃ or -CONHC ₂ H ₅ .

R ⁵ and R ⁶ are both preferably H.

In the most preferred single compounds, R is 2,4-dichlorophenyl or 2,4-difluorophenyl; -CONR ² R ³ is -CONH ₂ , -CONHCH ₃ or -CONHC ₂ H ₅ ; and R ⁵ and R ⁶ are H.

According to one embodiment of the invention, compounds of the formula:

OH N N-CH-CH ₀ -C ₉ -OCNR ² R ³

/ ² I ²

NO

provided wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, I, CF _3, dC ₄ alkyl and C ₁ -C ₄ -alkoxy, or R is a B-chloropyrid ^ -yl group is; R ^{2 is} H or C ₁ -C ₆ -alkyl and R ^{3 is} H, C ₁ -C ₆ -alkyl, benzyl, -CH ₂ CF ₃ or adamantyl, where the benzyl group is optionally substituted on its phenyl ring part by 1 or substituents, each independently selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, F, Cl, Br, J and CF ₃ , or R ² and R ³ together with the nitrogen atom to which they are attached form a group of formula

, wherein R ⁴ is H, C ₁ -C ₄ -alkyl, Cr-C ₄ alkanoyl or (C ₁ -C ₄ -alkoxy (carbonyl and their pharmaceutically acceptable salts.

According to a further embodiment of the invention, compounds of the formula OH R ⁵

N _'N-0 CH -C- C-CCNR ² R

¹ p

2 N R CH-

wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, J, CF ₃ , C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, or R a 5-chloropyrid-2-yl group wherein R ^{2 is} H or C ₁ -C ₆ -alkyl and R ^{3 is} H, C ₁ -C ₆ -alkyl, benzyl, -CH ₂ CF ₃ or adamantyl, the benzyl group optionally substituted on its phenyl ring part by 1 or 2 substituents, each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, F, Cl, Br, J and CF ₃ , or R ² and R ³ together with the Nitrogen atom to which they are attached, a group of the formula

or _ _N

, wherein R ⁴ is H, C ₁ -C ₄ -alkyl, Cz-C ₄ alkanoyl or (C ₁ -C ₄ alkoxy) carbonyl, and R ⁵ is H or CH _3; and their

pharmaceutically acceptable salts.

If the compounds of the formula (I) have at least one chiral center, the invention comprises the preparation of both

split as well as non-split forms.

The compounds of the formula (I) can be prepared from β-lactones of the formula

I ι

(A)

N, N-CH - C-CR ⁵

\ = N R R ° _

wherein R, R ⁵ and R ^{6 are} as previously defined for formula (I).

Thus, the process according to the invention comprises the following reaction:

0C I I

-O

OH R ⁵

N-CH-C-C-

N-CH-C

C-CONR ² R ³

L ί

wherein R, R ² , R ³ , R ⁵ and R ^{6 are} as defined for formula (I).

The reaction may be carried out by stirring the reaction components in a suitable solvent, e.g. As ethanol, at

Room temperature to be carried out to completion. If necessary, the reaction mixture can be heated to accelerate the reaction. The product can be isolated and purified in a conventional manner.

By one method, the lactones can be prepared as follows:

/ N

N-CH ₂ -C

R ⁵

+ BrZn-C-COO (C ₁ -C ₄ -

i) heat ii) H *

N-CH ₂ -C

OH R

  I

COO (C ₁ -C ₄ -alkyl)

RR ⁶

cyclize

(VIII)

Lactone A

In general, part of the product (VIII) cyclizes in situ under the reaction conditions to the intermediate lactone (A). The ester (VIII) and the lactone (A) can be separated by chromatography.

The esters (VIII) are useful in other synthetic methods. The lactone intermediates of formula (A) can be prepared by cyclization, preferably using an ester, according to the following scheme:

OH R ⁵

I i

N-CH.-C-C-COOQ

/ ² II ₆ ·

base

R R °

wherein Q = C ₁ -C ₄ -alkyl, phthalimido, succinimido or 1-benzotriazolyl.

These esters can be prepared as described in our own European Patent Application 0106515.

The cyclization can be carried out in the presence of a suitable base by stirring at room temperature. Preferred bases are

tertiary amine bases, e.g. Triethylamine, and alkali metal hydrides, e.g. For example, sodium hydride.

The compounds of the invention contain a chiral center or centers, and the invention includes the preparation

both the split and non-split forms.

-H- / OU \ l £.

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

The salts can be obtained by conventional procedures, e.g. By mixing solutions containing equimolar amounts of the free base and the desired acid, and the desired salt is collected by filtration if insoluble or by evaporation of the solvent.

Also included are the alkali metal salts which can be prepared in a conventional manner.

The compounds of formula (I) and their pharmaceutically acceptable salts are antifungal agents useful for controlling fungal infections in animals, including humans. They are useful, for example, in the treatment of tropical fungal infections in humans, caused among other organisms by species of Candida, Trichophyton, Microsporum or Epidermophyton, or in mucous membrane infections caused by Candida albicans (eg oral and vaginal candidiasis). , They may also be used in the treatment of systemic fungal infections, e.g. by Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

The in vitro evaluation of the antifungal activity of the compounds can be made by determining the minimum inhibitory concentration (MIC), which is the concentration of test compounds in a suitable medium that does not induce growth of the particular microorganism. In practice, a series of agar plates, each with the test compound in a certain concentration, are inoculated with a standard culture of, for example, Candida albicans, and each plate is then incubated at 37 ^° C. for 48 hours. The plates are then examined for the presence or absence of growth of the fungus and the corresponding MIC value recorded. Other microorganisms used in such assays may include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp, Microsporum spp, Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

The in vivo evaluation of the compounds may be performed at a range of dose levels by intraperitoneal or intravenous injection or by oral administration to mice inoculated with a strain of Candida albicans. The activity is due to the survival of a treated group of mice after entering an untreated group of mice after 48 hours of observation. The dose value at which the compound provides 50% protection (SD ₅₀ ) against the lethal effect of the infection is recorded.

For human use, the antifungal compounds of formula (I) may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or egg-shaped pills either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring and coloring agents , You can parenteral, z. As intravenous, intramuscular or subcutaneous injected. For parenteral administration, they are best used in the form of a sterile aqueous solution containing other substances, e.g. B.

enough salts or glucose to make the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of formula (I) is from 0.1 to 5 mg / kg (in divided doses) with either oral or parenteral administration. Thus, tablets or capsules of the compounds contain from 5 mg to 0.5 g of active compound for administration singly or two or more at a time, as appropriate. The physician will in any case determine the actual dose most appropriate for a single patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there may of course be isolated cases where higher or lower dosage ranges are beneficial, and they are within the scope of the invention.

Alternatively, the antifungal compounds of formula (I) may be administered in the form of a suppository or pessary, or they may be used topically in the form of a lotion, solution, cream, ointment or dusting powder.

For example, they may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they may be incorporated at a concentration of between 1 and 10% into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as required.

The compounds of formula (I) and their salts also possess activity against a variety of phytopathogenic fungi, including e.g. Various forms of rust, fire and mold, and the compounds are thus useful for treating plants and seeds to destroy or prevent such diseases.

The in vitro evaluation of the activity of the compounds against plant fungal can be determined by measuring their minimum inhibitory concentrations in the same manner as described above, except that the plates are incubated at 30 ° C for 48 hours or more before appearing or lack of growth

to be examined. - _____

Microorganisms used in such assays include Cochliobolus carbonum, Pyricularia oryzae, Glomerel fa cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoctonia solani.

For agricultural and horticultural purposes, the compounds and their agriculturally acceptable salts are preferably used in the form of an agent which is composed according to the particular use and purpose. Thus, the compounds may be applied in the form of dusting powders or granules, seed treatment sauces, aqueous solutions, dispersions or emulsions, dip solutions, sprays, aerosols or smoking agents. Agents may also be used in the form of dispersible powders, granules or granules or concentrates for dilution before use. Such agents may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture, and are prepared according to conventional procedures. The agents may also contain other active ingredients incorporated, e.g. As compounds with herbicidal or insecticidal activity, or another fungicide. The compounds and agents can be applied in numerous ways, e.g. For example, they may be applied directly to the plant foliage, stems, twigs or branches, seeds or roots or soil or growth medium, and may not only be used to eradicate a disease, but also prophylactically to protect the plants or seed be used against infestation.

embodiments

The following examples illustrate the invention. All temperatures are given in ° C: Example 1

(A) Preparation of 2- (2,4-dichlorophenyl) -3-ethoxycarbonyl-3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol and 4- ( 2,4-dichlorophenyl) -3,3-dimethyl-4- (1H-1,2,4-triazol-1-ylmethyl) -β-propiolactone

CH,

N N-CH ₀ -C + BrZn-C-COOC H _0,

² Λ I ^{2 5}

ι.

CH,

Cl

OH CH,

N-CH ₂ -CC-COOC ₂ H ₅

and

N-CH 1 -C-C-CH

2- (1H-1,2,4-triazol-1-yl) 2 ', 4'-dichloroacetophenone (2.56g) in dry tetrahydrofuran (20ml) and ethyl a-bromoisobutyrate (1.475ml) in dry ether (10ml ) were added simultaneously to granulated zinc (1.5 g) in toluene (10 ml) over 20 minutes.

The reaction mixture was then heated to 80 ° for 18 hours. The cooled reaction mixture was poured onto ice-cold sulfuric acid (0.2 N, 125 mL) and extracted with ether (200 mL). The ether extract was washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was flash chromatographed on silica (120 g) and eluted with 80% ethyl acetate / 20% hexane. The first fractions provided the title ester, which crystallized from ethyl acetate / hexane

Yield of pure product was 61 mg, mp 95-96 °.

Analysis for C ₁₆ H ₁₉ Cl ₂ N ₃ O _3,% Found: 11.1 C51,7H5,2N Calculated: N 11.3 C51,6H5,1

The later fractions yield on concentration of the title β-lactone, which was recrystallized from ethyl acetate / hexane

on pure product 240mg, Schm. 177 to 178 °.

Analysis for C ₁₄ H ₁₃ Cl ₂ N ₃ O _2,% Found C 51.8 H 3.9 N 12.8 Calculated: C 51.5 H 4.0 N 12.9

(B) Preparation of 3-carbamoyl-2- (2,4-dichlorophenyl-3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol

0-Q «= 0 I I

N-CH ₂ -CC-CH

N-CH ₀ -CC-CONH

- D- / OU

A solution of 4- (2,4-dichlorophenyl) -3,3-dimethyl-4- (1H-1,2,4-triazol-1-yl-methyl) -β-propiolactone (70 mg) in ethanol (4 ml) was treated with (6 ml) ammonia (0.88) and allowed to stand at room temperature for 5 days. The reaction mixture was then concentrated in vacuo and the residue partitioned between methylene chloride and water, and the organic extracts were washed with brine and dried (over MgSO 4). Solvent removal, followed by flash chromatography on silica (30g) and elution with a methylene chloride / ammonia mixture (93: 7: 1) gave the title compound, m.p. 162-163 ° (41mg).

Analysis for C ₄ H ₁₆ CI ₂ N ₄ O _2,% Found: N 15.9 C48,6H4,7 Calculated: C49,0 H 4.7 N 16.3

Example 2

Preparation of 2- (2,4-dichlorophenyl) -3-methyl-3- (N -methylcarbamoyl) -1- (1H-1,2,4-triazoM-yl) butan-2-ol 0-C-OOH CH,

-C-C-CONHOL

A solution of 4- (2,4-dichlorophenyl) -3,3-dimethyl-4- (1H-1,2,4-triazol-1-ylmethyl) -β-propriolacetone (200 mg) in ethanol (5 ml) was washed with a solution of 35 (vol .-%) methylamine in ethanol (5 ml) and the resulting solution is allowed to stand overnight at room temperature (20 °). After evaporation of residual methylamine and ethanol, the residue was triturated with hexane and the resulting solid crystallized from ethyl acetate / hexane to give the title compound, m.p. 145-146 °, (120mg)

Analysis for C ₁₅ H ₁₈ Cl ₂ N ₄ O ₂ ,% Found: C 50.2 H 5.0 N 15.9 Calculated: C 50.4 H 5.0 N 15.7

Example 3

(A) Preparation of 4- (2,4-dichlorophenyl) -4- (1H-1,2,4-triazol-1-ylmethyl) i3-propiolactone

OH - 0-C-O

1-CH ₂ -C-CH ₂ COOH

i) "HOBT / DCCD" ii) triethylamine

N 'I

N-CH ₂ -C-CH ₂

3-carboxy-2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) -butan-2-ol (948 mg) was dissolved in dry dioxane (20 ml), and then 1-hydroxybenzotriazole hydrate (0.61 g) and then dicyclohexylcarbodiimide (1.85 g) were added. The resulting mixture was stirred at room temperature (20 °) for 2 hours whereupon triethylamine (455 mg) was added and stirring was continued overnight (19 hours). The mixture was then poured into water (100 ml) and extracted with ethyl acetate (3 x 50 ml). The dicyclohexylurea precipitate was filtered off after the first extraction. The combined organic extracts were washed with water, dried (over MgSO ₄ ) and concentrated. The resulting residue was dissolved in a little methylene chloride and placed on a silica flash column (12 g "Kieselgel 60", 62-37 μηη, 230-400 mesh) in ether, eluting with ether (100 mL) and then 5 (v / v) .-% acetone in ether (300 ml), after collecting appropriate fractions, gave the title compound, 600 mg, m.p. 178-180 °

Analysis for C ₁₂ H ₉ Cl ₂ N ₃ O _2,% Found C 48.1 H 3.0 N 14.0 Calculated: C48,4H3,0N14,1.

(B) Preparation of 3- (N-methylcarbamoyl) -2- (2,4-dichlorophenyl) -1H- (1,2,4-triazol-1-yl) propan-2-ol

N V

0-C-O

II N-CH_-C-CH_ / ² I ²

OH

CH ₃ NH ₂ / C ₂ H ₅ OH

IT N-CH ₂ -C-CH ₂ CONHCH ₃

This reaction was carried out similar to Example 2 using the starting materials indicated in the Reaction Scheme to give the title compound. M.p. 151-154 °.

Calculated: C47.4H 4.3 N 17.0 Found: C47.3H4.35N 17.2.

Example 4 Preparation of 3-carbamoyl-2- (2,4-dichlorophenyl) -1H- (1,2,4-triazol-1-yl) propan-2-ol

O C-OH

N N

N-CH ₀ -C-CH ₀ CONH ₀

² I ^{2 2}

This reaction is similar to Example 1 (B) using the starting materials indicated in the reaction sequence to give the title compound, mp 144-145 °

Analysis for C ₁₂ H ₁₂ CI ₂ N ₄ O _2,% Calculated: C45,7 H 3.8 N 17.8 Found: 17.5 C45,5H3,8N.

Example 5

In the following, pharmaceutical agents for the treatment of fungal infections are illustrated:

(a) Capsule: 71 parts by weight of the compound of Example 1B or 2 are granulated with 3 parts of corn starch and 22 parts of lactose and then an additional 3 parts of corn starch and 1 part of magnesium stearate are added. The mixture is granulated again and filled into hard gelatine capsules.

(b) Cream: 2 parts by weight of the compound of Example 3 B are dissolved in 10 parts of propylene glycol and mixed into 88 parts of a vanishing cream base.

(c) Pessary: 2 parts by weight of the compound of Example 4 are suspended in 98 parts of a warm liquefied suppository base which is poured into molds and allowed to solidify.

The following preparations, in which all temperatures are given in C, illustrate the preparation of certain starting materials:

Production 1 Preparation of 1-cyano-2- (2,4-dichlorophenyl) -3- (1H-1,2,4-triazol-1-yl) -propan-2-ol

0 OH

+ NaCN

N-CH ₂ -C-CH ₂ CN

To 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) oxirane (6.7g) in dimethylformamide (198ml) at 60 ° was added sodium cyanide (2.84g). added dropwise in water (49 ml) over 25 minutes. It was heated for a further 5 hours at 60 °. The reaction mixture was then cooled, poured into water (900 ml) and extracted with (3 x 150 ml) ethyl acetate. The combined organic extracts were washed with saturated aqueous brine, dried (over Na ₂ SO ₄ ) and concentrated to dryness to give a pale yellow solid (6.1 g) which was triturated with ether. The residual solid was recrystallized from ether / methanol to give the title compound, 4.13g (56%), m.p. 217-219 °. Analysis for C ₁₂ H ₁₀ Cl ₂ N ₄ O,% Found: C 48.3 H 3.4 N 18.4 Calculated: C 48.5 H 3.4 N 18.8

Production 2 Preparation of 1-carboxy-2- (2,4-dichlorophenyl) -3- (1H-1-2,4-triazol-1-yl) -propan-2-ol

OH OH

* -CH _o -C-CH ₀ -CN

402 aq.

100 ^e / 18 h

\ N =

1-CH ₂ -C-CH ₂ -CO ₂ H

1-Cyano-2- (2,4-dichlorophenyl) -3- (1H-1,2,4-triazol-1-yl) -2-propanol (4 g, 13.9 mmol) was dissolved in 40% aqueous sulfuric acid ( 100 ml) and heated in an oil bath for 18 hours at 100 to 110 °. The solution was then cooled, diluted with water (200 ml) and made alkaline by the slow addition of solid sodium bicarbonate. The mixture was then extracted several times with ethyl acetate (3 x 100 ml) and the aqueous phase made acidic (pH 3) by the addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ether (3 x 150 ml), the combined ether extracts were washed once with water and then dried over magnesium sulfate. Evaporation of the ether gave the title compound as

pale yellow solid, 2.7 g (62%), mp 158-159 °.

Analysis for Ci ₂ H ₁₁ Cl ₂ N ₃ O ₃ ,%

Found: C46.35H3.5N 13.6 Calculated: C45.6 H3.5N13.3.

Likewise, 1-carboxy-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) -propan-2-ol, mp 185-187 °, was also prepared.

Found: C50.8H3.9N 14.8 Calculated: 51.0 H 3.9 N 14.8

Production 3

(i) Preparation of 2- (1H-1,2,4-triazol-1-yl) -2 ', 4'-dichloroacetophenone (Y)

This compound was prepared similar to the method described in GB-PS1512918:

CH "CO

V Vx

Acetonitrile * - ^cl reflux, 20 h

(ii) Preparation of 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) oxirane (Z)

H NCH ₂ CT "V-Cl trimethylsulphoxonium N / \ / iodide and Na hydride

(Y)

3.78 g (0.079 mol) of sodium hydride (50% dispersion in oil) were suspended with stirring in 20 ml of dry ether. The ether was then decanted and the sodium hydride dried in a stream of nitrogen. 100 ml of dry dimethylsulfoxide was added, then 17.34 g (0.079 mol) of dry powdered trimethylsulfoxonium iodide in portions over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20 ° C). 18.33 g (0.072 mol) of the compound (Y) as a solution in 50 ml of dry dimethyl sulfoxide were then added. The mixture was heated for 3 hours at 6O ⁰ C and then stood at room temperature overnight. The reaction mixture was cooled and quenched in ice. The product was then extracted into ethyl acetate (600 ml). The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated to a red resin. Column chromatography of the silica on silica eluting with ether gave the product (Z). On concentration, 6.62 g (34.4%) of the title compound (Z) was obtained as a resin which solidified on trituration. The pure product melted at 57 to 59 °

Analysis for C ₁₁ H ₉ Cl ₂ N ₃ O,% Found: C 48.6 H 3.3 N 15.3 Calculated: C 49.0 H 3.4 N 15.5.

activity data

(oral) PD ₅₀ values in mice in mg / kg:

Product of example PD ₅₀ (mg / kg)

1 (B) 3.1

2 0.6 3 (B) 0.2

4 0.2 _

Claims (1)

Ί- / OO Invention claim: 1. A process for the preparation of a compound of the formula OH R ⁵ I I ρ- * N-CH, -C-C-CONR R (D. wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, J, CF 3, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, or 5-chloropyrid-2-yl R ⁵ and R ^{6 are} each H or CH ₃ and either (a) R ^{2 is} H or C ₁ -C ₆ alkyl and R ^{3 is} H, C ₁ -C ₆ -alkyl, benzyl, phenethyl, phenyl, -CH ₂ -CF ₃ , adamantyl, pyridylmethyl, C ₃ -C ₇ -cycloalkyl, carbamoylmethyl, (C ₂ -C ₄ -alkenyl) methyl, 2-hydroxyethyl, 2- (dimethylamino) ethyl, 2- (methylthio) ethyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl or 2-phenoxyethyl, wherein the benzyl, phenethyl, phenyl and phenoxy groups are optionally ring-substituted by 1 or 2 substituents, each independently selected from C _r C ₄ alkyl , C ₁ -C ₄ -alkoxy, F, Cl, Br, J and CF ₃ , or (b) R ² and R ³ together with the nitrogen atom to which they are attached form a group of the formula