NO128546B - - Google Patents

Description

Process for the preparation of substituted acid hydrazides useful for therapeutic purposes.

The present invention relates to the preparation of substituted acid hydrazides with the general formula

in which R, means one with halogen and/or up to 4 carbon atoms containing alkyl mono- or disubstituted phenyl residue and R2 an alkyl residue or one up to 6 carbon atoms containing alicyclic or saturated, straight-chain or branched aliphatic carbon hydrogen residue as well as salts of these acid hydrazides. According to the invention, the acid hydrazide compounds defined above are prepared either by condensation of an acid of the general formula with a substituted hydrazine of the general formula in which R, and R2 have the meaning defined above in the presence of an N,N'-disubstituted carbodiimide or after i and per se known methods and possibly transfer of the obtained free acid hydrazide into a salt. On the one hand, the present invention relates to a new process for the production of substituted acid hydrazides. According to this new method, a carboxylic acid is condensed with a substituted hydrazine in the presence of an N,N'-disubstituted carbodiimide. For turnover, the acids or their salts can e.g. the alkali metal salts are used directly. A conversion into the reactive esters, halides, anhydrides etc. is superfluous. The N,N'-disubstituted carbodiimides used as condensation agents can e.g. is prepared by treating disubstituted urea derivatives with p-toluene sulphochloride in pyridine. In the reaction according to the invention, the corresponding urea derivatives are recovered. When suitable substituted carbodiimides are used, urea derivatives are obtained as a by-product which can be easily separated from the reaction product. As N,N'-disubstituted carbodiimide, one can e.g. use N,N'-dicyclohexylcarbodiimide.

The reaction can be carried out e.g. at a temperature between 0 and 50° C, preferably at room temperature or slightly elevated temperature. It is convenient to use a solvent. An organic solvent such as e.g. methylene chloride, chloroform, dioxane, tetrahydrofuran, dimethylformamide or acetonitrile as well as water.

On the other hand, the present invention relates to the production of substituted acid hydrazides according to formula I according to methods known per se. One can e.g. condense a reactive functional derivative of an acid of formula II, such as an ester, a halide, the anhydride or the amide, possibly under heating with a substituted hydrazine of formula III, one can heat those from the acids of formula II with hydrazine. According to another method, the hydrazide of an acid of formula II is reacted with a carbonyl compound and the hydrazone formed is reduced, e.g. by catalytic hydrogenation using platinum or palladium charcoal as a catalyst or by reaction with lithium aluminum hydride. As a carbonyl compound, one can e.g. use acetone, methyl ethyl ketone or benzaldehyde. The two reactions can occur simultaneously or one after the other. Under this, other unsaturated groups present in the molecule can be hydrated with.

According to the present invention, one can e.g. prepare the following acid hydrazides: 1-(p-chlorobenzoyl)-2-methyl-hydrazine, 1-(p-chlorobenzoyl)-2-tert-butyl-hydrazine, 1-(p-chlorobenzoyl)-2-isopropyl-hydrazine, 1-(p-chlorobenzoyl)-2-benzyl-hydrazine, l-(p-chlorobenzoyl)-2-phenylethylhydrazine, 1-(p-chlorobenzoyl)-2-isobutyl-hydrazine, 1-(o-chlorobenzoyl) -2-isopropyl-hydrazine, l-(m-chlorobenzoyl)-2-isopropyl-hydrazine, 1-(3,4-dichlorobenzoyl)-2-isopropyl-hydrazine, 1-(2,5-dichlorobenzoyl)-2-isopropyl -hydrazine, 1-(p-bromobenzoyl)-2-isopropyl-hydrazine, 1-(p-toiuyl)-2-isopropyl-hydrazine, l-(p-toluyl)-2-benzyl-hydrazine, 1-(p- toluyl) -2-isobutyl-hydrazine, 1-(p-isopropylbenzoyl)-2- benzyl-hydrazine, 1-(p-isopropylbenzoyl)-2-isopropyl-hydrazine, 1-(p-isopropylbenzoyl)-2-phenylethyl- hydrazine, 1-(o-toluyl)-2-benzyl-hydrazine, 1-(o-toluyl)-2-tert-butyl-hydrazine, l-(o-toluyl)2-isopropylhydrazine, l-(3,4 -dimethylbenzoyl)-2-isopropyl-hydrazine, 1-(2,5-dimethylbenzoyl)-2-benzyl-hydrazine and 1-(2,5-dimethylbenzoyl-2<>->sec.butyl-hydrazine.

From a pharmacological point of view, the acid hydrazides are particularly valuable, in which R 1 is a phenyl radical substituted by a halogen atom, in particular a p-chlorophenyl radical, and R 2 is the isopropyl or benzyl radical.

The substituted acid hydrazides obtainable according to the invention form well-defined salts with inorganic as well as with organic acids, e.g. with hydrohalic acids, such as hydrochloric acid, hydrobromic acid; hydroiodic acid, with other mineral acids, such as sulfuric acid, phosphoric acid, nitric acid and with organic acids, such as tartaric acid, citric acid, camphor sulpho acid, ethane sulpho acid, salicylic acid, ascorbic acid, maleic acid. mandelic acid etc. Preferred salts are the hydrohalides, especially the hydrochlorides. The acid addition salts are preferably prepared in an inert solvent by treating the hydrazine derivative with an excess of the corresponding acid.

The substituted acid hydrazides and the salts obtained by the invention inhibit monoamine oxidase. Certain representatives are distinguished by their pronounced antidepressant effect and have a weight-increasing effect in cachexia. They are a valuable addition to the pharmaceutical stock.

Example 1.

15 g of 3.4 dimethylbenzoic acid and 10.1 g of triethylamine are stirred in 200 cm<3> of acetonitrile with 11 g of isopropylhydrazine hydrochloride for 1 hour, after which 20.6 g of N N'-dicyclohexylcarbodiimide are added. It is then stirred for a further 3-4 hours at 25-30° C. The precipitated dicyclohexylurea is now sucked off and the filtrate is concentrated in vacuo. The remainder is triturated with ether. whereby triethylamine hydrochloride is left undissolved. The ether solution is shaken with a little sodium bicarbonate solution, whereby unreacted 3,4-dimethylbenzoic acid is removed. It is then shaken with dilute hydrochloric acid, whereby the formed 1-(3,4-dimethylbenzoyl)-2-isopropyl-hydrazine passes as hydrochloride in the aqueous phase. Now the pH of the aqueous phase is adjusted to 7-8 with caustic soda. Extraction with ether and evaporation of the solvent gives the crude condensation product, which is purified by recrystallization. The 1-(3,4-dimethylbenzoyl)-2-isopropyl-hydrazine thus prepared melts at 104-105° C.

Example 2.

7.4 g of isopropylhydrazine in 20 cm<3> of acetonitrile is added at room temperature with stirring to a suspension of 15.6 m-chlorobenzoic acid in 150 cm<3> of acetonitrile, whereby dissolution occurs. 20.6 g of N,N'-dicyclohexylcarbodiimide in 30 cm<3 >acetonitrile are then added dropwise with stirring over the course of 20 minutes, whereby the temperature rises slightly and at the same time dicyclohexylurea begins to precipitate. After 2 hours of further stirring, the precipitate is filtered off, the filtrate is evaporated to dryness in a vacuum, the residue is taken up in approx. 400 cm<3> ether, the undissolved material is filtered off, the ether solution is shaken out with 130 cm<3> l-n hydrochloric acid, the aqueous solution is made slightly alkaline with concentrated ammonia, and shaken out with ether, the ether extract is dried over sodium sulfate and evaporated and the residue is recrystallized a few times from petroleum ether-acetic ester mixtures. The thus produced 1-(m-chlorobenzoyl)-2-iso-propyl-hydrazine melts at 128.5-131.5°C.

Example' 3.

Tilt a suspension of 31.3 g of p-chlorobenzoic acid: in 1'5'00" cm3 of methylene chloride' is added' with stirring and at room temperature Il g of methylhydrazine, after which the solution obtained at 35° Give in the course of 15 minutes a solution of 41 g N,N'-dicyclohexylcarbodiimide in 150 cm<3> methylene chloride The suspension which forms is stirred for a further 5 hours without heating, after which the dicyclohexylurea formed is filtered off and the filtrate is extracted with cold 3-N hydrochloric acid After washing the acidic aqueous solution with ether, this is made alkaline with a concentrated ammonia solution in the cold, and the oil thus precipitated is taken up in methylene chloride. After drying and evaporation of the organic solvent, 25 g of a red oil-like residue is obtained, which, after distillation, in a high vacuum (boiling point 145 -150° C) is recrystallized from a mixture of acetic acid ethyl ester and petroleum ether in a ratio of 1:1. One obtains such a 1-(p-chlorobenzoyl)-2-methyl-hydrazine with a melting point of 93 .5—96.5° C.

Example 4.

A solution of 47 g of o-chlorobenzoic acid and 22.5 g of isopropylhydrazine in 500 cm<3> of methylene chloride is added dropwise at room temperature with vigorous stirring to a solution of 80 g of N,N'-dicyclohexylcarbodiimide in 80 cm<3 >' methylene chloride during 45 minutes, whereupon dicyclohexylurea begins to precipitate; during weak self-heating. After 3-4 hours of further stirring, the precipitate is scraped off and the filtrate is extracted with 3-N hydrochloric acid. The acidic solution is made alkaline with concentrated ammonia solution in the cold, whereby a white precipitate falls out. The alkaline suspension is shaken out with ether, the ether extract is dried over sodium sulfate, filtered and evaporated to dryness, and the residue is recrystallized from a mixture of water and ethanol in the ratio 2:1, whereby 8.5 g of 1-(o-chlorobenzoyl) -2-isopropyl-hydrazine with a melting point of 113-116° C is obtained.

Example 5.

15 g of p-isopropylbenzoic acid hydrazide (melting point 86-87° C, obtained from p-isopropylbenzoic acid ester and hydrazine in ethanol) is boiled overnight under reflux in 250 cm<3> of acetone, after which the resulting solution is evaporated to dryness and the residue recrystallized once from high-boiling

petroleum ether. In this way, 16.7 g of 1-(p-isopropylbenzoyl)-2-isopropylidene hydrazine with a melting point of 114-116° C is obtained.

16 g of this product is hydrated in 150 cm<3>

ethanol with 0.2 g of platinum oxide at room temperature and at atmospheric pressure until the calculated amount of hydrogen is absorbed. After removal of the catalyst, the filtrate is evaporated to dryness in vacuo and the residue is recrystallized from high-boiling petroleum ether and from a mixture of water and ethanol in a volume ratio of 5:1, whereby 9 g of pure 1-(p-isopropylbenzoyl ^-isopropylhydrazine with a melting point of 123-126°C is achieved.

Example 6.

Dissolve 38 g of p-chlorobenzoic acid hydrazide with a melting point of 165-166° C in 300 cm3 of alcohol. After adding 15 cm<3> of acetone and 0.3 g of platinum oxide, the mixture is shaken at atmospheric pressure and room temperature under water until the absorption of water stops, which is the case after approx. 4 hours. The filtered reaction solution is concentrated in vacuo and the residue is recrystallized from aqueous alcohol. This gives 1-(p-chlorobenzoyl)-2-isopropylhydrazine with a melting point of 131-132° C.

Example 7.

6.25 g of chlorobenzoic acid hydrazide in 50 cm<3 >ethanol. boiled with 3.9 g of benzaldehyde for 3 hours under reflux. After cooling, the formed precipitate is filtered off, washed with cold ethanol and dried. 8.7 g of 1-(p-chlorobenzoyl)-2-benzylidene-hydrazine with a melting point of 225-228° C are obtained. 12.9 g of this condensation product in 600 cm<3> of ethanol are hydrated with 0.3 g of platinum oxide at atmospheric pressure and room temperature. In the course of 7 hours, approximately 1300 cm<3> of water is absorbed. The filtrate is evaporated in a water jet vacuum to dryness, dissolved for purification in acetic acid ethyl ester and precipitated again with petroleum ether. You then get 4 g of 1-(p-chlorobenzoyl)-2-benzylhydrazine with a melting point of 124.5-125.5° C.

Example 8.

36.9 g of p-chlorobenzoic acid ethyl ester are boiled with 16.3 g of isopropylhydrazine for 60 hours under reflux. After cooling, the solid mass is digested with petroleum ether, sieved off and recrystallized from water and ethanol (in a ratio of 2:1) with the addition of animal charcoal. 1-(p-chlorobenzoyl)-2-isopropylhydrazine with a melting point of 131-132° C is obtained.

Claims (5)

1. Process for the production of substituted acid hydrazides useful for therapeutic purposes with the general formula: in which R( means a phenyl radical mono- or disubstituted with halogen and/or an alkyl group containing up to 4 carbon atoms, and Rsl an aralkyl radical or an alicyclic or saturated, straight-chain or branched aliphatic carbon hydrogen radical containing up to 6 carbon atoms, as well as salts of these acid hydrazides, characterized by condensing an acid with the general formula or its salts, e.g. alkali metal salts, with a substituted hydrazine of the general formula in which R, and R2 have the meaning defined above, in the presence of an N,N'-disubstituted carbodiimide, or that one condenses a reactive functional derivative of an acid with the general formula in which R has the meaning defined above, with a substituted hydrazine of the general formula in which R2 has the meaning defined above, or that one condenses the hydrazide of an acid with the general formula in which R, has the meaning defined above, with an aromatic, araliphatic or an alicyclic or saturated, straight-chain or branched aliphatic carbonyl compound containing up to 6 carbon atoms and reducing the hydrazone that is formed, simultaneously or subsequently, and optionally transferring the obtained acid hydrazides to a salt. 2. Method according to claim 1, characterized in that the condensation is carried out from an acid with the formula in which Rj has the meaning defined in claim 1, at a temperature between 15 and 30° in the presence of N,N'-dicyclohexylcarbodiimide. 3. Method according to claims 1 and 2, characterized in that an acid with the formula is used as starting compound in which Rt means a phenyl radical substituted with a halogen atom, e.g. the p-chloro-phenyl residue, respectively a reactive functional derivative thereof. . 4. Method according to claims 1 and 3, characterized in that isopropylhydrazine or benzylhydrazine is used as substituted hydrazine. 5. Process according to claims 1 and 3, characterized in that acetone or benzaldehyde is used as the carbonyl compound.