SU472503A3 - Method for preparing 3-aminopyrazolone-5 derivatives - Google Patents

Description

This invention relates to a process for the preparation of novel 3-aminopyrazolone-5 derivatives, which have biologically active properties.

The proposed method is based on the reaction known in organic chemistry for the preparation of 3-aminopyrazolone-5 derivatives by reacting arylhydrazines with p-amino-p-ethoxyacrylic acid ethyl ester or with cyano acetic ester.

The proposed method for producing 3-amnopyrazolone-5 derivatives of formula I

NH,

N N СНг- R

in tautomeric

which may be forms a, b, c, d

where R is phenyl substituted by 1 or 2 identical or different substituents selected from alkyl, phenyl, trifluoromethyl, nitro, cyano, carbonamido, sulfonamido or alkyl sulfonamido, or a fluorine atom, bromine or iodine; phenyl, monosubstituted with a sulfonalkyl, alkoxy, dialkyl, carbonamido or alkyl mercapto group; phenyl substituted by two identical

substituents selected from alkoxy or trifluoromethyl; phenyl substituted by two different substituents selected from alkyl, phenyl, trifluoromethyl, sulfonalkyl, halogen atom, alkoxy, trifluoromethoxy, alkylamino, cyano, carbonamido, sulfonamido or nitro; trichlorophenyl; 1,3-benzodioxolyl-5; indanyl-5; substituted or unsubstituted p-naphthyl; 5,6,7,8-tetrahydro-2-naphthyl; anthryl or fayantril. The method consists in the fact that the hydrazine of the formula II is R-CHg-NH-NH2 where R is as defined above, and reacts with acetic acid derivatives of the formula III ") CH-COX III Y where X is OXI-, alkoxy-, aralkoxy-, amino or alkylamino; Y is hydrogen; Y is nitrile; or Y and Y are together where Y is alkoxy, aryloxy, aralkoxyalkyl mercapto, aralkyl mercapto or aminogruin, in an inert solvent and the target product is isolated or the intermediate amidhydrazone of formula IV is removed with HH-CHy-R - where X and R have the above values, cyclization followed by isolation of the target product with a known procedure. The reaction of a compound of formula II with a compound of formula III is carried out in the presence of an acidic or basic catalyst when heated to 100 ° C. The intermediate amidhydrazone formed of formula IV is subjected to thermal cyclization or cyclization under the action of the base catalyst. The solvent used is: hydrocarbons, such as benzene, toluene, xylene; halocarbons, such as methylene chloride, chlorosyorm, carbon tetrachloride, chlorobenzene; alcohols, such as methanol, ethanol, propanol, butanol, benzyl alcohol, glycol monomethyl ether; ethers, such as tetrahydrofuran, dioxane, glycol dimethyl ether; amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, triamide hexamethylphosphoric acid; sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane or bases, such as pyridine, picoline, collidip, lutilin and quinoline. The main catalysts include: alkali metal hydroxides, sodium hydroxide, potassium carbonate; or alcohols, such as sodium alcohol or potassium carbonate. Inorganic or organic acids, such as hydrogen halides, sulfuric acid, sulfonic acids, such as toluenesulfonic acid or trifluoromethylsulfonic acid, are used as acid catalysts. In the case where cyanoacetic acid is used for the process, 1 mol of hydrazine of formula II is reacted with 1 mol of the cyanoacetic acid derivative of formula III, and 1 to 3 mol of the basic catalyst is added. In addition, the compounds of the formula I are isolated in vnde their salts or in free form by treating them with an equivalent amount of dilute acid. The compounds of formula I are purified by recrystallization from an appropriate solvent, or by dissolving in dilute sodium hydroxide, followed by filtration in the presence of animal charcoal and re-precipitated with dilute acids. In the case when a p-amino-acrylic acid derivative is used for the process, 1 mol of hydrazine of the formula I is reacted with 1 mol of the 3-amino-acrylic acid derivative of the formula III. A derivative of p-aminoacrylic acid in the free form or in the form of an acid addition salt is used. In the latter case, I mol of base is added to obtain the p-amino-acrylic acid derivative in free form. If the free form of p-aminoacrylic acid is used, then 1-10% acid catalyst is added. To neutralize the salt of the p-amino-acrylic acid derivative, a corresponding minor amount of base is added. The proposed method allows the preparation of the following compounds described by formula I: 3-amino-1- (3,4,5-trichlorobenzyl) -pyrazolone-5, 3-amino-1- (4-fluorobenzyl) -pyrazolone-5, 3- amino-1- (4-bromobenzyl) -pyrazolone-5, 3-amino-1- (4-chloro-3-bromobenzyl) -nirazolone-5, 3-amino-1- (4-fluoro-3-chlorobenzyl) - pyrazolop-5, 3-ampno - 1- (3,4 - dibromobenzyl) - pyrazolone-5, 3-amino-1- (4-bromo-3-chlorobenzyl) - pyrazolone-5, 3-amino-1- (4 -fluoro-3-bromobenzyl) -pyrazolone-5, 3-amino-1- (4-methylbenzyl) -pyrazolone-5, 3-amino-1- (4-methyl-3-chlorobenzyl) -pyrazolone-5, 3- ampno-1- (4-ethylbenzyl) -pyrazolone-5.

3-amio-1- (4-Xoiop-3-methylbenzyl) -pyrazolone-5,

3-amino-1- (4-fluoro-3-methylbenzyl) -pyrazolone-5,

3-amino-1- (4-tert-butylbenzyl) -pyrazolone-5,

3-amino-1- (2-chloro-3-methylbenzyl) -pyrazolone-5,

3-amino-1- (3 - chloro-3 - methylbenzyl) - pyrazolone-5,

3-amino-1- (3-bromo-5-methylbenzyl) -Nirazolone-5,

Z-amio-1 - (3,5 - dimethylbenzyl) - pyrazolone-5,

Z-amio-1- (4-nronil-3 - chlorbeisyl) - nirazolone-5,

3-amino-1- (4-bromo-3 - methylbenzyl) -Nirazolone-5,

3-amino-1- (4-phenyl benzyl) -pyr azolone-5,

Z-amnno-1- (3-phenylbeisyl) -pyrazolone-5,

3-amio-1- (3-phenyl-4-chlorbeisyl) -Nirazolone-5,

Z-amino-1- (4-phenyl-Z - methylbenzyl) - pyrazole on-5,

3-amino-1- (4-chloro-3-trifluoromethylbenzyl) pyrazolo-5,

3-amino-1- (3-chloro-4-trifluoromethylbenzyl) pyrazolone-5,

Z-amio-1- (4-fluoro-3 - trifluoromethylbenzyl) pyrazolo-5,

3-amino-1- (4-bromo-3 - trifluoromethylbenzyl) pyrazolone-5,

Z-amio-1- (Z-chloro-5 - trifluoromethylbeizyl) pyrazolone-5,

3-amino-1- (4-trifluoromethyl-3-methylbenznl) -nirazolo-5,

3-amino-1- (4-methyl-3-trifluoromethylbeizyl) -pyrazolone-5,

3-amino-1- (3,4 - dimethylbenzyl) - pyrazolone-5,

Z-amnio-1 - (2,5 - dimethylbenzyl) - pyrazolone-5,

Z-amio-1- (3,4 - trimethylbenzyl) - pyrazolone-5,

Z-amino-1 - (3,4 - tetramethylbenzyl) - pyrazolone-5,

3-amino-1- (3,4-tetramethylene - 5 - chlorobenzene) -pyrazolone-5,

3-amio-1- (3,4-dimethoxybenzyl) -pyrazolone-5,

3-amino-1- (3,4-methylenedioxybenzyl) -pyrazolone-5,

3-amino-1- (3-chloro-4 - methoxybenzyl) - pyrazolone-5,

3-amino-1- (4-chloro-3-methoxybenzyl) -pyrazolone-5,

3-amino-1- (4-methyl-3-methoxybenzyl) -pyrazolone-5,

Z-amino-1- (4-methoxy-Z-methylbenzyl) - pyrazolo-5,

3-amino-1- (4-nitrobenzyl) -pyrazolone-5,

3-amino-1- (2-nitrobenzyl) -pyrazolone-5,

3-amio-1- (4-nitro-3 - methylbenzyl) - pyrazolone-5,

H-aMnno-1- (Z-nitro-4-methoxybenznl) - pyrazolone-5,

3-amino-1- (3-nitrobenzyl) -pyrazolo-5,

3-amino-1- (2-methoxy-6-methylbenzyl) -pyrazolone-5,

3-amino-1- (2-methoxy-6-chlorobenzyl) -pyrazolone-5,

Z-amino-1- (2-nitro-6 - methylbenzyl) -pnrazolo-5,

3-amino-1- (3-cyaio-4-chlorobenzyl) -pyrazolo-5,

3-amio-1- (4-cyano-3-methylbenzyl) -pyrazolone-5,

3-amino - (4-iaio-3-methoxybenzpl) - pyrazolone-5,

3-amino-1- (4 - sulfonamidobenznl) - pyrazolone-5,

3-amino-1- (4 - N, N - dimethylsulfonamidobenzyl) -pyrazolone-5,

Z-amio-1 - (4 - carbonamidobenzyl) - pyrazolone-5,

3-amino-1 - (4 - N, N - dimethylcarbonamidobenzyl) -irazolone-5,

3-amino-1 - (3 - N, N - dimethylcarbonamidobenzyl) -pyrazolone-5,

3-amino-1- (naphthylmethyl-2) -pyrazolone-5,

3-amio-1- (1 - methylnaphthylmethyl - 2) -pyrazolone-5,

Z-amino-1 - (3 - chlornaftplmethyl - 2) - pyrazolone-5,

3-amino-1- (4-methylsulfonyl-3-chlorobenzyl) -pyrazolone-5,

3-amio-1- (3-methylsulfonyl-4-chlorobenzyl) -pyrazolone-5,

3-amnno-1- (3-methylsulfonyl-4-methylbenzyl) -pyrazolone-5,

3-amino- (4-methylsulfonyl-3-methylbenzyl) -pyrazolone-5,

3-amino-1- (4-sulfonamido-3-chlorobenzyl) -pyrazolone-5,

3-amino-1- (5,6-dichlorna naphthylmethyl-2) - pyrazolone-5,

3-amino-1- (6,8-dichlorna naphthylmethyl -2) -nirazolon-5,

3-amino-1- (5-chloro-naphthylmethyl-2) -pyrazolone-5,

3-amino-1- (4-methylsulfonyl-3 - bromobenzyl) -pyrazolone-5,

3-amino-1- (4-trifluoromethoxybenzyl) -pyrazolone-5,

3-amino-1- (3-trifluoromethoxybenzyl) -pyrazole-5,

3-amino-1- (4-trifluoromethoxy-3-chlorobenzyl) -pyrazolone-5.

Example 1. Getting 1- (and-brombenznl) Z-aminopyrazolone-5.

In 200 ml of ethanol, 9.2 g of sodium metal is dissolved. Then a mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of d-bromobenzyl hydrazine in 50 ml of ethanol is added at room temperature. The mixture is heated to 60 ° C for 2 hours, the precipitate is filtered off and the filtrate is evaporated, treated with water, the aqueous phase is shaken

with ether and acidified with dilute acetic acid. The crude product is recrystallized twice from alcohol to purify.

Obtain 17 g of the desired product with so pl. 139 ° C in the form of tangled needles. Yield 36% of theoretical.

Example 2. Getting 1- (p-bromobenzyl) Z-aminopyrazolone-5.

From 17.5 g of p-amino-α-ethoxyacrylic acid ethyl ester and 20 g of 4-bromo-sysyl hydrazine in alcohol with stirring for 5 hours at 50 ° C, 15.6 g of colorless crystals are obtained after the treatment described in example 1; m.p. 139 ° C. Yield 58% of theoretical.

Example 3. Getting 1- (p-fluorobenzyl) Z-aminopyrazolone-5.

From 17.5 g of p-amino-p-ethoxy-pacrylic acid ethyl ester and 13 g of 4-fluorobenzylhydrazine in ethanol with stirring for 5 hours at 60 ° C after the treatment described in example 1, 13.2 g of colorless crystals are obtained; m.p. 148 ° C. Output 63% of theoretical.

Example 4. Obtaining 1- (W-fluorobenzyl) 3-aminopyrazolone-5.

From 17.5 g of ethyl | 3-amino-3-ethoxyacrylic acid and 13 g of 3-fluorobenzyl hydrazine in ethanol, ppn stirring for 5 hours, after the treatment described in example 1, 11.3 g of colorless crystals are obtained; m.p. 129 ° C. Yield 55% of theoretical.

Example 5. Getting 1 - ("- methylbepzil) Z-aminopyrazolone-5.

17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 13.6 g of 4-methylbenzylhydrazine in 75 ml of pyridine are stirred for 8 hours at the component temperature, then the pyridine is distilled off under reduced pressure. A solution of 4.6 g of Na and 100 ml of ethanol is added to the residue and heated to 60 ° C for 1 hour. The alcohol is distilled off and treated with 100 ml of water. The aqueous phase is extracted with ether, clarified with charcoal and acidified. This gives 7.3 g of a yellow-colored precipitate, which, after recrystallization from alcohol, melts at 149 ° C.

Yield 36% of theoretical.

Example 6. Obtaining 1- (l4-methylbenzyl) 3-aminopyrazolone-5.

4.6 g of Na are dissolved in 100 ml of ethanol. To this solution is added a mixture of 12 g of cyanoacetic acid ethyl ester and 13.6 g of 3-methylbenzyl hydrazine. With stirring, nitrogen is passed through and heated to boiling for 5 hours. The solvent is removed, treated with water, taken up in ether and clarified with animal charcoal. After acidification with acetic acid, 10.3 g of colorless crystals are obtained which, after recrystallization from ethanol, melt at 92 ° C. Yield 51% of theoretical.

Prims) 7. Preparation of 1- (3,4-dnmstilbep. Chpl) -3-; 1Mii: l1 1 razolon-5.

From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 15 g of 3,4-dimethylbenzylhydrazine, analogously to Example 1, 16 g of colorless needles are obtained; m.p. 60 ° C. Yield 74% of theoretical.

Example 8. Obtaining 1- (2,4-dimethylbenzyl) -3-aminopyrazolone-5.

From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 15 g of 2,4-dimethylbenzylhydrazine, analogously to example 1, 14.3 g of a colorless crystalline powder are obtained; m.p. 151 ° C. Yield 66% of theoretical.

Example 9. Getting 1- (l-11itpobenzyl) Z-aminopyrazolone-5.

From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 16.7 g of 4-nitrobenzylhydrazine, analogously to Example 1, 17.3 g of yellowish crystals are obtained; m.p. 182 ° C. Yield 74% of theoretical.

Example 10. Preparation of 1- (g-nitrobenyl) -3-aminopyrazolone-5. From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine, as in Example 1, 12.3 g of yellow crystals are obtained; m.p. 163 ° C. Output 52% of theoretical.

Example P. Preparation of 1- (o-bromobenzyl) 3-aminopyrazolone-5.

42.4 g of 2-bromobenzylhydrazine are added dropwise in a stream of nitrogen to a solution of 33.4 g of methyl ester (3-amino-p-ethoxyacrylic acid and 1 g of p-toluenesulfonic acid in 250 ml

ethanol. While stirring for 15 hours at room temperature, the solution is evaporated in vacuo, the precipitated precipitate is filtered off with suction and dissolved in 2N. caustic soda solution. The alkaline solution is extracted with ether

and weakly acidified with dilute acetic acid. This gives 27.5 g of the expected product with an mp. 168-169 ° C (after recrystallization from ethanol). Yield 49% of theoretical.

Example 12. Preparation of 1- (3-bromo-4chlorobenzyl) -3-aminopyrazolone-5.

49 g of p-amino-p-ethoxyacrylic acid ethyl ester, together with 2 g of α-toluene sulfonic acid, is dissolved in 225 ml

ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine are added under nitrogen. Leave to stand overnight, then the precipitated precipitate is sucked off and recrystallized twice from ethanol; m.p. 171 - 172 ° C. Yield 40 g (43%

from theoretical).

Example 13. Preparation of 1- (3-chloro-4-bromobenzyl) -3-aminopyrazolone-5.

To a solution of 33.2 g of ramino-p-ethoxyacrylic acid ethyl ester and 1.5 g of toluenesulfonic acid in 150 ml of ethanol, 48.8 g of 4-bromo-chlorobenzylgndrazine are added dropwise in a stream of nitrogen. After repeated stirring for 2 hours, allow to stand. After 4 hours, the product crystallizes out, sucked off and twice a cross 9

steelized from ethanol; m.p. 145-146 ° C. Yield 37% of theoretical.

Example 14. Obtaining 1- (2,4,5-trichlorobenzyl) -3-aminopyrazolone-5.

54.7 g of p-amino-p-ethoxyacrylic acid ethyl ester and 2 g of p-toluenesulfonic acid are dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4,5-trichlorobenzylhydrazine in 200 ml of ethanol is added dropwise to this solution with nitrogen. After stirring for 2 hours, the mixture is left to stand overnight, then the precipitated precipitate is sucked off and dissolved in 2N. caustic soda solution. The alkaline solution is extracted several times with ether and slightly acidified with dilute acetic acid. 38 g of product are obtained which is melted after recrystallization from ethanol at 195-196 ° C. Exit 38% of theoretical.

Example 15. Obtaining 1- (3-chloro-4-methylbenzyl) -3-aminopyrazolone-5.

To a solution of 46.7 g of p-amipo-p-ethoxyacrylic acid ethyl ester and 1.5 g of l-toluenesulfonic acid in 200 ml of ethanol, 50 g of 4-methyl-chlorobenzylhydrazine are added dropwise in a stream of nitrogen. After stirring for 2 hours, a product is obtained which is filtered off with suction and recrystallized from ethanol; m.p. 130-131 ° C. Yield 35 g (50% of theoretical).

Example 16. Obtaining 1- (4-phenylbenzyl) -3-aminopyrazolone-5.

To a solution of 23.4 g (0.147 mol) of ethyl 3-amino-p-ethoxyacrylic acid and 1 g of p-toluenesulfonic acid in 100 ml of ethanol, a solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol is added dropwise in a stream of nitrogen. The temperature is now new from 22 to 32 ° C. The mixture was left to stand overnight, and then the solution was vacuumized under vacuum; w, the solution was extracted several times with ether. After adding dilute acetic acid to a weakly acid reaction, 13 g of product are obtained, which, after recrystallization from ethanol, melts at 185-186 ° C. Yield 33% of theoretical.

Example 17. The preparation of 1- (naphthyl-2-l1etnl) -3-aminopyrazolone-5.

To a solution of 37.5 g of ramino-p-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulfonic acid in 100 ml of ethanol a solution of 40.5 g of N (p-hydrazinomethylnaphthalene) is added dropwise in a stream of nitrogen. Stir for 2 hours. After further mixing, more. in the continuation of 2 hours, the product falls, it is sucked off and recrystallized from ethanol; m.p. 156-157 ° C. Yield 22 g (39% of theoretical).

At measure 18. Preparation of 1- (2,5-dimethylbenzyl) -3-aminopyrazolone-5.

In a solution of 28.2 g of p-amio-p-ethoxyacrylic acid ethyl ester and g of p-toluenesulfonic acid 8 with 130 ml of ethanol, 26.6 g of 2,5-methylbenzylhydrazine are added dropwise, the temperature rising from 25 to

ten

35 ° C. After stirring overnight, the precipitated precipitate is sucked off and recrystallized from ethanol; m.p. . Out; 20 g (52% of theoretical).

Example 19. The preparation of 1- (4-trifluoromethoxybenzyl) -3-amyiopyrazolone-5.

17.5 g of p-amino-p-ethoxy-pacrylic acid ethyl ester and 20.6 g of 4-trifluoromethoxybenzylhydrazine are worked up as in Example 1. 8.7 g of colorless crystals are obtained; m.p. 99C. Yield 32% of theoretical.

Prnmer 20. Received 1- (3.4-mstylenedioxybenznl) -3-aminopyrazolone-5).

17.5 g of p-amino-p-ethoxyacryloyl acid ethyl ester and 16.6 g of 3,4-methyl 1 D11oxybenzylhydrazine are used as described in Example 2. 12.1 g of colorless crystals are obtained; m.p. 218 ° C. Output 52% of theoretical.

Example 21. Preparation of 1- (5,6.7,8-tetrahydronaphthyl - 2-methyl - 3-aminopyrazolone-5.

17.5 g of p-etno-p-ethoxy-acrylic acid ethyl alcohol and 17.6 g of 3.4-tetramethlenlenbenznlhydrazine are treated in the same manner as in Example 1. 15.6 g of colorless crystals are obtained after recrystallization from alcohol; m.p. SWF. Crystallized with 1 mole

crystalline alcohol. Yield 54% of theoretical.

Example 22. Production of 1 - (o-methylbenznl) -3-amipopyrazolone-5. In a solution of 32 g of ethyl p-amino-p-ethoxyacrylic acid and 1.5 g of α-toluene sulfonic acid in 300 ml of ethanol at room temperature, 27.5 g of o-methylbenzylhydrazine dissolved in 100 ml of ethanol are added. The mixture is left to stand overnight, then the reaction mixture is evaporated in vacuo, the precipitated precipitate is filtered off with suction and recrystallized from ethanol; m.p. 138 ° C. Yield 15 g (37% of theoretical).

Example 23. Getting 1- (and-bromobenzyl) 3-aminonirazolone-5.

To a solution of 20.5 g of ethyl ester of p-amn-p-ethoxyacrylic acid and 1.5 g /; - toluenesulfonic acid in 200 ml of ethano.ch

26 g. of n-bromobenzylhydrazip are added dropwise in a stream of nitrogen. After stirring for 2 hours, it is left to stand overnight, then the precipitated precipitate is sucked off and recrystallized from ethanol; m.p. . Output

12 g (35% of theoretical).

Example 24. The resulting 1 - (. And-iodine, 1) 3-aminopyrazolone-5.

To a solution of 28.6 g of p-amn-p-ethoxyacrylic acid ethyl ester and 1.5 g / g-toluenesulfonic acid in 350 ml of ethanol, a solution of 45 g of w-iodobenzylhydrazine in 70 ml of tlnol is added dropwise. After uninterrupted during i-o -: ;; Extract the precipitate and recrystallize from ethanol, mp.

186 ° C. Yield 16 g (28% of theoretical).

eleven

Example 25. Getting 1 - (/ g-iodobenzyl) Z-aminopyrazolone-5.

To a solution of 16.2 g of p-amio-3-ethoxyacrylic acid ethyl ester and 1 g of l-toluenesulfonic acid in 250 ml of ethanol a solution of 25.5 g of pyodbenzyl hydrazine in 100 ml of ethanol is added dropwise in a stream of nitrogen. After stirring overnight, the solvent is removed in vacuo and the residue is recrystallized from ethanol. 15 g of product are obtained; m.p. 158 ° C. Yield 47% of theoretical.

Example 26. Obtaining 1- (o-fluorobenzyl) 3-aminonnazolone-5.

30.2 g of ethyl 3-amiato-3-ethoxyacrylic acid and 2 g of d-toluenesulfonic acid are dissolved in 300 ml of ethanol and 27.1 g of o-fluorobenzyl hydrazine are added in a stream of nitrogen. After stirring for 2 hours, it is left to stand overnight, then the precipitated precipitate is sucked off and converted from ethanol; m.p. 146 ° C. Yield 11 g (27% of theoretical).

Prnmer 27. Preparation of 1- (2-fluoro-5 chlorobenzyl) -3-aminopyrazolone-5.

In a solution of 19.8 g of ethyl ester of | 3-amnpo-3-ethoxyacrylic acid and 0.5 g of l-toluenesulfonic acid in 100 ml of ethanol, 21.6 g of 2-fluoro-5chlorobenzylhydrazine are nitrogenated in a stream of nitrogen ° C Newly up to 30 ° C. After stirring for 2 hours, the mixture is left to stand overnight, then the precipitated precipitate is sucked off and installed from ethanol; so nl 160 ° C. Yield 17 g (57 from the theoretical).

Example 28. Obtaining 1- (3,4-dibromobenzyl) -3-aminopyrazolone-5.

In a solution of 12.2 g of a-amino-p-ethoxyacrylic acid ethyl ester and 1 g of l-toluenesulfonic acid in 200 ml of ethanol, a solution of 21.6 g of 3,4-dibromobisylgndrazine in 50 ml of ethanol is placed in a stream of nitrogen. After stirring overnight, the solvent is charged in vacuo, then the precipitate formed is sucked off and non-recrystallized from ethanol; m.p. 182 ° C. Yield 11 g (41% of theoretical).

Example 29. Obtaining 1- (3-methyl-4chlorobenzyl) -3-aminoiirazolone-5.

To a solution of 19.1 g of p-amio-p-ethoxyacrylic acid ethyl ester and 1.5 g of α-toluenesulfonic acid in 200 ml of ethanol, 20.5 g of 3-methyl-4chlorobenzylhydrazine are added dropwise in a stream of nitrogen. The solution is stirred overnight, then the precipitated precipitate is sucked off and recrystallized from ethanol; m.p. 131 ° C. Yield 10 g (35% of theoretical).

Example 30. Getting - (p-tert-butylbenzyl) -3-aminopyrazolone-5.

To a solution of 22 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1 g of l-toluene of tercic acid in 100 ml of ethanol, 26.4 g of p-tert-bu12 are added in a stream of nitrogen

tilbenzylhydrazine, the temperature rising from 24 to 30 ° C. After stirring overnight, the solvent is removed in vacuo, to the oily residue

50 ml of petroleum ether. The product is obtained and it is recrystallized from ethanol; m.p. 126 ° C. Yield 8 g (24% of theoretical). Example 31. Preparation of 1- (l-isonronnylbenzyl) -3-aminopyrazolopa-5.

To a solution of 31.8 g of p-amino-p-ethoxyacrylic acid ethyl ester n 1 g of l-toluenesulfonic acid in 150 ml of thiaiol, in a stream of nitrogen, 32 g of l-isopronylbenznyl gndrazia are added. After stirring for 2 hours, leave to stand overnight. The precipitation is sucked off and recrystallized by nS ethanol; so nl . The output of 18.3 g (40% of theoretical).

Example 32. Preparation of 1- (indap11L-5methyl) -3-amyiopnrazolone-5.

To a solution of ns 14.8 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1 g of l-toluenesulfonic acid in 100 ml of ethanol, 15.1 g of 5-hydrazinomethylindane dissolved in 50 ml of ethanol are added dropwise in a stream of nitrogen. After stirring overnight, the precipitate is filtered off with suction and non-recrystallized from ethanol; m.p. 146 ° C. Yield 9 g (42% of theoretical).

Example 33. Preparation of 1 - (2-chloro-4-fluoro-benzyl) -3-aminonyrazolone-5.

To a solution of 49.2 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1 g of toluene sulfonic acid in 250 ml of ethanol, nanocrystalline in a stream of nitrogen 53.8 g of 2-chloro-4fluorobenznlhydrazine, the temperature rising from 22 to. It is then left to stand overnight and then sucked off.

precipitation and non-recrystallization from ethanol; m.p. 192 ° C. Yield 25 g (34% of theoretical).

Example 34. The resulting 1 - (., And-n-butoxybenzyl) -3-amnopyrazolone-5.

To a solution of 14.8 g of ramino-p-ethoxyacrylic acid ethyl ester and w, a mixture of l-toluenesulfonic acid in 80 ml of ethanol, 18 g of 3-n-butoxybenzylhydrazine are added dropwise in a stream of nitrogen. After mixing

for 2 hours, left to stand overnight. The precipitation is sucked off and recrystallized from ethanol; m.p. . Output 8 g (33% of theoretical).

Example 35: Preparation of 1- (3-methoxy-4 chlorobenzene) -3-aminopyrazolone.

To a solution of 50.5 g of ramino-p-ethoxyacrylic acid ethyl ester and 1.5 g of ltoluenesulfonic acid in 250 ml of ethanol

dropwise in a stream of nitrogen, 59 g of 4-chloro-Zmethoxybenzylhydrazine, then left to stand overnight. The precipitation is filtered off with suction and recrystallized from ethanol; T. Il. 148 ° C. Yield 30 g (38% of theoretical).

Example 36. Preparation of 1- (o-pitrobenzyl) -3-aiinopyrazolone-5.

To a solution of 45.5 g of Ramino-p-ethoxyacrylic acid ethyl ester and one pinch / g-toluenesulfonic acid in 200 ml of ethanol is added dropwise, in a stream of nitrogen 47.8 1-o-nitrobenzylhydrazine. The mixture was left to stand overnight, then the solvent was removed in vacuo, and a 2: 1 itpn-ethanol mixture was added to the residue. The precipitated product is mixed and recrystallized from ethanol; m.p. 190 ° C. Yield 23 g (34% of theoretical).

PRI me R 37. Preparation of 1- (Zn-irooxybeisyl) -3-aminopyrazolone-5.

To a solution of 55.6 g of ethyl ester (3-amino-3-ethoxyacrylic acid and 1 g / g of toluenesulfonic acid in 300 ml of ethanol, 77 g of 4-chloro-3-n-propoxybenzylhydrazine are added in a stream of nitrogen. After stirring overnight, the solvent is removed in vacuo, the product is filtered off with suction and recrystallized from ethanol, mp 143 ° C. Yield 25 g (25% of theory).

Example 38. Preparation of 1- (3-ethoxy-4chlorobenzyl) -3-aminopyrozolone-5.

To a solution of 35 g of ethyl p-amino-3-ethoxyacrylic acid and 1 g of p-toluenesulfonic acid in 200 ml of ethanol, in a stream of nitrogen, 45.5 g of 4-chloro-3-ethoxybepzilhydrazine are added in a stream of nitrogen. After stirring overnight, the precipitate formed is filtered off with suction and recrystallized from ethanol; m.p. 143 ° C. The output of 15.2 g (26% of theoretical).

Example 39. Preparation of 1- (3-trifluoromethyl-4-chlorobenzyl) -3-aminopyrazolop-5.

To a solution of 46.1 g of ethyl ester (3-amino-p-ethoxyacrylic acid and 2 g of α-toluenesulfonic acid in 250 ml of ethanol was added dropwise, in a stream of nitrogen, 67 g of 4-chloro-trifluoromethylbenzylhydrazine. After stirring overnight, the solvent was removed in vacuum, the residue is filtered off with suction and recrystallized from ethanol; so on. Ill. 132 ° C. Yield 25 g (30% of theoretical).

Example 40. Preparation of 1- (o-trifluorobenzyl) -3-aminopyrazolone-5.

To a solution of 38.2 g of ethyl ester (3-amino-p-ethoxyacrylic acid and 2 g of p-toluenesulfopic acid in 250 ml of ethanol was added dropwise in a stream of nitrogen, 46 g of 2-trifluoromethylbenzylhydrazine. After stirring overnight, the solvent was removed in vacuo and the residue was removed recrystallized from ethanol; mp 184 ° C. Yield 22 g (34% of theory).

Example 41. Preparation of 1- (g-ethylbenzyl) 3-aminoiirazolone-5.

14.2 g of 3-ethylbenzylhydrazine was added dropwise to a solution of 15.1 g of Ramino-p-ethoxyacrylic acid ethyl ester and one p-toluenesulfonic acid in 80 ml of ethanol, and the temperature increased from 22 to 30 ° C. After stirring overnight, the solvent is removed in vacuo and the solid residue is extracted from ethanol; T. Il. 73C. Output 5 i (24% of theoretical).

Example 42. Preparation of 1- (3-chloro-4 trifluoromethylbenzyl) -3-aminopyrazolone-5.

To a solution of 23.5 g of ramio-p-ethoxyacrylic acid ethyl ester and p-toluenesulphonic acid in 100 ml of ethanol and 11 are poured in a stream of nitrogen, 33 g of 3-chloro-4-trifluoromethylbeizylgndraz P1a. After stirring overnight, the precipitated product is filtered off with suction and recrystallized from ethanol; T. Il. 83 ° C. Yield 24 g (56% of theoretical).

Example 43. Preparation of 1- (3-trifluoromethylphenyl) -3-aminopyrazolone-5.

To a solution of 26.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and one w, EP01KI / g-toluenesulfonic acid in 100 ml

ethanol was added dropwise in a stream of nitrogen, 34 g of 4-methyl-3-trifluoro methyl benzyl hydrazine. After stirring overnight, the precipitated product is filtered off with suction and recrystallized from ethanol; mt pl. Yield 20 g (44% of

theoretical).

Example 44. Preparation of 1- (3,4-dichloro-1methyl naphthalene) -3-aminopyrazolone-5.

To a solution of 10.3 g of p-amio-p-ethoxyacrylic acid ethyl ester and one whisper / g-toluenesulfopic acid in 100 ml of ethanol is added, in a stream of nitrogen, 15.1 g of 1,2-dichloro-7 - hydrazinomethylnaphthalene. After stirring overnight, the precipitate is filtered off with suction and recrystallized from ethanol;

m.p. 200 ° C. The yield of 4.7 g (23% of theoretical).

Subject invention

40

Claims (5)

1. A process for the preparation of 3-aminoprazolone-5 derivatives of formula I NH. 45 N N 50 where R is phenyl, substituted with 1 or 2 odioac or various substituents selected from alkyl, phenyl, trifluoromethyl, nitro, cyano, carbonamido, sulfopamido or alkylsulfonamido or a fluorine atom, bromine or iodine; phenyl, monosubstituted, sulfonalkyl, alkoxy, dialkylcarbonamido or alkyl mercapto group; fennl mixed with two oddiac substituents selected from alkoxygroup or trifluoromethyl; phenyl, mixed with two different substituents selected from alkyl, phenyl, trifluoromethyl, sulfonalkyl, halogen atom, alkoxy, trifluoromethoxy, alkylamino, cyano, carbonam-, sulfonamlo or nitro groups; trichlorophenyl; 1,3-benzodoxolyl-5; indanyl-5; substituted or unsubstituted p-naphthyl; 5,6,7,8 tetrahydro-2-naphthyl; anthryl or phenanthryl; characterized in that hydrazine form, 1Y II R - CH2-NH-NH, II where R has DY and JK values, is reacted with an acetic acid derivative of formula III Y  1and where X is oxy-, alkoxy-, aralkoxy, polyalkylamino; Y hydrogen; Y Y - nitrile; or n Y - together group where Y is alkoxy, aryloxy, aralcoke, alkyl mercapto, aralkyl mercapto or amino; in an inert solvent medium, and the desired product is isolated with a known procedure or washed through amidhydrazone formula IV H, N with t -TO UN where X and R are as defined above, cyclized followed by isolation of the target product with a known procedure. 2. The method according to claim 1, wherein the reaction of compound II with compound III is carried out in the presence of an acidic or basic catalyst. 3. A method for and. 1, characterized in that the reaction of compound II with compound III is carried out at nygresanii to 100 ° C. 4. The method according to p. 1, About tl and tea that compound IV is subjected to cyclization. 5. The method according to n. 1, characterized in that compound IV is cyclized by the action of a basic catalyst.