SU703019A3 - Method of preparing indazole-3-carboxylic acid hydrazides of their salts - Google Patents

Description

(54) METHOD FOR OBTAINING INDAZOL-3-CARBIC ACID HYDRAZIDES OR THEIR SALTS of lkyl-3-indazolcarboxylate with hydrazine 1. However, in the literature there is no information about the compounds of the formula I, their preparation and properties. The proposed method for the production of indazole-3-carboxylic acid hyraides of the formula is that the hydride of indarol-3-carboxylic acid of the general formula where R is Rg. Has the above values, is reacted with a ketone or aldehyde of the general formula R o III) -, 5: -V,. where R4 and RS are as defined above, or with their derivative, the general formulas are /, u where R and Rj are as defined above. value; Rg is hydrogen, alkyl or alkanoyl C2.-C4 or both Rj together form alkylene or alkylene, in a solvent at 30-15 in the required case in the presence of organic or inorganic acid, and the resulting compound of Form I, where Rg and RT form a double bond between nitrogen and carbon atoms, if necessary, is reduced either by metal borohydride at 0-100 ° C, or diborane, obtained directly in the reaction mixture in the presence of a reducing compound, at (-20) - (+ 20) s, or hydrogen, activated metal catalyzator - nickel, palladium, cobalt or platinum, followed by separation of the target products in the form of free bases or their salts with organic or inorganic acids. The reaction of the compounds of Formula II with compounds of the formula III or ly as the rule is carried out in the presence of a solvent, maintaining a temperature of 20-150 ° C, preferably the boiling point of the reaction mixture. Compounds of formula III and IV are suitably added in excess. The excess can be easily removed later by distillation or extraction. This type of treatment is particularly advantageous if in compounds of formula III or IV R4 and RS is hydrogen or lower alkyl. These types of compounds are, for example, acetaldehyde, propionic aldehyde, butyraldehyde. in this case, the reaction proceeds easily without heat being supplied from the outside. Alcohols, for example methanol, ethanol, propanol, butanol, glycol, diethylene glycol, propylene glycol, glycerin, mono- and polyethers of polyhydric alcohols, for example methyl cellosolve, diglyme, ethers, for example diethyl ether, dibutyl ether, dioxane, tetrahydrofluoride can be used as solvents. , aromatic hydrocarbons, such as benzene, toluene, xylene, as well as acetic acid, dimethylformamide, dimethylacetamide, acetonitrile, and mixtures of these solvents. In the case of compounds of the formula III and IV, where R4 and Rg. - lower alkyl such as cacetone, methyl ethyl ketone or their halogen derivatives, are treated in the same way, but it is advisable to speed up the reaction by heating, in appropriate cases, the melting point of the reaction mixture. . . The reaction of compounds of formula II with compounds of formulas III or IV is preferably carried out in a melt. The water released during the reaction can be easily removed from. . melt. It is advisable to carry out the reaction at 100-140 ° C. The compounds of formula III and IV are added in excess, and then the excess is removed by extraction. . .. -. . In a melt reaction, the compound of formula III or IV and the compound of formula II are taken in approximately equivalent amounts, it is advisable to add in a molar ratio of 1.0-2, O. The reaction of compounds of the formula I with compounds of the formula III or IV can be carried out in appropriate cases in the presence of an inorganic or organic acid. Adding acid favors the reaction. It is especially advantageous to add an acid when Rg is a LOW alkyl or: alkanoyl ,. : The reduction can be carried out in an autoclave with hydrogen, activated; with metal catalysts such as nickel, palladium, cobalt, or platinum: and lower ali-phatic alcohol is used as the reaction medium. At the same time, it usually takes 10-50 hours to add one mole equivalent. Immediately thereafter, the catalyst is removed, the filtrate is evaporated and the residue is purified by recrystallization, | extraction or chromatography.

 The reduction is also conveniently carried out with metal borohydrides (sodium borohydride, potassium, lithium, Ksht and aluminum) in a lower alcohol or ether (e.g. dioxane, tetrahydrofuran, diethylene glycol dimethyl ether) at, in this case, the reaction time is 0.5-4 hours. Water is added to the reaction mixture and the product is taken up by filtration, extraction or evaporation. The reduction with sodium borohydride is particularly advantageous, with isopropanol being used as the solvent and the reaction is carried out at the boiling point of the mixture.

When diborane is reduced, the CONH-N CC group of the compound that needs to be hydrogenated can be converted without restoring. The CO group to the CONH-N-CH group. The reaction proceeds at (-20) - (+ 20) ° C, it is advisable to react at As It is preferred to use dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol methyl ether in the reaction medium.

It is better to carry out the reduction with diborane prepared directly in the reaction mixture in the presence of a compound to be hydrogenated, for example from sodium borohydride and boron trifluoride. In this case, the reaction proceeds extremely rapidly, generally less than a minute, and the product can be recovered after acidifying the reaction mixture using any of the above methods. ;

Example 1. 23.6 g of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide are boiled in a mixture of 5 ml of acetic acid and 100 ml of acetone with CONSTANT stirring for 2 hours. After cooling, a receive. 24 g (87%) of 5,6-dimethoxyindazole-3-carboxylic acid isopropylidene hydrazide, m.p. .

Example 2. 23.6 g of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide and 11 g of hexahydrobenzalde are boiled under stirring in 300 ml of ethanol for 2 hours. After cooling, 26.3 g (80%) of hexahydrobenzylidene hydrazide are obtained. 5,6-dimethoxyindazole-3-carboxylic acid. Mp. 230s. /

Example 3 50 g of hydrazide 5, dimethoxyindazole-3-carbonic acid and 20 g of cyclohexanone boil rt under stirring in 300 ml of methyl-, cellosolve, immediately poured into 1000 MP of methanol, osslazhday and get 56.2 g (85%) of diglohexyl-, dehydrazide 5,6-dimethoxyindazole-3-carboxylic acid, so pl. 290 C.

Example 4. 23.6 g of hydrazide 5,6-dimethoxyindazol-3-carboxy6 acid and 19 g N-benzylpiperidone are boiled in 300 ml of ethanol for 3 hours. After cooling, 33 g (81%) (N-benzylpiperylidene) - hydrazide 5,6-dimethoxy. Indazole-3-carboxylic acid, so pl. .

Example 5. Bg of 5-nitrofurfurylidene diacetate is suspended in 100 ml of ethanol, 5 ml of concentrated sulfuric acid are added to the suspension and mixed at 10-30 min. Then a solution of b g of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide is added to

5 with 100 ml of dimethylformamide, incubated for 24 hours at room temperature and 6.3 g (70%) of 5-nitrofurfurylidene hydrazide 5, b-dimethoxyindazole-3-carboxylic acid, m.p. 334 ° c.

0

Example 6. 12 g of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide are dissolved in 50 ml of acetaldehyde, stirred for 1 hour, the precipitate is filtered, washed with ether and

5 is dried, yielding 10.5 g of ethylidene hydrazide 5, b-dimethoxyindazole-3-carboxylic acid, m.p. 155 ° C. The product is boiled in 100 ml of isopropanol with 2 g of sodium borohydride for 4 hours.

0 Immediately after that, most of the isopropanol is distilled off, water is added to the residue, then 1 ml of acetic acid and finally 10 ml of ammonia, extracted with chloroform, evaporated and 11 g (83%) are obtained

5 ethyl hydrazide 5, b-dimethoxyindazole-3-carboxylic acid as a viscous oil.

Example 7 8 g of the product prepared as in Example 1 is stirred into 100 ml of diethylene glycol monomethyl ether with a calcium chloride tube. 3.7 g of α-tthuminium chloride are added. and a solution of 2 g of sodium borohydride prepared

5 with the named solvent. The mixture was stirred at 0 ° C for several hours, the resulting solution was diluted with 1000 ml of water. It is extracted with ethyl acetate and extrat

0 evaporated. The product obtained is recrystallized from ethanol and 5.2 g (66%) of 2,6-propylhydrazide 5,6-dimethoxyindazole-3-carboxylic acid are isolated, m.p. 177 ° C.

five

Example 8. 26 g of hydrazide 5, b-dimethoxyindazole-3-carboxylic acid is treated in a mixture of 30 ml of diethyl ketone and 100 ml of ethanol, as indicated in example 2. Obtained

0 24.8 g of the product is stirred in diethylene glycol dimethyl ether at a carbon dioxide tube. With stirring, 18 g of sodium borohydride is added in portions. The solution obtained after the addition of 20 ml of a 48% ethereal solution of boron fluoride was stirred for another 1-2 hours in the cold and immediately 500 g of crushed ice and 50 ml of concentrated hydrochloric acid were poured into the mixture. During foaming, a viscous substance is precipitated, which is extracted with chloro-form. Crude Product, bsa, made from pactSbpa; processed by ordinary methyds, pyrvyryo zllyoyoyova) from ethanol. Obtain 20 g (80%) of 3-pentylhydrazide 5,6-dimethoxyindazole-3-carboxylic acid, m.p. 180 ° C.

Approximately 9 p. 13.9 g of the product, PE) of the diluted one, as in Example 3, are boiled with 4 g of boron-sodium drift in 200 m of ibprrpanol for 2 hours, evaporated, and the mixture is added; water is extracted with chloroform, the extract is washed with water, dried and evaporated. dcTeiTdK: Pe1zekryyga1ovyovayut from ethanol, get 7.4 g (53%) cyclohexidhydrazide 5,6-dimethoxyindazol-3-carboxylic acid, so pl. 180 s.

Example 10. 4.6 g of hydrazide 5,6-dimethoxyindazole-3-carboxylic acid and 3.4 g of acetylnaphthalene are kept at 120-14 ° C for 1 h, cooled, the solidified mass is washed with 100 ml of hot methanol. A small pial of raw product is percrystalled from dimethylformamide, obtaining the product, melted at. The crude product is worked up as described in Example 8. 3.5 g (45%) of 1 (l-naphthylethyl) -hydrazide 5, b-di-leoxy-indium-3-carboxylic acid, m.p. .

ANhorii HO receive R-hydraoids .5, b-dialkoxyindazrl-3-carboxylic acid ..

Starting from the 5,6-dimethoxindazole-3-carboxylic acid hydrazide, get a combination / listed in Table 1 and Table 2. The compounds listed in Table 1 are prepared as in Example 2.,

Table 1

2-Oxybenzylidene88

4-Oxybenzylidene93

4-Chlorobenzylidene94

4-Bromobenzylidene 94

3,4-Methylenedioxybenzylidene

2-Aminobenzylidene 94

4-nitrobenzaldehyde 4-nitrobenzylidene 90

3, 4, S-TpHMeTOKCH-;

3, 4, 5 - trimethobenzaldehyde. sibenzylidene 95

1-Naphthylidene96

1-Phenylethyliden, 98

1- (4-Nitrophenyl) ethylidene99

1- (4-Methyl mercaptophenyl) ethylidene

296 314 325 301

273

352

289,294,230

318

97

226

70301910

Continuation of table 1