DE2240043A1 - (PHENYL-TOLYL) -1,2,4-TRIAZOLE AND METHOD FOR MANUFACTURING IT - Google Patents

Description

«CHTSANWAIT!

OR. JUR. DiPL-CHEM. WAITER BEU , '■ ¹ JL Aim um

AlFRfDHOEPPENER \ »*« ^MU «'l9«

DR. JUR: DtPL-CHtM. RJ. WOlFF DR. JUR. HANS CHR. AX

FRANKFURT AM MAIN-HOCHSt

Our number * 18 030

The Upjohn Company Kalamazoö, Michigan - V * St.Ai

(Phenyl-tolyl) -l, 2, ^ - triazoles and processes for their

Manufacturing.

The present invention relates to new JJ-tatolyl3-3,5-disubstituted-4H-l, 2,4-triazole, Process for their preparation and process for the preparation of substituted 2-C3 ~ substituted-5-aminomethyl-substituted- ^ H-l ^^ - triazol-Jl-yD-benzophenones. The invention also provides the pharmacologically acceptable acid addition salts of these connections.

The new compounds and the procedures for their Manufacturing can be represented as follows:

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I I

In the above formulas, R ₁ denotes hydrogen, an alkyl radical with 1 to 3 carbon atoms, a cycloalkyl radical with 3 to 8 carbon atoms, a phenyl, benzyl radical, a Kent of the formula -C ^ Oi ·. ', In which U ^{1 is} an alkyl radical according to the above

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Definition denotes, or a heterocyclic aromatic ring with 5 to 6 atoms, including 1 to 4 iieteroatomen in the form of oxygen, nitrogen or sulfur, R ¹¹ and R " ^{f are} alkyl radicals according to the above definition or together as _/ R"

-N a pyrrolidino, piperidino or cor-

R ¹¹¹ pholincrest, and Rp, R ^, R. and R _r denote carbon atoms, alkyl radicals according to the above definition, halogen atoms, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, amino -, alkanoylamino or dialkylamino groups, the carbon chains of which have 1 to 3 carbon atoms.

The process according to the invention consists in that a compound of the formula I or III with formaldehyde and a secondary amine of the formula , R ¹ '

HN in the R "and R" ¹ the

^X R ¹ "

have the above meaning, usually in an organic solvent, e.g. diglyme, at an elevated temperature, e.g. at 75 ° C to reflux temperature, treated to form the new compounds II from I or the known compounds IV from III. The compound II can be oxidized to the compound IV.

As examples of lower alkyl groups with 1 to 3 carbon atoms the methyl, ethyl, propyl and isopropyl radicals are given, as examples of cycloalkyl radicals with 3 b; s 8 carbon atoms of the cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl and cyclooctyl radical.

The carbon chain of the alkoxy, alkylthio, alkylsulfinyl, Alkylsulfonyl and J-dialkylamino groups containing 1 to 3 carbon atoms on v / eist, can be obtained by one of the above

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BATH ORIGINAL

lower alkyl radicals with 1 to 3 carbon atoms formed a.

The alkanoylamino groups with 1 to 3 carbon atoms are the formamide, acetamido and propionamido groups. Of the The term "halogen" includes fluorine, chlorine, bromine and iodine.

Heterocyclic aromatic ring systems with up to 4 keteroatoms in the form of nitrogen, oxygen and sulfur are thienyl, pyrrolyl, isopyrrolyl, oxazolyl, pyrazolyl, Triazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 1,2,5-oxadiazolyl, pyridazinyl, pyriraidinyl, Pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl-, 1,2,3,4- and 1,2,3,5-oxatriazolyl-, 1,2,3,4- and 1,2,3,5-thiatriazolyl-, 2H-, 1H- and 5H-tetrazolyl-, 1,2,3-, 1,2,4- and 1,2,5-thiadiazolyl-, Isoxauolyl, isothiazolyl, imidazolyl, 1,4,3,5-oxathiadiasinyl, 1,4,2,5-dioxadiazinyl, 1,4, ^ - 5-dithiadiazinyl, as-, s- and V-tetrazinyl-, 1,4,3-oxathiazinyl-, 1,4,2-dioxazinyl-, 1,4,2-dithiazinyl-, 4H-1,2,4-oxadiazinyl-, 2H-1,2,3-thiadiaEinyl-, 2H-1,2- and 4H-1,4-oxazinyl- and 2H-1.2 and 4H-1,4-thiazinyl radicals.

These substituents R can be represented by the following formulas will:

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240043

Thienyl

Pyrrolyl

Isopyrrolyl

Pyrazplyl

1,2,4-triazoyl

Cbcazolyl thiazolyl

■ Ar ί-JÜ

Isothiazolyl

1,2,3-CXadiazolyl 1,2,4-oxadiazoly1

Ν-

1,2,5-oxadiazolyl 1,3,4-

Pyridazinyl

P yrlmldlnyl

■ -Ö

1,2,4-5? riazlnyl a a pyridyl

C>

Pyrazinyl

1,2,3-triazinyl

4 3

4 pp

1,2,3,4-0 xatri-1,2,3,5-oxatrlazolyl azolyl

1,2,3,4-T. hlatri azoIy1

4 3

H - ι

azolyl 2H-tetrazolyl IH-atetrazolyl

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Sil-Tetrazoly! «Ls FT

1,2,3-? hfudUzolyl

Imldazoiyl

rl

^ oxazolyl

1 A, 3.5-0 xath lad I aza-nyl

CKaznyl * H-1,4-0p <aznyl

O-

sochlazolyl

azfnyl

hlazinyl

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ORIGINAL BATHROOM

These hetero-aromatic rings can be bonded in different ways Positions take place, e.g. as a 2-Furyx- ode: r 3-furyl, as can be seen from the list above.

The new compounds of the formula II including their Acid addition salads have sedating, tranquilizer, hypnotic, muscle-relaxing and antispasmodic effects in mammals and birds as well as in humans. When used as a feed additive, they increase the speed of growth and feed evaluation in cattle and poultry, the milk product! cn in mammals and the egg production in birds.

The acid addition salts provided according to the invention Compounds of formula II are the hydrochlorides, hydrobromides, Hydroiodides, sulfates, phosphates, cyclohexahsulfa— mate, methanesulfonates and the like. They are prepared by adding a compound of the formula II with an excess converts the acid in question.

The eedierende effect of 4- / 4-chloro ~ zt phenyl-o-tolyl.7-5-pyrrolidinomethyl-3-methyl-4H-1,2,4-triazole is demonstrated by the following tests on mice:

Chimney Test (Hed Exp 4_ _f 145 (1961)..): The effective dose for intraperitoneal $ 5o of the mice is (EDC ₀₎ 79 mg / kg. This test determines the ability of mice to climb up and off a vertical glass cylinder within 30 seconds. The mice fail to do this at the effective dose.

Shell test : Kice in Petri dishes (to cm diameter, height 5 cm, partly embedded in wood chips) climb out of the dish very quickly if they are untreated. Stay

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if the mice are in the dish for more than 3 minutes, there is evidence of tranquilization. The EDc ₀ corresponds to the dose of test compound at which 50 ^ of the mice remain in the dish. It is 40 mg / kg for the above compound in this test (intraperitoneal administration).

Pedestal test ; The untreated mouse exits a pedestal in less than 1 minute and climbs back onto the floor of the standard cage. Tranquilized mice remain on the pedestal for more than 1 minute. The ED (intraperitoneal administration) for the above compound is 79 mg / kg.

Nicotine antagonism test ; The test compound 4- / ~ * 4-chloroc-phenyl-o-tolyy-S-pyrrolidinomethylO-methyl-AILI, 2,4-triazole is administered to mice in groups of six by injection. Thirty minutes later, the animals, including untreated control animals, are injected with nicotine salicylate (2 mg / kg). Control animals show overstimulation, ie (1) continuous convulsions followed by (2) tonic extensor convulsions and (3) death. An intraperitoneal dose of 36 mg / kg of the test compound protects 505% of the mice against (2) and (3).

The new triazoles of the formula II are also important intermediates for the preparation of the known triazolo-benzophenone compounds of the formula IV, which are even more effective tranquilizers. For example, the 5-chloro-2 - / "~ 3-methyl-5- (pyrrolidinomethyl) -1,2,4-triazol-4-yl7-beneophenone has the following ED ₅ values:

Switching test: 1.3 mg / kg, Pedestal test: 2.3 mg / kg, Nicotine antagonism test (2) and (3): 0.4 mg / kg.

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For the following benzophenones IV, the values were according to found the table below :.

K Sch Ni

5-chloro-2- / ~ 3-methyl-4-dimethylamino-

methyl-4H-T _r 2,4-triazol-4-yl7-

benzophenone "~ 1.8 2.2 o.56

5-chloro-2- / ~ 3-methyl-5-diethylamino-

methyl7-4H-1,2,4-triazol-4-yl7-

benzophenone o, 6 1 »o o, 22

5-chloro-2- / ~ 3-methyl-5- (pyrrolidino-

metnyl) -4H-1,2,4-triazol-4-yl7-

benzophenone "" o, 7 1.3 o, 4

5-chloro-2- / ~ 3-methyl-5- (morpholino-;

methyl) -4H-1,2,4-triazol-4-yl7-

benzophenone 1, o 1.8 o, 5

5-chloro-2- / ~ 3-methyl-5- (piperidino -) - 4H-1 ^^ - lj hd

methyl) ^^ yj

benzophenone hydrochloride "" 1.4 2.8 o.8

K * chimney test

Sch »Cup test

P ■ Podium test

Ni β nicotine antagonism (3) test

Those suitable for the compounds according to the invention pharmaceutical forms are preparations for oral, parenteral and rectal use, e.g. tablets, Powder packets, sachets, coated tablets, capsules, solutions, suspensions, sterile injectable forms, suppositories and the like. Suitable diluents and carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, Corn starch, stearic acid, methyl cellulose and the like can be used in their manufacture. Oils, e.g. coconut

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- Io -

Nut oil, sesame oil, saffron oil, cottonseed oil, peanut oil and the like. Can be used to prepare solutions or suspensions be used. Sweeteners, colors and flavors can also be added.

For administration to mammals and birds, feed premixes with starch, oatmeal, dried fish meat, Make fish meal, wheat flour and the like.

The compounds of formula II are used as tranquilizers in doses of 0.1 to 10 mg / kg in oral or injectable PrepaxEten used to ease states of tension. In the case of the compounds of formula IV, the dose can be substantial lower no and for example at 0.1 to 2.0 mg / kg lie. The compounds of the formula II can be administered as feed additives in amounts of 0.003 to 50 mg / animal / day to accelerate growth and feed intake and to improve feed evaluation Cattle and poultry, to increase the production of food in mammals and the production of eggs in birds.

The preparation of the starting compounds I and III is illustrated in the following preparations.

When carrying out the process according to the invention, the starting compounds of the formulas I or III are heated in an organic solvent such as diglyme with formaldehyde, paraformaldehyde and water or formalin and a secondary amine or secondary amine hydrochloride and additional hydrochloric acid. The mixture is heated preferably to a temperature between 75 ° C and the reflux temperature of Gemisch3, which for diglyme at about 162 ⁰ C. Instead of diglyme, other solvents such as ethanol, n-propanol, n-butanol, dimethylformamide,

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Mono- or triglyme can be used, but diglyme is preferred. The secondary amine is in excess, preferably in the 1.2 to 4-fold stoichiometric Amount used · According to a preferred embodiment becomes formaldehyde ^ paraformaldehyde or formalin in one 2- to 10-fold excess over the stoichiometrically required Amount and the hydrochloric acid used in a 1.2 to 4-fold excess over the required amount. The response time, which is not critical, is usually between 6 and 48 hours. After the reaction has ended, the mixture is in a basic sodium or potassium hydroxide or carbonate solution and the product (II or IV) is in conventionally isolated and purified, e.g. by Extraction, trituration, chromatography, crystallization, combinations of these measures and the like.

The products of formula II can be oxidized to the corresponding benzophenones IV, e.g. with chromic anhydride in sulfuric acid (Jones reagent, see the following preparations).

The Mannich reaction with a triazole compound is new. It has hitherto been assumed that triazoles do not (or at least not to a significant extent) react with formaldehyde and secondary amines. . '.-. · 3-Ethyl-5-chloro-1,2,4-triazole and 1-phenylbenzotriazole, for example, do not condense (according to G. Bryant Bachman and LV Hersey, J. Am. Chem. Soc. 68, p. 2497 , 2nd column, last line and p. 2498, 1st column, 1st cell (1946)). Benzotriazoles reacted in Mannich syntheses, but with the formation of unstable products. Some diazines, for example 2,5-dimethylpyrazine (SM Linder and PE Spoerri, J. Am. Chem. Soc. 75, 1517 (1962)) produce a Mannich reaction only with three specific secondary amines, namely dimethylamine, piperidine and morpholine. In these cases, however, the products obtained were not those from a nuclear one

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Attack of the aromatic ring, but the compounds resulting from attack of the methyl side chains (ie 2,5-bis- (ε-methylaminoethyl) -pyrazine and 2 _f 5-bis- / ~ bis- / ~ dinethylaminoffiethy] _i 7-raethyl, 7 -pyrasin). It was therefore surprising that the triasol compounds of the formulas I and III can be converted into the stable end products II and IV in good yields, these not being caused by by-products such as, for example, compounds of the formula

CH ₂ -CH ₂ -N;

are contaminated.

Preparation 1

2-Aπlino-5-chlorobenzophenon-hydΓazon.

A mixture of 27.2 g (0.117 mol) of 2-amino-5-chloro-enzophenone

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BATH ORIGINAL

in 17o al-diethylene glycol and 23 ml (ο, 45 KoI) 99 '^ igeöi hydrasin hydrate was refluxed for a total of 7 hours. The solution was cooled to room temperature overnight * then the light green solid that had formed was mixed with 400 ml of water and extracted into benzene. The layers were separated and the benzene phase was dried over anhydrous magnesium sulfate and concentrated * 133-i33 _r 5 ° G *. /; ■■■:

Anal Ber. for C ^ -H ^ ClN-s:. .

C: 63.55; H: 4.35} Hi 17.1t; Eq: 14.43 »Ge £ .: G: 63.58j H: 4.95; ": 1? _f 32; GIi 14.35 »

A second fraction {6, o g, 21 ^) of the needle-shaped crystal « melted at 132-134 ° C.

Preparation 2

2-Amiao-2,5-dichlorobenzophenone hydrazone.

According to the instructions of preparation 1, 2-Αππ.ηο-2 ' , 5- dichlorobenzophenone with hydrazine hydrate in diethylene glycol is refluxed to give the title compound,

Preparation 3

2-Amino-5-cbior-2 ', 6'-difluorobenzophenone hydrazone.

According to the instructions for preparation 1, 2-amino-5-chloro-2 ¹ ₍ 6 ^l- difluorobenzophenone with hydrazine hydrate in diethylene glycol

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Refluxed to give the title compound.

Preparation 4

2-Aeino-2'-chloro ^ -nitrobenzophenone hydrazone.

According to the instructions for preparation 1, 2-amino-2 ^l «clalor-5 · nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol, whereby the title compound is obtained.

Preparation 5 - '. "

2-aeinobenzophenone hydrazone.

According to the instructions for preparation 1, 2-aminobent; ophenone is refluxed with hydrazine hydrate in diethylene glycol, wich «! nan receives the title compound.

Preparation 6

2-benzyl-4-chloroaniline.

16.1 g (245 millimoles) of potassium hydroxide pellets are crushed and dissolved in 85 ml of refluxing diethylene glycol. Volatile fractions are distilled off until the temperature of the liquid has reached 200 ° C. The solution is then cooled to room temperature and treated with 13.5 g (54.6 millimoles) of ^ -aeino-S-chlorobenzophenone hydrazone, while the slrupous liquid is gently heated again. At 100 ° C., all of the hydrazone has dissolved. The temperature will

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Maintained between 12o-15o C for 145 minutes until gas evolution ceases. After a total heating time of 1 1/2 stalls, the solution is cooled, poured into ice and extracted with benzene * The benzene phase is separated off, dried over anhydrous magnesium sulfate and concentrated to give an orange-colored oil. The distillation yields 9.9 g of 2-benzyl-4-chloroaniline (89.2 $) as a yellow oil, bp _n "125-14o ° C.

ο, ι

Anal. Ber. for C ,,, H _-10 ClN:

15 12

C: 71.72; H: 5.56; N: 6.44; Cl: 16.28. Found: C: 71.55; H: 5.51; N: 6.58; Cl: 16.16.

Preparation 7

2- (o-chlorobenzyl) -4-chloroaniline.

According to the instructions for preparation 6, 2-amino-2 ', 5-dichlorobenzophenone hydrazone is used refluxed with potassium hydroxide in diethyl glycol, giving the title compound receives.

Preparation 8

4-chloro-o <- (2,6-difluorophenyl) -o-toluidine.

According to the instructions for preparation 6, 2 ^ A.minb-5-chlor-2 ', 6 * difluorobenzophenone refluxed with potassium hydroxide, giving the compound.

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BAD ORKaINAt

Preparation 9

2- (o-chlorobenzyl) -4-nitroaniline.

According to the instructions for preparation 6, 2-amino-2'-chloro-5-nitrobenzophenone hydrazone is used refluxed with potassium hydroxide in diethylene glycol, whereby the Tit.elverbindungen receives.

Preparation 1 ο

2-benzylaniline.

According to the instructions of preparation 6, 2-amino-benzophenonhydrazone is used refluxed with potassium hydroxide in diethylene glycol to give the title compound.

Preparation 11

1-Acetyl-2- / ~~ N- (4-chloro-c * -phenyl-o-tolyl) -formimidoyl7hydrazine.

A mixture of 3.37 g (15.5 millimoles) of 2-benzyl-4-chloroaniline, 5.52 g (37.3 millimoles) of triethyl orthoformate and a catalytic amount of the starting amine hydrochloride is refluxed for 5 hours to distill off the ethanol. The orange solution is then allowed to come to room temperature cool, the crude oil obtained in this way will Dissolve in 25 ml of absolute ethanol and add 2.35 g (32, ο Millimoles) of acethydrazide added. After the solution has been stirred for 1/2 hour, a white solid precipitates. Then again Stirred for 2 1/2 hours, then the solid is in

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Dissolved ethyl acetate and recrystallized from ethyl acetate / hexane, 2.95 g (61? ^) 1-acetyl-2- / ~ "N- (4-chloro- & -phenyl-otolyl) -formimidoyl2-hydrazine in the form of fine needles • melting point of 17o, receives 5-173 ° C the melting point of the analyzes. sample was 174-175 ⁰ C.

Anal. Ber. for C ₁₆ H ₁₆₅

C: 63.68; H: 5.35; N: 13.93; Cl: 11.74 Found: C: 63.81; H: 5.22; K: 13.94; Cl: 11.57

A second fraction (0.8 g, 17 #) melted at 157-160 ⁰ C.

Preparation 12

1-Isonicotinoyl-2 - / "~ N- (4-chloro-cx-phenyl-o-tolyl)« ° formimidoylj [7 " hydrazine.

A mixture of 10.12 g (46.5 millimoles) of 2-benzyl-4-chloroaniline and 16.57 g (1o1.9 millimoles) of triethyl orthoformate was refluxed in a 50 ml round bottom flask while the ethanol was distilled off. After heating for an additional 2 to 4 hours, the liquid in the flask was cooled to room temperature, then the reaction mixture was dissolved in 100 ml of absolute ethanol. 13.2 g (96 millimoles) of isoniazid were added to this solution. The mixture (isoniazid is not very soluble in cold ethanol) was stirred overnight at room temperature, the solid was filtered off and dissolved in 700 ml of tetrahydrofuran, the solution was concentrated to 35o ml. Then hexane was added cautiously to the point where the cloudiness was just beginning. Thereafter, a white solid (5.3 g, 31 $) at the front melting point was obtained 173-178 ⁰ C. The melting point was increased to 180-182 ° C. by recrystallization from tetrahydrofuran. A sample recrystallized from dimethylformamide / water melted at 193-194 ° C.

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The mother liquors of the first crystallization gave 3.67 g (22 $) of a white powder of melting point 178-182 ⁰ G. The analytically pure sample of 1-isonicotinoyl-2 ^ ~ * N- (4-chloro-phenyl C * o-tolyl) -formimidoyl7-hydräzins had a melting point of 18o to 182 C.

Preparation 13

1-Acetyl-2- / ~ * N - / "~ 4-chloro- <X- (o-chlorophenyl) -o-tolyl7-iormimidoylj-hydrazine.

According to the instructions of preparation 11, 2- (o-chlorobenzyl) -4-chloroaniline and triethyl orthoformate are refluxed, then after heating for 4 hours at room temperature treated with acetylhydrazide to give the title compound received.

Preparation 14

1-Propionyl-2- / ~ N - / "4-chloro-0 < _k - (2,6-difluorophenyl) -o-tolyl_7-IT-hydrazine.

According to the instructions of preparation 11 were 4-chloro-cy- (2,6-difluorophenyl) -o-toluidine and Orthoamenenäuretriethyleater refluxed, then after 5 hours of heating at Treated room temperature with propionic acid hydrazide to give the title compound.

Preparation 15

1-Cyclopropylcarbonyl-2- / ~~ N- / ~ o (- (o-chlorophenyl) -4-nitro-otolylj-formimidoylj-hydrazine.

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According to the instructions of preparation 11, 2- (o-chlorobenzyl) -4-nitroaniline were used and triethyl orthoanic acid at reflux boiled and after 5 hours "at room temperature with cyclopropylcarbonylhydrazide treated, with the title compound received.

Preparation 16

1-Benzoyl-2 - / "~ N- (c * -phenyl-o-tolyl) -formimidoyl-7-hydrazine.

According to the procedure of preparation 11 were 2-benzylaniline and triethyl orthoformate are refluxed and then after 5 hours at room temperature with benzoyl hydrazide treated to obtain the title compound.

Preparation 17

1-ethoxalyl-2- / ~ N - / '^ / - (o-chlorophenyl) -4-nitro-o-tolyl7-formimi d ο y 3.7- hy d r a ζ i η »

According to the instructions for preparation 11, 2- (o-chlorobenzyl) -4-nitroaniline and triethyl orthoformate were refluxed and treated with ethyloxalylhydrazide after 5 hours at room temperature to give the title compound.

Preparation 1β

~~ --4H-1,2,4-triazole.

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28.4 g (94.2 rillimoles) of 1-acetyl-2- -chlor- «- (phenyl) -o-tolyl.7 ~ forn <iinidoyl7-hydrazone

and given 400 ml diglyme. The mixture is heated to reflux temperature and at 120 ° C. all of the solid starting material has dissolved. Then 20 ml of pyridine are added and the solution is refluxed overnight (20 hours). Under reduced pressure, about 200 ml of pyridine, water and diglyme are removed by distillation, and the remaining cold reaction solution is mixed with 1500 ml of hexane (ρ.Λ.). Rubbing in an ice bath gives 20.0 g ($ 787) of 4- / ~ 4 ~ chlorine- «- (phenyl) -o-tolyl_7-3-methyl-4H-1,2,4-triazole with a melting point 135-139 ° C. The analysis sample is obtained by recrystallization from ethyl acetate / hexane, P. 142 ⁰ C.
Anal. Ber. for C ₁₆ H ₁ ClN ₅ :

C: 67.72; H: 4.97; H: 14.81; Cl: 12.5o. Found: C: 67/39; H: 4.98; II: 14.99; Cl: 12.61.

Preparation 19

4- / 4-chloro-oi- (phenyl) -o-to ^ 17-5- (4-pyridyl) -4H-1,2,4-triazole.

3.64 g (Io, o Nillimol) 1-isonicotinoyl-2- / ~ N- (4-chloro-C <phenyl-o-tolyl) -formimidcy ^ -liydrazine are filled into a 2oo ml round bottom flask together with 60 ml diglyme, then the mixture is refluxed. At a pot temperature of around 150 ° C, all of the starting material has dissolved. The mixture is refluxed for a further 3 hours, then the solution is allowed to cool overnight. The slightly cloudy liquid \ .is dried over what no rf r eggs Kagnesiumsiumsulfat / Uatriuctuilfat and filtered. Then 900 ml of hexane are added, the crystallization is initiated by grinding and the

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Mixture is placed in the refrigerator. The resulting light brown solid is filtered off, giving 2.33 g ($ 679) 4 ~ / ~ 4-chloro-oi- (phenyl) -o-tolyl7-3- (4-pyridyl) -4H- ■ 1,2 , 4-triazole, mp 138-142 ⁰ C. The analytical sample v / urde by recrystallization first from -wässrigem methanol (platelets, F. 145-146 ° C) and then from ethylacetate / hexane (white prisms, mp 145 -146.5 ^P C).

Preparation 2o

4 - / "" 4-chloro-o * - (o-chlorophenyl) -o-tolyl7-3-methyl-4H-1,2,4-triazole.

According to the instructions of preparation 18, T-acetyl-2- / ~ H- / ~ 4-chloro-0 <- (o-chlorophenyl) -o-tolyl7-foriaiiDidoyl7-hydrazine heated with i> iglynie and pyridine, whereby the title compound receives.

Preparation 21

-CX - (2,6-difluorophenyl) -o-tolyl7-3-ethyl-4H-1,2,4-triazole. ■

According to the instructions for preparation 18, 1-propionyl-2 - / "11 - /""4-ChIOr-C / - (2 _# 6-üifluorophenyl) -o-tolyl7-formimidoyl7-hydrazine is heated with - ^ iglyme and pyridine, where you get the Tite! connection.

@ DIQ Q / 1 11

Preparation 22

4- / ~ οί - (o-chlorophenyl) -4-nitro-o-tolyl _i 7-3-cyclopropyl-4H-1., 2 _i 4-triazole.

According to the instructions for preparation 18, I-cyclopropylcarbonyl-2 - / "" N - / "" öi - (o-Chlorophenyl) -4-nitro-o-tolyl.7-i * ormimidoyl.7-hydrazine heated with diglyrae and pyridine to give the title compound.

Preparation 23

4- / 1 * - (Phenyl) -o-tolyl7-3-phenyl-4H-1,2,4-triazole.

1-Benzoyl-2 - / "~ N- (oi-phenyl-o-tolyl) -formimidoy3L7-hydrazine is heated with diglyme and pyridine according to the instructions for preparation 18, whereby the title compound is obtained.

Preparation 24

- (o-Chlorophenyl) -4-nitro-o-tolyl7-3-ethoxycarbonyl-4H-1,2,4-triazole.

According to the instructions for preparation 18, i-ethoxalyl-2 - / "* N - /" "o ( - (o-chlorophenyl) -4-nitro-o-tolyl7-fοrmimidoy! ^ - hydra zin heated with ^ iglyme and pyridine, whereby the title compound receives.

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Preparation 25

2'-Benzoyl-4'-chloropracetanilide.

81.5 g (1.037 mol) of acetyl chloride are added to a solution of 2oo, og (0.864 KoI) 2-aniino-5-chlorobenzophenone and 68.4 g (0.864 mol) of pyridine in 4 ml of dry ether with stirring . The mixture is kept at room temperature for 2 hours and then treated with 500 ml of water. The layers are separated, the ether phase is dried over anhydrous sodium sulfate and concentrated. When the residue crystallizes from ethyl acetate / Skellysolve B: 124.0 g of 2'-BCnZOyI ^ ¹ -chloroacetanilide, F * are obtained. 114-115 ° C and two other fractions of 2'-benzoyl-4'-chloroacetanilide: 67.8 g, melting 113,5-1H _f 5 ° C and 33 ο g, mp 113-114 ⁰ C.

Preparation 26 '

6-Clilor-4-phenyl-2- (iH) -quinoline.

It was prepared according to the method of A.E. Drukker and C.I. Judd, J., Heterocyclic Chem. 3, 359 (1966) (conversion of 2'-benzoyl-5'-chloroacetanilide worked with sodium hydroxide), the yield was $ 77. Two further manufacturing processes have been described by S.O. Bell, T.S. Sulkowski, C. Gochman and S.J. Childrens, J.Org.Chem. 27: 562 (1962); G.A. Reynolds and CR. Hauser, «1. Amer. Chem. Soc. 72, 1852 (195o).

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Preparation 27

2, e-dichloro - ^ - phenylquinoline.

It was made according to the method of A.E. Drukker and CI. Judd, J. Heterocyclic Chem. 3, 359 (1966), yield 62 #.

Preparation 28

e-chloro ^ -hydrazino- ^ - phenylquinoline.

A mixture of 2.7 g (0.01 mol) of 2,6-dichloro-4-phenylquinine and 6.8 g of hydrazine hydrate was refluxed with stirring in a nitrogen atmosphere for 1 hour and concentrated in vacuo. The residue was suspended in warm water, the solid was filtered off, dried and recrystallized from ethyl acetate / Skellysolve B. 1.81 g ($ 67) of 6-chloro-2-hydrazino-4-phenylquinoline with a melting point of 156.5-157 ° C. were obtained. Anal. Ber. for C ₁₅ H ₁₂ ClN:

C: 66.79; H: 4.49; Cl: 13.15; N: 15.58; Found: C: 67.15; H: 4.65; Cl: 13.19; N: 15.32.

Preparation 29

7-chloro-1-methyl-5-phenyl-s-triazolo / ~ "4,3-α7quinoline.

A mixture of 1.4 g (o, oo52 Hol) 6-chloro-1-hydrazino-4-pheny quinoline, 925 g (0.057 mol) of triethyl orthoacetate and 100 ml of xylene were added in a nitrogen atmosphere with stirring Boiled under reflux for 2 hours 40 minutes. Y / uring this

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The ethanol formed during the reaction was removed through a short column packed with glass coils. The mixture was then concentrated to dryness in vacuo and the residue was crystallized from methanol / ethyl acetate, which gave 1.02 g of T-chlorine-i -methyl-S-phenyls-triazolo / ~ 4,3-α7-quinoline with a temperature of 253.5-255 ° C. and 0.26 g with a temperature of 253.5-255 ° C. (83.9% yield) was crystallized from Hethylenchlorid / methanol, melting point 252.5 to 253.5 ⁰ C
Anal. Ber. for C ₁₇ H ^ ₂ ClN ₅ :

C: 69.5o; H: 4.12; Cl: 12, o7 ;, N: 14,, 31. Found: C: 69.39; H: 4.02; Cl: 12.1o; N: 14.49.

Preparation 3ο

5-chloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone (oxidation of 7-chloro-1-methyl-5-phenyl-s-triazolo / "~ 4,3-a7-quinoline). .

A suspension of $ 2.94 (0.01 mol) 7-chloro-1-methyl-5-phenyl-s-triazolo ^ ~ 4,3-α7quinoline in 1 ml of acetone was cooled with stirring in an ice bath and slowly with a Added solution which had been prepared by adding 2 g of sodium periodate to a suspension of 2oo mg of ruthenium dioxide in 35 ml of water with stirring. The mixture turned dark. Another 8 grams of sodium periodate was added over the next 15 minutes. The ice bath was removed and the mixture was stirred for 45 minutes. An additional 4 g of sodium periodate was added and the mixture was stirred at room temperature for 18 hours and then filtered. The pesticide was washed with acetone and the combined filtrates were evaporated in vacuo. The residue was suspended in water and

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extracted with methylene chloride. The üxtrakt was concentrated and dried over anhydrous potassium carbonate, the residue was chromatographed on silica gel with 1oo g lofi i'iethanol / 9o chromatographed £ ethyl acetate, and fractions were collected ml of 5o. The product was eluted in fractions 1o to 2o and was crystallized from ethyl acetate. In this case, one o received, 4O5 g, mp 168 to 169.5 ° C, and o, 291 g, mp 167.5 to 169 ⁰ C (23.4 / 0th The analytically pure sample melted at 168 ⁰ C.
Anal. Ber. for C ₁₆ H ₁₂ ClN ₅ O:

C: 64.54; H: 4.06; Cl: 11.91; N: 14.11. Found: C: 64.56; H: 4.35; Cl: 11.97; 11.93; N: 14.29.

Preparation 31

5-chloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone.

A solution of 0.357 g (0.021 mol) of silver nitrate in 1.8 ml of water was treated with 4.1 ml of 1N sodium hydroxide solution while stirring. A warm solution of 326 mg of 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3-carboxaldehyde methanol solvate in 15 ml of methanol was added to the resulting silver oxide suspension with stirring, the resulting mixture v / urde stirred in nitrogen at room temperature for a further 18 hours. The solid was then filtered off and washed with water and methanol. The filtrate was freed from methanol in vacuo, the resulting aqueous solution was cooled in an ice bath, neutralized with hydrochloric acid and extracted with chloroform. The residue of the extract was crystallized from ethyl acetate, which gave 0.162 g of 5-chloro-2- (3-ynethyl-4H-1,2,4-triazol-4-yl) -benzophenone with a melting point of 169.5- 171 ⁰ C

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Preparation 32

6-chloro-4- (2,6-difluorophenyl) -2-hydrazinoquinoline.

According to the instructions of preparation 1, 2,6-Mchlor-4- (2,6-difluorophenyl) -quinoline was obtained refluxed with hydrazine hydrate to give the title compound. '

Preparation 33

7-chloro-1-methyl-5- (2,6-difluoropheny1) -s-triazolo / 4,3- & 7-quinoline.

Following the procedure of Preparation 29, 6-chloro-4- (2,6-difluoropheny1) -2-hydrazinoquinoline was made and triethyl orthoacetate in xylene is refluxed to give the title compound received.

Preparation 34

5-chloro-2 ", 6'-difluoro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone.

According to the instructions for preparation 3o, 7-chloro-1-methyl-5- (2,6-difluorophenyl) -s-tria2olo / 4,3-α-7quinoline was treated at low temperature with sodium periodate and ruthenium dioxide to give the title compound.

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Preparation 35

6-chloro-4- (o-chlorophenyl) -2-hydrazinoquinoline.

According to the instructions of preparation 1, 2,6-dichloro-4- (ochlorphenyl) -quinoline was made reacted with hydrazine hydrate under reflux to obtain the title compound.

Preparation 36

7-chloro-1-methyl-5- (o-chlorophenyl) -s-triazolo / 4,3-alpha-7quinoline.

Following the procedure of Preparation 29, 6-chloro-4- (o-chlorophenyl) -2-hydrazinoquinoline was made and triethyl orthoacetate in xylene is refluxed to give the title compound received.

Preparation 37

2.5-dichloro-2- / 3-methyl-4H-1 _l 2,4-triazol-4-yl7 ^ enzophenone.

According to the instructions of preparation 3o, T- (o-chlorophenyl) -s-triazolo / ~ 4,3-α7quinoline oxidized at low temperature with sodium periodate and ruthenium dioxide, whereby the title compound was obtained.

Preparation 38

5-nitro-6-propyl-4- (m-trifluoromethylphenyl) -2-hydrazinoquinol- i "

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According to the instructions for preparation 1, 2-chloro-5-nitro-'6- ■ propyl-4- (m-trifluoromethylphenyl) -quinoline with hydrazine hydrate reacted under reflux to obtain the title compound.

Preparation 39
6-nitro-7-propyl-1-ethyl-5- (m-trifluoromethylphenyl) -s-triazolo-

According to the instructions for preparation 2Q , 5-nitro-6-propyl-4- (m-trifluoromethylphenyl) -2-hydrazinoquinoline and orthopropionic acid triethyl ester were refluxed in xylene to give the title compound.

Preparation 4ο

6-nitro-5-propyl-2- (3-ethyl-4H-1,2,4-triazol-4-yl) -3 ⁸ - (trifluoromethyl) benzophenone.

According to the instructions for preparation 3o, δ-nitro-T-propyl-ethyl-5- (m-trifluoromethylphenyl) -s-triazolo / 4,3-a7-quininoline was used at low temperature with sodium periodate and ruthenium dioxide oxidized to give the title compound.

example 1

4- / ~ * 4-chloro- ^ i -phenyl- o-tolyl7-5-pyrrolidinomethyl-3-methy; 4K-1,2,4-triazole.

309 809 / 11SS

- 3ο -

^ 240043

A mixture of 0.60 ml 37 # formalin (0.22 g, 7.4 I4illinol) jo, 250 ml pyrrolidine (boiling point 85 ° C, o, 213 g, 3. o Hillimol) and 1, oo ml 2, On hydrochloric acid was dissolved in 2.0 ml diglyme in a 20 ml flask equipped with a reflux condenser and magnetic stirrer. Then, 2835 g (i _f oo Hillimol) solid 4- / ~ * - ^chlorine - <* - phenyl-o-tolyl / ^ - methyl ^ Hi, 2,4-triazole were added and the mixture was left on for 16 hours Steam bath boiled under reflux. The mixture was then cooled and poured into 5% aqueous sodium hydroxide solution, which was extracted with benzene. The benzene phase was dried over anhydrous magnesium sulfate, concentrated and diluted with hot ethyl acetate and hexane. Upon cooling, 2o8 g (56.7 $) of colorless prisms were obtained from the o melting point 138-142 ⁰ C (decomposition). Recrystallization from ethyl acetate / hexane gave 0.156 g of 4- / ~ 4-chloro-o (-phenyl-o-tolyl7-5-pyrrolidinomethyl-3-methyl-4H-1,2,4-triauene from P. 141 -144 ⁰ C
Anal. Ber. for C ₂₁ H ₂₃ ClN ₄ :

C: 68.74; H: 6.32; N: 15.28; Cl: 9.66. Found: C, 68.6o; H: 6.3o; N: 14.95; Cl: 9.64.

Example 2

4 - / "4-chloro-δ / - (o-chlorophenyl) -o-tolyl7-5-piperidinomethyl-3-ethyl-4H-1,2,4-triazole.

According to the formula of Example 1, 4- / ~ 4-chloro-crf- (ochlorphenyl) -o-tolyl7-3-ethyl-4H-1,2,4-triazole, dissolved in diglyme, "with formalin, piperidine and 2N hydrochloric acid at 100 ° C refluxed to give the title compound.

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Example 3

4 - / "~ 4-chloro-c * - (o-chlorophenyl) -o-tolyl7-5-pyrrolidinomethyl-3-methyl-4H-1,2,4-triazole.

According to the procedure of Example 1, 4-, £ ~ 4-chloro-crf- (ochlorphenyl) -o-tolyl7-3-niethyl-4H-1,2,4-triazole ,, dissolved in diglyme, with formalin, pyrrolidine and 2N hydrochloric acid at 100.degree heated to reflux to give the title compound.

Example 4

4- / ~ 4-Nitro-ci- (o-chlorophenyl) -o-tolyl7-5-aimethylaminomethyl-3 (4-pyridyl) -4H-1,2,4-triazole.

According to the procedure of Example 1, 4- / ~ 4-Mitro-c £ - (o-chlorophenyl) -o-tolyl7-3- (4-pyridyl) -4H_1,2,4 ~ triazole, dissolved in diglyme, with formalin, dimethylamine and 2N hydrochloric acid heated under reflux at 100 ° C., the title compound being obtained received.

Example 5

4- / ~~ 4-Nitro- c <- (o-chlorophenyl) -oethyl-4H-1,2,4-triazole.

Following the procedure of Example 1, 4 ~ / '~ 4-nitro-o <(chlorophenyl) -o-tolylJ ^ -cyclopropyl ^ Hi, 2,4-triazol ₃ in diglyme, treated with ■ ^c ormalin _i Iiorpholin and 2n Hydrochloric acid heated under reflux at 100 ° C, the titlever = »

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22400A3

got bond.

Example 6

4 - / "" 4-Nitro-C * - (o-chlorophenyl I-o-tolyl I-S-diethyl E.minomethyl-3-ethoxycarbonyl-4H-1, 2 , 4-triazole.

According to the procedure of Example 1 was 4 - / "~ 4-nitro-o (- (ochlorphenyl) -o-tolyl.7-3-ethoxycarbonyl-4H-1,2,4-triazole, dissolved in diglyme, refluxed with formalin, diethylamine and 2N hydrochloric acid at 100 ° C. to give the title compound.

Example 7

4 - / ^ (- I ^> henyl-o-tolyl.7-5-dipropylaminoinethyl-3-phenyl-4H-1,2,4 · triazole.

Following the procedure of Example 1, 4- / ö (-phenyl-otolyl7-3-phenyl-4H-1,2,4-triazole, dissolved in diglyme, was added Formalin, dipropylamine and 2N hydrochloric acid were heated under reflux at 100 ° C. to give the title compound.

Example 8

"oi - (m-bromophenyl) -o-tolyl7-5-piperidinomethyl 3-cyano-4H-1,2,4-triazole.

Following the procedure of Example 1, 4 - / "6-Methylthiooi, - (m-bromophenyl) -o-tolyl7-3-cyano-4H-1,2,4-triazole, in Diglvme

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dissolved, with formalin, piperidine and 2N hydrochloric acid at 100 ° C heated to reflux to give the title compound.

Example 9

4 - / "5-Ethylsulfonyl- o / - (p-dipropylaminophenyl) -o-tolyl7-5-diisopropylaminomethyl-3-chloro-4H-1,2,4-triazole.

According to the procedure of Example 1 was 4 - / "" 5-Äthylsulfonyl- ^ - (p-dipropylaminophenyl) -o-tolyl7-3-chloro-4H-1,2,4-triazole, dissolved in diglyme, with formalin, isopropylamine and 2N hydrochloric acid heated under reflux at 100.degree. C., the titre compound being obtained.

Example 1o

4- ^ 3-propylsulfynyl- o (- (o-ethylthiophenyl) - _o -tolyl7-5-piperidinomethyl-4H-1,2,4-triazole.

According to the procedure of Example 1, 4- / ~ 3-propylsulfinyl- (o-ethylthiophenyl) -o-toly] _7-4H-1,2,4-triazole, dissolved in diglyme, with formalin, piperidine and 2N hydrochloric acid at 100 ° C refluxed to give the title compound i

Example 11

5-chloro-2 - / "" 3-methyl-5- (pyrrolidinomethyl) -4H-1,2,4-triazol-4-yl7-benzophenone.

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■ - 34 -

A solution of 3, ο ml 37 / Sigem formalin (1.11 g or 37, ο millimoles), 1.25 ml of distilled (85 ⁰ C) pyrrolidine (1 »° 7 g, 15, o millimoles) and 7.5o ml of 2N hydrochloric acid in 10.0 ml of diglyme was placed in a 50 ml flask equipped with a reflux condenser and magnetic stirrer. Then 1.488 g of 5-chloro-2- (3-methyl-4H-1,2,4-triazol-4-y1) -benzophenone were added, then the gas above the reaction vessel was evacuated several times and replaced with nitrogen. The solution was then refluxed in a nitrogen atmosphere for 17 hours, then poured into about 40 ml of 5% aqueous sodium hydroxide solution and extracted 4 times with 30 ml of benzene each time. The benzene extracts were combined, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator (Rotavap). The resulting diglyme solution was heated on a steam bath, diluted with hexane and allowed to cool. This gave 1.o4 g of a white solid which was recrystallized from ethyl acetate / hexane and, in the process, 0.82 g of 5-chloro-2 - / "~ 3-niethyl-5" (pyrrolidinomethyl) -4H-1,2,4 triazol-4-yl, 7 ^ enzophenon in the form of white needles melting at 169.5 to 171.5 ⁰ C .ergab. Anal. Ber. for C ₂₁ H ₂₁₄

C: 66.22; H: 5.56; N: 14.71; Cl: 9.31. Found: C: 66.00; H: 5.84; N: 14.44; Cl: 8.94.

Example 12

5-chloro-2- / ~ 3-methyl-5- (pyrrolidinomethyl) -4H-1,2,4-triazol-4 yl2 [-benzophenone.

A solution of Jones reagent (chromic anhydride, sulfuric acid, 1.0 ml) was added to a solution of 0.380 g of 4- / ~ 4-

added triazole in 1.0 ml of acetic acid. The mixture was

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Boiled under reflux for 3 hours, cooled and poured into 5% aqueous Poured sodium hydroxide solution and extracted iait chloroform. The chloroform phase was dried with magnesium sulfate and concentrated. The residue became from ethyl acetate / hexane crystallized, this gave the 5-chloro-2 - / "~ 3-methyl-5- (pyrrolidinomethyl) -4H-1,2,4-triazol-4-yl, 7-t> en2ophenone from P. 169-17O ° C.

Example 13

") -4H-1,2,4-triazole-4-

yl7-fcenzophenone.

A mixture of 3.3 ', o ml of 37% formalin (1.1 g, 37 millimoles), 1.31 ml of morpholine (1.31 g, 15.0 millimoles) and 7.5 ml of 2N hydrochloric acid, Dissolved in 10 ml diglyme, it was put into a magnetic stirrer and a reflux condenser equipped 50 ml flask was filled. Then 1.488 g (5.0 millimoles) of solid 5-chloro-2- ^ "3-methyl-1,2,4-triazol-4-yl7-enzophenone added all at once and the solution was refluxed for 24 hours. Then the mixture was dissolved in 5% aqueous sodium hydroxide solution poured, extracted with benzene, the benzene extract was dried over magnesium sulfate and put on a rotary evaporator constricted. The resulting oil was chromatographed on a column (silica gel G, 1o # methanol / chloroform al. Eluent). 100 ml and 50 ml fractions were collected. Fractions 20 and 21 contained that pure product, fraction 22 mainly contained the product contaminated with an unknown substance with a lower value Rf value. When rubbing the fractions 2o and 21 in ether The product separated out in the form of a guinmi-like residue, and after removing the ether in a vacuum it «

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if 500 mg of solid 5-chloro-2- / 3-methyl -!? - (morpholino-

3o °

methyl) -4H-1 ^, A-triazol-'i-yl. T-benzopnenone, mp 128-130 ° C

u
Melting point 128.5-130.5 ° C.

During recrystallization, 35o mg quills with a melting point of 1
Anal. Ber. for

₂₁₁₄

C: 63.56; H: 5.34, N: 14.12; Cl: 8.93; Found: C, 63.41; H: 5.37; K: 14.21; Cl: 9, o8.

Example 14

5-chloro-2 ', 6'-difluoro-2- (3-diethyl-5-dimethylaiainoniethyl-4H-1 ^^ - triazole - ^ - ylJ-benzophenon.

According to the procedure of Example / were 5-chloro-2 ', 6'-difluoro-2- (3-methyl-4H-1 _t 2,4-triazol-4-yl7henzophenon, Uimethylamin, formalin, diglyme and hydrochloric acid with stirring on Refluxed to give the title compound.

Example 15

2,5-dichloro-2- (3-methyl-5-diethylaminoethyl-4H-1,2,4-triazol-4-ylJbenzopHLenone.

According to the procedure of Example 11, 2 ', 5-dichloro-2 - / "" 3-diethyl-4H-1,2,4-triazol-4-yl7 ^ enzophenone, diethylamine _f formalin, diglyme and hydrochloric acid were refluxed with stirring boiled to give the title compound.

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Example 16

6-nitro-5-propyl-3'-trifluoromethyl-2 / ~ 3-ethyl-5-dipropylaminomethyl-4H-1, 2,4-triazol-4-yl7 ^l3enzo Ph ^enone ·

6-Nitro-5-propyl-3-trifluoromethyl-2- (3-ethyl-4H-1,2,4-triazol-4-yl7 "benzophenone, Dipropylamine, formalin, diglyme and hydrochloric acid among Stir refluxed to give the title compound received.

Example 17

5-nitro-2 ', 6-di (methylthio) -2- (3-ethoxycarbonyl-5-pyrrolidino methyl-4H-1,2,4-triazol-4-yl7 "benzophenone.

Following the procedure of Example 11 were 5-nitro-2 ', 6-di- (methylthio) -2- (3-ethoxycarbonyl-4H-1,2,4-triazol-4-yl) -benzophenone, Pyrrolidine, formalin, diglyme and hydrochloric acid are refluxed with stirring to give the title compound received.

Example 18

5-Bromo-4'-ethylsulfonyl-2- (3-cyano-5-morpholinomethyl-4H-1,2,4 triazol-4-yl) benzophenone.

Following the procedure of Example 11 were 5-bromo-4'-ethylsulf onyl-2- / ~ "3-cyano-4H-1,2,4-triazol-4-yl, 7-henzopherion, Morpholine, formalin, diglyme and hydrochloric acid were refluxed with stirring to give the title compound.

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Example 19

5-DimethylaiBino-3'-trifluoromethyl-2- / -3-bromo-5-piperidinomethyl-4H-1,2,4-triazol-4-y2; 7-henzophenone.

Following the procedure of Example 11 were 5-dimethylamino-3'-trifluoromethyl-2- (3-bromo-4H-1,2,4-triazol-4-yl) -benzophenone, Piperidine, formalin, diglyme and hydrochloric acid are refluxed with stirring to give the title compound received

Example 2o

3-Propylsulfinyl-2, 4 ^f -diethyl-2- (3-propy1-5-diisopropylaminomethyl-4H-1,2,4-triazol-4-yl) -benzophenone.

Following the procedure of Example 11 were 3-propylsulfinyl-2 ', 4'-diethyl-2- (3-propyl-4H-1,2,4-triazol-4-yl) -benzophenone, Diieopropylamine, formalin, diglyme and hydrochloric acid with stirring arr. Boiled under reflux, whereby the title compound received.

Example 21

.4 _t 4 ^l -Dimethoxy-6-methyl-2 - / "" 3-fluoro-5-diisopropylaminomethyl-4H-1,2,4-triazol-4-yl, 7-t) enzophenone.

4,4'-Diinethoxy-6-methyl-2- / ~ "3-i" luoro-4H-1,2,4-triazol-4-yl, 7henzophenone were prepared according to the procedure of Example 11 , Diisopropylaniin, formalin, diglyme and hydrochloric acid refluxed with stirring to give the title compound.

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Example 22

5-cyano-2 ^l-chloro-2 - / "3- (4 ~ pyridyl) -5-piperidinomethyl-4H-1,2,4-triazol-4-yl7benzophenon.

Following the procedure of Example 11, 5-cyano-2'-chloro-2- ^ ~ 3- (4-pyridyl) -4H-1,2,4-triazol-4-yl7benzophenone, piperidine, Formalin, diglyme and hydrochloric acid refluxed with stirring to give the title compound.

Example 23

5-chloro-2- / ~~ 3-ir.ethyl-5-piperidinomethyl '-4H-1,2,4-triazol-4-yl7t> enzophenone hydrochloride.

According to the procedure of Example 11 5-Chloro-2- (3-raethyl · 4H-1 _r 2,4-triazol <-4-yl) - _"f benzophenone piperidine, formalin, diglyme and hydrochloric acid with stirring in a nitrogen atmosphere at reflux boiled, the 5-chloro-2 - / "~ 3-methyl-5- (piperidinomethyl) -4H-1,2,4-triazol-4-yl7henzophenone hydrochloride with a melting point of 226-245 ° C (dec. ) received.

Following the procedure of the above examples, other starting compounds of the formulas I or III can be used in the products II and IV are transferred. For example, you can get the following connections:

-Trifluoromethyl-6- bromo-W -phenyl-o-tolyl7-5-morpholino ~

4- / ~ 4-Dipropylamino-6-methyl - ^ - (p-fluorophyl) -o-tolyl7-5-piperidinomethyl-3-propyl-4H-1,2,4-triazole, 4- / ~ 4-Fluoro-6-acetylamino-o ^ - (p-propylsulfinyl) -o-tolyl7-5-pyrrolindomethyl-3- (2-pyridyl) -4H-1,2,4-triazole,

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4 - / "~ 5-Isoprqpyl-G-methyl- r / - (o-ethylthiophenyl-o-tolylJ-S-morpholinomethyl-3-pyridyl-4H-1,2,4-triazole, 4 - /" ~ 6- Ethylsulfiny l- £ ~ d - (o-propy lpheny 1) -o-tolyl7-5-dime thy 1-aminomethyl-4H-1,2,4-triazole,

4 - / "~ Phenyl-o-tolyl7-5-piperidinomethyl-4K-1,2,4-txiasol, 4- / o / - (o-chlorophenyl) -o-tolyl _> 7-5-pyirolidinomethyl-4H-1 , 2,4-triazole,

4- / o ^ - (o-chlorophenyl) -o-toly2.7-5-piperidinoniethyl-3-ethyl-4H-1,2,4-triazole,

4- / ~ * 4 _f 6-üimethyl- CJi-io-chlorophenylJ-o-tolyl ^ ZS-nioTpliolino- · methyl-5-methy1-4H-1,2,4-triazole,

4 - / "~ 5-Chlor- oi -phcnyl-o-toly2 _; 7-5-diethylaIainolπethyl- · 3- Cote trazinyl) -4H-1, 2,4-triazole,

5-nitro-2- (3-pyrazolyl-5-dimethylaminomethyl-4H-1,2,4-triazol-4-yl) -laenzophenone,

5,6-dicyano-2'-bromo-2- (3-imidasolyl-5-morpholino-methyl-4II-1,2,4-triazol-4-yl) - "benzophenone,

3,6-Dipropy 1-2 ^f , 4'-diethyl-2- (3-ethyl-i? -Dipropylamine © iEethyl-4Ii-1,2,4-triazol-4-yl) -benzophenone,

5-fluoro-2 »-diethylamino-2- (3-cyano-5-piρeri · dinolnethyl-4H-1,2,4-triazol-4-yl) -" benzophenone,

5-diisopropylamino-2 ^l -propylthio-2- (3-broia-5-pyrrolidinomethyl ^ 4H-1,2,4-triazol-4-yl) -benzophenone, 6-ethylthio-2- (3-fluoro-5- dipropylaminomethyl-4H-1, 2,4-triazol-4-yl) benzophenone,

5,4 '-6' trichloro-2 / ~ 3- (1,2,3-triazinyl) -5- »orpliolinoine thyl-4H-1,2 ψ 4-triazol-4-yl7 ^ en2
4,3 ' _T 5' -Triynethyl-2 - / "3- (2-1,2,4-triazol-4-yl7toe: nzophenon _t

2'-chloro-3- (pyrrrolyl) -S-propylaninomethyl ^ Ii-i _r 2,4-trI-azole _T 4-yl-benzophenoii, and the like.

These compounds and the products of the above examples can be converted into pharmacologically acceptable acid addition salts

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be transferred by treating them with the acid in question, e.g. with hydrochloric acid, sulfuric acid, hydrobromic acid, Acetic acid, lactic acid, tartaric acid, cyclohexanecarboxylic acid,. Cyclohexanesulfamic acid, citric acid or. like. implements.

309809/1185

Claims (1)

Patent claims: 1. 4- (α-Pheny 1-o-tolyl) -5-methylamino-4H-1,2,4-triazoles of the general formula R " wherein R. is hydrogen, an alkyl radical with 1 to 3 carbon atoms, cycloalkyl radical with 3 to 8 carbon atoms, phenyl radical, benzyl radical, a radical of the formula -COOR ', wherein R ¹ denotes an alkyl radical as defined above, or a heterocyclic aromatic ring with 5 up to 6 atoms with 1 to 4 heteroatoms in the form of oxygen, nitrogen or sulfur, R "and R" are ¹ alkyl radicals as defined above or together as .R " -NC represent a piperazino, N'-alkyl or N'-arylpiperazino, pyrrolidino, piperidino or morpholino radical, and R ₂ , R _{1 , Ri 4} and E 1. Hydrogen atoms, alkyl radicals as defined above, halogen atoms, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alky! Sulfonyl, 3 0 9 8 09/116 5 22-043 A lkano y! Amino-. '. Amino - / or dialkyl amino groups, the carbon of which is produced Have 1 to 3 carbon atoms, mean and their pharmacologically acceptable acid addition salts. 3. 4- [il-chloro-a- (o-chlorophenyl) -o-tQ "ly lj; -5 ~ methyl-3-methyl ~ 4H-1,2, ii-triazole / ' ^ ₀ Process for the preparation of the compounds of the following formula II or XV II wherein R ₁ , R ^11. , R ^ttr , R ₂ * ^ τ » ^ and R_ have the meaning given in claim 1» characterized in that a compound of the formula I or 3 098 09 [} wherein R ₁ , Rp »R ,, Rj. and R, - have the meaning given in claim 1, heated with aqueous formaldehyde solution, diet hy lenglykoldimethy lather, hydrochloric acid and a secondary amine of the formula R ¹ ^ NH-R ¹ ". 5. The method according to claim h _t, characterized in that that is used as starting material 'J-chloro-'l-ta-phenyl-o-tolylJ-, ^3-methyl-1 IH-l, 2, ¹ l-triazole. 6. The method according to claim 4, characterized in that that one works at the reflux temperature of the mixture. 7. The method according to claim ¹ J and 5, characterized in that using pyrrolidine the ^ - (Jj-chloro-tphenyl-o-tolyl) -5-pyrrolidinomethyl-3-methyl- ¹ IH-l, 2, ⁱ l-triazole. 8. The method according to claim ¹ I, characterized in that the starting material used is 5 ~ chloro-2- (3-methy 1- ¹ JH-1,2, M-triazol · 4-yl) benzophenone and pyrrolidine as the secondary amine . 309809/1 165 224ÖO43 9. The method according to claim 4, characterized in that the starting material used is S-chlorine ^^ C ^ -methyl-JlH-l, 2, ¹ I-triazole-i | -Yl) ^ benzophenone and morpholine as the secondary amine . 10. The method of claim ¹ I, characterized in that measured: as Ausgangsniaterial 5-Ghlor-2- (3-niethyl- l ^ ^J 4H, 2, ¹ l 'triazol ^"1 i ^<r' yl) benzophenone and use piperidine as secondary amine *. For:; Th & üpjiojfo G <? Mpany 509809/1185 ORIGINAL