DD231789A5 - 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

Process for the preparation of triazole derivatives 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

^ \ '! 2 IT N-CH ₉ -CC-CONR R (D.

W Ί 1 *

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;

2 Ί

either (a) RH or Cj-Cg-alkyl and R ^J H,

C 1 -C -alkyl, benzyl, phenethyl, phenyl, -CH ₃ CF ₃ , adamantyl, pyridylmethyl, C ₃ -C -cycloalkyl, carbamoylmethyl, (C ₃ -C ₄ -alkene)

y is 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

2 C ₁ -C ₄ -alkoxy, F, Cl, Br, J and CF ₃ , or (b) R and

R ^J together with the nitrogen atom to which they are attached form a group of the formula

wherein R ^{4 is} H, C -C alkyl, C ₃ -C alkanoyl or (CC ₄ alkoxy) carbonyl;

RH or CH and R ° is H or CH ₃ , as well as their pharmaceutically and agriculturally acceptable salts.

The invention further provides

agricultural agent which is 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 ₃ H ₅ and R ^{3 is} H, C -C alkyl, p-chlorobenzyl, p-chlorophenethyl, p-methylphenethyl, -CH ₂ CF ₃ , 1-adamantyl, 4-pyridy methyl, cyclopropyl, carbamoylmethyl, -CH-.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) r2 and R ^ taken together with the nitrogen atom to which they are attached form a group of the formula

-NO, -NN-COCH ₃ , -NN-COOC ₂ H ₅ , "N Γ * ¹ ^ ~ ^Ν

The group -CONR R

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

R and R are both preferably H.

In the most preferred single compounds, R is

2,4-dichlorophenyl or 2,4-difluorophenyl; -CCMR ² R is - 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

\ 1 2 3

N. N-CH-CH ₀ -C ^ -CCNRR

provided wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from F, Cl, Br, I, CF _3, C.-C ₄ alkyl and C ₁ -C ₄ -alkoxy, or R a 5-chloropyrid-2-yl group;

R ^{2 is} H or C ₁ -C 6 -alkyl and R ^{3 is} H, C ₁ -C ₅ -

Alkyl, benzyl, -CH-CF., Or adamantyl, wherein the benzyl group is optionally substituted on its phenyl ring part by 1 or 2 substituents, each independently selected

2 under C.-C ₄ alkyl, C 1 -C 4 alkoxy, F, Cl, Br, J and CF, or R

and R together with the nitrogen atom to which they are attached form a group of the formula

-N \., -N ooder _ _N

in which R ^{4 is} H, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkanoyl or (C ₁ -C -alkoxy) carbonyl, and pharmaceutically acceptable salts thereof.

According to a further embodiment of the invention are connec tions of the formula

OH R ⁵

^ \ ¹ I 2 3

N N-CH-C ₀ -C CCNRR

Λ * ι I

^ NR CH ₃

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 or R 5-chloropyrid-2 -yl group is,

R ^{2 is} H or C 1 -C 6 alkyl and R ^{3 is} H, C 1 -C 8 alkyl, benzyl, -CH ₂ CF ₃ or adamantyl, wherein the benzyl group is optionally substituted at its phenyl ring portion by 1 or 2 substituents each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, F, Cl, Br, J and CF- or R ² and R together with the nitrogen atom to which they are attached form a group of the formula

-N

where R is H, C ₁ -C -alkyl, C ₃ -C -alkanoyl or (CC.-alkoxy) carbonyl, and R is H or CH ₃ ; and their pharmaceutically acceptable salts.

The compounds of the formula (I) are prepared according to the invention from the following acids (or their acylating derivatives):

OH R ⁵

N-CH ₂ -C -c-COOH (B)

• Ν RR ⁶

wherein R, R and R are as defined for formula (I).

These acids can in turn be prepared from the corresponding nitriles.

The nitriles in which R and R are H can

be prepared according to the following general method:

CN ⁰ OH

N-CH -CH -C _{0 0} K N-CH-CH -C _{9 9} CN

/ I ² \ / * ι

R II ^ = N R

The preferred source of cyanide ions. are the alkali metal cyanides, especially sodium and potassium cyanide. In a typical procedure, compound (II) and sodium or potassium cyanide are combined together in a suitable organic solvent, e.g. As dimethylformamide, up to 100 ⁰ C, preferably 65 to 7 0 ⁰ C, for z. B. heated for 6 hours. Preferably, the cyanide is added to the solution of oxirane via z. B. dripped for 0.5 hours. After cooling the reaction mixture and pouring it into water, the desired product can be isolated and purified by conventional techniques.

The starting materials for formula (II) are in many cases known compounds (see, for example, published European Patent Application No. 44605 of I.C.I) or can be prepared by routine methods as known to those skilled in the art. B .:

Cl.

NH + Br-CH ₇ CO /

"N

or (b)

Cl

K ₂ CO ₃ ,

Acetonitrile, reflux, 20 h CL

N is N-CH ₂ CO-C ^{7 N} > -C1

"Ν

Trimethylsulfoxonium iodide and NaH

N-CH - C

CH

Cl

Cl

N Br

i) n-BuLi / -78 C

ii) CH CCN (CH I / O C

¹ och.

Br / 48% aq.HBr / 100C,

/ O, 5h

N N-CH CO 1,2,4-oriazole,

Cl

OC, 2 days

ylsulf-

oxonium hexoxide, CH2 aq. NaCe (20%) 7 Cetrimide, 2h, 6O ⁰ C COCH Br

> N

N-CH ₂ -

CH.

Cl

The nitriles in which R ⁵ and R ⁶ each

H or CH ₃ can be prepared in the following general way:

0 R ⁵ 'OH R ⁵

N N-CH ₀ -C DHC-CN / fftarke Base ^ N-CH-CC-CN

ii) H®

The preferred strong base is n-butyllithium. In a typical procedure, the nitrile is dissolved in a suitable solvent, e.g. B. dry tetrahydrofuran (THF) and the resulting solution was then cooled to about -7 0 ⁰ C. A solution of n-butyllithium in hexane is then slowly added dropwise. After about 1 hour of stirring at -7 0 ⁰ C, the ketone (III) in a suitable solvent, z.-B. dry THF, slowly added dropwise. After about 1 hour of stirring at -7 0 ⁰ C glacial acetic acid is added in a little THF, and the reaction mixture is allowed to warm to 0 ⁰ C. The product can then be isolated and purified in a conventional manner. When one of the groups R 1 and R _{3 is} H and the other is CH ₃ IS, the product exists in two diastereoisomeric forms and these can often be separated by chromatography (see Example 29A).

The starting materials of formula (III) are either known compounds or can be prepared by conventional methods (see, for example, Preparations 3 (i) and 4 (B)).

The nitriles can then be converted in a conventional manner to the corresponding acids, e.g. with aqueous sulfuric acid, be hydrolyzed. The process according to the invention can be illustrated as follows:

OH R ⁵ R ² R ³ NH OH R ⁵

N is N-CH-C-C-COHNN-CH-C-C-CONRV

Compound (V) is preferably used in the form of its "functional equivalent as acylating agent", e.g. As acid chloride or bromide, a mixed anhydride of the formula:

OH R ⁵ OO

^ I! Ii B

N is N-CH ₀ -CCCOC- (C ₁ -C ₆ -alkyl) (VI),

\ / ² ii ₆ ^{l 4}

^ = N RR

or as C.-C.-alkyl, succinimido, phthalimide »or benzotriazol-1-yl esters.

All of these "functional equivalents" are conventionally prepared from the acid (V). The acid chlorides and bromides are, for example, by reacting the acid with thionyl chloride or bromide, the mixed anhydrides by reacting with a C 1 -C 6 alkanoyl chloride, the C 1 -C 4 alkyl esters by simple esterification, and the succinimido, phthalimido- and benzotriazoyl-1-yl-ester by reacting with N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide.

In fact, the compounds (V) in the form of their Succinimidoester the formula

OH R ⁵ O N N-CH "-C-C-CON I (VII)

i ₆

RR-0

used. Thus, in a typical procedure, dicyclohexylcarbodiimide, dissolved e.g. B. in dry dioxane, to a solution of the acid (V) and N-hydroxysuccinimide in z. B. added dry dioxane. After stirring for a few hours at room temperature and filtering, the reaction is generally carried out by stirring the solution of compound (VII) with the amine RR NH at room temperature for a few hours in e.g. As dry dioxane completed, whereupon the product can be isolated and purified by conventional means.

When the compound (V) is reacted in its free acid form, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

The C 1 -C 4 alkyl esters can also be prepared as follows:

, R ⁵

N N-CH ₀ -C + BrZn-C-COO (C ₁ -G. alkyl)

/ ² II

N R R °

i) heat ii) H ^§

OH R ⁵

i ι

N '' N-CH-C-C-COO (C ₁ -C -alkyl) (VIII)

^ = N R R

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

The benzotriazol-1-yl esters have the formula:

OH R ⁵ O N-CH - C-CCON N (IX).

/ ² II ₆

N RR

They can be made as stated above.

Thus, in a typical procedure, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and the acid (V) are allowed to react at room temperature for a short time in e.g. B. dry dioxane stirred together

The reaction is generally terminated by stirring the resulting intermediate (IX) with the amine ^RZ R NH at room temperature until completion, after which the product is purified by conventional means

Measures can be isolated and cleaned.

The compounds of formula (I) contain a chiral center or centers and the invention involves the preparation of both the split and un-split forms.

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. Example, 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 obtained 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 can also be used in the treatment of systemic fungal infections, triggered z. 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 given 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 can be done in a number

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 will generally be 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 , They can be parenteral, e.g. intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution containing other substances, ζ. For example, 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, such as tablets or capsules containing the compounds 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 each case determine the actual dose most suitable for a single patient and it will be determined by age, vary according to the weight and the response of the particular patient.The above dosages are exemplary of the average case, there may of course be individual cases where higher or lower

More dosage ranges are advantageous, 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 plant pathogens. Fungi, including z. 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. · -_.- · -. "

Microorganisms used in such assays include Cochlio ¹ -bolus carbonum, Pyricularia oryzae, Glomerella 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 according to the particular use

and the desired 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.

Examples of execution:

The following examples illustrate the invention. All temperatures are given in ⁰ C:

example Preparation of 2- (2,4-dichlorophenyl) -1- (morpholinocarbonyl) '- 3

(1H-1,2,4-triazol-i-yl) propan-2-ol .Monohydrat

ΟΉ '. OH

S * NCHCCHCOH i) "DCCD / NHS" N ^

^V = N

N-CH ₂ -C-CH ₂ -CO ₂ H i) "DCCD / NHS" N N-CH ₂ -C-CH ₂ CON

N, X- ^ v-Cl ii) morpholine

N, N'-Dicyclohexylcarbodiimide ("DCCD", 110 mg, 0.5 ^C mmol) dissolved in dry dioxane (5 mL) was added to a solution of 1-carboxy-2- (2,4-dichlorophenyl) -3- {iH -1,2,4-triazol-1-yl) propan-2-ol (150mg, 0.5mmol) and N-hydroxysuccinimide ("NHS", 60mg, 0.5mmol) in dry dioxane (10mL ) and the mixture is stirred for 2 hours at room temperature. The precipitate was filtered off, washed with dry dioxane (10 ml) and the filtrate and washings then combined to give a solution of morpholine (300 mg, 3.4 mmol) in dry dioxane (2 ml). The resulting solution was left at room temperature for 18 hours, diluted with ethyl acetate (100 ml), washed three times with saturated brine and dried over magnesium sulfate. Concentration of the filtrate gave an oil (300 mg), which was then chromatographed on (10 g) silica (60H silica gel) eluting with CH ₂ Cl ₂ containing 2% by volume isopropyl alcohol and 0.2% by volume aqueous ammonium hydroxide (specific gravity 0.880). contained, was chromatographed. The title compound was selected after concentration.

fractions obtained as a colorless solid, 110 mg (57%), mp. 92 to 93 °.

Analysis for ^c -j ₆ ^H -, ₈ ^N ₄ ^Cl ₂ ^O 3 " ^H 2 ° ' ^%

Found C 47.8 H 4.7 N 13.9

Calculated C 47.8 H5.0 N 13.9

Examples 2 to 27

The following compounds were prepared similarly to the previous examples starting from the same acid, DCCD / NHS and the appropriate amine:

OH

^ 1

N is N-CH ₀ -C-CH ₀ -R 2-2

-N

Step Example] κ ¹ -; ; '" (° C) .Analysis,% theoretically in brackets CH N -2 -CONHCH ₃ _-- ·: .- 151-3 ° (identical to the product of example 5) 3 -CONHCH (CH.) _ 105-107 ° 50.7 5.2 15.3 (50.6 5.1 15.7) 4 -CON (CH ₃ ) ₂ 125-126.5 ° 48.95 4.65 16.3 (49.1 4.7 16.4) 5 -CNHCH ₂ - / ^ \ - C 1 Glass 64-65 ° 52.15 3.95 12.5 (52.05 3.9 12.8)

example R ¹ Schrrp. cc) Analysis,% theoretically in parentheses. C HN rrihydrat) 4.4 5.6 14.4 14.6) 6 -CON NCOCH ₃ "Glass 63-5 ° (as 45.3 (45.1 Kemihydrate) 5.1 5.2 15.0 15.1) 7 -CON - NCO ₀ C ₀ H ₁ . \ / * ^{2 5} Glass 58-60 ° (as 49.2 (49.1 5.05 4.9 15.0 15.2) 8th -CON Glass 40-41 " 52.4 (52.2 5.5 5.4 15.0 15.1) 9 -CON (C ₂ H ₅ ) ₂ Glass 60-62 ° 51.9 (51.8 4.8 • 4.7 15.8 16.3) 10 ·. ". -CONHC ₂ H ₅ . 129-130 ° 49.0 (49.0 6.1 - - 5.8 12.0 12.5) 11: - -CONH (l-adamantyl) .._ 91-92 ° _. 58.7 (58.8 > femihydrate) 4.3 16.5 16.8) 12 " -CONHCH ₂ - ^ y Glass 48-50 ° (as 52.3 (52.1 3.5 3.3 13.6 14.1) 13 -CONHCH ₂ CF ₃ Glass 60-62 ° 42.6 (42.3 6.1 6.1 14.1 14.0) 14 -CONH (CH ₂ ) ₅ CH ₃ 114-116 ° 54.2 (54.1

example R ¹ / 15 -M; -cone Mp. Analysis,% theoretically in parentheses H 4:05 N 12.0 C 4.6 4.1 15.6 12.4) 16 -CONHCH ₂ CH ₂ -T Λ Cl 122-123 ° 50.6 4.5 15.8) 14.7 (50.7 4.2 12.2 14.5) 142-143 ° 52.9 4.2 12.3) 17 -CONH (CH ₂ ) ₂ CH ₃ (52.9 Hydrochloride) 15.3 (when 4.8 14.0 15.4) 169-170 ° 45.7 4.9 14.2) 12.8 18 -CONHCH ₂ CONh ₂ (45.8 (as hydrochloride H-hydrate) 12.9) 40.6 16.9 188-191 ° (40.2 16/08) 1 9 ' -CONHCH ₂ -CH-CH ₂ (when Qxalat 1/2 Hydrate) 45.4 4.3 20 -CONHCH ₂ C (CH ₃ ) - - , Glass (45.4 4.1 53.2 5.9 135-137 ° (53.0 5.8 21 -CONHCH ₂ CH ₂ OH (when 1/4 hydrate) 46.1 4.4 t 22 -CONH (CH ₂ ) ₂ - \ / - ^CH 3 143-145 ° (46.2 4.6 ι 58.2 5.1 144-145 ° (58.2 5.1

example R ¹ η y _n Mp. I Analysis, theoretically in C H Brackets N 5.1 14.2) 23 I ₂ ) 107-110 ° (as dihydrochloride dihydrate) 38.8 5.2 13.6 mol cyclo -CONH (CH ₂ ) ₂ N (CH ₃ ) ₂ -CONHCH ₂ CH ₂ SCh ₃ (38.8 5.4 10.9 (contains 1 hexane) 5.3 11.0) 24 102-105 ° 56.6 4.5 13.3 -CONH- / Λ-Cl. -CON (CH ₃ ) (CH [CH ₃ (56.5 4.5 13.2) 25 154-156 ° 42.6 4.0 4.1 11.9 11.9) (42.3 5.3 15.2 26 ' 137-9 ° 51.0 (51.1 5.4 15.1) 27 ^: 131-2 ° 51.7 (51.8

Example 28

The following compound was prepared similarly to Example 1, starting from 1-carboxy-2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) propan-2-ol, DCCD, NHS and methylamine: _0H

M.p. 129 to 131 ° analysis for C ₁ , H ₄ F.

Found: Calculated:

C 52.8 H 4.9 N 19.3 C 52.7 H 4.8 N 18.9

N-CH ₀ -C-CH ₀ CONHCH ₀ . / ^l l 2 3

-N

Example? 9

A. Preparation of 3-cyano-2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol (2 diastereoisomeric forms)

_n-BuLi / C ₂ H ₅ CN

OH CH.

N-CH ₂ -C-CH-CN.

Propionitrile (1.21g) in dry THF (50ml) was cooled to -72 °. A solution of n-butyllithium as a solution in n-hexane (14.2 ml, 1.55 m) was then added slowly, keeping the temperature of the reaction mixture at -45 ° or below - (1H-1,2,4-triazol-1-yl) -2 ', 4'-dichloroacetophenone (2.56 g) in dry THF (50 ml) was added slowly with stirring over 20 minutes, the temperature of the mixture At this temperature, stirring was continued for 1 more hour and then at -10 ° for 0.5 hour when glacial acetic acid (10 ml) in dry THF (15 ml) was added (20 °) was basified with solid sodium bicarbonate to pH 8 and extracted with ethyl acetate (3 × 75 ml) The combined organic extracts were washed three times with water, dried (concentrated over MgSO 4), and ether (30 ml). was given to the back / what a

white crystalline solid and a yellow solution. The solid was filtered off, dissolved in a small volume with methylene chloride and applied to a flash chromatography column containing 18 g of silica of grain size corresponding to a sieve mesh of 62 to 37 μπτ (silica gel 60 of 230 to 400 mesh) in ether (11 x 2 cm diameter) , Elution was carried out with 5% (vol.) Acetone in ether at 0.069 bar (1 psi). The diastereoisomer 1 of the title compound was eluted first, 0.79 g, mp 178-180 °.

Analysis for

Found: Calculated:

O,%

C 50.0 H 3.8 N 17.9 C 50.2 H 3.9 N 18.0

Then the diastereoisomer 2 of the title compound was eluted, 0.244 g, mp 202-205 °.

Analysis for

Found: Calculated:

C 50.4 C 50.2

H 3.9 H 3.9

N 17.6 N 18.0

B. Preparation of 3-, carbamoyl-2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol hemihydrate and 3-carboxy-2-yl (2,4-dichloro- phenyl) -1- (1H-1,2,4-triazol-1-yl) -butan-2-ol

OH CH.

-CH ₂ -C-CH-CN

/ I 40% N / ^ .Cl »

wassr. H ₂ SO ₄

OH CH

N-CH ₀ -C-CH-CONH

OH CH,

N-CH ₂ -C-CH-COOH

3-Cyano-2- (2,4-dichlorophenyl) -1- (iH-1,2,4-triazol-1-yl) -butan-2-ol (700 mg, diastereoisomer 1 from the previous example) became 5 , Heated for 5 hours at 90 to 95 ° in 40 (VoI -.)% Aqueous sulfuric acid. The solution was then stirred at room temperature (20 °) for 19 hours whereupon saturated aqueous sodium bicarbonate solution was added to raise the pH to 8.0.

The solution was then extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with water, dried (over MgSO 4) and concentrated to give the title 3-carbamoyl compound, 105 mg,. 215-217 ° after trituration with ether.

Analysis for C ₃ H 4 Cl ₂ N ₄ O ₃ .1 / 2H ₂ O,% (3-carbamoyl compound)

Found: C 46.8 H 4.5 N 15.5

Calculated: C 46.2 H 4.5 N 15.6

The aqueous phases obtained in the ethyl acetate extractions were combined, acidified to pH 2.0 with dilute hydrochloric acid and extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with water, dried (over MgSO ₄ ) and concentrated to give the title acid. After trituration with ether, the pure acid, 485 mg, mp. 236-238 °, was obtained.

Analysis for C ^ H., Cl ₀ NO-,%

Found: C 47.0 H 3.9 N 12.4

Calculated: C47.3H4, ON12.7.

C. Preparation of 2- (2,4-dichlorophenyl) -3- (N -methylcarbamoyl) -1- (TH-1, 2,4-triazol-1-yl) butan-2-ol

OH CH.

II ³

OH CH,

N N-CH-C-CH-COOH ΐΓ.ΗΟΒΤ / DCCD ¹¹ N ^ VcH "-C-CH-CONHCH / * | :> \ / ² I

Cl ii) CH ₃ NH ₂ .

 N

_cl

3-carboxy-2- (2,4-dichlorophenyl) -1- (1H-1,2,4-triazol-1-yl) -butan-2-0I (330 mg) was added to dry dioxane (10 ml) , then 1-hydroxybenzotriazole hydrate (HOBT, 203 mg) and dicyclohexylcarbo-. diimide (DCCD, 618 mg). After stirring at room temperature (20 ° C) for 1 hour, methylamine (278 mg, 33% by volume solution in ethanol) was added and stirring was continued overnight (20 hours). Thereafter, the resulting precipitate of dicyclohexylurea was filtered off. The filtrate was poured into water (50 ml) and solid sodium bicarbonate added to pH 8.

The mixture was then extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were washed with water, dried (over MgSO ₄ ) and concentrated. The residue was dissolved in one volume of methylene chloride and chromatographed on a silica flash column (Merck "Kieselgel 60") in ether. Elution with ether (100 mL) followed by 15 vol.% Ethanol in ether (300 mL) afforded, by collecting the appropriate fractions, the title compound, 29 mg, mp 242-244 °.

Since the filtered dicyclohexylurea contained an additional amount of the title compound, it was dissolved in a small amount of methanol and added to (3 g) silica (Merck "Kieselgel 60").

- 2 ¹ ^ -

and the resulting slurry is then brought to a 10g flash column of this material in ether. Elution with

10 (vol.)% Ethanol in ether and collecting the appropriate fractions, followed by recrystallization from isopropanol afforded an additional amount of the title compound, (81 mg).

Analysis for C ₁₄ H ₁

Found: Calculated:

C 48.9 H 4 CX) N 1 6 2 C 49.0 H 4 , 7 N 1 6 3 example 30

(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) -propiolactone ~ 2

CH

N-CH ^ -C + BrZn-C-COOC-H ,.

1 LD

1 .

CH,

OH CH

N-CH - CC-COOC-H ₁ . .._ _.2 1 2 5

and

- 26 -

2- (1H-1,2,4-triazol-i-yl) 2 ', 4'-dichloroacetophenone (2.56 g) in dry tetrahydrofuran (20 ml) and ethyl o-bromoisobutyrate (1.475 ml) in dry ether (10 ml) were added simultaneously to granulated zinc (1.5 g) in toluene (10 ml) over 20 minutes. The reaction mixture was then heated to 80 ° C for 18 hours The cooled reaction mixture was poured onto ice-cold sulfuric acid (0.2N, 125ml) and extracted with ether (200ml) The ethereal extract was washed with brine (over MgSO4). The residue was flash chromatographed on silica (120 g) and eluted with 80% ethyl acetate / 20% hexane The first fractions afforded the title ester, which was crystallized from ethyl acetate / hexane, yield of pure product 61 mg, m.p. 95 to 96 °.

Analysis for C _1g H Cl ₃ N ₃ O ₃ ,%

Found: 'C 51.7 H5.2 N11.1

Calculated C 51.6 H 5.1 N 11.3

The later fractions gave on concentration the title β-lactone, which was recrystallized from Ethylacetai / hexane, yield of pure product 240 mg, mp 177-178 °. This β-lactone has been used in other synthetic methods.

Analysis for C ₁ .H., Cl ₉ NO% "

Found: ^{| 4} '° ^z ° C 51.8 H 3.9 N 12.8

Calculated: C 51.5 H4.0 N 12.9

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

OH CH _n OH CH ₃

N is N-CH ₀ -CC-COOC ₀ H ₁ . NH _o / C _o H _c OH N ^ N-CH ₀ -CC-CONH,

Cl

To a solution of 2- (2,4-dichlorophenyl) -S-ethoxycarbonyl-S-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol (75 mg) in ethanol ( 5 ml) was added aqueous ammonia (specific gravity 0.88, 12 ml) and the solution left for 8 days at room temperature (20 °). The solvent was then removed in vacuo, the residue partitioned between methylene chloride and water and the organic extracts washed with brine and dried (over MgSO ₄ ). Removal of the solvent followed by flash chromatography on silica (30 g) and elution with a mixture of methylene chloride / methanol / ammonia (93: 7: 1) gave the title compound, m.p. 162-163 ° (34.5 mg).

Analysis for C ₁₄ H ₁₆ Cl ₂ N ₄ O ₂ /%

Found: C 48.8 H4.7 N 15.8

Calculated: C 49.0 H4.7 N 16.3

(C) 3-Carbamoyl-2- (2,4-dichlorophenyl) -1 - (1H-1,2,4-triazol-1-yl) -propan-2-ol was found to be useful similarly to (A) and (B) above Starting materials produced; Size 144-5. Analysis for C ₁₂ H ₁₂ Cl ₂ N ₄ O ₂ ,% calc .: C 45.7 H 3.8 N 17.8 Found: C 45.5 H 3.8 N 17.5

Example 5 ~ 1

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

(a) Capsule: 71 parts by weight of the compound of Example 1 or 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 3OC 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 5 are suspended in 98 parts of a warm, liquified suppository base which is poured into molds and allowed to solidify.

The following Preparations, in which all temperatures are given in • ⁰ 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

OH I + NaCN 7> N "N-CH" -C-CH CN

/ JL

.cl

Cl

To 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) oxirane (6.7 g) in dimethylformamide (198 ml) at 60 ° was added sodium cyanide (2, 84 g) in water (49 ml) was added dropwise 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 × 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, 4.13 g (56%), m.p. 217-219 °.

Analysis for C ₂ H Cl ₂ N ₄ O /%

Found: C 48.3, H3.4, 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-I , 2, 4-triazol-1-yl) propan-2-ol

OH OH

W N-O-C-CH ₀ -CN AOZ aq. H.SO., N, N-CH _n -CC

CH ₀ -C-CH ₀ -CN AOZ aq. H ₀ SO ₇ Cl

100 * / 18 h

Cl Ci

1-Cyano-2- (2,4-dichlorophenyl) -3- (1H-1,2,4-triazol-i-yl) -2-propanol (4 g, 13.9 mmol) was dissolved in 40% aqueous Dissolved 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 × 100 ml) and the aqueous phase made acidic (pH 3) by addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ether (3 × 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 a pale yellow solid, 2.7 g (62%), m.p. 158-159 °.

Analysis for C ₁₂ H ₁₁ Cl ₂ N ₃ O ₃ ,% Found:

Calculated: - .. _;

C 46.35 H 3.5 N 13.6 C 45.6 H 3.5 N 13.3.

Similar to the preparations 1

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

₂ NO

Analysis for Found: Calculates:

(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-PS 1 512 918:

C 50, 8th H 3 , 9 N 1 4 ,8th C 51, O H 3 , 9 N 1 4 ,8th Production 3

-JO-NIiH + Br. CH-CO - // \\ - Cl K.C0-, N ^x IJCH-C- / ye ^{1 + HBr}

v / \ / \ ι y = -i

V = ¹ N / acetonitrile V = UI Cl

Cl reflux, 20 h

(ii) Preparation of 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole)

1-ylmethyl) oxirane (Z) 0

N NCH-C- / V-Cl trimethylsulphoxonium

iodide and Na hydride

Cl

Cl

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 (0.07 9 mol) of dry powdered trimethylsulfoxonium iodide in portions over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20 ⁰ 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 to 60 ^° C. for 3 hours 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 resin on silica eluting with ether gave the product Z. Concentration reduced to 6.62 g (34.4%) of the title compound (Z) as a resin which solidified upon trituration, and the pure product melted at 57-59 °.

Analysis for C ₁₁ H Cl N ₃ O,%

Found: C 48.6 H 3.3 N 15.3

Calculated: C 49.0 H3.4 N 15.5.

Preparation 4 (A) Preparation of 2-chloro-2 '/ 4'-difluoroacetophenone

+ ClCH COCl

- 31 -

AlCl.

Chloroacetyl chloride (113 g, 1.0 mol) was added to a stirred mixture of 1, 3-difluorobenzene (114 g, 1.0 mol) and anhydrous aluminum chloride (146.6 g, 1.1 mol) at room temperature (20 ^° C.). dripped. The mixture was stirred at 50 to 55 ^° C. for a further 5 hours. Methylene chloride (48.5 ml) was added slowly, allowing the mixture to cool to room temperature. The methylene chloride layer was separated, washed with water (2 x 320 ml) and the solvent removed by distillation under reduced pressure to leave a pale yellow solid (180 g).

A portion of the crude product (145 g) was prepared from n-hexane (4 35 ml) crystallized to give the title compound (113 g, 73%), mp. 47 to 49 ⁰ C gave (literature mp. Loud D.Ehlers, H Bercher and A. Grisk, J. Prakt. Chem., 315 , 1169 (1973): 46.5 ⁰ C). IR (KBr) and NMR (CDCl-j) were consistent with the desired structure.

(B) Preparation of 2 ', 4'-difluoro-2- (1H-1,2'-4-triazol-1-yl) acetophenone hydrochloride . , ....

FO

ii

EtoAc,

Et-N

.HCl

To a mixture of 1,2,4-triazole (30.4 g, 0.44 mol) and triethylamine (15.1 g, 0.15 mol) in refluxing ethyl acetate (186 ml) was added a solution of 2-chloro Added 2 ', 4'-difluoroacetophenone (38.1 g, 0.2 mol) in ethyl acetate (80 ml). The mixture was refluxed for 6 hours, then cooled to room temperature and the insoluble fractions filtered off. The filtrate was washed with water (2 × 200 ml), and then the solvent was distilled off under reduced pressure. The crude product was dissolved in ethyl acetate (150 mL), then 25 w / v% HCl gas in isopropanol was added. The

Mixture was granulated at ⁰ ° C for 1 hour and then the solid was collected by filtration and dried to 167-170 ⁰ C, to give the title compound (21.6 g, 40%), mp.. IR (KBr) and NMR (DMSO) were consistent with the desired structure.

This intermediate was characterized as the free base prepared by the following technique:

To a stirred slurry of sodium bicarbonate (16.8 g, 0.2 mol) and 1,2,4-triazole (27.6 g, 0.4 mol) in refluxing toluene (18 ml) was added a solution of 2- Chloro-2 ', 4'-difluoroacetophenone (38.1 g, 0.2 mol) in toluene (45 ml) was added. The mixture was stirred at reflux for 3 hours and the water formed during the reaction was removed with a Dean-Stark trap. The reaction mixture was cooled to room temperature and then water (180 ml) was added. The toluene layer was separated and the solvent distilled off under reduced pressure. The resulting pale brown solid was recrystallized from 1: 1 ethyl acetate / n-hexane (70 ml) crystallized to give the title compound (3.9 g), mp 103 to 105 ⁰ C, resulted.. IR (KBr) and NMR (CDCl ) - were consistent with the desired structure.

Analysis for C ₁₀ H ₇ F ₃ N ₃ O,%

Found: C53.6H3.15N 18.7

Calculated: 'C 53.8 H 3.2 N 18.8

2- (2,4-Difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) oxirane was then prepared from the product of Section (B) above by the method of Preparation 3 (ii) ,

Activity data (oral) PD ₅ values in mice in mg / kg:

Product of the example PD (mg / kg)

1 ^ 20

2 0.4

3 0.1

4 0.4

5 0.1

⁶ / v / 30

7 3.1

8 -w 40

• 9 - 0.4

10 0.2

11 ^ 20

12 1.5

13 0.4

14 _ 2.2

15 0.1

¹⁶ 0.6

17 0.2

¹⁸ 0.2

1 ⁹ 0.4

Product of the example _PD ( _mg / _kg

20 3.5

21 2.2

22 ~ * .2

23 4-2

24 4.2

25 0.1

26 3.1

27 0.2

28 0.3

29C 0.2

3OB 3,1

3OC o, 2.

Claims (5)

invention claim N ^ N-CH-C-C-CONH ² R ³ -NR ^b. wherein R is phenyl optionally substituted by 1 to 3 subunits each independently selected from F, Cl, Br, J, CF ₁ -C ₄ -Al] CyI and C ₁ to C, alkoxy, or a 5-chloro-pyrid-2-yl 5 6
Group is, R and R respectively H or CH-. and either (a) R ^{2 is} H or C 1 -C 4 -alkyl 3 lb. and RH, Cj-Cg-alkyl ;, benzyl, phenethyl, phenyl, -CH ₂ -CF, 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 group is optionally substituted by 1 or 2 substituents each independently selected from C ₁ -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, a group of the formula or -N NR _t 4, worm RH, C ₁ -C.-alkyl, C ₀ -C, alkanoyl or (C ₁ -C -alkoxy) carbonyl, characterized in that a compound of formula OH R ⁵
N-CH_-C-C-C00H (V) or an acylating derivative thereof, wherein R, R and R are as defined above, with a compound of the formula 2 3 R R NH, 2 3
wherein R and R are as defined above. 2. The method according to item 1, characterized in that the acylating derivative is an acid chloride or bromide, a mixed anhydride or a C.-C.-alkyl, Succinimido-, Phthalimido- or -Benzotriazol-1-ylester of the acid (V ). 3. The method according to item 2, characterized in that R and R are both H. 4. The method according to item 3, characterized in that a C.-C. alkyl ester of the compound (V) is used and that R ² and R ^{3 are} both H. 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.