CH632487A5 - Process for preparing novel cyanoacetanilide derivatives - Google Patents

Abstract

Novel hydroxyethylidene-cyanoacetanilides of the formula Ia, and their tautomeric form Ib, are prepared by reacting a cyanoacetanilide, which is appropriately substituted in the benzene ring, in the presence of an anhydride of a lower fatty acid, to give an alkoxyethylidene-cyanoacetanilide, and then hydrolysing the latter compound. The alkoxyethylidene-cyanoacetanilide, which is obtained as an intermediate, can, prior to the hydrolysis, be reacted with a secondary amine to give a dialkylaminoethylidene-cyanoacetanilide. The latter route is suitable, in particular, for compounds having substituents which are sensitive to acid or alkali, since the hydrolysis readily proceeds under mild conditions. The symbols in the formulae Ia and Ib have the meaning given in Patent Claim 1. The compounds of the formulae Ia and Ib, and their physiologically tolerated salts, exhibit strong antiinflammatory, analgesic, anthelmintic, antimycotic and fungicidal effects. Even the alkoxyethylidene-cyanoacetanilides and the dialkylaminoethylidene-cyanoacetanilides which are obtained as intermediates display antiinflammatory and analgesic effects. <IMAGE>

Description

The invention relates to a process for the preparation of new hydroxyethylidene-cyanoacetic anilides of the formula Ia or their tautomeric form Ib

(Ia)

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 1-4 fluorine and / or chlorine atoms, or a methyl - Or ethyl mercapto group, R2 is a hydrogen atom, a halogen atom, a methyl or ethyl group, a trifluoromethyl group or a methoxy group and R3 is a hydrogen atom, a chlorine atom, a methoxy group or R1 and R2 together are 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 one

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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 are a 3,4 -0-CH2-0 group.

The radicals are particularly preferably

R1 is a fluorine, chlorine or bromine atom or a methyl, 65 trifluoromethyl or methoxy group,

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

R3 is a hydrogen atom

3rd

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

Suitable salts of the compounds of the general formula I are alkali metal salts such as lithium, sodium, potassium salts, ammonium salts, alkaline earth metal salts such as magnesium, potassium or zinc salts, iron salts and salts with organic bases, for example amines or tetraalkylammonium hydroxides.

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 .

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In addition to those listed in the preparation examples, the following may be mentioned as compounds prepared 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-diehlor-, -3,5 -dichloro-, -2,6-dichloro-, -3-chloro-2-methyl-, -5-chloro-2-methyl-, -3,4-methylenedioxy-, -3-ethoxy-, 3,5- bis-trifluoromethyl-, -2,4,6-trichloro-, -2-chloro-4-methoxy-, -2-trifluoromethyl-4-chloro-, -3-methylthio- and -4-ethylthio-anilide) .

The process according to the invention is characterized in that a cyanoacetic anilide of the formula II

in which R1, R2 and R3 have the meaning given above for formulas Ia and Ib, with an orthoacetic acid ester of the formula III

in the

CH3-C (OR4) 3

(HI),

R4 denotes an alkyl radical with up to 4 carbon atoms, in

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Presence of an anhydride of a lower fatty acid, preferably in the presence of acetic anhydride, advantageously with the addition of catalytic amounts of Lewis acids and optionally with the addition of a solvent at a temperature between +20 and + 180 ° C to an alkoxy-ethylidene-cyanoacetic anilide of the formula IV

R 0N ^ h3

and or

S

(iv).

/ C \ / °

i \ C c

. : not specified

E—

R ^

\

r3 r2

in which R'-R4 have the meanings given above, and then reacting and isolating the isolated alkoxyethylene-cyanoacetic anilide of the formula IV in alkaline or in acidic aqueous solutions, optionally with the use of organic solvents which are completely or partly miscible with water at a temperature between - 30 and +150 ° C, hydrolyzed.

When the cyanoacetic anilides of the formula II are reacted with an orthoacetic acid ester of the formula III, the reaction temperature is preferably between + 60 and +150 ° C, in particular between + 85 and +140 ° C. In this process step, any low-boiling compounds formed can at least partially be distilled off from the reaction mixture. If one accordingly works at the boiling temperature of the reaction mixture, the reaction temperature can vary during the reaction, in particular increase, depending on whether or in what amounts low-boiling substances formed during the reaction are distilled off.

The reaction is preferably carried out at normal pressure, but it can of course also be carried out at lower or higher e.g. at the autogenous pressure of the reaction mi45

in a closed vessel. The reaction times are between 0.5 and 48 hours, preferably between 1 and 12 hours.

Variant b) of the process according to the invention for the preparation of the compounds of the formula I is characterized in that the alkoxyethylidene-cyanoacetic anilide of the formula IV prepared as described above is expediently using a solvent at a temperature between -40 and + 160 ° C with a se-55 secondary amine of formula V

60

hn

00,

rc

65 in the R5 and R6, which may be the same or different, each an alkyl radical having 1 to 4 carbon atoms or together an alkylene chain having 2 to 5 carbon atoms, a -CH2CH2-0-CH2CH2- or

632487

-ch2ch2n

R?

ch2ch2-

-Grouping, in which R7 has the meaning of an alkyl group having 1 to 4 carbon atoms or a benzyl group, is implemented and the dialkylaminoethyl-cyanoacetic anilide derivative of the formula VI formed in the process

R-

> 6 ^

N ^ C ^ CH:

NC

and or

(Vi)

/

see. J. Org. Chemistry Vol. 35, 2849 (1970) in particular page 2852, Z-E nomenclature in the R * -R3 the above and Rs and R6 20 ter use of a water-miscible organic the given in the formula V. Have meanings, hydrolyzed un-solvent.

acidic or alkaline conditions, possibly under

The process according to the invention proceeds according to the following scheme:

z-

c 0

Ia -

7

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The methyl or ethyl ester is preferably used as the orthoacetic acid ester of the formula III.

The term Lewis acids means anhydrous salts of the elements boron, aluminum, zinc, cadmium, mercury, thallium, titanium, zirconium, tin, lead, phosphorus, arsenic, antimony, iron, cobalt and nickel.

If Lewis acids are used as catalysts in the preparation of compounds of the formula IV according to the invention, the following salts are preferably used: boron trifluoride, boron trichloride, A1C13, ZnCl2, ZnBr2, ZnJ2, Zn (CH3C02) 2, Zn2P207, ZnS04, HgCl2, Hg (CH3C02) 2, HgS04, TiCl4, SnCl4, PC13, POCl3, PC15, SbBr3, SbCl3, SbCl5, SbOCl, (Sb0) 2S04, FeCl3, FeS04 or Fe2 (S04) 3. The catalysts can be used in amounts of 0.005-5 mol% or more, based on the compounds II.

If the reaction is carried out using a solvent, hydrocarbons, halohydrocarbons, ethers and nitriles can be used as such, provided that these compounds are inert under the reaction conditions, i.e. contain no additional functional groups that can lead to side reactions.

Examples include: petroleum ether, n-hexane, toluene, xylenes, benzene, 1,2-dichloroethane, carbon tetrachloride, tetrachlorethylene, diisopropyl ether, dioxane, tetra-hydrofuran, glycol and diglycol dimethyl ether and / or acetonitrile.

The reaction of the anilides II with compounds of the formula III is preferably carried out without using a solvent.

In the reaction of the cyanoacetanilides of the formula II with an orthoacetic acid ester of the formula III in the presence of an anhydride of a lower fatty acid, for example in the presence of acetic anhydride, the reaction conditions and the proportions in which the reactants and optionally the catalysts are used can vary widely. This means that the cyanoacetanilides of the formula II in an excess of up to 35%, the orthoacetic acid esters of the formula III in an excess, for example up to 200% or more, advantageously 20 to 100%, in each case based on the other reaction component, but also in a stoichiometric amount Ratio can be used. The same applies to the amount of carboxylic anhydride to be used, preferably acetic anhydride. The carboxylic anhydride is advantageously used in a stoichiometric excess, preferably from 20 to 170%, based on the larger of the two components, the anilide of the formula II or the orthoester of the formula III. In addition, the orthoacetic acid ester and the carboxylic anhydride need not be used all at once at the beginning of the reaction, but these reaction components can be added to the reaction batch in portions or continuously at different rates in the course of the reaction. Furthermore, during the reaction, different portions of volatile portions which are formed, either in portions or continuously, can be distilled off under normal, positive or negative pressure. With this measure, the reaction temperature can be influenced in the desired manner.

The alkoxyethylidene-cyanoacetic acid anilides of the formula IV can be isolated in various ways. If they are obtained directly as crystalline compounds during the reaction, they are isolated and, if necessary, purified by recrystallization from suitable solvents such as ether, isopropyl ether, benzene, toluene, ethyl acetate, dimethoxyethane, tetrahydrofuran, chloroform or carbon tetrachloride or by column chromatography. Essentially, the purification is a removal of unreacted starting cyanoacetanilide, which is often obtained in different proportions together with the reaction product in crystalline form.

If there are no crystalline substances after the reaction, the reaction products can e.g. after separating off low-boiling fractions by distillation and in non-polar solvents such as saturated acyclic or cyclic hydrocarbons, e.g. N-hexane, cyclohexane easily soluble fractions by washing with these, using suitable solvents such as ether, isopropyl ether, benzene, toluene, ethyl acetate, dimethoxyethane, tetrahydrofuran, chloroform or carbon tetrachloride to crystallize and, if necessary, further purified in the usual way.

Depending on the reaction conditions and the residues RL-R4, the new alkoxyethyl-den-cyanoacetanilides formed in the reaction fall as an E / Z stereoisomer mixture, where the ratio of the stereoisomers can be very different, or sometimes as a pure E or Z shape. One or both of the stereoisomers can be obtained relatively easily in pure form from the stereoisomer mixtures by separating the mixture by means of conventional measures such as, for example, fractional crystallization or column chromatography.

Examples of alkoxyethylidene-cyanoacetanilides of the formula IV which can be prepared according to the invention as intermediates or as direct precursors of the hydroxyethylidene-cyanoacetanilides of the formula Ia or Ib are the following: ethoxyethylidene-cyanacet- (3-trifluoromethyl-, -3-chloro , -3-bromo-, -3-iodo-, -4-bromo-, -3,4-dichloro-, -3,4-methylenedioxy-, -2-methyl-3-chloro-, -2-methyl- 5-chloro-, -4-methoxy-, -4-fluoro-, -4-chloro-, -3,5-dichloro-, -3,5-bis-trifluoromethyl-, -4-chloro-2-trifluoromethyl- , -2,4-dichloro, -2-ethoxy-, -3- (tetra-fluoro-ethoxy) -, -3- (l, l, 2-trifluoro-2-chloroethoxy) -, -3- methyl-thio-, -3-chloro-4-methyl- and -3,4-dimethoxy-anilide).

The hydrolysis of the alkoxyethylidene-cyanoacetic acid anilides of the formula IV to the corresponding enols of the formula Ia or their tautomeric keto form Ib can be carried out under alkaline or acidic conditions in homogeneous or heterogeneous systems. The hydrolysis conditions can be varied within a wide range with regard to the concentration of the acids or alkalis used and with regard to the composition of the reaction medium. You can work in water alone or with the addition of different amounts of water-miscible solvents. Examples of such solvents are: (C1-C3) alkanols and alkane diols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, acetonitrile, glycol monomethyl or ethyl ether, dimethylformamide, dimethyl sulfoxide and / or (C3-C4 ) -Ke-tone.

The reaction times can be up to 24 hours, as is known, reaction times are inversely related to the reaction temperature, i.e. shorter reaction times are required at higher temperatures.

Furthermore, the hydrolysis can also be carried out in a 2- or 3-phase system. In the case of a 3-phase system, the rule is that either the cyanoacetanilide derivative of the formula IV to be hydrolyzed or the hydrolysis product of the formula Ia or Ib or both substances are present as a solid phase. It is therefore possible that a solid phase is always present in the hydrolysis batch, which at the beginning consists of a compound of the formula IV and at the end of the reaction of a pure hydrolysis product of the form

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mei la or Ib or can consist of a mixture of starting material and hydrolysis product.

The alkaline hydrolysis is preferably carried out in an aqueous medium, optionally with the use of the abovementioned solvents, at an alkali concentration of 0.2 to 8 N at a temperature between 20 and 100 ° C. Sodium or potassium hydroxide solution or sodium or potassium carbonate solutions are preferably used as alkalis. The alkalis are used in at least equimolar amounts, preferably in a 20% or greater excess.

In this embodiment of the hydrolysis, the hydrolysis products are wholly or partly in solution as the sodium or potassium salt. In the case of acidification, the corresponding hydroxyethylidene-cyanoacetanilide of the formula Ia or the tautomeric form Ib is precipitated in mostly crystalline form.

The acidic hydrolysis is preferably carried out in an aqueous medium with the use of water-miscible solvents, as specified above, at an acid concentration of 1N to 12N at a temperature between 20 and 100 ° C. Suitable solvents which are advantageously added here are (C1-C3) alkanols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, glycol monomethyl ether, acetone and / or acetonitrile. The hydroxyethylidene-cyanoacetic anilides of the formula Ia or Ib formed in the hydrolysis precipitate in crystalline form either directly or after partial or complete evaporation of the organic solvent used as solubilizer.

In variant b) of the process according to the invention, where the alkoxyethylidene-cyanoacetic anilides of the formula IV are first converted into a compound of the formula VI by the action of a secondary amine, the process is preferably carried out in the presence of neutral organic solvents at a temperature between 20 and 100 ° C. . Preferred solvents are 1,2-dimethoxyethane, ether, dioxane, tetrahydrofuran, (Ci-C3) alkanols, carbon tetrachloride, tetrachlorethylene and / or acetonitrile. The response times are up to 8 hours.

The hydrolysis of the dialkylaminoethylidene cyanoacetic acid anilide derivatives of the formula VI can in turn be carried out in the acidic or alkaline range. With regard to the use of organic solvents which are completely or partially miscible with water, the same applies as for the hydrolysis of the enol ethers of the formula IV. The reaction conditions can vary widely with regard to the composition of the reaction medium, acid or base concentration and temperature, and the reaction times which can be up to can be up to 8 hours depend very much on the reaction conditions. In acidic hydrolysis, which is generally preferred in this process stage, it is preferred to work with acid concentrations of n / 100 to 6N at a temperature between 0 and 70 ° C. This gives the compounds of the formula Ia or Ib. The alkaline hydrolysis is preferably carried out with alkali lyes or alkali carbonate solutions with a content of 0.2 N to 8 N, the alkali salts of the compounds of the formula Ia or Ib being present in whole or in part in solution after the reaction. Acidification gives the crystalline, acidic hydroxyethylidene-cyanoacetanilides of the formula Ia or Ib from the salts. The alkaline hydrolysis of compounds IV and VI is carried out with at least equimolar amounts of alkali. Excesses of 30 to 500%, in particular 100 to 300%, or more are preferably used.

As examples of dialkylaminoethyl-cyanoacetic anilide derivatives of the formula VI, which according to the invention as

Intermediates or as direct precursors of the hydroxyethylidene cyanoacetanilides Ia or Ib can be prepared, the following are mentioned:

(1-dimethylamino, 1-diethylamino, 1-dipropylamino, 1-dibutylamino, 1-pyrrolidino, 1-piperidino, 1-morpholino, I-N-methyl-piperazino-ethylidene) -cyanoacetic acid - (3-trifluoromethyl-, -3-chloro-, -3-bromo-, -3-iodo-, -3,4-dichloro-, -3,4-methylenedioxy-, -2-methyl-3-chloro- , -2-methyl-5-chloro, -4-methoxy, -4-fluoro, -4-chloro, -3,5-dichloro, -3,5-bis-trifluoromethyl-, - 4-chloro-2-trifluoromethyl-, -2,4-dichloro, -2-ethoxy-, -3- (tetrafluoro-ethoxy) -, -3- (l, l, 2-trifluoro-2-chloroethoxy ) -, -3-methylthio-, -3-chloro-4-methyl- and -3,4-di-methoxy-anilide).

In addition, other (1-dialkylaminoethylidene) -cyanoacetic anilides can also be prepared by the process according to the invention.

Surprising in this variant of the process is the easy hydrolyzability of the substituted (1-dialkylaminoethylidene) cyanoacetic anilides of the formula VI under acidic conditions. The compounds of the formula VI are hydrolyzed much more rapidly than the enol ethers of the formula IV under weakly acidic conditions at a pH above 0. Because of this, this variant of the process can then advantageously be used to prepare compounds of the formula Ia or Ib can be used if these contain acid- or alkali-sensitive substituents, especially if one has to reckon with changes in the substituents during alkaline hydrolysis.

It is also surprising that the compounds of the formula IV are hydrolyzed alkaline substantially more rapidly than under acidic conditions, although enol ethers, this class of compounds are the compounds of the formula IV, and it is generally known that they are acidic in the presence of water Conditions can be split very easily.

The cyanacetanilides of the formula II required as starting materials can be prepared according to the methods described in Brit. Patent 930 808 (Americ. Cyanamid Co.) described methods and the orthoacetic acid esters of formula III according to methods known from the literature (cf. Houben-Weyl-Müller, Methods of Organic Chemistry, TV. Ed. Stuttgart 1965, Vol. 6,

Part 3, p. 295).

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 the compounds I are first formed in the form of their alkali metal, alkaline earth metal or ammonium salts or as salts of organic bases and exist as such in solution in one of the types of preparation, these salts of the compounds I can optionally be purified by recrystallization by evaporation of the solvents used. 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 Lead salts, be isolated. Sodium, potassium, calcium or magnesium alcoholates of lower alcohols, sodium, potassium, ca, magnesium or ammonium hydroxide, sodium, potassium, calcium, magnesium or ammonium carbonate can be used as bases or bicarbonate and sodium, magnesium or calcium hydride, ammonia or sodium amide, or organic bases, such as tertiary amines. When using alkali or alkaline earth alcoholates, it is advantageous in addition to

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optionally used solvents to work in the presence of a lower alcohol. 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 could be demonstrated on the carrageenan ingestion test (Winter, CA et al. -Proc. Soc. Exp. Biol. Med. 111, 544 (1962)) and on the adjuvant arthritis of the rat (Pearson, CM, Wood, FD-arthrite. Rheumat. 2,440 (1959)).

The analgesic effects were determined on the mouse writhing test (Siegmund, E. et al. - Proc. Soc. Exp. Biol. Med. 95, 729 (1957) and on the Randall-Selitto test of the rat [Randall L. 0., Selitto, JJ - Arch. Int. Pharmacodyn. 111, 409 (1957)].

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

The intermediate products of the formula IV and the formula VI which are obtained in the process according to the invention also have antiphlogistic and analgesic effects to varying degrees. Since these compounds each represent the direct precursor of the compounds of the formula Ia or Ib which have a strong anti-inflammatory and / or analgesic action, their action may be related to that of the latter compounds.

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 can furthermore serve as intermediates for the preparation of pharmacologically and / or chemotherapeutically active compounds. The same also applies to the compounds of the formula IV and VI to be prepared as intermediates.

EXAMPLES Example 1

Hy_droxyäthyliden-cyanoacetic acid- (3-chloroanilide) a) Äthoxyäthyliden-cyanoacetic acid- (3-chloroanilide)

A mixture of 117 g (0.6 mol) of cyanoacetic acid (3-chloroanilide), 150 g (0.93 mol) of orthoacetic acid ethyl ester, 190 g (1.86 mol) of acetic anhydride and 60 mg of anhydrous zinc chloride was stirred and refluxed for 3 hours cooked. Low-boiling fractions were then distilled off over a 15 cm high Vi-greux column at a bath temperature of 120 ° C. over the course of 2.5 hours. After cooling and standing overnight, the deposited kri632 487

stalline substance, isolated by suction. After washing with ether and drying, 100 g of crystals were present. After dilution with ether, a further 11 g of crystals were obtained from the filtrate. These crystalline products still contained portions of cyanoacetic acid (3-chloroanilide) and were therefore boiled out with 300 ml of CHC13. The CHC13 extract was removed hot from undissolved solid. During cooling, 32 g of pure ethoxyethylidene-cyanoacetic acid (3-chloroanilide) crystallized out of the extract as a uniform compound (Z or E form). The portion undissolved in CHC13 was extracted twice in the same way with CHC13 (300 ml or 150 ml). A further 30 g of the above-mentioned compound were obtained from the CHC13 extracts on cooling. 4 g remained undissolved and, according to TLC, also represented almost pure ethoxyethylidene-cyanoacetic acid (3-chloroanilide), which still contained traces of the starting material. The combined CHC13 mother liquors were concentrated to about 300 ml, the precipitate which formed was filtered off with suction, and the mixture was a mixture of reaction product and starting anilide. About 100 ml of ether was added to the filtrate, after which a further 26 g of almost pure ethoxyethylidene-cyanoacetic acid (3-chloroanilide) in the form of the stereoisomer mixture precipitated out in crystalline form. This portion was purified by recrystallization from CHC13. A total of 66 g (= 41.5% yield) of ethoxyethylidyethanoic acid (3-chloroanilide) was obtained in the form of the pure Z or E stereoisomer of mp. 165-166 ° C. and 22 g (= 14% yield) as a mixture of stereoisomers of Mp 121-123 ° C.

Analysis: C13H13C1N202 calc .: C 59.0 H 4.9 Cl 13.4% MG 264.7 found: C 59.0 H 4.9 Cl 13.7% MG 264; 266 b) Hydroxyethylidene-cyanoacetic acid- (3-chloroanilide) 26.5 g (0.1 mol) of the ethoxyethylidene compound prepared under (a) were mixed with 150 ml of 4N sodium hydroxide solution and heated to 75 ° C. for 10 minutes with stirring . After adding 400 ml of water, the mixture was allowed to cool to 20 ° C., filtered through diatomaceous earth and the filtrate was acidified to pH 1. The precipitated crystalline precipitate was filtered off, washed with water until neutral and free of salt and dried. 22.5 g (= 95% yield) of pure hydroxyethylidene-cyanoacetic acid (3-chloroanilide) of mp 169-170 ° C. were obtained.

The IR spectrum of this compound was identical to that of the same compound that had been obtained in a different way according to DE-OS 2 524 929.

Example 2 Hydroxyethylidene-cyanoacetic Acid

(3-trifluoromethyl-anilide) a) ethoxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide)

A mixture of 68.5 g (0.3 mol) of cyanoacetic acid (3-trifluoromethyl-anilide), 66 g (0.41 mol) of orthoacetic acid tri-ethyl ester, 77 g (0.75 mol) of acetic anhydride and 40 mg of zinc chloride became 3 Cooked at reflux for hours at 110 ° C bath temperature.

Low-boiling fractions were then slowly distilled off over a 20 cm high Vi-greux column in 2.5 hours at a bath temperature of 120 ° C., the distillation pressure being reduced to 350 torr for 5 minutes.

After cooling and standing for 16 hours, the reaction mixture was completely crystallized. The mixture was diluted with 200 ml of ether: isopropyl ether 1: 1, the crystals were filtered off and washed with isopropyl ether. After drying, 49.5 g of a stereoisomer mixture (according to TLC and NMR spectrum) of ethoxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide) [3-ethoxy-2-cyano-crotonic acid- (3-tri-

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fluoromethyl anilide)] with an mp. of 135-137 ° C (55.5% yield).

Analysis: C14Hj3F3N202 calc .: C 56.4 H 4.4 F 19.2 N 9.4% MG 298.3 found: C 56.4 H 4.5 F 19.3 N9.2% MG 298 An analog The run carried out, in which no zinc chloride was added, gave 41.5 g of a stereoisomer mixture of the ethoxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide), in which one form (Z- or E-) was strongly enriched, with an mp from 125-127 ° C.

b) hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide)

A mixture of 30 g (0.1 mol) of ethoxyethylidene-cyanoacetic acid (3-trifluoromethyl-anilide), 1.3 liters of ethanol and 750 ml of 6N hydrochloric acid was heated to 64-65 ° C. with stirring for 12 hours and then suction filtered while warm. The filter residue was washed neutral with water and dried.

21 g of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl anilide) [2-cyano-3-hydroxy-crotonic acid (3-trifluoromethyl anilide)], mp. 181-182 ° C. (= 78 % Yield).

This product agrees in the melting point and IR spectrum with the same compound produced in another way according to DE-OS 2 524 929.0.

Example 3

Hydroxyethylidene-cyanoacetic acid- (3,4-dichloroanilide) a) Ethoxyethylidene-cyanoacetic acid- (3,4-dichloroanilide)

A mixture of 115 g (0.5 mol) of cyanoacetic acid (3,4-dichloroanilide), 110 g (0.675 mol) of orthoacetic acid triethyl ester, 128 g (1.25 mol) of acetic anhydride and 50 mg of zinc chloride was added for 2.5 hours 115 ° C bath temperature cooked at reflux. Thereafter, low-boiling fractions were distilled off over a 20 cm Vigreux column with stirring over a period of 2 hours at a bath temperature of 118-120 ° C. The reaction mixture, which had crystallized completely after cooling and standing for 10 hours, was diluted with isopropyl ether and suction filtered. The solid washed out with ether (134 g) was, according to TLC, a mixture of both stereoisomers of the ethoxyethylidene compound and unreacted starting anilide. The product was dissolved in 650 ml of boiling CHC13, 200 ml of ether were added and the product which had crystallized out was filtered off with suction. This gave 61 g of a pure stereoisomer (Z or E form) of the ethoxyethylidene-cyanoacetic acid (3,4-dichloroanilide) [3-ethoxy-2-cyano-crotonic acid (3,4-dichloroanilide)] (= 41 % Yield) of mp 155-157 ° C.

Analysis: C13H12C12N202 calc .: C52.0 H 4.4 Cl 23.6 N9.4% MG 299.2 found: C 52.0 H 3.9 Cl 24.0 N9.4%

MG 298; 300; 302 (mass spectroscopic)

The CHC13 / ether mother liquor was evaporated and the residue boiled with 700 ml of CC14. 26 g of cyanoacetic acid (3,4-dichloroanilide) remained undissolved. The CC14 extract was evaporated. The remaining residue was dissolved in 200 ml of CHC13, filtered off from small amounts of undissolved matter and 50 ml of ether were added to the filtrate. Thereupon 9 g of the other pure stereoisomer (E or Z form; this is the stereoisomer with the higher RF value in the DC; solvent CH2C12 / C2H5OH 10: 1, silica gel pre-assembled plates Merck F 254) with an mp from 159-161 ° C (= 6% yield). The combination gave the correct analysis values corresponding to the gross formula.

b) hydroxyethylidene-cyanoacetic acid- (3,4-dichloroanilide)

Analogously to the method described in Example (1) under (b), starting from 30 g (0.1 mol) of the ethoxyethylidene compound, 25.5 g (94% yield) of hydroxyethyli-den-cyanoacetic acid (3,4-dichloroanilide) obtained from mp. 208-210 ° C.

Examples 4-8

According to the procedure described in Examples (2) and (3) in each case under (a), the following were obtained: ethoxyethylidene-cyanoacetic acid- [3- (l, 1,2-trifluoro-2-chloro-ethoxy) anilide], C1sH14C1F3N203, Mp 102-103 ° C (Z or E form), yield: 21%. Ethoxyethylidene-cyanoacetic acid- (3-bromoanilide),

C13H13BrN202, mp 196-197 ° C (Z or E form), yield: 50%.

Ethoxyethylidene-cyanoacetic acid- (4-methoxy-anilide), Ci4H16N203, mp. 166-167 ° C (Z- or E-form), yield: 30%.

Ethoxyethylidene-cyanoacetic acid- (3-chloro-2-methyl-anilide), C14H15C1N202, mp. 171-173 ° C (Z- or E-form), yield: 42%.

Ethoxyethylidene-cyanoacetic acid- (5-chloro-2-methyl-anilide), C14H15C1N202, mp. 208-210 ° C (Z- or E-form), yield: 72%.

Methoxyethylidene-cyanoacetic acid (3-chloroanilide) as an additional precursor for the hydroxyethylidene compound C12HUC1N202 to be prepared according to Example (lb), mp. 118-120 ° C. (E or Z form), yield 7%; Mp

157-158 ° C (Z or E form), yield 10%.

In order to separate the two stereoisomers and to separate small amounts of cyanoacetic acid (3-chloroanilide), it is advisable in this case to carry out column chromatography on silica gel (Merck) from methylene chloride / benzene 1: 1, the column then being eluted with CH2C12. The composition of the eluate fractions was checked by TLC. The connections are in the order:

a) low-melting stereoisomer,

b) higher melting stereoisomer,

c) cyanoacetic acid (3-chloroanilide)

eluted.

The above ethoxyethylidene compounds were converted into the corresponding 2-hydroxyethylidene-cyanoacetanilides by the procedure described in Example (1) under (b); one thus obtained:

Hydroxyethylidene-cyanoacetic acid- [3- (l, 1,2-trifluoro-2-chloro

ethoxy) anilide], m.p. 140-141 ° C. Hydroxyethylidene-cyanoacetic acid- (3-bromoanilide), mp 178-179 ° C.

Hydroxyethylidene-cyanoacetic acid- (4-methoxy-anilide), mp. 151-152 ° C.

Hydroxyethylidene-cyanoacetic acid- (3-chloro-2-methyl-anilide),

164-165 ° C. Hydroxyethylideh-cyanoacetic acid- (5-chloro-2-methyl-anilide), mp. 127-129 ° C.

Example 9

560 mg (2 mmol) of ethoxyethylidene-cyanoacetic acid (5-chloro-2-methyl-anilide) were mixed with 8 ml of methanol and 70 ml of 0.5N sodium hydroxide solution and stirred at 65 ° C. for 30 minutes. After filtering the solution over diatomaceous earth, the filtrate was acidified with sulfuric acid, the precipitate was filtered off with suction, washed with salt-free water and dried. 465 mg (= 93% yield) of hydroxyethylidene-cyanoacetic acid (5-chloro-2-methyl-anilide) were obtained, mp 128-129 ° C.

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Example 10 Dimethylaminoethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide)

A mixture of 20.9 g (0.07 mol) of ethoxyethylidene-cyanoacetic acid (3-trifluoromethyl anilide) and 80 ml of 1,2-dimethoxyethane was passed at 30-46 ° C. with stirring until a supersaturation of a dimethylamine gas stream a. The resulting solution was stirred for 1 hour while passing a weak stream of dimethylamine and then evaporated in vacuo. The remaining residue was suspended in ether, suction filtered and washed with ether. After drying, 16 g (= 80% yield) of dimethylaminoethylidene-cyanoacetic acid (3-trifluoromethyl-ani-lid) [2-cyano-3-dimethylamino-crotonic acid (3-trifluoromethyl-anilide)] were obtained Mp 127-128 ° C.

Analysis: Ci4H14F3N30 calc .: C56.6 H4.7 F 19.2 N14, 1% MG297.3 found: C 56.3 H 4.7 F 19.5 N 14.2% MG 297

(mass spectroscopic) According to this procedure were produced:

Dimethylaminoethylidene-cyanoacetic acid- (3-chloroanilide),

C13H14C1N30 (MW 263.7), mp 146-148 ° C. Dimethylaminoethylidene-cyanoacetic acid- (3-bromoanilide), C13H14BrN30 (MW 308.2), mp 141-142 ° C (from ethyl acetate).

Dimethylaminoethylidene-cyanoacetic acid- (3-chloro-2-methyl-anilide), C14H16C1N30 (MW 277.8), mp. 134-135 ° C (from ethyl acetate).

Dimethylaminoethylidene-cyanoacetic acid- (5-chloro-2-methyl-anilide), C14H16C1N30 (MW 277.8), mp. 142-143 ° C (except 1,2-dimethoxyethane).

Example 11

(4-methyl-piperazinoethylidene) -cyanoacetic acid- (3-trifluoromethyl-anilide)

To a mixture of 15 g (0.05 mol) of 2-ethoxyethyl-den-cyanoacetic acid (3-trifluoromethyl anilide) and 100 ml of 1,2-dimethoxyethane was added a solution of 5.3 at 30 ° C. in 15 minutes g (0.053 mol) of N-methylpiperazine in 10 ml of 1,2-dimethoxyethane and stirred at 45 ° C. for 1 hour, a solution being formed. This was evaporated in vacuo. The residue crystallized when ether was added. The mixture was boiled and the crystals (11 g) were filtered off with suction. After concentrating and adding isopropyl ether, a further 4.5 g of crystalline compound were isolated from the filtrate. The crystals were recrystallized from CC14. This gave 12.4 g (70.5% yield) of pure (4-methyl-piperazinoethylidene) -cyanoacetic acid- (3-trifluoromethyl-anilide), mp. 129-130 ° C.

Analysis: C17H19F3N40 calc .: C 58.0 H 5.4 F 16.2 N15.9% MG 352.4 found: C 58.0 H 5.2 F 15.8 N 15.6% MG 352

(mass spec.) In accordance with this procedure, the following were also produced:

Piperidinoethylidene-cyanoacetic acid- (3-chloroanilide),

C16H18C1N30 (MW 303.8), mp 138-139 ° C (from ethyl acetate).

Piperidinoethylidene-cyanoacetic acid- (5-chloro-2-methyl-ani-lid), Ci7H20C1N3O (MW 317.8), mp. 133-134 ° C (from ethyl acetate).

632 487

Example 12

A mixture of 9 g (0.03 mol) of dimethylaminoethyl-den-cyanoacetic acid- (3-trifluoromethyl-anilide), 60 ml of ethanol and 200 ml of 2N hydrochloric acid was stirred at 35 ° C. for 4.5 hours. The solid was then suctioned off, washed with water until neutral and free from salt and dried.

8.0 g (= 99% yield) of hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl-anilide) of mp.

179-180 ° C.

According to this working method were produced:

a) from piperidinoethylidene-cyanoacetic acid- (3-chloroanilide)

Hydroxyethylidene-cyanoacetic acid (3-chloroanilide), mp. 170-171 ° C (94% yield).

b) from (4-methylpiperazinoethylidene) -cyanoacetic acid- (3-tri-fluoromethyl-anilide) hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide), mp. 179-181 ° C (98% yield).

c) from dimethylaminoethylidene-cyanoacetic acid- (3-bromani-

lid) Hydroxyethyliden-cyanoacetic acid- (3-bromoanilide), mp. 178-179 ° C (96% yield).

Example 13

A mixture of 4.5 g (0.015 mol) of dimethylamino-ethylidene-cyanoacetic acid (3-trifluoromethyl-anilide), 70 ml of ethanol and 100 ml of 0.1N hydrochloric acid was stirred at 30 ° C. for 10 hours, after which the product was filtered off with suction. The crystalline substance washed and dried with water until neutral weighed 3.7 g (= 91.5% yield) and was pure hydroxyethyl-3-trifluoromethyl-anilide (mp.

179-181 ° C.

Example 14

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl

-anilide) -cyclohexylammonium salt 27 g (0.1 mol) of 2-hydroxyethylidene-cyanoacetic acid- (3-tri-fluoromethyl-anilide) were suspended in 100 ml of methylene chloride, stirred and added dropwise at room temperature with 11 g (0.11 mol ) Cyclohexylamine added. The resulting mixture was then evaporated, leaving a solid product which could be washed out with cyclohexane. After drying, 27 g (= 73% yield) of hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl-anilide) -cyclohexylammonium salt of mp. 157-159 ° C. were obtained.

Analysis: Ci8H22F3N302 calc .: C58.5 H6.0 NI 1.4% MG369.4 found: C 58.5 H 6.0 N 11.1%

Example 15

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 11.5 g (0.11 mol ) Diethanolamine was added and the mixture became homogeneous during the dropping. When the clear brown solution was evaporated, a solid residue remained which, after washing out with cyclohexane, contained 32 g (= 76% yield) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl-anilide). -Diethanolammonium salt hemihydrate of mp. 96-98 ° C delivered.

Analysis: with 1/2 H2OC16H20F3N3O4 calc .: C50.0 H 5.5 N 10.9% MG 375.4 found: C50.3 H5.8 NI 1.0%

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Claims (5)

632487 2 PATENT CLAIMS 1. Process for the preparation of new Hydroxyäthylidencyanessigsäureaniliden of formula Ia or its tautomeric form Ib OH C. II c O NC (Ia) 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 25th grappe, a trifluoromethyl group or a methoxy group and R3 is a hydrogen atom, a chlorine atom or a methoxy group, or R1 and R2 together are the -0-CH2-0 group, and their salts, characterized in that a cyanacetic acid anilide of the formula II (II), in which R1, R2 and R3, which in the formulas Ia and R4 are an alkyl radical having 1 to 4 carbon atoms, have the meaning given in Ib, with an ortho-presence of an anhydride of a lower fatty acid, in the case of a acetic acid esters of formula III at a temperature between + 20 and +180 ° C to an alk oxyethylidene-cyanoacetic anilide of the formula IV CH3-C (OR4) 3 (III), and or (IV), h r 0 ch- C. II G NC 0 e- in the R \ R2, R3 and R4 the above mentioned hydrolyzed between - 30 and +150 ° C and given have interpretation, and then converting the alkoxyethyl compound of a formula I obtained into its salt by adding liden cyanoacetic anilide of the formula IV at a temperature of a base. 2. Process for the preparation of new hydroxyethylidediazanoic acid anilides of the formula Ia or their tauto- form Ib 632 487 ch. Oh C. II C. / \ / NC C I. HN (la) V 0 R r " ./IV • h y HN (Ib) 0 R R R- R " 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 represent a hydrogen atom, a chlorine atom or 20 a methoxy group, or R2 and R1 together represent the -0-CH2-0 group, and their salts, characterized in that one of a cyanoacetic anilide Formula II in which R1, R2 and R3 have the meaning given above for formulas Ia and Ib, with an ortho-acetic acid ester of the formula III CH3-C (OR4) 3 (III), in which R4 denotes an alkyl radical having 1 to 4 carbon atoms, in the presence of an anhydride of a lower fatty acid, at a temperature between + 20 and +180 ° C. to form an alk-oxyethylidene-cyanoacetic anilide of the formula IV CH .. * \ 3 , or R ^ O CH. C. II C. and or NC Z- / \ ^ (IV), c i HN R R- C. II c / \ ^ NC C I. HN E- 0 R R " R- R ' in which R1, R2, R3 and R4 have the meaning given above, and then reacting and reacting the alkoxyethylidene-cyanoacetic anilide of the formula IV at a temperature between - 40 and -1-160 ° C with a secondary amine of the formula V Hm: R- R (v) 60 in which R5 and R6, which may be the same or different, each have an alkyl radical with 1 to 4 carbon atoms or together an alkylene chain with 2 to 5 carbon atoms, a -CH2CH2-Q-CH2CH2- or one 65 -ch2ch2n r 7 -Group, ch2CH2- 632487 4 in which R7 represents alkyl having 1 to 4 carbon atoms or benzyl, mean, and the dialkylamino-ethylidene-cyanoacetic acid anilide derivative of the formula VI formed in the process R ■ CH, \? / \ 6 C. II c / \ ^ NC C Z- 0 and or (vi), in which R1, R2 and R3 and R5 and drolys and optionally an obtained compound of R6 have the meaning given for formula V, formula 25 is converted into its salt by adding a base.