NO164295B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE FLUORED BENZYLTRIAZOL COMPOUNDS. - Google Patents

Description

The invention relates to an analogous method for manufacturing

ling of therapeutically useful, fluorinated 1-(α-phenylalkyl)-1H-1,2,3-triazole compounds of formula

in which Ph means an i o-position with fluorine and optionally in addition a further halogen atom substituted phenyl residue, alk means Cj,-C3-alkylidene, R^ means hydrogen, C1-C4-alkyl, or an unsubstituted or with C^-C4- alkanoyl or C 1 -C 4 -alkyl substituted carbamyl group, and R 2 means an unsubstituted or with C 1 -C 4 -alkanoyl or C 1 -C 4 -alkyl substituted carbamyl-

group.

As additional halogen substituents of Ph, halogen atoms come

with atomic numbers up to and including 35, such as fluorine or chlorine in consideration.

The C 1 -C 5 alkylidene is, for example, methylene, further ethylidene, 1,1-propylidene or 2,2-propylidene (isopropylidene).

Ci-C4-alkyl is, for example, methyl or, in other words, ethyl,

propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl.

With C1-C4-alkanoyl or C1-C4-alkyl substituted carbamyl is

especially with C 1 -C 4 -alkanoyl mono- or with C 1 -C 4 -alkyl disubstituted and means for example N -C 1 -C 4 -alkanoylcarbamyl,

primarily N-C2-C4-alkanoylcarbamyl, such as acetylcarbamoyl or N,N-di-C1-C4-alkylcarbamyl, such as N,N-dimethylcarbamyl or N,N-diethylcarbamyl.

The new compounds of formula I have valuable pharmacological properties, in particular a pronounced anticonvulsant effect, which can be shown, for example, in mice by means of a clear metrazole antagonism in - dose ranges from 30 to 300 mg/kg p.o., both in mice and rat by means of a pronounced protective effect against electroshock-triggered convulsions in dose ranges of approx. 1 to approx. 50, in most cases from approx. 1 to approx. 25 mg/kg p.o. Comparison experiments carried out with the following compounds prepared according to the invention: 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, I; 1-(o-Fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, II; 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, III; 1-(6-chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, IV; 1-(o-Fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, V; 1-(6-Chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4-carboxamide, VI; 1-(2,5-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, VII; with the structurally closest known compounds 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide, IX and 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4, 5-dicarboxamide, X according to EP-A1-114 347, as well as 1-(o-chlorobenzyl)-5-amino-1H-1,2,3-tr iazole-4-carboxylic acid e-piperidide, XI according to GB- PS-1511195 gave the values indicated in the following table for the effective dose ED50 (at 1 hour pre-application):

The compounds (I) to (VIII) produced according to the invention consequently differ from known, structurally analogous compounds (IX) to (XI) according to the state of the art by having a significantly stronger effect and are consequently excellently suitable for the treatment of convulsions of different genesis, for example for the treatment of epilepsy, and can be used as anticonvulsants, for example antiepileptically active substances in pharmaceuticals.

The invention primarily relates to the preparation of compounds of formula I, in which Ph means o-fluorophenyl or 2,6-difluorophenyl, alk stands for methylene, R 1 means hydrogen or unsubstituted carbamyl and R 2 is unsubstituted carbamyl.

The invention preferably relates to the preparation of compounds of formula I, in which Ph means 2,6-difluorophenyl, alk means methylene, R^ means hydrogen, C^-^-alkyl, such as methyl or a residue Rg>°g R2 DetYr carbamyl, N- C2~C5-alkanoylcarbamyl, such as acetylcarbamyl or N,N-di-C^-C4-alkylcarbamyl, such as dimethylcarbamyl.

The invention relates above all to the preparation of compounds of formula J, where Ph means o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluoro-phenyl, alk stands for methylene and 8^ and R2 means both carbamyl, further compounds of formula I in which Ph means 2,6-difluorophenyl, alk means methylene, R 1 means hydrogen or carbamyl and R 2 means carbamyl.

The process for producing the compound of formula I is based on methods known per se and is characterized by the fact that

a) amidates a compound of the formula in a known manner

wherein R'i means hydrogen, C 1 -C 4 alkyl or a group of

the formula -COOR3 and R'2 means a group -C00R3, whereby R3 is C^-C^-alkyl, or R'i is hydrogen or C^-C^alkyl and R'2 is halocarbonyl, or

b) reacts a compound of the formula

with a compound of the formula

which may possibly exist-in tautomeric form,

in which Ri means C1-C4-alkyl, Yj means hydroxy and Y2 means hydrogen or Rj means hydrogen, carbamyl or C1-C4-alkyl

and Y1 and Y2 together form an additional bond, whereby R2 in each case is carbamyl, or

c) reacts a compound of the formula

in which Z stands for reactively esterified hydroxy, with 1,2,3-triazole-4,5-dicarboxamide and, if desired, in the compound of formula I obtained according to a), b) or c) the unsubstituted carbamyl group R2 is acylated and possibly R! .' The transfer of the aforementioned groups R'2 and optionally R'^ to optionally C^-C^-alkylated carbamyl according to method variant a) takes place in the usual way by; ammonolysis, respectively aminolysis (reaction with ammonia or a Ci-C4 alkylamine).

In the case of the ammonolysis, respectively the aminolysis, one works, if necessary, in the presence of a condensing agent, preferably in an inert solvent. Condensing agents are basic condensation agents, above all ammonia, respectively amines used for the aminolysis in excess, starting from the carboxy present in the halide form, further alkali metal hydroxides or carbonates or tertiary: organic nitrogen bases, such as trilower alkylamines or tertiary heteroaromatic nitrogen bases, such as triethylamine or pyridine.

A particularly preferred embodiment of this method variant is characterized by reacting a compound of formula I', in which R'2 means a group -COOR3 and R'1 means hydrogen, C1-C4~alkyl or optionally a group

-COOR3, with an excess of ammonia or a di-Ci-C4-alkylamine, and, if desired, in a compound obtained by the process, where R2 and optionally R^ means unsubstituted carbamyl, Ci-C4-alkanoylates R2 and optionally R^ . The starting substances (I') can, as long as they are not known, be prepared in the usual way, for example by reacting an azide of the formula with a compound of the formula for example in an analogous way as described under method variant b). If necessary, primarily obtained esters or nitriles with the formula I', (R'2 = esterified carboxy or cyano) can be hydrolyzed to the corresponding acid under basic conditions, e.g. with the aid of aqueous-alcoholic caustic soda, or primarily or by hydrolysis of corresponding esters or nitriles obtained acids with the formula (I, R'2 = As starting materials with formula III for method variant b) for example compounds with the formula Rj-CEC-R2 are taken into consideration (Illa) and R1-C(=0)-CH2-R (IHb) (the compound Illb is the tautomeric form of the compound

(III; Yi = OH,

Y2 = H) ).

The reaction of the compounds with II and III takes place in the usual way, preferably in an inert solvent, if necessary in the presence of a condensing agent, and/or at an elevated temperature. Inert solvents are, for example, aromatic or aliphatic hydrocarbons, such as benzene or toluene, or ethers such as tertiary butoxymethane, tetrahydrofuran and dioxane.

Preferred embodiments of this method are, for example, the reaction of an azide of formula II with a compound of formula Illa in benzene or dioxane at 60-120°C, preferably boiling temperature.

The starting substances with formula III and partly with formula II are known. New starting substances with formula II can be obtained as analogous formation methods of the known ones, for example by reacting a compound of formula Ph-alk-Z IV, in which Z means a reactive, esterified hydroxy such as halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane-, ethanebenzene, p-toluene- or p-bromobenzenesulfonyloxy or fluorosulfonyloxy, with an alkali metal azide, e.g. with sodium azide, for example dimethylsulfoxide or dimethylformamide, or by reacting an alcohol of formula IV (Z = hydroxy) in the presence of triphenylphosphine, and an azidodicarboxylic acid ester, e.g. azidocarboxylic acid diethyl ester with nitric acid, for example in toluene.

In starting materials IV according to process variant c), reactive esterified hydroxy means, for example, halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy or optionally substituted benzenesulfonyloxy, such as methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy or fluorosulfonyloxy.

The reaction takes place in the usual way, for example in the presence of a basic condensing agent, or advantageously using 1H-1,2,3-triazole components as salt, if necessary under heating, preferably in a solvent or diluent. Basic condensing agents are, for example, salt-forming basic condensing agents with the 1H-1,2,3-triazo component, such as alkali metal alcoholates, e.g. sodium methanolate or sodium ethanolate, alkali metal or alkaline earth metal amides, e.g. sodium amide, or lithium isopropylamide. The transfer of the 1H-1,2,3-triazole components into one of their salts is preferably carried out in advance, e.g. by turnover with one of the aforementioned bases. Solvents for carrying out the reaction in the presence of an alcoholate are preferably corresponding alcohols and when carried out in the presence of amides, for example, aprotic, organic solvents, such as phosphoric acid lower alkyl amides, e.g. hexamethylphosphoric acid triamide, alkanoic acid amide, e.g. dimethylformamide, or dilave alkyl sulphoxides, e.g. dimethyl sulfoxide. According to the method, isomers formed as by-products are optionally separated from the desired compounds of formula I.

Starting substances f ene IV can, if they are not already known, be prepared in the usual way. Thus compounds of formula IV are obtained, for example, by esterifying a corresponding alcohol (IV, Z = hydroxy) in a reactive manner, e.g. using thionyl chloride, phosphorus tribromide, or a sulfonyl chloride.

As conversion reactions for compounds obtained by the method to other compounds of formula (I) special mention must be made of substitution reactions on N-unsubstituted or N-monolower alkyl substituted carbamyl groups B£ and/or R^ as well as the division of isomer mixtures obtained by the method.

Consequently, in compounds of formula (I) by treatment with a C1-C4-alkanoylating agent, N-unsubstituted carbamyl can be converted to N-C1-C4-alkanoylcarbamyl.

Ci-C4-alkanoylating agents are, for example, Ci-C4-alkancarboxylic acid anhydrides such as acetic anhydride or the mixed anhydride of formic and acetic acid, resp. Ci-C4-alkanecarboxylic acid chlorides such as acetyl chloride. The turnover with these takes place in the usual way if necessary in the presence of a base, e.g. of triethylamine or pyridine, resp. in the case of the reaction with acid anhydrides in the presence of mineral acid, e.g. of sulfuric acid.

Separation of isomer mixtures, such as, for example, mixtures of compounds of formula I, as well as isomers thereof formed according to the method, takes place in the usual way. They can, for example, be separated due to the different physical properties of the components by normal physical separation methods, e.g. by fractional crystallisation, chromatography procedures etc.1.

Procedures for the production of new starting materials, e.g. with formula I', which was especially developed for the production of the compounds with formula I, especially by starting material selection that leads to the compounds with formula I indicated initially as preferred, as well as their use as intermediates can likewise be an object of the invention.

The invention will be explained in more detail by some examples.

Example 1

73.5 g (0.25 mol) of 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 1000 ml of methanol. 250 g of ammonia are then pressed into the autoclave and left for 24 hours at 100°C. It is then cooled, the crystallized product is sucked off, washed with methanol, and recrystallized from dioxane/toluene. One obtains 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 197-199-C.

The starting material can e.g. is prepared in the following way: To a solution of 41.5 g (0.275 mol) of o-fluorobenzylazide in 50 ml of toluene heated to 90°C, a solution of 40 g (0.282 mol) of acetylene dicarboxylic acid dimethyl ester in 500 ml of toluene is added dropwise. After 5 additional hours at 90°C, the toluene is removed and, after cooling, the crystallized substances are filtered off with suction. After recrystallization from a mixture of diethyl ether and petroleum ether (1:1), l-(o-fluorobenzyl)-lH-l, 2,3-triazole-4,5-dicarboxylic acid dimethyl ester of mp 49-51°C.

Example 2

59 g (0.26 mol) of 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acids are heated with 300 ml of thlonyl chloride for 1 hour at reflux. Excess tlonyl chloride is then distilled off under vacuum, the remaining 1-(o-fluorobenzyl)-1H-1,2,3-trilazole-4-carboxylic acid chloride is dissolved in 500 ml of toluene and this solution is added dropwise at 5-10°C to 500 ml of a concentrated aqueous ammonia solution. The precipitated product is filtered off with suction, washed with water and recrystallized from ethanol. One thus obtains 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 220-222°C.

The starting material can e.g. produced in the following way:

A solution of 50 g (0.33 mol) o-fluorobenzylazide, 23.1 g (0.33 mol) propynecarboxylic acid and 400 ml toluene is stirred for 24 hours at 70°C. The precipitated product is filtered off after cooling to room temperature and washed first with toluene and then with diethyl ether. One thus obtains 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid of m.p. 151°C during decomposition.

Example 3

Analogous to that discussed in example 1, when starting from 2,6-difluorobenzyl azide and acetylenedicarboxylic acid dimethyl ether over 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester ( m.p. 62-65°C) give 1-(2,6-difluorobenzyl)-1H-1,2,3-trilazole-4,5-dicarboxamide of m.p. 203-2O5<*>C (from methanol). ;Example 4 ;Analogous to example 2, when starting from 2,6-difluorobenzylazide over 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid of m.p. 160-162°C with decomposition (from acetonitrile) obtain 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 273-24CC (from ethanol). ;Example 5 ;Analogously as described in examples 1-4, one can further prepare: 1-(2,3-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(2,4-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and 1-(2,5-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide. ;Example 6 ;In an analogous way as described in example 2, from l-(6-chloro-2-fluoro-benzyl)-lH-1,2,3-triazole-4-carboxylic acid, l-(6-chloro -2-fluoro-benzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 274-276°C (from glacial acetic acid). ;The starting material can e.g. is prepared as follows: A mixture of 98 g (0.678 mol) 6-chloro-2-fluorotoluene, 91.5 g (0.678 mol) sulfuryl chloride, and 0.2 g dibenzoyl peroxide is stirred for 3 hours at 100-110°C and is then distilled. 6-Chloro-2-fluoro-benzyl chloride is thus obtained, boiling point 15 = 78-82° C. To a suspension of 47 g (0.722 mol) of sodium azide in 400 ml of dimethylsulfoxide, 123 g (0.687 mol ) 6-chloro-2-fluoro-benzyl chloride. After stirring for 4 hours at room temperature, dilute with 1 liter of ice water and extract with cyclohexane. After the solvent has been distilled off, the residue is distilled. Thus, 6-chloro-2-fluoro-benzyl-azide is obtained, boiling point 15 <=> 99-100°C. 27.5 g (0.15 mol) of 6-chloro-2-fluoro-benzylazide and 10.5 g (0.15 mol) of propynecarboxylic acid in 300 ml of toluene are heated for 3 hours at 90°C. After cooling, the crystals are suctioned off and recrystallized from acetonitrile. One thus obtains 1-(6-chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4-carboxylic acid of m.p. 182°C during decomposition. ;Example 7 ;In an analogous way as discussed in example i, when starting from 6-chloro-2-fluoro-benzylazide and acetylenedicarboxylic acid dimethyl ester over l-(6-chloro-2-fluoro-benzyl)-lH-l, 2,3-trilazo-4,5-dlcarboxylic acid dlmethyl ester (m.p. 88-90°C) get 1-(6-chloro-2-fluoro-benzyl)-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 214-216'C (from glacial acetic acid). ;Example 8 ;Analogously as described in example 1, one wants from 2,5-difluorobenzylazide (boiling point 15 = 82-84°C) over 1-(2,5-difluoro-benzyl)-1H-1,2, 3-triazole-4,5-dicarboxylic acid dimethyl ester obtain 1-(2,5-difluorobenzyl )-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 191-192°C (from dioxane/toluene). ;Example 9 ;In an analogous way as in example 1, 2,4-difluorobenzylazide (boiling point 15 = 80-83°C) over 1-(2,4-difluorobenzyl)-1H-1,2,3 -triazole-4,5-dicarboxylic acid dimethyl ester of m.p. 75-76°C (from cyclohexane) obtain 1-(2,4-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 183-185°C (from dioxane/toluene). ;Example 10 ;Analogous to example 1, by reaction with dimethylamide, 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid (N,N-dimethyl )amide of m.p. 130-133°C (from tertiary butoxymethane). ;Example 11 ;Analogous to example 1, one will get 1-( 2,3-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 183-185°C (from acetic ester/benzene). ;Example 12 ;Analogous to example 2, from l-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, l-(2,6-difluorobenzyl)-5- methyl-1H-1,2,3-triazole-4-carboxamide of m.p. 208-210°C (from methanol). ;The starting material is prepared as follows: ;One dissolves 2.53 g (0.11 mol) of sodium in 60 ml of alcohol, then adds a mixture of 16.9 g (0.1 mol) of 2,6-difluorobenzylazide and 14.3 g (0.11 mol) of acetic acid ester in 60 ml of alcohol and heat to reflux for 18 hours. After adding 120 ml of sodium hydroxide solution, it is allowed to boil for a further 2 hours under reflux, diluted with 200 ml of water and acidified while cooling with hydrochloric acid to pH 1. The precipitated product is filtered off with suction, washed first with water, then with ether and dried. One thus obtains 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid of m.p. 166-167°C. ;Example 13 ;Analogous to example 1, from l-[l-(2,6-difluorophenyl)-ethyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester, l-[l-(2,6- difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxamide of m.p. 205-207°C (from methanol). ;The starting material is prepared as follows: ;By reducing 10.2 g (66 mmol) of 2,6-difluoroacetophenone with 2.5 g (65 mmol) of lithium aluminum hydride in ether, 1-(2,6-difluorophenyl)ethanol is obtained as a colorless oil . ;One dissolves 10 g (63 mmol) of 1-(2,6-difluorophenyl)ethanol in 150 ml of nitric acid solution (1.2 N in toluene), adds 22.8 g (200 mmol) of trifluoroacetic acid, and allows it to stand 24 hours at room temperature. After dilution with 300 ml of hexane, it is first washed with water, then with acid-free sodium bicarbonate solution, dried over sodium sulfate and the solvent is removed at 40-50°C under reduced pressure. The residue is dissolved in 1,100 ml of hexane, filtered through 50 g of silica gel and evaporated again. Thus, 1-(2,6-difluorophenyl)-ethyl azide is obtained as a colorless oil. 6.5 g (35 mmol) of 1-(2,6-difluorophenyl)ethylazide and 2.45 g (35 mmol) of propynecarboxylic acid in 50 ml of toluene are heated for 24 hours at 60-70°C. After cooling, it is extracted with 100 ml of n-sodium hydroxide solution, and after acidification with hydrochloric acid, 1-[1-(2,6-difluorophenylethyl)-1H-1,2,3-triazole-4-carboxylic acid of m.p. 135-138°C during decomposition. ; 7.1 g (26.6 mmol) of 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid is heated with 150 ml of ethanol and 1 ml of sulfuric acid for 10 hours during reflux. After working up, 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid ethyl ester of m.p. 118-121°C. ;Example 14 ;Analogous to example 1, from l-{2-[2-(2,6-difluorophenyl)-propyl]>-lH-1,2,3-triazole-4-carboxylic acid, l-{2-[ 2-(2,6-difluorophenyl)propyl]}-1H-1,2,3-triazole-4-carboxamide of m.p. 203-205°C (from methanol). ;The starting material is prepared as follows: ;To 28 g (150 mmol) of 2,6-difluorobenzoic acid ethyl ester in 200 ml of ether, slowly add 120 ml of a 3-molar solution of methylmagnesium chloride in tetrahydrofuran. After refluxing for 1 hour, working up with 105^-ig ammonium chloride solution yields 2-(2,6-difluorophenyl)-propan-2-ol (boiling point-^ = 74-76°C). 20.6 g (120 mmol) of 2-(2,6-difluorophenyl)-propan-2-ol are dissolved in 300 ml of nitric acid solution (IN in benzene) and mixed with 22.8 g (200 mmol) of trifluoroacetic acid. After 24 hours at room temperature, dilute with hexane, wash with water and then with acid-free sodium bicarbonate solution, dry with sodium sulfate, evaporate the solvent and distill the residue. This gives 2-(2,6-difluorophenyl)-2-azidopropane (boiling point = 85-87°C). 10 g (51 mmol) of 2-(2,6-difluorophenyl)-2-azido-propane are reacted with 3.6 g (51 mmol) of propynecarboxylic acid in 100 ml of toluene and worked up as described in example 13. One thus obtains l-{ 2-[2-(2,6-difluorophenyl)propyl]}-1H-1,2,3-triazole-4-carboxylic acid of m.p. 173° C during decomposition. ;After esterification of this acid with 50 ml ethanol and 0.5 ml conc. sulfuric acid, 1-{2-[2-(2,6-difluorophenyl)propyl])-1H-1,2,3-triazole-4-carboxylic acid is obtained as a pale yellow, viscous oil, which can be used without further purification for the reaction with ammonia. ;Example 15 ;Analogous example 1 is desired, starting from 2-(2,6-difluorophenyl)-2-azido-propane and acetylenedicarboxylic acid dimethyl ester over l-{2-[2-(2,6-difluorophenyl)propyl] }-lH-l,2,3-triazole-4,5-dicarboxylic acid dimethyl ester (m.p. 100-102°C) get l-{2-[2-(2,6-difluorophenyl)-propyl]>-lH-l ,2 , 3-1r iazole-4,5-dicarboxamide of m.p. 177-178°C (from acetic acid/hexane). ;Example 16 ;16.9 g (0.1 mol) of 2,6-difluorobenzylazide and 8.3 g (0.1 mol) of but-2-yne carboxamide are heated in 20 ml of dioxane for 16 hours at 100°C. After the evaporation of the dioxane, the desired isomers are separated by column chromatography. One thus obtains 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide of m.p. 208-210°C, (from methanol). ;Example 17 ;2.81 g (10 mmol) 1-(2,6-difluorophenyl)-1H-1,2,3-triazole-4,5-dicarboxamide, 20 ml of acetic anhydride and 2 drops of sulfuric acid, heated for 3 hours at 80°C. After cooling, stir with 100 ml of water for 1 hour at 20-25°C, filter off the precipitated product and wash with water. After recrystallization from 75 ml of methanol, 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-di(N-acetyl)carboxamide of m.p. 136-i38°C. ;Example 18 ;In an analogous way as in example 17, one also obtains 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-(N-acetyl)-carboxamide of m.p. 205-207°C (from dioxane-toluene). Example 19 1.4 g (12.5 mmol) of acetylene dicarboxylic acid diamide is dissolved at 60<*>C in 10 ml of dimethylsulfoxide. 1.69 g (10 mmol) of 2,6-difluorobenzylazide is added and it is allowed to stir for 16 hours at 80°C.

It is diluted with 25 ml of water, aspirated, stirred with 50 ml of water and allowed to stir for 30 minutes at 50-60° C, aspirated again, dried and recrystallized from dioxane/ethanol. One obtains 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide of m.p. 203-205°C.

Claims (5)

1. Analogous process for the production of therapeutically useful, fluorinated 1-(o-phenyl lower alkyl)-1H-1,2,3- triazole compounds of formula in which Ph means an i o-position with fluorine, and optionally i addition with a further halogen atom, substituted phenyl radical, alk means C1-C5-alkylidene, Rj_ means hydrogen, C-1-C4-alkyl or an unsubstituted or C1-C4-alkanoyl or C1-C4-alkyl substituted carbamyl group and R2 stands for an unsubstituted or C1-C4-alkanoyl or C1-C4-alkyl substituted carbamyl group, characterized in that one a) amidates a compound of the formula in a known manner wherein R'i means hydrogen, C1-C4-alkyl or a group, of the formula -C00R3 and R'2 means a group -C00R3, whereby R3 is C1-C5-alkyl, or R'^ is hydrogen or C1-C4- alkyl and, R'2 is halocarbonyl, or b) reacts a compound of the formula with a compound of the formula which may possibly exist in tautomeric form, in which Ri means C1-C4 alkyl, Y^ means hydroxy and Y2 means hydrogen or R^ means hydrogen, carbamyl or C1-C4 alkyl and Y1 and Y2 together form an additional bond, whereby R2 in each case is carbamyl, or c) reacts a compound of the formula in which Z stands for reactively esterified hydroxy, with 1,2,3-triazole-4,5-dicarboxamide and, if desired, in the compound of formula I obtained according to a), b) or c), the unsubstituted carbamyl group R2 and optionally Ride. 2. Analogous process according to claim 1 for the production of 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, characterized in that corresponding starting materials are used. 3. Analogous method according to claim 1 for the production of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, characterized in that corresponding starting materials are used. 4. Analogous method according to claim 1, for the production of 1-(2,5-difluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide, characterized in that corresponding starting materials are used. 5. Analogous method according to claim 1, for the production of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5-di(N-acetyl)carboxamide, characterized in that corresponding starting materials are used.