NO763569L - - Google Patents

Description

"Process for the preparation of triazole derivatives".

This invention relates to an analogous process for the preparation of 1,2,3-triazole derivatives which have sedative activity.

According to the invention, a triazole derivative with the formula is produced:

1 2 where R and R are independently selected from the group consisting of hydrogen atoms and carboxy-, phenyl-, alkyl-(C^-C^), amino-, 1-piperidinecarbonyl- and hydroxyalkyl- (C, - C.) radicals, or 12 14 R and R together mean a 1,3-butadienylene radical, so that together with the two carbon atoms in the triazole ring to which they are attached, they form a benzene radical, one of R 3 and R 4, together with the dotted circle , means two double bonds, and (a) when R 1 and R 2 are hydrogen atoms, R 3 is a radical selected from the group consisting of alkyl (C 1 -C 2 ); phenylalkyl (C 8 -C 2 ) wherein the alkyl substituent is a linear chain; phenylalkyl (C 8 -C 4 ) wherein the alkyl substituent is a branched chain; di-, tri- and tetrahalogen-substituted phenylalkyl (C7-C22) where the halogen substitution is on the phenyl ring; penta-halogen-substituted phenylalkyl (Cg - C12^ where the halogen substitution is on the phenyl ring; mono-halogen-substituted naphthylalkyl (C-^~C, ,) where the halogen substitution is on the naphthyl ring; ortho- or meta-monohalogen-substituted phenylalkyl (C_, - C^2) ; para-halo-substituted phenylalkyl (Cg - C^2); mono-, di- or trialkyl- (C^- C^) substituted phenylalkyl (C^- C^2) where the alkyl substitution is on the phenyl ring ;

ortho- or meta-mono-alkoxy-(C^-C^) substituted phenylalkyl wherein the alkyl substituent is (C^-C^); mono-, di- or trihaloalkyl- (C^-C^) substituted phenylalkyl (C7-C^2) where the haloalkyl group contains from 1 to 5 halogen atoms and is substituted on the phenyl ring;

cycloalkyl-(C 1 -C 8 )substituted alkyl (C 1 -C 8 ); mono-di- or tri-halo-substituted benzoylalkyl (C 8 -C 4 );

thienylalkyl (C 1 -C 4 ); mono-cyano-substituted phenylalkyl (C 1 -C 2 ) where the cyano substitution is on the phenyl ring; mono-nitro-substituted phenylalkyl (C7-C2) where the nitro group is substituted on the phenyl ring; mono- to hexa-halogen-substituted benzhydryl wherein the halogen substitution is on the phenyl ring; mono-, di- or tri-halogen substituted cinnamyl wherein the halogen substitution is on the phenyl ring; mono-, di- or tri-alkoxycarbonyl-^Cl~ C4^ substituted phenylalkyl (C7-C^2) where the alkoxycarbonyl substitution is on the phenyl ring; quinolylalkyl

(C^Q- c^_ c)) ; mono-, di- or tri-hydroxy-substituted phenylalkyl (C7-C-^) wherein the hydroxy substitution is on the phenyl ring; phenylalkenyl (C 8 -C 2 ); 3-indole alkyl

(Cg - C^4); mono-, di- or tri-amino-substituted phenylalkyl (C 1 -C 2 ) wherein the amino substitution is on the phenyl ring; mono-, di- or tri-halogen-substituted phenylalkyloxy (C7-C12) wherein the halogen substitution is on the phenyl ring; chlorophenoxyalkyl (C7-C12); chlorohydroxy-phenylalkyl (C 1 -C 2 ); mono-, di- or tri-halogen substituted phenoxy; mono-, di- or tri-halogen substituted benzoyl; and mono, di- or tri-hydroxy-substituted phenylalkyl (C7-C^2) where the hydroxy substitution

is on the alkyl chain; and

(b) when R"<*>" and R<2> are hydrogen atoms, R^ is a radical selected from the group consisting of phenylalkyl (C? - C^2); ortho-halo-substituted phenylalkyl (C7-C-j^ ' meta-chloro-substituted phenylalkyl (C7-C^2); para-bromo-substituted phenylalkyl (C7-C^2); di- or tri-halo-substituted phenylalkyl ( C7-C^2) where the halogen substitution is on the phenyl ring; mono-, di- or tri-haloalkyl-fc7-C^2) where the haloalkyl substitution is on the phenyl ring;

mono-, di- or tri-alkyl-(C 1 - CA ) substituted phenylalkyl (C 1 - C 2 ) wherein the alkyl substitution is on the phenyl ring; pyridylalkyl (C 1 -C 8 ); mono-, di- or tri-halogen substituted benzoylalkyl (Cg - C-^) where the halogen substituent is on the phenyl ring; and

(c) when R 1 and R 2 are independently selected from the group consisting of hydrogen atoms and carboxy-, phenyl-, alkyl-(C-, - CA), amino-, 1-p pyridinecarbonyl- and hydroxyalkyl-12

(C, - CA) radicals, provided that at least one of R and R is different from a hydrogen atom, R is a radical selected from the group consisting of alkyl (C 1 ); phenylalkyl (C 0 -C 10 ) wherein the alkyl substituent is branched; mono,

o 12

di- or tri-halo-substituted phenylalkyl (C7-C^2)

wherein the halogen substitution is on the phenyl ring; mono-, di- or tri-haloalkyl- (C^-CA) substituted phenylalkyl (C-, - c-|_q) where the haloalkyl group contains from 1 to 5 halogen atoms and is substituted on the phenyl ring;

and

(d) when R 1 and R 2 together mean a 1,3-butadienylene radical,

is one of R and R selected from the group consisting of phenylalkyl (C0-Clr.); and di-, tri- and tetra-substituted

o IO

phenylalkyl (C^- C^Q) where the halogen substitution is on the phenyl ring.

It will be noted that the compounds of formula I may contain at least one asymmetric carbon atom, especially when an alkyl chain

12 3 4

in R , R , R or R is branched. The racemic form of such a compound can therefore be split into two optically active forms. It should be understood that this invention includes the racemic form of a compound of formula I, and in addition any optically active enantiomeric form which has the useful properties of the compounds prepared according to the invention, as later defined, and it is generally known how to resolves a racemate into its optically active isomers and determines their biological properties.

It will also be understood that when R 3 in the above formula is a substituent, so that all valences on the nitrogen atom to which it is attached are saturated, the two double bonds will be arranged so that one is in the 2,3 position and the other in The 4.5 position. When, on the other hand, R<4> is a substituent, the double bonds will be in the 1,5 and 3,4 positions.

3

A particular meaning for R in group (a) above is one selected from the group consisting of hexyl, phenethyl, phenylpropyl, 1-phenethyl, dichlorobenzyl, trichlorobenzyl, 1-(dichlorophenyl)ethyl, chloronaphthylmethyl -, 1-(2-chlorophenyl)ethyl-, 2-iodobenzyl-, 2-fluorobenzyl-, 3-chlorobenzyl-, 2-chlorobenzyl-, 3-fluorobenzyl-, 2-bromobenzyl-, (2-chlorophenyl)propyl-, (2-chlorophenyl)pentyl-, 3-bromobenzyl-, 1-(2-chlorophenyl)propyl-, 1-(2-fluorophenyl)ethyl-, 1-(2-bromo-phenyl)ethyl-, 1-(2- chlorophenyl)-2-methylpropyl-, 1-(4-chlorophenyl)ethyl-, methylbenzyl-, 2-methoxybenzyl, trifluoromethylbenzyl-, 1-(trifluoromethylphenyl)ethyl-, cyclohexylmethyl-, fluorobenzoylmethyl-, fluorobenzoylethyl-, thienylmethyl -, cyanobenzyl, nitrobenzyl-, chlorobenzhydryl-, chlorocinnamyl-, methoxycarbonylbenzyl-, quinolylmethyl-, hydroxybenzyl-, 3-phenylprop-2-enyl-, 3-indolylethyl-, aminobenzyl-, chlorobenzyloxy-, chlorophenoxyethyl-, chlorohydroxybenzyl-, chlorophenoxy, fluorobenzoyl, chlorobenzoyl and 1-hydroxy-1-phenethyl radicals.

4

A particular meaning for R in group (b) above is one selected from the group consisting of phenethyl, 2-fluorobenzyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-bromobenzyl, dichlorobenzyl -, trifluoromethylbenzyl, methylbenzyl, pyridylmethyl, fluorobenzoylethyl and fluorobenzoylmethyl radicals.

1 2

A special meaning for R and R in group (c) above-

for, is one selected from the group consisting of hydrogen atoms and carboxy, phenyl, methyl, ethyl, amino, 1-piperidinecarbonyl and hydroxymethyl radicals, and a particular meaning for R 3 is one selected from the group consisting of hexyl, phenethyl, dichlorobenzyl, chlorobenzyl, 1-(chlorophenyl)ethyl, 1-(fluorophenyl)ethyl and trifluorobenzyl radicals.

3 4

A particular meaning for R or R in group (d) above is one selected from the group consisting of phenethyl, phenylpropyl and dichlorobenzyl radicals.

A special group of compounds are such in group

(a) above wherein R 3 is a radical selected from the group consisting of phenylalkenyl (C 8 -C 12 ); 3-indolealkyl (C 8 -C 1A ); mono-, di- or tri-amino-substituted phenylalkyl (C-, - C.^) where the amino substitution is on the phenyl ring: mono-, di- or tri-halogen-substituted phenylalkyloxy (C-, - C^2) where the halogen substitution is on the phenyl ring; mono-, di- or tri-halogen substituted phenoxy; and mono-, di- or tri-halogen substituted benzoyl;

and those in group (c) above in which at least one of R 1 and R 2 is an amino or 1-piperidinecarbonyl radical.

A preferred group of compounds are those where R<4>, together with the dotted circle, means two double bonds, R"*" is a hydrogen atom, and R 2 is a hydrogen atom or a methyl radical1.

A particularly preferred group of compounds are those where R 4 , together with the dotted circle, means two double bonds, R 1 is a hydrogen atom, R 2 is a hydrogen atom or a methyl radical and R 3 means a radical with the formula:

in which R 5 means a hydrogen atom or a methyl, ethyl or iso-propyl radical and R 5 means a 2-chloro-, 2-bromo-, 3-bromo-, 4-chloro-, 2,3-dichloro- , 2,5-dichloro or 2,6-dichloro substituent, but the compound 1-(4-chlorobenzyl)-1H-1,2,3-triazole is excluded.

Special compounds produced according to the invention are listed in the examples.

A preferred compound prepared according to the invention is one selected from the group consisting of 1-(2-chlorobenzyl)-1H-1,2,3-triazole, 1-[3-(2-chlorophenyl)propyl]-1H -1,2,3-triazole, 1-(3-bromobenzyl)-1H-1,2,3-triazole, 1-(2,4-dichlorobenzyl)-1H-1,2,3-triazole, 1-( 2-iodobenzyl)-1H-1,2,3-triazole, 1-(2,3,6-trichlorobenzyl)-1H-1,2,3-triazole, 1-(2,6-dichlorobenzyl)-1H-1 ,2,3-triazole, 1-(2,5-dichlorobenzyl)-1H-1,2,3-triazole, 1-(2-hydroxybenzyl)-1H-1,2,3-triazole, l-[1- (2,5-dichlorophenyl)ethyl]-1H-1,2,3-triazole, l-[ 1-(2,6-dichlorophenyl)ethyl]-1H-1,2,3-triazole, l-[l- (2-fluorophenyl)ethyl]-1H-1,2,3-triazole, l-[1-(2-bromophenyl)ethyl]-1H-1,2,3-triazole, 3-[2-(1H-1 ,2,3-triazol-1-yl)-ethyl]indole and 1-[1-(2-chlorophenyl)-2-methylpropyl]-1H-1,2,3-triazole.

A particularly preferred compound prepared according to the invention is 1-[1-(2-chlorophenyl)ethyl]-1H-1,2,3-triazole.

According to the invention, the triazole derivatives can be prepared by methods that are known per se for the production of chemically analogous compounds, for example by a method

12 3 4

where R , R , R and R have the meanings given above, and which are characterized by:

(1) for those compounds where R 1 and R 2 are both hydrogen atoms, decarboxylation of a compound with the formula:

7 8

where R and R are independently selected from the group consisting of hydrogen atoms and carboxy radicals,

wherein at least one of R 7 and R 8 is a carboxy radical;

(2) reaction of a triazole of the formula:

where the dotted circle means two double bonds, and the hydrogen atom is bound to any of the three nitrogen atoms, with a compound of the formula 9 9 3 R -X where R has the above meaning for R when R together with the dotted circle means two double bonds, and R 9 also has the meaning given above for R 4 , where R 3 together with the dotted circle means two double bonds, and X means a chlorine, bromine or iodine atom; (3) for those compounds where R 4 , together with the dashed 1 2 circle, means two double bonds and R and R are independently selected from hydrogen atoms and carboxy-, phenyl-, alkyl-, 1-priperidinecarbonyl- and hydroxyalkyl radicals, reaction of an acetylene compound with

the formula:

where R^° and R^ are independently selected from hydrogen atoms and carboxy-, phenyl-, alkyl- (C^-C^), 1-piperidinecarbonyl- and hydroxyalkyl- (C^-C^) radicals, with an azide with the formula: (4) for those compounds where R 3 means a mono-, di- or tri-aminophenylalkyl radical, reduction of the corresponding mono-, di- or tri-nitrophenylalkyl derivative; (5) for the compounds where R 3 means a mono-, di- or tri-halogen-substituted phenylalkyloxy- or mono-, di- or tri-halogen-substituted phenoxy radical1, oxidation of the corresponding mono-, di- or tri -halogen-substituted phenylalkyl- or mono-, di- or tri-halogen-substituted phenyl derivatives with a peracid; (6) for a compound where R 3 is a 2-hydroxy-2-phenethyl radical, reaction of an epoxide with the formula:

with a triazole of the above formula IV; (7) for the compounds where R"<*>" is a carboxy- or 1-.. 2 piperidinecarbonyl radical, R is an amino or alkyl radical, and R 4, together with the dotted circle, means two double bonds, reaction of a compound with the formula:

where R means an alkoxy- (C, - CA), hydroxy- or

13

1-piper idmyl radical, and R is an alkyl (C 1 - CA ) or cyano radical, with an azide of the above formula VI; or (8) for those compounds where R 3 is a mono-, di- or tri-hydroxy substituted phenylalkyl radical, hydrolysis of the alkoxy radical in a triazole derivative where the radical corresponding to txl R 3 is a mono-, di- or tri-hydroxycarbonylphenylalkyl radical, wherein the alkoxycarbonyl substituent has from 1 to 6 carbon atoms.

In method (1), the decarboxylation can be carried out

by heating at an elevated temperature, for example a temperature of 150-250°C.

In method (2), the transaction can be carried out conveniently

by reacting a sodium salt of a compound of the formula IV with a compound of the formula R -X in a diluent or solvent. The sodium salt can be prepared by reacting a compound of the formula IV with a base such as sodium methoxide, sodium ethoxide or sodium hydride. The diluent or solvent can be, for example, methanol, ethanol, ethanol/water or dimethylformamide. The turnover can be accelerated or completed

by the application of heat, for example by heating to the boiling point of the diluent or solvent.

In method (3), the reaction is conveniently carried out in a diluent or solvent, for example acetone or toluene, and it can be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or solvent.

In method (4), the reduction can be carried out with hydrogen in the presence of a catalyst, for example a palladium-on-charcoal catalyst. The hydrogen can, for example, be at atmospheric pressure or at a pressure of up to 5 atmospheres, and the reduction can be carried out in a diluent or solvent such as ethanol.

In method (5), the peracid can be, for example, peracetic acid, and the oxidation can be carried out, for example, by heating the reactants in a diluent or solvent, for example acetic acid, at a temperature up to the boiling point of the diluent or solvent.

In method (6), the reaction can be carried out in a diluent or solvent, for example xylene, and it can be accelerated or completed by the application of heat, for example by heating to the boiling point of the diluent or solvent.

In method (7), the reaction can conveniently be carried out using the sodium salt of the compound of formula VIII

in a diluent or solvent such as methanol or ethanol. The reaction can be accelerated or completed by heating to the boiling point of the diluent or solvent.

In method (8), the hydrolysis can be carried out with a base, for example sodium hydroxide, in a diluent or solvent such as water or ethanol/water, and it can be accelerated or completed by heating to the boiling point of the diluent or solvent.

Evaluation with laboratory animals shows that the present novel compounds have sedative activity when administered in a therapeutically effective amount. Efficacy and the required dose vary, as is usual in this industry, with the species being treated, the particular deficiencies being treated, the weight of the animals and the method of administration. The tranquilizers present also have a sedative effect in larger doses. The compounds produced according to the invention are administered in doses of from approx. 0.1 mg to 600 mg per kilo of body weight, 1 to 4 times per day. A preferred dose, with regard to optimal results and low administration rate, is from approx. 0.2 mg to 300 mg per kilo of body weight 1 to 4 times per day.

The sedative properties of the new compounds produced according to the invention can be determined by several different tests. Among the tests that can be used are, for example, the rotating rod test (FMA), the antioxotremorine test, the shock-induced aggression test and the amphetamine toxicity test on a collection of mice, which can be performed as follows:

Rotating stick test (FMA)

The response for each test drug was obtained using the inability of trained animals to walk on a rotating wooden rod (28 mm in diameter, 6 revolutions per minute)

for one minute. Six albino male mice of 18-22 g that had not fasted were used, per group, and the administration was by intraperitoneal injection.

The animals were tested at 0, 15, 30, 60, 90, 120, 150 and 180 minutes after the injection. The time to peak effect after the injection was determined, and the quantal response at this dose was used to plot the curve. ED^, ED5Q, and EDgg were determined graphically.

In the rotating-rod test, FMA means the ED^en. dose that results in 1% of the animals falling from the pole. FMA ED.-Q°9EDgg are doses that result in respectively 50 and 99% of the tested mice falling down from the rotating rod.

1-(2-Chlorobenzyl)-1H-1,2,3-triazole, when assessed by the rotating rod test, had an ED₂Q of 132 mg/kg body weight. 1-(2,3,6-trichlorobenzyl)-1H-1,2,3-triazole, when assessed by the same test, had an ED,_0 at 47 mg/kg body weight, and 1-(p-trifluoromethylbenzyl)- 1H-1,2,3-triazole had an EDgg of 148 mg/kg body weight.

The anti-tremorin test

A group of six female mice, 18-22 g, that had not fasted, were injected intraperitoneally with the drug under investigation. 10 minutes before the peak FMA effect time, a subcutaneous injection of 350 µg/kg of oxotremorine was administered. Tremors were assessed subjectively per animals on a scale of 0 to 3, and the total response of the whole group was compared with the response of a comparison group.

1-(3-Phenylpropyl)-1H-1,2,3-triazole, when assessed by the antioxotremorin test, provided 33% protection against tremors at FMA ED50 (100 mg/kg). In the same test, 1-(2-chlorobenzyl)-1H-1,2,3-triazole gave 50% protection against tremors at FMA ED5Q (148 mgAg)

and 1-(3-bromobenzyl)-1H-1,2,3-triazole gave 100% protection against tremors at FMA EDgg (200 mg Ag).

Shock-induced aggression test

Two non-fasted male albino mice (20-25 g) were placed for 2 minutes on an electrified grid. The number of seconds the mice were engaged in fighting activity was recorded and compared with the results for a comparison group. Five pairs of mice were used per dose of test drug.

1-(2,6-Dichlorobenzyl)-1H-1,2,3-triazole reduced, in the shock-induced aggression test by FMA ED^ (25 mgAg), the aggressive behavior by 62%. 2-[3-(4-fluorobenzoyl)propyl]-2H-1,2,3-triazole at FMA ED^ (100 mg/kg) reduced aggressive behavior by 6% and 1-(2-chlorocinnamyl)-1H-1 ,2,3-triazole at FMA ED5Q (100 mgAg) reduced aggressive behavior by 44%.

Amphetamine toxicity test in collection of mice

Groups of six non-fasted male albino mice (20-25 g) were injected intraperitoneally with the test drugs, and 60 minutes later, amphetamine sulfate, 50 mgAg, was administered intraperitoneally, and the animals were placed in subgroups of three in plexiglass bedroom. The number of animals that were alive after 4 hours was recorded. Each dose of the test drug was tested once on three different days, and the results were pooled. A comparison group that received only the mediator of the drug was tested in the same way.

In the amphetamine toxicity test, 1-(2-chlorocinnamyl)-1H-1,2,3-triazole produced a 58% reduction in deaths at FMA ED^q

(100 mgAg). In the same test, 1-(1-hexyl)-1H-1, 2, 3-triazole reduced deaths by 42% in FMA ED5Q(79 mgAg) -

In all the tests described above, soluble drugs were dissolved in distilled water and insoluble drugs were suspended in aqueous 0.5% carboxymethylcellulose or 0.25% agar. The injection volume was kept constant at 5 mlAg. The triazole derivatives produced according to the invention can thus be used in the form of a pharmaceutical mixture, and in particular one suitable for oral administration, together with a pharmaceutically acceptable diluent or a carrier.

Since the novel compounds prepared according to the invention are effective by oral administration, they can be compounded into any suitable oral dosage form, such as tablets, capsules, syrups, elixirs, suspensions or other solid or liquid forms that can be prepared by methods well known in the industry. Thus, the compounds in question can be mixed with a suitable diluent, such as lactose or kaolin, and encapsulated, or they can be combined with suitable binders and expanding agents and compressed into tablets. Furthermore, a liquid pharmaceutical agent can be obtained by dissolving, dispersing or suspending the compounds formulated according to the invention with a suitable aromatized liquid. The present novel and known compounds are also considered active by parenteral and rectal administration.

Examples of compositions for the formation of tablets, capsules, liquids, parenteral agents and suppositories containing the new and known compounds produced according to the present invention are described below. One skilled in the art will obviously recognize that the following compositions represent only one method of forming such pharmaceutical compositions and it will be obvious that the size of the tablets or capsules or the strength of the dosage form may be suitably varied to satisfy the particular requirements, such as the specified dosage amount. Each dose unit can, for example, conveniently contain from approx. 15 to 5,000 mg of active ingredient mixed with a diluting amount of a pharmaceutically acceptable carrier. Any of the well known suitable pharmaceutical carriers may be used to form acceptable dosage forms so as to provide an effective amount or therapeutically effective amount of the compound to be administered.

All the ingredients are combined, mixed and then pressed together into uneven lumps. The uneven lumps should then be ground to form granules that will pass through a 14 to 16 mesh sieve. The granules can then be re-compressed into tablets using a suitable compression mold to form tablets each weighing 280 mg.

Capsule containing 200 mg 1-(2-thienylmethyl)-1H-1,2,3-triazole

The ingredients are mixed so that the active ingredient is distributed evenly in all the lactose. The powder is packed in an empty gelatin capsule No. 1.

3

Suspension containing 50 mg per 5 cm with

2-(4-bromobenzyl)-2H-1,2,3-triazole

The tragacanth is hydrated with sufficient water to form a smooth paste and to this is added 2-(4-bromobenzyl)-2H-1,2,3-triazole, followed by amaranth which has previously been dissolved in water. The wild cherry syrup is then added and then distilled water is added up to a volume of 1000 ml.

Injectable composition containing 5 mg of 1-(-phenylpropyl)-1H-benzotriazole per ml. Suitable for intramuscular, intraperitoneal or subcutaneous injection

The above-mentioned ingredients are combined, made clear by filtration, filled into medicine glasses, closed and placed in an autoclave.

Suppository containing 200 mg

1-(3-Nitrobenzyl-1H-1,2,3-triazole

Cocoa butter is melted and 1-(3-nitrobenzyl)-1H-1,2,3-triazole hydrochloride is dispersed in the melted mass and it is stirred until smooth. The resulting molten mass is poured into suppository form and quenched. Suppositories are removed from the mold and packed.

The invention is illustrated, but not limited, by the following examples:

Example 1

17 g (0.062 mol) 1-(3-phenylpropyl)-4,5-dicarboxy-1H-1,2,3-triazole gave on heating to 200-225°C and distillation under reduced pressure of approx. 0.1 mm Hg, 1-(3-phenylpropyl)-1H-1,2,3-triazole. The product distilled over at 128-129°C/0.15 mm Hg as a colorless liquid. This liquid immediately changed to a solid state on cooling, yielding a white solid, m.p. 65-66°C.

The 1-(3-phenylpropyl)-4,5-dicarboxy-1H-1,2,3-triazole used as starting material can be prepared as follows: A two liter three-necked flask was fitted with a mechanical stirrer and reflux condenser . To a stirred suspension of 65 g (1.0 mol) sodium azide in a mixture of one liter of 95% vol/vol ethanol and 25 ml water, 200 g (1.0 mol) - phenylpropyl bromide. The reaction mixture was heated under reflux for 24 hours. A 250 mL portion of the reaction mixture was evaporated to dryness by stripping the solvent at 45°C under aspirator vacuum. The product, 27 g of -phenylpropyl azide as a yellow liquid, was immediately used in the next step. A 500 ml three-necked flask was fitted with a mechanical stirrer, addition funnel, thermometer and reflux condenser. To a stirred solution of 19.1 g (0.167 mol) of acetylene dicarboxylic acid in 60 ml of acetone, 27 g (0.167 mol) of phenylpropyl azide in 25 ml of acetone were added dropwise. After 15 ml of the azide solution was added to the reaction mixture, the temperature of the reaction mixture was raised to 55°C and the remainder of the azide was added within 25 minutes. • The reaction mixture was evaporated to dryness by solvent stripping at 45°C under aspirator vacuum. The product, 1-(3-phenylpropyl)-4,5-dicarboxy-1H-1,2,3-triazole, was a pale yellow solid, m.p. 117-120°C. Recrystallization from water gave a white solid, m.p. 128-129°C.

Example 2

A solution of 31.8 g (0.25 mol) of impure n-hexyl-

azide in 200 ml of acetone was added dropwise to a stirred solution of 28.52 g (0.25 mol) of acetylene dicarboxylic acid in 200 ml of acetone at reflux temperature. The reaction mixture was stirred and heated under reflux for 24 hours. The reaction mixture was evaporated to dryness under aspirator vacuum at 40°C. The remaining yellow oil was basified with 200 mL of 10% w/v aqueous sodium hydroxide while cooling in an ice bath. This solution was extracted with diethyl ether. The aqueous layer was acidified with 75 ml of concentrated hydrochloric acid. An impure white solid, 9.5 grams, m.p. 90-91°C, was obtained. This solid, 1-n-hexyl-4,5-dicarboxy-1H-1,2,3-triazole, was decarboxylated by heating in an oil bath at 210-220°C. The remaining oil was distilled under reduced pressure to give a colorless liquid boiling at 134-135°C/3.8 mm Hg, which was identified as 1-(1-hexyl)-1H-1,2,3-triazole .

Example 3

10.3 g (0.09 mol) of acetylene dicarboxylic acid was added to 75 ml of acetone. 19.0 g (0.09 mol) of 2,5-dichlorobenzyl azide dissolved in 70 ml of acetone was added dropwise to this solution under reflux. The reaction mixture was refluxed overnight and then evaporated to dryness under aspirator vacuum at 40°C. The remaining solid was washed with diethyl ether to remove unreacted starting materials. The solid was filtered to give 21.3 g of crude material. The crude product was recrystallized from a 50:50 v/v 95% v/v ethanol/water mixture to give a white solid, 1-(2,5-dichlorobenzyl)-4,5-dicarboxy- 1H-1,2,3-triazole hydrate, m.p. 179-182°C.

Example 4

To a stirred solution of 7.6 g (0.33 mol) of sodium metal reacted in 150 ml of methanol, 22.7 g (0.33 mol) of 1H-1,2,3-triazole were added in one portion. 2-Chloromethylthiophene, 44 g (0.33 mol), was added dropwise at 5-10°C using an ice bath for cooling. When the addition of the halide was complete and the ice bath was removed, the reaction temperature gradually rose to 39°C and then fell to room temperature. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C to give a yellow liquid as residue. Low boiling impurities were removed by vacuum distillation of the yellow liquid and the pot residue was chromatographed on a silica gel G column. The fractions were eluted with benzene.

Evaporation of the solvent gave a brownish solid. Vacuum sublimation with heat gave 1-(2-thienylmethyl)-1H-1,2,3-triazole, m.p. 55-57.5°C.

Example 5

To a stirred solution of 7.1 g (0.13 mol) of sodium methoxide in 50 ml of methanol, 9.1 g (0.13 mol) of 1H-1,2,3-triazole was added in one portion. 3-Methylbenzyl chloride, 19.0 g (0.13 mol), was added in one portion to this solution. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a sintered glass funnel to remove sodium chloride. - The filtrate was evaporated to dryness under aspirator vacuum at 40°C. The residue was distilled under reduced pressure to remove low-boiling fractions. The vessel residue was triturated with methylene chloride and solids were filtered off. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of benzene-petroleum ether (b.p. 60-110°C). The solid was filtered, washed with petroleum ether and dried to give 1-(3-methylbenzyl)-1H-1,2,3-triazole, m.p. 66.5-67°C.

Example 6

To a stirred solution of 6.9 g (0.3 mol) of sodium metal reacted in 150 ml of methanol, 20.7 g (0.3 mol) of 1H-1,2,3-triazole was added in one portion. 3-Nitrobenzyl chloride, 56.6 g (0.3 mol), was added to this solution in one portion at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then filtered through a sintered glass funnel to remove sodium chloride, and the filtrate was then evaporated to dryness under aspirator vacuum at 40°C. The residue was extracted with chloroform and the chloroform layer was washed twice with water. The organic layer was dried over Na 2 SOA, filtered, and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether, filtered and washed with hexane. The solid was sublimed at 130-135°C/o.1 mm Hg and the first sublimate was washed away until the solid began to sublimate. The sublimed solid was recrystallized from 25 mL of boiling methanol to give a pale yellow solid, m.p. 97-97.5°C, identified as 1-(3-nitrobenzyl)-1H-1,2,3-triazole.

Example 7

To a stirred solution of 1.9 g (0.08 mol) of sodium metal dissolved in 60 ml of methanol, 5.7 g (0.08 mol) of 1H-1,2,3- triazole. The reaction mixture was cooled to room temperature and 19.5 g (0.08 mol) of 1-(2-chlorophenyl)ethyl chloride was gradually added. Diethyl ether (10 mL) was then added to help dissolve the halide. The reaction mixture was stirred at room temperature for 72 hours, and then the reaction mixture was filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C. The residue was extracted with methylene chloride and a further amount of sodium chloride was filtered off. The filtrate was evaporated to dryness and the remaining oil was distilled off under reduced pressure. A yellow liquid distilling over at 40-43°C (0.4 mm Hg) was column chromatographed on a silica gel G column, and the fractions were eluted with benzene and benzene diethyl ether. An almost pure fraction was rechromatographed on a silica gel G column and eluted with diethyl ether. A pale yellow liquid, identified as 1-[(2-chlorophenyl)ethyl]-1H-1,2,3-triazole, was obtained as product.

Analysis calculated for Cl0H10N3Cl (m.v. 207.6):

C, 57.84%; H, 4.85%; N, 20.23%; Cl, 17.07%. Found: C, 57.62%;

H, 4.7 2%; N, 19.88%; Cl, 17.34%.

Example 8

To a stirred solution of 1.8 g (0.079 mol) of sodium metal reacted in 25 ml of methanol, 5.4 g (0.079 mol) of 1H-1,2,3-triazole was added in one portion. α-(2-chlorophenyl)benzyl chloride,

18.7 g (0.079 mol), was added in one portion to this solution. Diethyl ether (10 mL) and benzene (10 mL) were added to assist

to dissolve the halide. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C. The residue was triturated with chloroform and the solid was filtered off. The filtrate was evaporated to dryness and the remaining liquid was vacuum distilled to remove low boiling impurities. The vessel residue was dry column chromatographed on a silica gel G column (1.25 x 38 cm) and the fractions were eluted with benzene. A light brown solid, m.p. 94-96°C, was obtained as product, and identified

as 1-[α-(2-chlorophenyl)benzyl]-1H-1,2,3-triazole.

Example 9

To a stirred solution of 3.4 g (0.15 mol) of sodium metal reacted in 150 ml of methanol, 10.4 g (0.15 mol) of 1H-1,2,3-triazole was added in one portion. 3,4-Dichlorobenzyl chloride, 29.3 g (0.15 mol), was added in one portion. The reaction mixture was stirred at room temperature for 24 hours and then filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C to give a dark viscous liquid. This material was extracted with methylene chloride, and a further amount of sodium chloride was filtered off. This filtrate was evaporated to dryness and the remaining liquid partially converted to a solid state. The solid was filtered off and washed with diethyl ether. This white solid was vacuum sublimed by heating and then chromatographed on a silica gel G column, the fractions being eluted with methanol diethyl ether (5:95 v/v). 1-(3,4-dichlorobenzyl)-1H-1,2,3-triazole, m.p. 85-87°C, was thus obtained.

Example 10

To a stirred solution of 3.4 g (0.15 mol) of sodium metal reacted in 175 ml of methanol, 10.4 g (0.15 mol) of 1H-1,2,3-triazole was added in one portion. This solution was stirred for 15 minutes and then cooled to 10°C. o-chlorocinnamyl chloride, 28.06 g (0.15 mol), was then added in one portion. A slurry was immediately formed. The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was then filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C to give a yellow liquid with some solids. This material was washed with water and extracted with chloroform. The organic layer was cooled with water, separated and dried over anhydrous MgSOA. Magnesium sulfate was removed by filtration and the filtrate was evaporated to dryness to give a yellow liquid. Low-boiling impurities were distilled off under reduced pressure and the pot residue was dissolved in 50 ml of diethyl ether. By adding 50 ml of hexane to the ethereal solution, a full solid was obtained. This solid was vacuum sublimed by heating, then chromatographed on a silica gel G column and the fractions eluted with ether. The nearly pure fractions were evaporated to dryness to give a pale yellow solid. This solid was resublimated under vacuum to give 1-(2-chlorocinnamyl)-1H-1,2,3-triazole, m.p. 37-38°C.

Example 11

To a stirred solution of 3.4 g (0.15 mol) of sodium metal reacted in 100 ml of methanol, 10.4 g (0.15 mol) of 1H-1,2,3-triazole was added in one portion. This solution was stirred for 10 minutes, and then 33.3 g (0.15 mol) of 8-bromomethylquinoline was gradually added in one portion. Additional methanol, 100 mL, was added to aid in dissolution. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into 250 ml of water and the organic material was extracted with 250 ml of chloroform. The chloroform layer was washed five times with water to remove sodium bromide. The organic layer was dried over MgSO 4 , filtered and the chloroform was stripped off under aspirator vacuum at 40 C. The remaining liquid, which solidified on cooling to room temperature, was triturated with ether and the solid was filtered off. By vacuum sublimation with heating, but obtained 8-(1H-1,2,3-triazol-1-ylmethyl)-quinoline, m.p. 72-75°C.

Example 12

To a stirred solution of 3.4 g (0.15 mol) of sodium metal reacted in 125 ml of methanol, 10.4 g (0.15 mol) of 1H-1,2,3-triazine was added in one portion. 2-methoxycarbonylbenzyl bromide,

34.4 g (0.15 mol), was added gradually to this solution at room temperature. After the addition was complete, the temperature was gradually raised to 50°C and a water bath was used. The reaction mixture was stirred at room temperature for .24 hours. The reaction mixture was then filtered through a sintered glass funnel to remove sodium bromide, and the filtrate was extracted with chloroform and washed four times with equal volumes of water. The chloroform layer was dried over MgSOA, filtered and the filtrate was evaporated to dryness under aspirator vacuum at 40°C. The remaining liquid, when triturated with diethyl ether, gave a white solid. The solid was washed with diethyl ether and dried to give 1-(2-methoxycarbonylbenzyl)-1H-1,2,3-triazole, m.p. 84-85°C.

Example 13

To a stirred solution of 2.1 g (0.09 mol) of sodium metal reacted in 100 ml of methanol, 6.1 g (0.09 mol) of 1H-1,2,3-triazole was added in one portion. 2-Iodobenzyl bromide, 26.4 g (0.09 mol), was added gradually to this solution at room temperature. Methanol

(100 mL) was added to aid in the dissolution of the halide. The reaction mixture was stirred at room temperature for 24 hours and then the reaction mixture was evaporated to dryness under aspirator vacuum at 40°C. The residue was extracted with chloroform and sodium bromide was filtered off. The filtrate was dried over MgSO 4 and chloroform was stripped off under aspirator vacuum at 40°C.

The remaining oil was extracted with diethyl ether and the ether layer was decanted. A solid precipitated when a small amount of hexane was added to the ethereal solution. This yellow solid was sublimed under vacuum to give 1-(2-iodobenzyl)-1H-1,2,3-triazole, m.p. 62.5-63.5°C.

Example 14

To a stirred solution of sodium methoxide, 23.5 g (0.435 mol), in 150 ml of methanol, 15.0 g (0.217 mol) of 1H-1,2,3-triazole was added in one portion. When the mixture had cooled to room temperature, 2-chloromethylpyridine hydrochloride, 35.7 g (0.217 mol), was added in one portion and the mixture was stirred overnight. The reaction mixture was filtered through a sintered glass funnel to remove sodium chloride. The filtrate was evaporated to dryness under aspirator vacuum at 40°C and extracted with chloroform. The organic layer was washed twice with water, dried over Na 2 SO 4 and filtered. The filtrate was evaporated to dryness. The residue was dry column chromatographed on a 60 x 3 cm column of dry column grade silica gel-G, and the fractions were eluted with diethyl ether.

The fractions containing the 2-substituted isomer [detected by thin-layer chromatography (TLC) silica gel GF/ether, Rf 0.65-0.7] were combined and distilled at 63-66°c/0.1 mm Hg for to give 2-(2-pyridylmethyl)-2H-1,2,3-triazole.

Example 15

To a stirred solution of sodium methoxide, 12.7 g

(0.217 mol), in 100 ml of methanol 1H-1,2,3-triazole, 15.0 g (0.217 mol) was added in one portion. ^-Chloro-p-fluorobutyrophenone, 43.4 g (0.217 mol), was added in one portion at room temperature. The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a sintered glass funnel and the filtrate was evaporated to dryness under aspirator vacuum at 40°C. The residue was chromatographed on a 60 x 3.8 cm column of dry-column-grade silica gel-G, and the fractions were eluted with diethyl ether,

and ether-methanol (75:25 v/v). The faction that contained

1-substituted isomer (detected by TLC silica gel GF/ether, R f 0.25), was vacuum sublimed under reduced pressure. The product, 1-[3-(p-fluorobenzoyl)propyl]-1H-1,2,3-triazole, m.p. 68-69.5°C, was obtained.

The fractions containing the 2-substituted isomer (detected by TLC silica gel GF/ether, Rf 0.5) were again chromatographed on an identical column with benzene as eluent.

The fractions containing the 2-substituted isomer (TLC detection) were sublimed at 80-100°C/0.1 mm Hg. The sublimate became

washed off and discarded until TLC showed that almost pure 2-substituted isomer had sublimed. This material was resublimated at 75-80°C/ 0.1 mm Hg to give a white solid, m.p. 46-48°C, identified as 2-[3-(p-fluorobenzoyl)propyl]-2H-1,2,3-triazole.

Example 16

To a stirred solution of 2.3 g (0.10 mol) of sodium metal reacted in 60 ml of methanol, 6.9 g (0.10 mol) of 1H-1,2,3-triazole were added in one portion. 2-trifluoromethylbenzyl bromide, 25.0 g (0.10 mol), was gradually added to this solution at room temperature. The reaction mixture was stirred at room temperature for 24 hours, then filtered through a sintered glass funnel to preferably sodium bromide. The filtrate was evaporated to dryness under aspirator vacuum at 40°C and the residue was triturated with chloroform and the solid was filtered off. The filtrate was evaporated to dryness and the remaining oil was distilled under reduced pressure. Fractions distilling over at 34-66°C/0.15 mm Hg were combined and dry column chromatographed on a silica gel-G column eluting with hexane and 50:50 v/v hexanediethyl ether in that order. A pale yellow liquid, identified as 2-(2-trifluoromethylbenzyl)-2H-1,2,3-triazole, was obtained from the diethyl ether-hexane eluate.

Analysis calculated for C,^HQN_F_ (m.v. 227.2):

IO o j j

C, 52.87% J H, 3.55%; N, 18.49%; F, 25.09%. Found: C, 52.82%;

H, 3.79%; N, 18.29%; F, 24.84%.

Example 17

To a stirred solution of 28 g (0.50 mol) of sodium methoxide in 300 ml of methanol, 59.5 g (0.50 mol) of 1H-benzotriazole was added in one portion. Phenethyl bromide (92.5 g, 0.5 mol) was added in one portion to the reaction mixture. The reaction mixture was then stirred and heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and the solid was filtered off. The crude product was washed with 200 ml of water to remove sodium bromide. The product, 2-phenethylbenzotriazole, gave on recrystallization from methanol a white solid, m.p. 77-78°C.

The original filtrate (methanol solution) was concentrated to 100 ml and filtered. The filtrate was evaporated to dryness by solvent stripping at 50°C under aspirator vacuum. The remaining material was distilled under reduced pressure at 120-122°C and 0.10 mm Hg. The distilled product was chromatographed on a silica gel G column eluting with methylene chloride-diethyl ether (90:10 v/v) to give 1-phenethylbenzotriazole, m.p. 35-36°C.

Example 18

To a stirred solution of 2.8 g (0.12 mol) of sodium metal reacted in 75 ml of methanol, 14.3 g (0.12 mol) of 1H-benzotriazole were added at slightly higher than room temperature. 2,6-Dichlorobenzyl chloride, 23.5 g (0.12 mol), was added at 40°C. The reaction mixture was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature and the solid was filtered off. This solid was chromatographed on a silica gel G column eluting with chloroform to give 1-(2,6-dichlorobenzyl)benzotriazole, m.p. 133-135°C.

Example 19

o-chlorobenzyl azide, 35.1 g (0.21 mol), and 3-hexyne, 17.2

g (0.21 mol), was stirred and heated under reflux for 5 days in 125 ml of toluene. The solvent and unreacted 3-hexyne were distilled off by heating and exhaust vacuum. The residue was fractionated to give two fractions. The first fraction, b.p. 62-64°c/ 0.3-0.35 mm Hg, was identified by infrared spectrum as the starting azide. The second fraction, b.p. 167 -171°c/0.3-035 mm Hg, was redistilled through a 15 cm Vigreaux column at 147-148 C/0.25 mm Hg to give a pale yellow liquid.A portion of the distillate was dissolved in 100 ml of diethyl ether , and HCl gas was bubbled into the solution until stripping was complete. The solid was filtered, washed with diethyl ether, and air-dried to give a pale yellow solid. This solid was recrystallized from 50 mL of acetone to give a white solid, which was suspended in H 2 O, basified with Na 2 CO 3 to about pH 10 and extracted with chloroform. The organic layer was washed with H 2 O, dried over MgSO 4 and flash evaporated. The residue was vacuum dried to give a

slightly darkened colorless liquid, which was identified as 1-(2-chlorobenzyl)-4 r5 -diethyl-LH-1,2,3-triazole,

Analysis calculated for ci3Hi5<N>3cl (now.249.7):

C, 62.52%; H, 6.46%; N, 16.82%. Found: C, 62.54; H, 6.55%. Example 20

o-chlorobenzyl azide, 50.3 g (0.3 mol), and but-2-yne-1,4-diol, 25.8 g (0.3 mol), were stirred and heated under reflux for 24 hours in 150 ml of toluene. The solvent was distilled off by aspirator vacuum and the residue was triturated with hexane to effect transition to solid form. The solid was filtered and air-dried. The dry solid was dissolved in 300 ml of methanol and boiled for 1/2 hour with decolorizing carbon (3 g). The mixture was cooled and poured directly onto a 15 x 3.8 cm column of activated silica gel-<3 and was eluted with an additional 300 mL of methanol. The volume was reduced to 150 ml and 600 ml of diethyl ether was added and the mixture was cooled in a dry ice/acetone bath with stirring to cause solidification. The solid was cold-filtered, washed with diethyl ether, then with hexane and then air-dried. The solid was recrystallized twice from 60 ml of acetone. This solid was dissolved in 150 ml of acetone, boiled with decolorizing carbon (0-g) and filtered through diatomaceous earth. The filtrate was concentrated to 60 ml and cooled. The crystallized product was filtered, washed with diethyl ether and dried to give 1-(2-chlorobenzyl)-4,5-bis(hydroxymethyl)-1H-1,2,3-triazole, m.p. 92.5-93°C.

Example 21

Phenyl-acetylene, 36.6 g (0.36 mol), and o-chlorobenzylazide, 30.0 g (0.18 mol), in 175 ml of toluene were stirred and heated under reflux for 24 hours. The reaction mixture was cooled in a dry ice-acetone bath and was cold-filtered to remove most of the 4-phenyl isomer. The filtrate was evaporated to dryness under aspirator vacuum at 40°C and the residue was vacuum distilled. The fraction boiling at 173-183°C/0.1 mm Hg solidified on cooling. This solid was recrystallized from 300 mL of petroleum ether (b.p. 60-110°C) to give a white solid, mp 77-79°C, identified as 1-(2-chlorobenzyl)-5-phenyl-1H- 1,2,3-triazole.

The procedures described in Examples 1 [Procedure (1)], 4 [Procedure (2)], 17 [Example 60] or 19 [Procedure (3)] were repeated using appropriate starting materials, and the compounds listed in the the following examples 22-64 in Tables I, II and III, were obtained:

TABLES I, II, III

Footnotes

1. Distillation.

2. Recrystallization from ethanol.

3. Recrystallization from cyclohexane.

4. Sublimation.

5. Chromatography on silicon dioxide using benzene/ether.

6. Chromatography on silicon dioxide using ether.

7. Calculated for C13<H>16N3Cl: C, 62.52%; H, 6.41%; N, 16.83%;

Cl, 14.19%. Found: C, 62.39%; H, 6.41%; N, 16.84%;

Cl, 14.16%.

8. Sublimation of solid from ether/hexane.

9. Sublimation of solid matter from ether.

10. Chromatography on silicon dioxide using benzene. 11. Chromatography on silicon dioxide using cyclohexane/ether. 12. Chromatography on silicon dioxide using methanol. 13. Chromatography on silicon dioxide using methylene chloride.

14. Recrystallization from petroleum ether.

15. Recrystallization from ethanol/water.

16. Recrystallization from ethanol.

Example 65

The procedure described in the first part of Example 1 was repeated using the appropriate starting material, and the decarboxylation was carried out at 160-175°C, and 1-(1-phenethyl)-1H-1,2,3-triazole was obtained as a white solid, m.p. 48-50°C.

Example 66

The procedure described in example 20 was repeated,

using 1-(2-chlorophenyl)ethyl azide and but-2-yne as starting materials, and one obtained 1-[1-(2-chlorophenyl)ethyl]-4,5-dimethyl-1H-1,.2 , 3-triazole, m.p. 79-80°C.

Example 67

The procedure described in example 20 was repeated,

using 1-(2-chlorophenyl)ethyl azide and hex-3-yne as starting materials, and 1-[1-(2-chlorophenyl)ethyl]-4,5-diethyl-1H-1,2 was obtained, 3-triazole as a yellow liquid with a refractive index of 1.54321 at 20°C.

Example 68

The procedure described in example 20 was repeated,

using 1-phenylethyl azide and hex-3-yne as starting materials, and 1-(1-phenylethyl)-4,5-diethyl-1H-1,2,3-triazole was obtained, m.p. 78-79°C.

Example 69

To a suspension of 30.5 g (0.7 mol, 57% w/w in oil dispersion) of sodium hydride in 400 ml of diethyl ether, 6 ml of diethyl ether was slowly added. Then 50 g (0.7 mol) of 1H-1,2,3-triazole was added dropwise, whereby the reaction mixture was maintained at reflux. The reaction mixture was stirred for 1 hour at room temperature, a further 200 ml of diethyl ether was added and then it was stirred under reflux for three hours. The reaction mixture was cooled to room temperature and 2 ml of ethanol was carefully added. 100 ml of diethyl ether was added and the solution was filtered and the solid was washed with 200 ml of hexane and dried under vacuum. The sodium salt of 1H-1,2,3-triazole was used without further purification.

31.4 g (0, 15 mol) α-methyl-2,5-dichlorobenzyl chloride. The reaction mixture' was heated under reflux for 24 hours and then cooled to room temperature. The mixture was decanted from a gummy material and the liquid was diluted with 150 ml of water and extracted with 150 ml of chloroform, the layer was washed twice with water and dried over MgSOA. After the desiccant was filtered off, and the chloroform removed under aspirator vacuum, the residue was dry column chromatographed on a silica gel G column. Hexane and then diethyl ether, in that order, were used as eluents,

and 1-[1-(2,5-dichlorophenyl)ethyl]-1H-1,2,3-triazole was obtained as a white solid, m.p. 52.5-53.5°C.

The procedure described in Example 69 was repeated using suitable starting materials, and the compounds listed in the following Examples 70 to 74 in Table IV were obtained.

TABLE IV

Footnotes

1. Diethylene glycol dimethyl ether was used as solvent. 2. The product purified by chromatography on silicon dioxide with ether. Calculated for Ci:LH12ClN3: C, 59.60%; H, 5.46%; N, 18.95%;

Cl, 15.99%. Found: C, 59.40%; H, 5.69%; N, 18.89%;

Cl, 15.87%.

Example 75

Propiolic acid, 39 mL (0.63 mol), was stirred and heated to reflux in 600 mL of acetone. 1-(2-Chlorophenyl)ethyl azide, 114.3 g (0.63 mol), was added dropwise over 20 minutes. The reaction mixture was stirred and heated under reflux for 24 hours and then evaporated to dryness under aspirator vacuum at 40°C. The residue was cooled and triturated with 300 ml of a 1:4 v/v mixture of ether and hexane to give a white solid. Recrystallization from ethyl acetate gave 1-(2-chlorophenyl)ethyl-4-carboxy-1H-1,2,3-triazole, m.p. 150°C (with cleavage). 20 g (0.08 mol) of 1-[1-(2-chlorophenyl)ethyl-4-carboxy-1H-1,2,3-triazole was placed in a 250 ml round bottom flask and heated in an oil bath (160-180°C) until the evolution of C02~ gas had ceased. The residue was cooled and dissolved in 200 ml of 20% w/v HCl and washed twice with 200 ml of methylene chloride. The aqueous layer was neutralized with granular Na 2 CO 3 and extracted three times with diethyl ether. The organic layer was dried over MgSOA and evaporated to give an amber liquid. The product, 1-(2-chlorophenyl)ethyl-1H-1,2,3-triazole, distilled at 142-144°c/0.6 mm as a pale yellow liquid.

The 1-(2-chlorophenyl)ethyl azide used as starting material can be prepared as follows:

To a stirred solution of 81.5 g (1.3 mol) sodium azide

in 600 ml of ethanol-water (1:1 volume/volume) 113.5 (0.65 mol) of 1-(2-chlorophenyl)ethyl chloride was added in one portion. The mixture was heated under reflux for 24 hours. About. half of the ethanol was first removed under aspirator vacuum, and then the mixture was extracted twice with 300 ml of diethyl ether. The ether layer was washed with water and dried over anhydrous MgSO 4 . The desiccant was filtered off and the diethyl ether was removed under aspirator vacuum. The 1(2-chlorophenyl)ethyl azide obtained as a residue was used immediately.

The procedures described in the first and second parts of Example 75 were repeated using suitable starting materials, and the compounds listed in the following Examples 76 to 80 in Table V were obtained.

Example 81

A 100 ml flask fitted with an air condenser was charged with 10.2 g (0.05 mol) of 3-[2-(4-carboxy-1H-1,2,3-triazol-1-yl)ethylindole and heated in an oil bath to 200-210°C until the evolution of C02 gas had ceased. The residue was cooled and taken up in 100 ml of methanol and treated with decolorizing carbon on a steam bath, then filtered and the filtrate was slowly diluted with H 2 O to precipitate 3-[2-(1H-1,2,3-triazol-1- yl)ethylindole as a fine cream-colored solid which, after drying in vacuo, had a m.p. at 104-105°C.

The starting material used in the above process can be obtained as follows: A solution of 10.9 g (0.061 mol) of 3-(2-chloroethyl)indole in 75 ml of ethanol was combined with 7.9 g (0.121 mol) of NaN 2 in 50 ml of H 2 O and was refluxed for 24 hours. The ethanol was distilled off with aspirator vacuum and the residue was diluted with 200 ml H 2 O and extracted with diethyl ether. The ether solution was washed with H 2 O and dried over MgSO 4 . Evaporation of the ether gave 3-(2-azidoethyl)indole characterized by the presence of characteristic bands in the infrared spectrum, especially indole N-H (3350 cm ) and -N3 (2080 cm<_1>).

11.1 g (0.061 mol) of 3-(2-azidoethyl)indole in 25 ml of acetone were added dropwise to a reflux solution of 4.3 g (0.061 mol) of propiolic acid in 75 ml of acetone. The mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, 200 ml of diethyl ether was added and stirred to obtain 3-[2-(4-carboxy-1H-1,2,3-triazol-1-yl)-ethyl-indole. Another product was obtained by adding 500 ml of hexane. The two products were recrystallized from acetone/diethyl ether (1:2 v/v) to give a light brown solid, m.p. 192-194°C (with cleavage).

Example 82

Catalytic reduction of 18.1 g (0.088 mol) of 1-(2-nitrobenzyl)-1H-1,2,3-triazole was carried out in a Faar apparatus in 200 ml of ethanol at 3.5 atmospheres of hydrogen pressure and with 1 .0 g of 5% w/w Pd-on-carbon as catalyst. The transaction took place quickly and was completed within 1/2 hour. The catalyst was filtered off and the filtrate was cooled to approximately -35°C in a dry ice/acetone bath and was quickly filtered. The solid was washed with diethyl ether and then with hexane, and was air-dried to give 1-(2-aminophenyl)-1H-1,2,3-triazole, m.p. 122-124°C. Example' 83

10 g (0.051 mol) of 1-(2-chlorobenzyl)-1H-1,2,3-triazole were melted by heating with an oil bath (120°C) and 150 ml of preacetic acid (40% v/v in acetic acid) was added at a rate which kept the temperature above 100°C. The mixture was then refluxed for 1 hour at 105°C. Most of the acid was distilled off and the residue was cooled to room temperature and diluted with 150 ml of f₂O. The solution was then basified with Na 2 CO 2 and then treated with NaHSO 2 . The product was extracted with chloroform and recrystallized from ethanol/diethyl ether (1:2 v/v) to give 1-(2-chlorobenzyloxy)-1H-1,2,3-triazole, m.p. 97.5-98.5°C. Example 84

1-(2-Chlorophenyl)-1H-1,2,3-triazole, 6.6 g (0.04 mol), prepared by decarboxylation of the corresponding 4,5-dicarboxytriazole, was melted by heating with an oil bath at 105°C, and 50 ml peracetic acid (40% volume/volume in acetic acid) was then added dropwise. The product was isolated in a similar manner to Example 83 and was recrystallized from ethyl acetate-hexane (2:1 v/v) to give 1-(2-chlorophenoxy)-1H-1,2,3-triazole, m.p. . 102-103°C.

Example 85

10.4 g (0.15 mol) 1H-1,2,3- triazole as a solution in 25 ml of dimethylformamide at such a rate that the temperature was kept below 45°C. After the addition was complete, the mixture was heated to 50°C and stirred for 1 hour. The solution was cooled to room temperature and 26.3 g (0.15 mol) o-chlorobenzoyl chloride was then added dropwise, keeping the temperature below 35°C with a cold water bath. The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 500 ml of ice water and filtered. The solid product was taken up in 100 ml of chloroform and washed twice with 50 ml of 12% w/v HCl, dried over MgSOA, filtered and the filtrate was evaporated. Trituration with hexane gave 1-(2-chlorobenzoyl)-1H-1,2,3-triazole, m.p. 76-76.5°C.

Example 86

To a stirred solution of 10.5 g (0.15 mol) 1H-1,2,3-triazole in 300 ml xylene, 18 g (0.15 mol) styrene was added in one portion. The reaction mixture was stirred and heated under reflux for five hours. After cooling to room temperature overnight, an oily ylene-insoluble material was separated from the reaction mixture. Low-boiling (b.p. less than 135°C, 0.1 mm) impurities were removed by distillation and the reddish residue solidified after trituration in 100 ml of diethyl ether. The solid was vacuum-sublimated by heating,

then chromatographed on a silica gel G column and fractions were eluted with diethyl ether, chloroform and chloroform-methanol (95:5 v/v), in that order. The product obtained was 1-(1-phenyl-1-hydroxyethyl)-1H-1,2,3-triazole, m.p. 88-90°C.

Example 87

In one portion, 5.4 g (0.08 mol) of sodium azide. The reaction mixture was heated under reflux for 24 h, then diluted with 200

ml of water and extracted with diethyl ether. The ether layer was dried over MgSOA and the drying agent was filtered off. Removal of ether under aspirator vacuum gave the corresponding azide which was used in the next step without purification. A stirred solution of acetylene dicarboxylic acid, 4.5 g (0.04 mol), in 75 ml of acetone was heated to reflux and 8.4 g of the above azide was added in one portion. The reaction mixture was stirred and heated under reflux for 24 hours. The residue obtained after removal of acetone under aspirator vacuum was triturated with 25 ml of chloroform and the solid was filtered off. The filtrate was evaporated to dryness under aspirator vacuum. The residue was treated with 25 ml of a saturated solution of NaHCO 3 and extracted with diethyl ether. The aqueous phase was acidified to pH 1 and was again extracted with diethyl ether. The ether was removed under aspirator vacuum and the residue was decarboxylated by heating at 185-190°C for 1 hour. The material solidified on cooling and the product, 1r-[1-(2-chloropheny1)-2-methylpropyl]-1H-1,2,3-triazole, was vacuum sublimed on heating to give a pale yellow solid with sm.p. 66-68°C.

Example 88

To a stirred solution of 4.6 g (0.2 mol) of sodium metal reacted in 200 ml of absolute ethanol, 25 g (0.2 mol) of ethyl acetoacetate were added in one portion. After stirring for 10 minutes, 36.3 g (0.2 mol) of 1-(2-chlorophenyl)ethyl azide (preparation described in example 75) was added dropwise over the course of 10 minutes. The mixture was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated to dryness under aspirator vacuum at 40°C. The residue was treated with 200 ml of diethyl ether and the mixture was filtered. The filtrate was treated with 300 ml of a saturated ethereal solution of hydrogen chloride and washed with an equal volume of water. The layers were quickly separated and a white solid precipitated from the organic layer. The solid gave, after recrystallization from ethyl acetate and drying at 60°C overnight, 1-[1-(2-chlorophenyl)ethyl]-4-carboxy-5-methyl-1H-1,2,3-triazole, sm . 190 oC (with cleavage).

Example 89

To a newly prepared solution of sodium methoxide from

1.5 g (0.066 mol) of sodium metal in 100 ml of methanol, 10.0 g (0.066 mol) of 1-cyano-acetylpiperidine was added and it was stirred for 15 minutes. o-Chlorobenzyl azide, 11.0 g (0.066 mol), was then added dropwise, and the mixture was stirred overnight at room temperature and then refluxed for three hours. The cooled mixture was poured onto 1000 ml of E 2 O and the product was extracted with 200 ml of methylene chloride. The organic phase was washed with Et 2 O and dried over MgSOA. The solution was concentrated to 50 ml on a buffer bath and 50 ml of hexane was added to give a yellow solid. This product, after recrystallization from 30 ml of methanol, gave 5-amino-1-(2-chlorophenylmethyl)-4-(1-piperidinecarbonyl)-1H-1,2,3-triazole as a white solid, m.p. 136-137°C.

Example 90

The procedure described in example 89 was repeated using 1-(2-chlorophenyl)ethyl azide as starting material, and 5.-amino-1-[1-(2-chlorophenyl)ethyl]-4-(1- piperidinecarbonyl) - 1H-1,2,3-triazole as a white solid, m.p. 133-134°C.

Example 91

1-(2-acetoxybenzyl)-1H-1,2,3-triazole, 2.5 g (0.01 mol) was stirred in 25 ml of a 10% w/v NaOH solution by heating on a water bath for 2 hours. The mixture was cooled to room temperature and extracted with diethyl ether. The aqueous phase was

slowly and carefully acidified to pH 4, then filtered and extracted with chloroform, washed with water, dried over MgSOA, filtered and evaporated with aspirator vacuum. The product, 1-(2-hydroxybenzyl)-1H-1,2,3-triazole, was purified by column chromatography on silica gel-G using diethyl ether as eluent.

The 1-(2-acetoxybenzyl)-1H-1,2,3-triazole used as starting material can be prepared as follows: o-cresyl acetate, 37.5 g (0.25 mol), was stirred in 400 ml of carbon tetrachloride and 0.5 g of benzoyl peroxide was added in one portion. Over 10 minutes, N-bromosuccinimide, 44.4 g (0.25 mol), was gradually added. The reaction mixture was heated at reflux for 4 hours and then cooled to room temperature. The solid was filtered off, washed with 200 ml of carbon tetrachloride and discarded. The filtrate and washings were combined and the solvent was removed under aspirator vacuum. The residue obtained was 2-bromomethyl-phenylacetate.

To a stirred solution of 32.5 g (0.5 mol) sodium azide

in 200 ml of 95% v/v aqueous ethanol, 57.3 g (0.25 mol) of 2-bromomethylphenyl acetate was added in one portion. The mixture was heated under reflux for 24 hours. Almost all the solvent was removed by aspirator vacuum and the residue was taken up in 250 ml of water and was extracted twice with 150 ml of diethyl ether. The ether layer was washed with H 2 O and dried over MgSOA. The desiccant was filtered off and the ether was removed under aspirator vacuum. The product, 2-azidomethylphenyl acetate, was used directly in the next step.

Acetylene dicarboxylic acid, 26.1 g (0.25 mol), was stirred

in 250 ml of acetone and heated to reflux temperature. Over 10 minutes, 2-azidomethylphenyl acetate, 47.8 g (0.25 mol), was added dropwise. The mixture was refluxed with stirring for 24 hours. The mixture was then cooled and the solvent was removed by aspirator vacuum. The residue was triturated with diethyl ether and hexane to give a solid product, 1-(2-acetoxybenzyl)-4,5-dicarboxy-1H-1,2,3-triazole.

This product was decarboxylated by heating in an oil bath at 170-200°C until CO 2 evolution ceased. The residue was cooled and purified by column chromatography on silica gel-G with hexane and ether as eluents, to obtain 1-(2-acetoxy-benzyl)-1H-1,2,3-triazole.

Example 92

1-(4-acetoxy-2-chlorobenzyl)-1H-1,2,3-triazole, 2.7 g

(0.01 mol) was suspended in 25 ml of water in a 50 ml<1>s beaker

and 4.6 g (0.04 mol) of sodium carbonate was gradually added. The mixture was heated with occasional stirring for 1 1/2 hours on a steam bath, then cooled to room temperature and extracted with an equal volume of diethyl ether. The aqueous phase was gradually acidified with concentrated acid to pH 4. The solid was filtered off and washed with 30 ml of diethyl ether and 30 ml of hexane. The solid was purified by dry column chromatography on a silica gel G column using diethyl ether as eluent to obtain 1-(4-hydroxy-2-chlorobenzyl)-1H-1,2,3-triazole as a white solid, m.p. 176-178°C.

The 1-(4-acetoxy-2-chlorobenzyl)-1H-1,2,3-triazole used as starting material can be obtained as follows: 4-chloro-3-methyl-phenyl-acetate, 44.5 g (0.24 mol), was dissolved in 400 ml of carbon tetrachloride and 0.8 g of benzoyl peroxide was added in one portion. Over 10 minutes, 42.7 g (0.24 mol) of N-bromosuccinimide was gradually added. The reaction mixture was heated under reflux for two hours and then cooled to room temperature. The solid was filtered off, washed with 200 ml of carbon tetrachloride and discarded. The filtrate and washings were combined and the solvent was removed under aspirator vacuum. 3-(bromomethyl)-4-chlorophenyl acetate was obtained as a residue.

To a stirred suspension of 6.8 g (0.075 mol) of sodium triazole in 100 ml of dry diethylene glycol dimethyl ether, 19.8 g (0.75 mol) of 3-(bromomethyl)-4-chlorophenyl acetate were carefully added in one portion. After the reaction temperature had dropped from 50°C to room temperature (about 1 hour), the reaction mixture was heated under reflux for 4 hours. The reaction mixture was cooled and a water-soluble solid was filtered off. The filtrate was diluted with 400 ml of water and extracted twice with 350 ml of diethyl ether. The ether layer was washed four times with 300 ml of water, once with an equal volume of saturated NaCl solution and was dried over MgSOA. The desiccant was filtered off and the filtrate was reduced to dryness by aspirator vacuum. The residue was column chromatographed on a silica gel G column using hexane, diethyl ether-hexane (1:1 v/v) and ether, in that order, as eluents. Partially pure material was then absorbed onto silica gel-G in a nylon column (60 x 4.4 cm) developed with diethyl ether, and the column was sectioned at 2.5 cm intervals.

An almost pure segment was desorbed with diethyl ether and the silica was filtered off. The filtrate was reduced to dryness, the residue was dissolved in 5 ml of chloroform and spotted on two thin-layer chromatography plates (size 20 x 20 cm, 2000 µl in thickness), then eluted twice with diethyl ether. Pure 1-(4-acetoxy-2-chlorobenzyl)-1H-1,2,3-triazole was desorbed with diethyl ether from the silica scraped from the plates with R 0.5-0.8.

Claims (1)

Analogy method for the production of physiological active triazole derivatives of the general formula where R 1 and R 2 are independently selected from the group consisting of hydrogen atoms and carboxy-, phenyl-, alkyl-(C^-C^), amino-, 1-piperidinecarbonyl- and hydroxyalkyl- (C. - C.) 12 ±4 radicals, or R and R together mean a 1,3-butadienylene radical, so that together with the two carbon atoms in the triazole ring to which they are attached, they form a benzene ring, one of R 3 and -R 4, together with the dotted circle, means two double bonds, and 12 3 (a) when R and R are hydrogen atoms, R is a radical selected from the group consisting of alkyl (C 1 -C 8 ); phenylalkyl (Cg - c^2 ) where the alkyl substituent is a linear chain; phenylalkyl (C 8 -C 2 -C 2 ) wherein the alkyl substituent is a branched chain; di-, tri- and tetrahalo-substituted phenylalkyl (C^ - C^2 ) where the halogen substitution is on the phenyl ring; penta-halo-substituted phenylalkyl (Cg - C^2 ) wherein the halogen substitution is on the phenyl ring; mono-halogen-substituted naphthylalkyl (C-^ i~ C^ g) where the halogen substituent is on the naphthyl ring; ortho- or meta-monohalogen-substituted phenylalkyl (C 1 -C 2 )» para-halogen-substituted phenylalkyl (C 8 -C 12 ); mono-, di- or trialkyl- (C^ - C^ ) substituted phenylalkyl (C_, - c^2 ) wherein the alkyl substitution is on the phenyl ring; ortho- or meta-mono-alkoxy (C^ - C^ ) substituted phenylalkyl where the alkyl substituent is C, 1 - C^ ; mono-, di- or tri-haloalkyl-(C1 - C^ ) substituted phenylalkyl (C? - C^2 ) where the haloalkyl group contains from 1 to 5 halogen atoms and is substituted on the phenyl ring; cycloalkyl-(C 3 , - CoQ ) substituted alkyl (C 3 -C 8 ); mono-, di- or tri-halo-substituted benzoylalkyl (C 8 -C 4 ); thienylalkyl (C 1 -C 1 ); mono-cyano-substituted phenylalkyl (C? - C^2 ) where the cyano substitution is on the phenyl ring; mono-nitro-substituted phenylalkyl (C^ - C-j .2 ^ where the nitro group is substituted on the phenyl ring; mono- to hexa-halogen-substituted benzhydryl where the halogen substitution is on the phenyl ring; mono-, di- or tri-halogen-substituted cinnamyl where the halogen substitution is on the phenyl ring; mono-, di- or tri-alkoxycarbonyl- (C^ - C^) substituted phenylalkyl (C-, - C^2 ) where the alkoxycarbonyl substitution is on the phenyl ring; quinolylalkyl (C10 - C]_5^ J mono-, di- or tri-hydroxy-substituted phenylalkyl (C7 - C12 ) where the hydroxy substitution is on the phenyl ring; phenylalkenyl (Cg - C-^); 3-indole-alkyl (Cg - C^^); mono-, di- or tri- amino-substituted phenylalkyl (C^ - C-^ ) where the amino substitution is on the phenyl ring; mono-, di- or tri-halogen-substituted phenylalkyloxy (C^ - C^2 ) where the halogen substitution is on the phenyl ring; chlorophenoxyalkyl (C^ - C -^) J chlorohydroxy-phenylalkyl (C 1 - C 2 ); mono-, di- or tri-halo-substituted phenoxy; mono-, di- or tri-halo-substituted benzoyl; and mono-, di- or tri-hydroxy-substituted phenylalkyl (C^ - C^2 ) where the hydroxy substitution is on the alkyl chain; and 12 A (b) when R and R are hydrogen atoms, R is a radical selected from the group consisting of phenylalkyl (C 1 -C 2 ); ortho-halo-substituted phenylalkyl (C 1 -C 2 ); meta-chloro-substituted phenylalkyl (C 1 -C 2 ); para-bromo-substituted phenylalkyl (C 1 -C 2 ); di- or tri-halo-substituted phenylalkyl (C 1 -C 2 ) where the halogen substitution is on the phenyl ring; mono-, di- or tri-haloalkyl-(C 1 to C 4 ) substituted, phenylalkyl (C 1 to C 12 ) wherein the haloalkyl substitution is on the phenyl ring; mono-, di- or tri-alkyl (C 1 -C 4 ) substituted phenylalkyl (C 1 -C 12 ) where the alkyl substitution is on the phenyl ring; pyridylalkyl (C 8 -C 4 ); and mono-, di- or tri-halogen-substituted benzoylalkyl (Cg - C^ -j ) where the halogen substitution is on the phenyl ring; and 1 2 (c) when R and R are independently selected from the group consisting of hydrogen atoms and carboxy-, phenyl-, alkyl-(C, to C. ), amino-, 1-piperidinecarbonyl- and hydroxyalkyl-12 (C. - C .) radicals, provided that at least one of R and R is different from a hydrogen atom, R 3 is a radical selected from the group consisting of alkyl (Cg); phenylalkyl (Cg - c12 ) where the alkyl substituent is branched; mono-, di- or tri-halogen substituted phenylalkyl (C 1 -C 2 ) where the halogen substitution is on the phenyl ring; mono, di- or tri-haloalkyl- (C-^ to C^ ) substituted phenylalkyl (C^ - C^ q ) where the haloalkyl group contains from 1 to 5 halogen atoms and is substituted on the phenyl ring; and (d) when R 1 and R 2 together mean a 1,3-butadienylene radical, 3 4 is one of R and R selected from the group consisting of phenylalkyl (C„ - C,.J; and di-, tri- and tetra-halo-substituted phenylalkyl o 10 (C_, - C1Q ) where the halogen substitution is on the phenyl ring, characterized by :(1) for the compounds where R 1 and R 2 are both hydrogen atoms, decarboxylation of a compound with the formula: where R 7 and R 8 are independently selected from the group consisting of hydrogen atoms and carboxy radicals, Whereas at least one of R^ and R^ is a carboxy radical, and R^ and R^ have the meanings stated above; (2) conversion of a triazole with the formula: where the dotted circle means two double bonds, and the hydrogen atom is bonded to any of the three nitrogen atoms, and R 1 and R 2 have the meanings given above, with a compound 9 9 with the formula R -X where R has the meaning stated above for R 3 when R 4 together with the dotted circle means two double bonds, 9 4 and R also has the meaning stated above for R , when R 3 together with the dotted circle means two double bonds, and X means a chlorine, bromine or iodine atom; (3) for those compounds where R 4, together with the dotted one 1 2 circle, means two double bonds and R and R are independently selected from hydrogen atoms and carboxy, phenyl, alkyl, 1-piperidinecarbonyl and hydroxyalkyl radicals, reaction of an acetylene compound of the formula: where R"^ and R"^ are independently selected from hydrogen atoms and carboxy-, phenyl-, alkyl- (C^ - C^), 1-piperidinecarbonyl- and hydroxyalkyl- (C, - C^) radicals, with a azide with the formula: where R 3 has the meaning indicated above; (4) for those compounds where R 3 means a mono-, di- or tri-aminophenylalkyl radical, reduction of the corresponding mono-, di- or tri-nitrophenylalkyl derivative; (5) for those compounds where R 3 means a mono-, di- or tri-halogen-substituted phenylalkyloxy or mono-, di- or tri-halogen-substituted phenoxy radical, oxidation of the corresponding mono-, di- or tri-halogen respectively -substituted phenylalkyl or mono-, di- or tri-halo-substituted phenyl derivatives with a peracid; (6) for a compound where R"^ is a 2-hydroxy-2-phenethyl radical, reaction of an epoxide with the formula: with a triazole of the above formula IV; (7) for the compounds where R"*" is a carboxy or 1-piperidinecarbonyl radical, R 2 is an amino or alkyl radical, and R 4, together with the dotted circle, means two double bonds, reaction of a compound with the formula: hrvaodr ikR al12, boeg tyR r 13 ebt eatylkr okest y- alk(Cyl± , - <-> (CC4 , .)- , hCy■.d) roeklslye- r ceylalenr ora1-dpikipaelr,idinyl-with an azide with the above given formula VI, where R has the meaning given above; or' (8) for those compounds where R 3 is a mono-, di- or tri-hydroxy-substituted phenylalkyl radical, hydrolysis of the alkoxycarbonyl group in a triazole derivative where, the radical corresponding to R 3 is a mono-, di- or tri-hydroxycarbonylphenylalkyl radical , the alkoxycarbonyl substituent having from 1 to 6 carbon atoms.