CH629755A5 - Process for the preparation of cyanoacetanilide derivatives - Google Patents

Description

629755

PATENT CLAIM cyanacetic anilides of formula Ia or their tautomeric

Process for the preparation of new hydroxyethylidene form Ib

NC

/ 1 \ y-

0

H

(Ib)

in which R1 is a halogen atom, a methyl or ethyl group which can be substituted by 1 to 3 fluorine and / or chlorine atoms, a methoxy or ethoxy group which can be substituted by 1 to 4 fluorine and / or chlorine atoms, or a Methyl or ethyl mercapto group; R2 represents a hydrogen atom, a halogen atom, a methyl or ethyl group, a trifluoromethyl group or a methoxy group and R3 represents a hydrogen atom, a chlorine atom or a methoxy group, or R2 and R1 together represent the -0-CH2-0 group and their Salts, characterized in that cyanoacetone of the formula II

20th

25th

OCN

R (III) 3

CH-

0

\ /

CH,

CN

in the presence of basic compounds at a temperature between -70 and +140 ° C with an isocyanate of formula III

30 in which R1, R2 and R3 have the meaning given in the formulas Ia and Ib, and optionally reacting a salt of a hydroxyethylidene-cyanoacetic acid anilide of the formula Ia or Ib by adding a strong acid into a compound of the formula Ia or Ib transferred.

(II),

40

The invention relates to a process for the preparation of new hydroxyethylidene-cyanoacetic anilides of For-45 mei la or their tautomeric form Ib in which R1 is a halogen atom, a methyl or ethyl group which can be substituted by 1 to 3 fluorine and / or chlorine atoms , a methoxy or ethoxy group, which can be substituted by 1 to 4 fluorine and / or chlorine atoms, or a methyl or ethyl mercapto group; R2 on

Represents a hydrogen atom, a halogen atom, a methyl or 65 ethyl group, a trifluoromethyl group or a methoxy group and R3 represents a hydrogen atom, a chlorine atom or a methoxy group, or R1 and R2 together represent the -0-CH2-0 group and their salts.

The radicals are preferably

R1 represents a halogen atom, a methyl, ethyl or trifluoromethyl group, a methoxy or ethoxy group or an ethoxy group substituted by 3 fluorine atoms and one chlorine atom or 4 fluorine atoms;

R2 represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a methoxy group;

R3 is a hydrogen atom;

and R1 and R2 together form a -0-CH2-0 group in the 3,4-position.

The radicals are particularly preferably

R1 is a fluorine, chlorine or bromine atom or a methyl, trifluoromethyl or methoxy group;

R2 represents a hydrogen atom, a chlorine or bromine atom or a trifluoromethyl group;

R3 is a hydrogen atom;

and R1 and R2 together form a -0-CH2-0 group in the 3,4-position.

The salts of the compounds obtainable according to the invention are alkali metal salts such as lithium, sodium and potassium salts; Ammonium salts; Alkaline earth metal salts such as magnesium and calcium salts; Zinc salts; Iron salts and salts with organic bases, such as, for example, amines or tetraalkylammonium hydroxides, can be considered.

Sodium, potassium, ammonium, magnesium or calcium salts and salts with amines having 2 to 8 carbon atoms, such as, for example, piperidine, triethylamine, N-ethylpiperidine, N-methylmorpholine, cyclohexylamine or diethanolamine, are preferred .

In addition to those listed in the preparation examples, the following may be mentioned as compounds obtainable according to the invention:

Hydroxyethylidene-cyanoacetic acid- (3-bromo-, -3-fluoro-, -3-iodo-, -3- (r, r, 2'-trifluoro-2'-chloroethoxy) -, -3- (tetrafluoro- ethoxy) -, -4-bromo-, -4-methoxy-, -4-chloro-, -4-fluoro-, -3,4-di-chloro-, -2,3-dichloro-, -3.5 -dichloro-, -2,6-dichloro-, -3-chloro-2-methyl-, -5-chloro-2-methyl-, -3,4-dioxymethylene-, -3-ether-oxy-, 3, 5-bis-trifluoromethyl-, -, 2,4,6-trichloro-, -2-chloro-4-metoxy-, -2-trifluoromethyl-4-chloro, -3-methylthio- and -4-ethylthio -anilide).

The process according to the invention for the preparation of hydroxyethylidene-cyanoacetic anilides of the formula Ia or their tautomeric form Ib is characterized in that cyanoacetone of the formula II

CH, 0

V

C {(II),

CN

Appropriately in the presence of an aprotic solvent and in the presence of basic compounds at a temperature between - 70 and +140 ° C with an isocanate of the formula III

OCN

629 755

in which R1, R2 and R3 have the meaning given in the formulas Ia or Ib, and, if appropriate, subsequently, by adding an equivalent amount or an excess of a mineral and / or a strong organic acid, the compounds of the formula Ia or Ib releases the salts formed during the reaction.

The reaction is preferably carried out in the presence of an aprotic solvent at a temperature between 0 and 110 ° C., in particular between 10 and 85 ° C. Examples of solvents are hydrocarbons such as pentane, hexane, isooctane, petroleum ether, benzene, toluene, xylenes and cyclohexane and / or diethyl ether, isopropyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, acetonitrile, dichloroethane, tetrachlorethylene and, if necessary, tertiary amines Lower poly-chloroalkanes such as methylene chloride, chloroform and / or carbon tetrachloride can also be used as bases.

Basic compounds which are advantageously used in equimolar amounts or in an up to 20% excess are, for example, tertiary amines, alkali metal alcoholates of lower alcohols, sodium hydride, alkali metal hydroxides or alkali metal and alkaline earth metal carbonates. Tertiary amines, sodium or potassium alcoholates or sodium hydride are preferably used.

After the reaction, the compounds Ia or Ib formed are in the form of salts, from which the acidic compounds of the formula Ia or Ib are advantageously released in the presence of water by adding an equivalent amount or a slight excess of an acid, preferably a mineral acid are then often already in crystalline form and can be isolated by filtering. It is sometimes advantageous to use a water-miscible solvent in this process step, preferably lower alcohols, 1,2-dimetoxyethane and / or acetonitrile, since this measure keeps impurities in solution and the cyanoacetic anilide derivatives of the formula Ia or Ib in a more filterable form.

The cyanoacetone used as the starting material can be prepared by Dahn and Hauth Helv. Chim. Acta 47, 1424 (1964). As described there and in some other publications (cf. Beilsteins Handbuch der organ. Chemie IV. Edition, Volume 3, p. 659), the cyanoacetone polymerizes very easily, especially under alkaline and acidic conditions. However, it is not necessary for the process according to the invention to be isolated in pure form. Since by-products can easily be separated off after the reaction with isocyanates of the formula III, the cyanoacetone to be used can be used as the starting material in the state which occurs, for example, in the acidic cleavage of tert-butyl 2-cyanoacetoacetic acid. For this split, e.g. Toluenesulfonic acid used as a catalyst [cf. Helv. Chim. Acta 47, 1424 (1964)], it is not necessary to remove this acid before the reaction with isocyanate. The cyanoacetic anilide derivatives of the formula Ia or Ib released by acidification from their salts generally crystallize so well that they can easily be separated from accompanying substances.

The hydroxyalkylidene-cyanoacetic anilides of the formula Ia or Ib are acidic compounds which, according to their NMR spectra, are predominantly in the enol form Ia. When FeCl3 is added, they give a brown-red to wine-red color reaction.

If, in one of the types of preparation, the compounds I are initially formed in the form of their alkali metal, alkaline earth metal or ammonium salts or as salts of organic bases and are present as such in solution,

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629755

Evaporation of the solvents used clean these salts of the compounds I if necessary by recrystallization. On the other hand, salts of these compounds can be prepared by adding an equimolar amount of a suitable base, advantageously with the use of solvents which are inert to the bases, and after evaporation of the solvent or by adding other solvents which are used to separate the Salts are isolated. Sodium, potassium, calcium or magnesium alcoholates of lower alcohols, sodium, potassium, calcium, magnesium or ammonium hydroxide, sodium, potassium, calcium, magnesium or ammonium carbonate or - bicarbonate and sodium, magnesium or calcium hydride, ammonia or sodium amide or organic bases, such as tertiary amines, are used. When using alkali or alkaline earth alcoholates, it is advantageous to work in the presence of a lower alcohol in addition to any solvents that may be used. If the above-mentioned hydroxides, carbonates and / or bicarbonates are used as bases, it is advantageous to work in the presence of water and / or lower alcohols, where appropriate other organic solvents can also be used.

Sodium or potassium methylate or ethylate, potassium tert-butoxide, sodium, potassium or ammonium hydroxide, sodium or potassium carbonate or bicarbonate, ammonia or sodium hydride are preferably used as bases.

The compounds of the formula Ia or Ib have strong anti-inflammatory and analgesic effects. The anti-inflammatory effects are demonstrated by the carrangeen paw edema test [Winter, C.A. et al. - Proc. Soc. Exp. Biol. Med. 111, 544 (1962)] and on the adjuvant arthritis of the rat [Pearson, C.M., Wood, F.D. - Arthrite. Rheumatism. 2,440 (1959)].

The analgesic effects were tested on the mouse writhing test [Siegmund, E. et al. - Proc. Soci Exp. Biol. Med. 95, 729 (1957)] and on the Randall-Selitto test of the rat [Randall, L.O., Selitto, J.J. - Arch. Int. Pharmacodyn. 111.409 (1957)].

The new hydroxyethylidene-cyanoacetic anilides of the formula Ia or Ib and their physiologically acceptable salts, preferably their sodium, potassium, magnesium, calcium or ammonium salts, can be used as medicaments. The new compounds can be used as antiinflammatory and analgesic agents in a mixture with the usual pharmaceutical carriers. Solid preparations are used for this, e.g. can be administered as tablets, dragees, capsules or suppositories or also liquid preparations which e.g. can be applied as drops, syrups or injection solutions. These anti-inflammatory and / or analgesic agents can preferably contain 3 to 90% of compounds of formula Ia or Ib.

In addition, anthelmintic, antifungal and fungicidal effects were found for compounds of the formula Ia or Ib.

The compounds of the formula Ia or Ib prepared according to the invention can furthermore serve as intermediates for the preparation of pharmacologically and / or chemotherapeutically active compounds.

example 1

A solution of 5.5 g (30 mmol) of 2-cyanoacetoacetic acid tert-butyl ester in 60 ml of benzene was mixed with 190 mg (1 mmol) of p-toluenesulfonic acid hydrate and 1 hour on

Reflux cooked. After adding 3 drops of water, the mixture was heated under reflux for a further 2.5 hours. Thereafter, small portions of crystalline substance (2-cyanoacetoacetic acid) were filtered off and the filtrate was evaporated in vacuo at a bath temperature of 30 ° C. A colorless oil remained, which was crude cyanoacetone (according to GC 87%). This product was mixed with 4.67 g (25 mmol) of 3-trifluoromethylphenyl isocyanate and 50 ml of CH2C12. 2.74 g (27 mmol) of triethylamine were added dropwise to the resulting solution in 6 minutes with stirring. The solution, which heated up to near the boiling point, was refluxed for 1 hour and then evaporated in vacuo. The residue was mixed with 40 ml of water and 10 ml of methanol, the mixture was shaken vigorously and then acidified with 6N hydrochloric acid. In the process, a precipitate fell out, which in a short time became a crystal mass. A suspension was formed by adding ethanol, which was suctioned off. The filter residue was washed out with water / methanol 3: 1 and finally with a little methanol and dried. 5.65 g (= 70% yield, based on tert-butyl cyanoacetoacetate) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethylanilide), mp. 181 to 182 ° C., are obtained.

Example 2

Starting from 5.5 g (30 mmol) of tert-butyl cyanoacetoacetate, 3.2 g of crude, benzene-containing cyanoacetone, which still contained about 1 mmol of p-toluenesulfonic acid, were prepared by the procedure described in Example 1. This product was dissolved in 25 ml of anhydrous tetrahydrofuran and at + 5 to +12 ° C with stirring and with exclusion of moisture in a mixture of 900 mg of 80% sodium hydride oil suspension (= 30 mmol NaH) in 40 ml of absolute tetrahydrofuran dropped in. A solution of 5.8 g (29 mmol) of 3-bromophenyl isocyanate in 40 ml of tetrahydrofuran was then added dropwise to the mixture at 0 to + 5 ° C. while stirring, and the mixture was then stirred at 50 ° C. for 30 minutes. After evaporating the reaction mixture in vacuo, the residue was mixed with 40 ml of ice water and 10 ml of methanol and shaken, then 5.5 ml of 6N hydrochloric acid were added. The precipitate that crystallized out. By adding ethanol, the initially oily precipitate was brought into a good suction form. After suction filtration, the filter residue was washed out with ethanol / water 1: 1 and methanol and recrystallized from methanol. 4.3 g (51% yield, based on tert-butyl cyanoacetic acid) of pure hydroxyethylidene (3-bromoanilide), mp 178-180 ° C., were then obtained.

Example 3

As described in Example 1, starting from 5.5 g (30 mmol) of tert-butyl cyanoacetoacetate, 3.1 g of crude cyanoacetone were prepared. This was dissolved in 20 ml of anhydrous acetonitrile and added dropwise at about 0 ° C. while stirring in a mixture of 850 mg of 80% NaH oil suspension and 50 ml of absolute acetonitrile. A solution of 3.7 g (27 mmol) of 4-fluorophenyl isocyanate in 20 ml of absolute acetonitrile was then added dropwise to the mixture with stirring. The temperature was allowed to rise to 35 ° C., stirring was continued for 1 hour at 35 ° C. and the mixture was evaporated in vacuo. The residue was worked up as described in Example 2. After recrystallization of the crude product from ethanol and a little water, 3.60 g (= 55% yield) of pure hydroxyethylidene-cyanoacetic acid (4-fluoroanilide) of melting point 170 to 171 ° C.

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Examples 4 to 8 The following were prepared according to the procedure described in Examples 1 and 2:

Hydroxyethylidene-cyanoacetic acid- (4-bromoanilide), mp. 207 bis

209 ° C, yield 55%. Hydroxyethylidene-cyanoacetic acid- (3,4-dichloroanilide), mp.

209 to 210 ° C, yield 57%. Hydroxyethylidene-cyanoacetic acid (2-ethoxyanilide), mp. 110

up to 111 ° C, yield 32%. Hydroxyethylidene-cyanoacetic acid- (2,4-dichloroanilide), mp.

140 to 141 ° C, yield 56%. Hydroxyethylidene-cyanoacetic acid- (4-chloro-2-trifluoromethyl-anilide), mp. 131 to 133 ° C, yield 51%.

Example 9

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide) -cyclohexylammonium salt

27 g (0.1 mol of 2-hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide)) were suspended in 100 ml of methylene chloride, stirred and 11 g (0.11 mol) of cyclohexylamine were added dropwise at room temperature The mixture was evaporated to leave a solid product which could be washed out with cyclohexane. After drying, 27 g (= 73% yield) of hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-

5,629,755

anilide) -cyclohexylammoniumsalz of mp. 157 to 159 ° C obtained.

Analysis: C18H22F3N302 calculated:

s C 58.5 H 6.0 N 11.4 MG 369.4%

found:

C 58.5 H 6.0 N 11.1%.

Example 10

Hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl anilide) diethanolammonium salt 30 g (0.11 mol) of 2-hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) were suspended in 100 ml of ethyl acetate, stirred and added dropwise at room temperature with i5 11 , 5 g (0.11 mol) of diethanolamine were added. The mixture became homogeneous during the dropping. When the clear brown solution was evaporated, a solid residue remained which, after washing out with cyclohexane, 32 g (= 76% yield) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoro-20 methyl-anilide) -diethanolammonium salt hemihydrate, mp 96 to 98 ° C delivered.

Analysis: C16H2oF3N304 calculated with '/ 2H20:

C 50.0 H 5.5 N 10.9 MG 375.4%

25 found:

C 50.3 H 5.8 N 11.0%.

s