PL141652B1 - Process for preparing novel derivatives of triazole - Google Patents

Description

The subject of the invention is a method for preparing new triazole derivatives of the general formula 1, wherein R1 is a phenyl radical, optionally containing 1-3 identical or different substituents, such as fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, (Cr-C4) alkyl and (C1-C4) alkoxy groups, or R1 is a 5-chloropyridyl-2 group, R2 is a hydrogen atom or a (C1-C6) alkyl radical, R3 is a hydrogen atom, a (C1-C6) alkyl radical, a benzyl radical, a phenylethyl radical, a phenyl radical, a -CH2CF3 group, an adamantyl radical, a pyridylmethyl radical, a (C3-C7) cycloalkyl radical, a carbamoylmethyl radical, a (C2-C4) alkenylmethyl radical, a 2-hydroxyethyl group, 2-(dimethylamino)-ethyl, 2-(methylthio)-ethyl, 2-(methylsulfinyl)-ethyl, 2-(methylsulphonyl)-ethyl or 2-phenoxyethyl, wherein these benzyl, phenylethyl, phenyl and phenoxy groups may contain identical or different substituents in ring 1 or 2, such as (C1-C4) alkyl groups, (C1-Ca) alkoxy groups, fluorine, chlorine, bromine and iodine atoms and trifluoromethyl groups, or R2 and R3 together with the nitrogen atom to which they are bonded form a group of formula 2, 3, 4 or 5 or a group of formula 6, wherein R4 is a hydrogen atom, a (C1-C4) alkyl radical, a (C2-C4) alkoxy group or a (C 1 -C 4 )/alkoxy/carbonyl group, R 5 is a hydrogen atom or a methyl radical, and R 6 is a hydrogen atom or a methyl radical. The invention also includes the preparation of acid addition salts of the compounds of formula I, which are acceptable for use in pharmacology and agriculture. The compounds prepared by the method according to the invention have fungicidal activity and can be the active substance of fungicides for use in agriculture and agents for combating fungal infections in humans. Compounds of formula I, in which R 1 is a phenyl radical with 1-3, especially 1 or 2, identical or different substituents, such as fluorine, chlorine, bromine and iodine atoms, and a trifluoromethyl group, have advantageous properties. For example, R1 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, and especially the 2,4-dichlorophenyl, 4-chlorophenyl or 2,4-difluorophenyl group, and most preferably the 2,4-dichlorophenyl or 2,4-difluorophenyl group.2 141652 Compounds of formula 1, in which R is a hydrogen atom, a methyl or ethyl radical and R3 is a hydrogen atom, an (O-C6) alkyl radical, a p-chlorobenzyl group, a p-chlorophenylethyl group, a p-methylphenylethyl group, a group of the formula -CH2CF3, a 1-adamantyl group, a 4-pyridylmethyl group, cyclopropyl, carbamoylmethyl, a -CH2CH=CH2 group, a 2-hydroxyethyl group, a 2-(dimethylamino)ethyl group, a 2-(methylthio)ethyl group, a 2-(methylsulfinyl)ethyl group, a 2-(methylsulphonyl)ethyl group, a p-chlorophenyl group or a 2-(p-chlorophenoxy)ethyl group, or R3 and R3 together with the nitrogen atom to which they are bonded form a group of formula 2, 3 or 5, or a group of formula 6, wherein R4 is a -COCH3 group or a -COOC2H5 group. In the compounds of formula 1, the group of formula -CONR2R3 is preferably a -CONH2 group or a -CONH-alkyl group, in which the alkyl radical contains 1-4 carbon atoms, especially a -CONH2 group, -CONHCH3 or -CONHC2H5. Both symbols R5 and R6 preferably represent hydrogen atoms. The most advantageous properties are possessed by compounds of formula 1, in which R1 represents a 2,4-dichlorophenyl or 2,4-difluorophenyl group, the group of formula -CONR2R3 is a -CONH2, -CONHCH3 or -CONHC2H5 group, and R5 and R6 represent hydrogen atoms. According to the invention, compounds of formula 1 described above are prepared by reacting new compounds of formula 7, in which R1, R5 and R6 have the meanings given above, with an amine of formula R2R3NH, in which R2 and R3 have the meanings given above. These reactions are carried out by mixing both reaction components in a suitable solvent, e.g. ethanol, at room temperature, until the process is complete. Sometimes it is advantageous to heat the reaction mixture. The product is isolated and purified by known methods. Lactones of formula 7 are prepared by the reaction described in Scheme 1. In the formulae appearing in this scheme, R 1 , R 5 , and R 6 have the meanings given above. The compounds of formula 8 obtained are cyclized to obtain compounds of formula 7. Sometimes this cyclization occurs already during the reaction described in the scheme, yielding a mixture of esters of formula 8 and lactones of formula 7. Such mixtures are separated chromatographically. Esters of formula 8 are also useful in other synthetic processes. Lactones of formula 7 can also be prepared by cyclization of compounds of formula 9, wherein R1, R5, and R6 are as defined above, and Q is a (C1-C4) alkyl, phthalimide, succinimide, or 1-benzotriazolyl group. Compounds of formula 9 can be prepared by the method described in European patent application No. 0106515. The cyclization process is carried out in the presence of a suitable base, with stirring at room temperature. Tertiary amines, e.g. triethylamine, or alkali metal hydrides, e.g. sodium, are preferably used as bases. The compounds of formula I have one or more chiral centers and the invention covers the preparation of these compounds in the form of mixtures as well as separated into individual diastereoisomers. The compounds of formula I are optionally converted by conventional methods into acid addition salts, e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid or methanesulfonic acid. The compounds prepared by the method according to the invention are effective against various fungi causing plant diseases, including various types of rusts and molds, and can therefore be used to control these pests or to protect plants against attack by these fungi. In vitro studies have shown that these compounds are effective against microorganisms such as Cochliobolus carbonum, Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea, and Rhizoctonia solanii. As mentioned in the introduction, compounds of formula I, as well as their pharmacologically acceptable acid addition salts, can also be used to combat fungal infections in humans and other mammals. Studies have shown that these compounds, when administered to humans, combat local infections caused by organisms such as Candida, Trichophyton, Microsporum, and Epidermophyton, and mucosal infections caused by Candida albicans (e.g., vaginal thrush). These compounds can also be effectively used to combat systemic infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma, and Blastomyces.141652 3 The ability of compounds of formula 1 to combat fungal infections was assessed by determining the minimum inhibitory concentration of these compounds, at which a given microorganism ceases to grow. The tests were conducted on agar plates containing a specific concentration of the test compound and infected, for example, with Candida albicans, after which each plate was cultured at 37°C for 48 hours. The plates were then examined to determine whether the microorganism had grown or its growth had been inhibited. In this way, the value of the above-mentioned minimum inhibitory concentration was determined. Similar studies were carried out with Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides imitis, and Torulopsis glabrata. The in vivo evaluation of the compounds of formula I was carried out by administering various doses of these compounds intraperitoneally, intravenously, or orally to mice infected with a strain of Candida albicans. Observations were made over a 48-hour period, comparing the number of these mice that persisted with the treatment with the corresponding number of mice from the control group, in which the mice were infected but not treated with the test compound. Based on this, the dose of the compound that provides 50% protection (PD50) in mice against the lethal effects of the microorganism was determined. In human medicine, compounds of formula 1 are administered with a carrier selected depending on the method of administration. These agents may take the form of tablets, capsules, solutions, suspensions, and sterile solutions, preferably aqueous, for parenteral administration. The daily dose of compound 1 for humans, when administered orally or parenterally, is 0.1-5 mg per 1 kg of body weight, with this dose divided into several smaller doses. These compounds can also be used in the form of suppositories, creams, ointments, and powders for sprinkling. For example, they can be used in the form of a cream containing the compound of formula I and an aqueous emulsion of polyethylene glycol, or in the form of an ointment containing 1-10% by weight of the compound of formula II in white, soft paraffin, optionally with the addition of fixatives and preservatives. Example 1. A. 2-(2,4-dichlorophenyl)-3-ethoxycarbonyl-3-methyl-1-(1H-1,2,4-triazolyl-1)-butanol of formula X and 4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,2,4-triazolyl-1-methyl)-propiolactone of formula VIIa (Scheme 2). 2.56 g of 2-(1H-1,2,4-triazolyl-1)2',4'-dichloroacetophenone (Formula 11) in 20 ml of anhydrous tetrahydrofuran and 1.475 ml of ethyl a-bromoisobutyrate in 10 ml of anhydrous tetrahydrofuran were added simultaneously, within 20 minutes, to 1.5 g of granulated zinc. The mixture was then kept at 80°C for 18 hours, then cooled, poured into 125 ml of ice-cold 0.2 N sulfuric acid and extracted with 200 ml of ether. The extract was washed with aqueous sodium chloride solution, dried over MgSO 4 and evaporated under reduced pressure. The residue is chromatographed on 120g of silica, eluting with a mixture of 80% ethyl acetate and 20% hexane. Initially, fractions give the ester of formula 10 and after recrystallization of the crude product from ethyl acetate and hexane, 61 mg of pure product is obtained, melting point 95-96°C. Analysis. Formula C16H19Cl2N3O3.%C %H %N found: 51.7 5.2 11.1 calculated: 51.6 5.1 11.3. After evaporation of further fractions, the β-lactone of formula 7a is obtained and after recrystallization from ethyl acetate and hexane, 240 mg of pure product is obtained, melting point 177-178°C. Analysis. Formula C14H13Cl2N3O2.%C %H %N found: 51.8 3.9 12.8 calculated: 51.5 4.0 12.9 B. 3-Carbamoyl-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol of formula Ia (Scheme 3). To 75 mg of 2-(2,4-dichlorophenyl)-3-ethoxycarbonyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 5 ml of ethanol was added 12 ml of aqueous ammonia solution (density 0.88) and the mixture was left for 8 days at room temperature. Then the solvent was evaporated under reduced pressure and the residue was shaken. with methylene chloride and water.4 141652 The organic solution is washed with aqueous sodium chloride solution, dried over MgSO 4 and the solvent is evaporated. The residue is chromatographed on 30 g of silica, eluting with a mixture of methylene chloride, methanol and ammonia (97:7:1). 34.5 mg of compound Ia are obtained, melting at 162-163°C. Analysis: Formula C 14 H 16 Cl 2 N 4 O 2 . %C %H %N found: 48.8 4.7 15.8 calculated: 49.0 4.7 16.3 Example II. 2-(2,4-Dichlorophenyl)-3-methyl-3-(N-methylcarbamoyl)-(1H-1,2,4-triazolyl-1)-butan-2-ol of formula Ib (Scheme 4). A solution of 200 mg of 4-(2,4-dichlorophenyl)-3,3-dimethyl-4-(1H-1,2,4-triazolyl-1-methyl)-propiolactone in 5 ml of ethanol was treated with 5 ml of a 35% (v/v) solution of methylamine in ethanol and the resulting solution was left at room temperature overnight. Then the remaining methylamine and ethanol were evaporated and the residue was triturated with hexane. The obtained solid product was recrystallized from ethyl acetate-hexane to give 120 mg of compound of formula Ib, melting at 145-146°C. Analysis. Formula O5H18Cl2N4O2.%C %H %N found: 50.2 5.0 15.9 calculated: 50.4 5.0 15.7 Examples. A. 4-(2,4-dichlorophenyl)-4-(1H-1,24-triazolyl-1-methyl)-O-propiolactone of formula 7b (Scheme 5). To a solution of 948 mg of 3-carboxy-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazolyl-1)-butanol in 20 ml of anhydrous dioxane was added 0.61 g of 1-hydroxybenzotriazole hydrate and then 1.85 g of dicyclohexylcarbodiimide and stirred for 2 hours at room temperature. Then 455 mg of triethylamine was added and stirring was continued for 19 hours. The resulting mixture was poured into 100 ml of water and extracted with three 50 ml portions of ethyl acetate, filtering off the precipitate of dicyclohexylurea after the initial extraction. The combined extracts were washed with water, dried over MgSO 4 , evaporated, and the residue was dissolved in a small volume of methylene chloride and added to a chromatography column containing 12 g of silica in ether (Kieselgel 60, Merck, grain size 0.035-0.062 mm). Eluting was carried out with 100 ml of ether and then 300 ml of ether containing 5% by volume of acetone, yielding 600 mg of compound 7b, melting at 178-180°C, from the appropriate fractions. Analysis Formula C12H9Cl2N3O2.%C %N %N found: 48.1 3.0 14.0 calculated: 48.4 3.0 14.1 B 3-(N-Methylcarbamoyl)-2-(2,4-dichlorophenyl)-1H-1,2,4-triazolyl-1)-2-propanol of formula Ic (Scheme 6). This compound was prepared in a manner analogous to that described in Example 2, using the compound of formula 7b, melting at 151-154°C, as starting product. Analysis. Formula C13H14Cl2N4O2.%C %H %N found: 47.3 4.35 17.2 calculated: 47.4 4.3 17.0 Example IV. 3-Carbamoyl-2-(2,4-dichlorophenyl)-1H-1,2,4-triazolyl-1-apropanol of formula Id (Scheme 7). From the compound of formula 7b, proceeding in a manner analogous to that described in Example 1B, the compound of formula Id is prepared, melting at 144-145°C. Analysis. Formula C12H12Cl2N4O2.%C %H %N found: 45.5 3.8 17.5 calculated: 45.7 3.8 17.8141652 5 The following is a description of the preparation of the starting products used in some of the examples. Example 5 1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol. To a solution of 6.7 g of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-oxirane in 198 ml of dimethylformamide was added dropwise over 25 minutes, and the mixture was stirred for 25 minutes. The mixture was stirred at 60°C for 5 hours, then cooled, poured into 900 ml of water, and extracted with three 150 ml portions of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over Na2SO4, and evaporated to dryness, giving 6.1 g of a pale yellow solid. This product was triturated with ether and recrystallized from ether/methanol, giving 4.13 g (56% of theory) of the title compound, melting at 217-219°C. Analysis. Formula C12H10Cl2N4O.%C %H %N found: 48.3 3.4 18.4 calculated: 48.5 3.4 18.8 Example VI. Preparation of 1-carboxy-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazolyl-1)-propan-2-ol (Scheme 8). 4 g (13.9 mmol) of 1-cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazolyl-1)-propan-2-ol was dissolved in 100 ml of a 40% aqueous solution of sulfuric acid and kept in an oil bath at 100-110°C for 18 hours. The mixture was then cooled, diluted with 200 ml of water and made alkaline by the slow addition of solid sodium bicarbonate. The mixture was then extracted with three 100 ml portions of ethyl acetate, and the aqueous phase was acidified with dilute orthophosphoric acid to pH 3. The aqueous phase was then extracted with three 150 ml portions of ether. The combined ether extracts were washed once with water, dried over MgSO4, and the ether was evaporated, yielding 2.7 g (62% of theory) of the title compound. The product was pale yellow and melted at 158-59°C. Analysis. Formula C12H11Cl2N3O3.%C %H %N found: 46.35 3.5 13.6 calculated: 45.5 3.5 13.3 In an analogous manner, 1-carboxy-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazolyl-1)-2-propanol is prepared, melting point 185-187°C. Analysis. Formula C12H11F2N3O3.%C %H %N found: 50.8 3.9 14.8 calculated: 51.0 3.9 14.8 Example VII. Preparation of 2-(1H-1,2,4-triazolyl-1(2',4'-dichloroacetophenone) and subsequently 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazolyl-1-methyl)oxirane) The compound of formula (11) is prepared in a manner similar to that described in British Patent Specification No. 1,512,918. In the second stage of the process, 3.78 g (0.079 mole) of sodium hydride (50% dispersion in oil) is mixed with 20 ml of anhydrous ether, the ether is separated by decantation and the sodium hydride is dried in a stream of dry nitrogen. To the obtained product was added 100 ml of anhydrous dimethyl sulfoxide, followed by the portionwise addition over 15 minutes of 17.34 g (0.079 mol) of dry, powdered trimethylsulfoxonium iodide. The resulting mixture was stirred for 30 minutes at room temperature, then a solution of 18.83 g (0.072 mol) of compound 11 in 50 ml of anhydrous dimethyl sulfoxide was added and the mixture was heated at 60°C for 3 hours. The mixture was then left at room temperature overnight, stirred with ice, and extracted with 600 ml of ethyl acetate. The extract was dried over MgSO4 and concentrated to give a red resinous residue. This product is chromatographed on silica, eluting with ether, and after evaporation of the appropriate fractions, 6.62 g (34.4% of theory) of the compound of formula 12 is obtained. The product has the consistency of a resin, which hardens on trituration, giving a solid product with a melting point of 57-59°C.6 141652 Analysis. Formula C11H9Cl2N3O.%C %H %N found: 48.6 3.3 15.3 calculated: 49.0 3.4 15.5 The data concerning the activity of the compounds described in the examples are given below, namely the PD50 values for these compounds when administered orally to mice. Compound of Example IB II IIIB IV PD number 50 mg/kg 3.1 0.6 0.2 0.2 Patent claims 1. A method for preparing new triazole derivatives of the general formula 1, wherein R1 is a phenyl radical, optionally containing 1-3 identical or different substituents, such as fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, (C1-C4) alkyl and (C1-C4) alkoxy groups, or R1 is a group 5-chloropyridyl-2, R2 represents a hydrogen atom or a (C1-C*)alkyl radical, R3 represents a hydrogen atom, a (C1-C6)alkyl radical, a benzyl, phenylethyl, phenyl radical, a -CH2CF3 group, an adamantyl, pyridylmethyl, (C3-C7)cycloalkyl, carbamoylmethyl, (C2-C4)alkenylmethyl radical, a 2-hydroxyethyl, 2-(dimethylamino)ethyl, 2-(methylthio)ethyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl or 2-phenoxyethyl group, wherein these benzyl, phenylethyl, phenyl and phenoxy groups can contain 1 or 2 in the ring identical or different substituents, such as (C1-C4) alkyl groups, (C1-C4) alkoxy groups, fluorine, chlorine, bromine and iodine atoms and trifluoromethyl groups, or R2 and R3 together with the nitrogen atom to which they are bonded form a group of formula 2, 3, 4 or 5 or a group of formula 6, in which R4 is a hydrogen atom, a (C1-C4) alkyl radical, a (C2-C4) alkanoyl group or a (C1-C4) alkoxy-carbonyl group, and R5 and R6 in formula 1 are identical or different and represent hydrogen atoms and methyl radicals, as well as salts of these compounds, characterized in that the new compound of formula 7, in which R1, R5 and R6 have the above-mentioned meaning, is reacted with an amine of formula R2R3NH, in which R2 and R3 have the meanings given above, and the resulting compound of formula 1 is optionally converted by known methods into an acid addition salt acceptable for use in pharmacology and/or agriculture. 2. The method according to claim 1, characterized in that the reactions are carried out in an ethanol medium at a temperature close to room temperature. 3. The method according to claim 1, wherein the reaction is carried out in an ethanol medium at a temperature close to room temperature. A process according to claim 1 or 2, characterized in that the compound of formula 7, in which R1 is a 2,4-dichlorophenyl group and R5 and R6 are hydrogen atoms, is reacted with ammonia. 141652 OH p5 rfJ-CH2-C-C-C0NF^R3 R1 R« Formula 1 "N '\ -O -O Formula 2 Formula 3 Formula A Formula 5 Formula 6 9 o-c l^-CH2-C-C-R* Hi I | R< R«141652 O R5 I Cj1"O*? + BrZn-C-C00(Cr-C4alkyl) R' , R6 I) heating ii) He OH R5 and i N\l ^-CH2-C-C-COO (Ci-C4alkyl) M and i R1 R6 Formula 8 Scheme 1 •O1 OH Rs -CHz-ó-c-cooa I I R' R* Formula 9141652 O "N cr Formula 11 ,^\.A N*JCH2C-CH2 hJ i C1 Cl Formula 42 O CH, ^Oj-CHrC + BrZn-C-C0OC2H! fnrcl ch, NlOrll Cl OH CH3 O-CHrÓ-Ó-CCOCzHs Cl and Cl tfar 10 o II o-c N^N-CHrC-C-CHs ^ ' CH, Cl scheme 2 Cl W*<** 7tf141 652 X z: o X IX — 0-0-0 o «o * i 5-o M o I // \N o o W o •o 1 O < « I i- I 0-0-0 o * O I o o M O M CO O fi § O HI o c s l »o « .8 fi ZL O O # KI) Cl O N X U (A i O OJ o-O I I o-o o /Vo er t141652 O , " O* oo CM o o -ii c-C5 cJ i % i £ c ^ £ H Printing Workshop of the Polish People's Republic Office. Edition: 100 copies. Price: 130 PLN. PL PL PL PL PL PL PL PL PL

Claims (1)

1.