DE2555685A1 - Hydroxyethylidene-cyano-acetanilides - with antiinflammatory and analgesic activity - Google Patents

Abstract

Hydroxyethylidene-cyanoacetanilides of tautomeric structure (I) and their salts are new: In the formula, R1 is halogen, 1-2C alkyl opt. substd. by 1-3 F and/or Cl atoms, 1-2C alkoxy opt. substd. by 1-4 F and/or Cl atoms, or 1-2C alkylthio; R2 is H, halogen, Me, Et, CF3 or MeO; R3 is H, Cl or MeO; R1 and R2 can also form an OCH2O group. Cpds. (I) are anti-inflammatory agents and analgesics, and also have anthelmintic, antimycotic and fungicidal activity. A typical cpd. is N-(3-chlorophenyl)-hydroxyethylidene-cyanoacetamide. In an example, this is prepd. by reacting N-(3-chlorophenyl)cyanoacetamide with triethyl orthoacetate and hydrolysing the prod.

Description

New cyanoacetic anilide derivatives, process for their preparation

position and agents containing these compounds The invention relates to new hydroxyethylidene-cyanoacetic anilides of the general formula Ia or its tautomeric form Ib in which R1 is a halogen atom, a methyl or ethyl group which can be substituted by 1-3 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, a hydrogen atom, a halogen atom, a methyl or ethyl group, a trifluoromethyl group or a methoxy group and 2 denotes a hydrogen atom, a chlorine atom, a methoxy group, and where R1 and R2 together represent the -O-CH2-0- Grouping can mean, as well as their physiologically 'compatible salts.

The radicals R¹ are preferably a halogen atom, a methyl, ethyl or trifluoromethyl group, a methoxy or ethoxy group or one with 3 fluorine atoms and a chlorine atom or 4-fluorine atoms substituted ethoxy group, R2 a hydrogen atom, a halogen atom, a trifluoromethyl group or a methoxy group, R³ a hydrogen atom, and R¹ and R² together represent a -Q-CH2-O group in the 3,4-position.

The radicals R1 are particularly preferably fluorine, chlorine or Bromine atom or a methyl, trifluromethyl or methoxy group, R2 a hydrogen atom, a chlorine or bromine atom or a trifluoromethyl group R3 a hydrogen atom, and R1 and R2 together represent a -0-CH2-O group in the 3,4-position.

As salts of the compounds of the general formula according to the invention I come alkali salts such as lithium, sodium, potassium salts, ammonium salts, alkaline earth salts such as magnesium, aalcium or zinc salts, iron salts and salts with organic Bases, such as, for example, amines or tetraalkylammonium hydroxides, are suitable.

Sodium, potassium, ammonium, magnesium or calcium salts are preferred as well as salts with amines with 2 to 8 carbon atoms, such as piperidine, .triethylamine, N-ethylpiperidine, N-methyl-morpholine, cyclohexylamine or diethanolamine.

In addition to those listed in the preparation examples, the following may be mentioned as compounds according to the invention: Hydroxyethylidene-cyanoacetic acid-3-bromo-, -3-fluoro-, -3-iodo-3- (1 ', 1', 2'-trifluoro-2 '-chloro-ethoxy) -, -3- (tetrafluoroethoxy) -, -4-bromo-, -4-methoxy-, -4-chloro-, -4-fluoro-, -3,4-dichloro-, -2 , 3-dichloro, -3,5-dichloro, -2,6-dichloro, - 3-chloro-2-methyl-, -5-chloro-2-methyl-, -3,4-dioxymethylene, -3-ethoxy-, 3, 5-bis-trifluoromethyl-, -2,4,6-trichloro-, -2-chloro-4-methoxy-, -2-trifluoro-methyl-4-chloro-, -3- methylthio- and -4-ethylthio-anilide), the invention also relates to a process for the preparation of hydroxyethylidene-cyanoacetic anilides of the formula Ia or its tautomeric form Ib, which is characterized in that a1) a cyanoacetic anilide of the formula in which R1, R2 and R3 have the meaning given above for formulas Ia and Ib, with an orthoacetic acid ester of the formula CH3-C (OR4) 3 III in which 4 R is an alkyl radical with up to 4 carbon atoms, in the presence of an anhydride 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 +200 and +1800C to form an alkoxyethylidenecyanoacetic anilide of the formula in which R1 - z have the meanings given above, and then the isolated alkoxyäthylidencyangsäureanilid of the formula IV in alkaline aqueous solutions, optionally with the use of wholly or partially water-miscible organic solvents at a temperature between -300 and + 150 ° C , hydrolyzed.

When implementing the cyanoacetic anilides of the formula II with a Orthoacetic acid ester of the formula III, the reaction temperature is preferably between +600 and + 150 ° C, especially between +850 and + 1400C. In this process step you can optionally formed low-boiling compounds at least partially distill off from the reaction mixture.

If one works accordingly at the boiling point of the reaction mixture, so the reaction temperature can vary during the reaction, in particular rise, depending on whether or not

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 heard at lower levels or e.g.

at the autogenous pressure of the reaction mixture in a closed vessel, get lost. The reaction times are between 0.5 and 48 hours, preferably between 1 and 12 hours.

A variant a2) 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 under a1), advantageously with the use of a solvent, at a temperature between -40 ° and + 160 ° C , with a secondary amine of the formula in which R5 and R6, which can be identical or different, each have an alkyl radical with 1 to 4 carbon atoms or together one. Alkylene chain with 2 to 5 carbon atoms, a -C2CH2-O-CH2CH2- or -Grouping in which R7 has the meaning of an alkyl group with 1 to 4 carbon atoms or a benzyl group, is converted and the dialkylaminoethylidene-byanacetic anilide derivative of the formula formed in this way in which Rl - R3 have the meanings given above and 2 and R 6 have the meanings given for the formula V, hydrolyzed under acidic or alkaline conditions, optionally using a water-miscible organic solvent.

Process a) according to the invention proceeds according to the following scheme: *) see J. Org. Chemistry Vol. 35, 2849 (1970) in particular page 2852, z - E - nomenclature The methyl or ethyl esters are preferably used as orthoacetic acid esters of the general formula III.

Under the name Lewis acids are anhydrous salts of the elements Boron, aluminum, zinc, cadmium, mercury, thallium, titanium, zirconium, tin, lead, Understand phosphorus, arsenic, antimony, iron, cobalt and nickel.

Provided Lewis acids as catalysts in the preparation according to the invention of compounds of the formula IV are used, the following salts are preferred used: boron trifluoride, boron trichloride, AlCl3, ZnC12, ZnBr2, ZnJ2, Zn (CH3CO2) 2, Zn2P207, ZnSO4, HgC12, Hg (CH3CO2) 2, HgSO4, TiCl4, SnCl4, PCl3, POCL3, PCl5, SbBr3, SbCl5, SbOCl, (SbO) 2SC4, FeSO4 or Fe2 (S04) 3. The catalysts can be used in quantities of 0.005-5 mol or more based on the compounds II can be used. *) SbCl3 **) FeCl3 Unless the reaction is carried out using a solvent can, as such, hydrocarbons, halogenated hydrocarbons, ethers and Nitriles can be used, provided these compounds are subject to the reaction conditions are inert, i.e. do not contain any additional functional groups that could lead to side reactions being able to lead.

Examples include: petroleum ether, n-hexane, toluene, 2 xylenes, Benzene, 1,2-dichloroethane, carbon tetrachloride, tetrachlorethylene, diisopropyl ether, Dioxane, tetrahydrofuran, glycol and diglycol dimethyl ethers and / or acetonitrile.

The reaction of the anilides II with compounds of the Formula III carried out without the use of a solvent.

In the reaction of the cyanoacetanilides of the general formula IX with an orthoacetic acid ester of the formula III in the presence of an anhydride of a lower one . Fatty acid, for example in the presence of acetic anhydride, the reaction conditions and the proportions, in which the reactants and optionally the Catalysts applied vary widely. That means the cyanoacetanilade of the formula II in an excess of up to 35 56, the ortho-acetic acid esters of the formula III in an excess, for example up to 200 0 / o or more, expediently 20 to 100 56, in each case based on the other reaction component, but also in stoichiometric Ratio can be used. The same applies to the amount to be used of carboxylic acid anhydride, preferably acetic anhydride. The carboxylic acid anhydride is advantageous in a stoichiometric excess, preferably from 20 to 170 56, based on the larger of the two components, the anilide of the formula II or the orthoester of formula III is used. In addition, the orthoacetic acid ester and the carboxylic acid anhydride can not be used all at once at the beginning of the reaction; Reaction components at different rates in the course of the reaction be added in portions or continuously to the reaction mixture. Farther can also be used in portions or continuously during the reaction Fraction of volatile components produced under normal, positive or negative pressure distill off. With this measure, the reaction temperature can be adjusted Influence way.

Isolation of the alkoxyethylidene cyanoacetic anilides formed of the general formula IV can be carried out in various ways. Unless they are direct occur as crystalline compounds in the implementation, they are isolated and, if necessary, by recrystallization from suitable solvents such as, for example Ether, isopropyl ether, benzene, toluene, Ethyl acetate, dimethoxyethane, Tetrahydrofuran, chloroform or carbon tetrachloride, or by column chromatography cleaned. Essentially, the purification is a separation of unreacted starting cyanoacetanilide, which is often in different proportions is obtained in crystalline form together with the reaction product.

If there are no crystalline substances after the reaction, then you can the reaction products, e.g. after separating off the low-boiling components by distillation as well as in non-polar solvents, such as saturated acyclic or cyclic solvents Hydrocarbons, e.g. n-hexane, cyclohexane easily soluble parts by washing with these, with the help of suitable solvents such as ether, isopropyl ether, Benzene, toluene ethyl acetate, dimethoxyethane, tetrahydrofuran, chloroform or carbon tetrachloride brought to crystallization and optionally further purified in the usual way will.

The new alkoxyethylidene-cyanacetanilides formed during the reaction of the general formula IV fall depending on the reaction conditions and the radicals R1 - R4 as E / Z stereoisomeric mixture, the ratio of the stereoisomers can be very different, or sometimes as a pure E or Z shape. From the stereoisomer mixtures can either or both stereoisomers by separating the mixture using conventional Measures such as fractional crystallization or column chromatography can be obtained relatively easily in pure form.

Examples of Alkoxyäthyliden-cyanacetanilide of the formula IV, which according to the invention as intermediate products or as direct precursors of the hydroxyethylidene cyanacetanilide the formula Ia or Ib can be prepared are the following: Ethoxythylids -cyanacet- (3-trifluoromethyl-, -3-chloro-, -3-bromo-, -3-iodo-, -4-bromo-, -3,4-dichloro-, -3,4-dioxymethylene, -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- (tetrafluoroethoxy) -, -3- (1,1,2-trifluoro-2-chloroethoxy) -, -3-methylthio-, -3-chloro-4-methyl- and -3, 4-dimethoxy-anllid).

The hydrolysis of the alkoxyäthyliden-cyanoacetic anilides of the general Formula IV to the corresponding pinoles of the formula Ia or their tautomeric keto form Ib can be used under alkaline or acidic conditions over a wide temperature range run in homogeneous or heterogeneous systems. The hydrolysis conditions can in terms of the concentration of acids or alkalis used as well with respect to the composition of the reaction medium within a wide range can be varied. You can use water alone or with the addition of different amounts work with water-miscible solvents. As examples of such solutions el are: (C1-C3) -alkanols and alkanediols, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, acetonitrile, glycol monomethyl or ethyl ether, dimethylformamide, Dimethyl sulfoxide and / or (C3-C4) ketones.

The reaction times can be up to 24 hours, how is known, reaction times are inversely related to the reaction temperature, d.1i. shorter reaction times are required at higher temperatures.

Furthermore, the hydrolysis can also be carried out in a 2- or 3-phase system are executed. In the case of a 3-phase system, it is usually a matter of that either the cyanoacetanilide derivative of the formula IV to be hydrolyzed or the Hydrolysis product of the general formula Ia or Ib or both substances as a solid phase are present. It is therefore possible that there is always a solid phase in the hydrolysis batch is present, which at the beginning of a compound of formula IV and at the end of Reaction from a pure hydrolysis product of the formula Ia or Ib or from a mixture can consist of starting material and hydrolysis product.

The alkaline hydrolysis is preferred in an aqueous medium, if appropriate with the use of the above-mentioned solvents at an alkali concentration from 0.2 to 8 N at a temperature between 200 and 1000C. As alkalis caustic soda or potassium hydroxide solution or sodium or potassium carbonate solutions are preferred used. The alkalis are in at least equimolar amounts, preferably in one 20 show or larger excess used.

The hydrolysis products are found in this embodiment of the hydrolysis wholly or partly as a sodium or potassium salt in solution. With acidification that will corresponding hydroxyeth -. ylidene. cyanoacetanilide of the formula Ia or the tautomeric Form Ib precipitated in mostly crystalline form.

The acid hydrolysis is preferably used in an aqueous medium Water-miscible solvents designated in more detail from above at an acid concentration from 1N to 12N at a temperature between 20 ° and 100 ° C.

As solvents, which are advantageously added here, come <c1 -C3) alkanols tetrahydrofuran, 1,2-dimethoxyethane, dioxane, glycol monomethyl ether, Acetone and / or acetonitrile in question The Hydroxyäthylidenidenidenessigsäureanilide formed in the hydrolysis of the formula Ia or Ib fall either directly or partially or completely Evaporation of the organic solvent used as a solubilizer kr) n from.

Bea the inventive variant a2) of the process, or the Alkoxyäthyliden-dyanessigäsureanilide of formula IV initially by the action of a secondary amine in a compound of formula VI are converted, is preferred in the presence of neutral organic Solvents worked at a temperature between 200 and 100 ° C. As a solvent are preferably 1,2-dimethoxyethane, ether, dioxane, tetrahydrofuran, (C1-C3) alkanols, Carbon tetrachloride, tetrachlorethylene and / or acetonitrile in question. The response times are up to 8 hours.

The hydrolysis of the Dialkylaminoäthyliden -cyanessigsäureanilid derivatives of the formula VI can in turn be carried out in the acidic or alkaline range. With regard to the use of organic wholly or partially miscible with water The same applies to solvents as to the hydrolysis of the enol ethers of the formula IV. The reaction conditions can be related to the composition of the reaction medium, Acid or base concentration and temperature vary greatly, the reaction times, which can be up to 8 hours are very dependent the reaction conditions away. In acid hydrolysis, which is generally preferred at this stage of the process is, is preferably with acid concentrations of n / 100 to 6N at a temperature worked between 0 ° and 700C. This gives the compounds of the formula Ia or Ib. The alkaline hydrolysis is carried out with alkaline solutions or alkali carbonate solutions a content of 0.2 N to 8 N carried out, after the reaction the alkali salts of the compounds of the formula Ia or Ib are completely or partially dissolved. By When acidified, the crystalline, acidic hydroxythylidene-cyanacetanilides are obtained from the salts of formula Ia or Ib. In the alkaline hydrolysis of the compounds IV and VI one works with at least equimolar amounts of alkali. Excesses are preferred from 30 to 500 0.0, in particular 100 to 300 56, or more are used.

As examples of Dialkylaminoäthyliden --cyanessigsäureanllid derivatives of the formula VI, according to the invention as intermediates or as direct precursors Hydroxyäthyliden-cyanacetanilide Ia and Ib can be prepared are the following named: (1-dimethylamino, 1-diethylamino, 1-dipropylamino, 1-dibutylamino, 1-pyrrolidino-, 1-piperidino-, 1-morpholino-, 1-N-methyl-piperazino-ethylidene) -cyanacetic acid- (3-trifluoromethyl-, -3-chloro-, -3-bromo-, -3-iodo-, * -3,4-dichloro-, -3,4-dio: methylene-, -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- (1,1,2-trifluoro-2-chloroethoxy) -, -3-methylthio-, -3-chloro-4-methyl- and -3, 4dimethoxy-anllid) 'In addition, other (1-dialkylaminoethylidene) -cyanoacetic anilides can also be used after can be produced by the method according to the invention.

What is surprising about this variant of the process is the ease with which it can be hydrolyzed the substituted (1-dialkylsminoäthyliden cyanoacetic anilides of the formula VI under acidic conditions The compounds of formula VI become under weakly acidic conditions Conditions at a pH that is above O, hydrolyzed much faster than the enol ethers of the formula IV. Because of this, this variant of the process then advantageously used for the preparation of compounds of the formula Ia or Ib if they contain acid- or alkali-sensitive substitutes, in particular if one reckons with the change of substituents in the case of alkaline hydrolysis got to.

It is also surprising that the compounds of the formula IV are alkaline are hydrolyzed much faster than under acidic conditions, although they are of enol ethers, this class of compounds is concerned with. the connections of formula IV, is generally known to be in the presence of water under acidic Conditions can be split very easily.

The cyanoacetanilides of the formula II required as starting materials can after the in the Brit. U.S. Patent 930,808 (Americ. Cyanamid Co.) Process and the Orthoessig.Äureester of the formula III according to methods known from the literature (see Houben-Weyl-Müller, Methods of Organic Chemistry, IV. Edition Stuttgart 1965, Vol. 6, Part 3, St 295).

The invention also relates to a process b) for the preparation of compounds of the formula I, which is characterized in that a dialkylaminoethylidene-acetic anilide of the formula is used in which R5 and R6, which can be the same or different, preferably the same, each represent a (C1-C4) -alkyl radical or together an alkylene chain with 2-5 carbon atoms and R, R and R3 represent the formula Ia and Ib have given meaning, in the presence of an over the reactant inert, aprotic solvent initially at a temperature between -70 ° and + 50 ° C with chloro- or fluorosulfonyl isocyanate and then with a tertiary amine of the formula in which R8, R9 and R10, which can be the same or different, denote alkyl radicals with a total carbon number between 3 and 12, and two of these radicals together can denote an alkylene chain with 2 - 5 carbon atoms and / or an N, N- Dimethyl and / or diethylanide of a lower (C1-C4) carboxylic acid and / or N-methyl and Z or N-ethyl-2-pyrrolidone at a temperature between -30 ° and + 253C and then the reaction mixture, optionally after evaporation of the solvent is weakly alkaline, preferably with an excess of dilute aqueous alkali metal bicarbonate solution and then the dialkylaminoethylidene cyanoacetic anilide of the general formula VI from the lipophilic nose by crystallization or by means of column chromatography and isolated in the manner already described for the compound of the formula I So can the (1-dialkylaminoethylidene) -cyanessigsäureanilide of the general formula VI prepared by this process, in the Z- and / or E-form are present, can be converted into the corresponding compounds of the general formula Ia or Ib by the methods specified in the process described first by acid or alkaline hydrolysis: Suitable inert aprotic solvents are, for example, methylene chloride, chloroform, carbon tetrachloride, tetrachlorethylene or 1,2-dicellorethane.

Substituted starting materials are preferred for this process Anilides of the formula VII are used in which R5 and R6 are a methyl or ethyl group or together denote a tetra- or pentamethylene radical and Rh,, R2 and R3 denote in the *) The wavy line as a bond means that the Z- and / or the E-shape may exist Formula Ia and Ib specified particularly preferred Have meanings. The main sulfonyl isocyanate used is chlorosulfonyl isocyanate Triethyl-, tripropyl- and / or triethyl-, tripropyl- and / or are preferred as tertiary amines of the formula VIII Tributylamine and / or N-methylpiperidine and, as carbonamides, N, N-dimethylformamide or acetamide is used.

A preferred embodiment of the process according to the invention-b) consists in diluting at a temperature between -400 and -50C in each case Solutions of an anilide of the general formula VII and of chlorosulfonyl isocyanate in CH2Cl2, CHCl3 and / or ClCH2CH2Cl in equimolar amounts flow together evenly leaves.

The dilution of such solutions is approximately in the case of anilide 12-33 parts by weight of solvent per part by weight of anilide, in the case of the isocyanate about 10-20 parts by weight of solvent per part of isocyanate.

The mixture can then be used to complete the reaction hold at -100 to + 100C for another 0.25 - 2 hours.

Thereafter it is advantageous at a temperature between -25 ° and + 100C at the same time or successively dimethylformamide or dimethylacetamide and / or one of the above tertiary amines, optionally diluted with one of the above-mentioned chloroalkanes, added, whereby the sum of carbonamide and tertiary amines is preferably about 2-4 moles per mole of chlorosulfonyl isocyanate. The reaction solution is then in the partially or completely evaporated state with a dilute aqueous Sodium or potassium bicarbonate solution containing 1 - 2.5 equivalents of bicarbonate per mole Contains chlorosulfonyl isocyanate, mixed. The undissolved lipophilic fractions are extracted with CH2Cl2, CHCl3 and / or ether. The extract residue becomes ordinary chromatographed on a silica gel column, the crystalline from the eluates Cyanoacetic anilide -Derivatives of the formula VI is obtained.

The (1-dialkylaminoethylidene) cyanacetic anilide required as starting materials Derivatives of the formula VII can, for example, start out according to known methods of the corresponding acetoacetic anilides through the action of secondary amines (see e.g. Ber. dtsch. chem.

Ges. 25 (1892), 776; German patent specification 967,642).

Chlorine and fluorosulfonyl isocyanate are known methods (cf. Graf, Angel Chem. 80 (1968), 179).

The invention also relates to a process c) for the preparation of substituted cyanoacetic anilides of the formula Ia or its tautomeric form Ib, which is characterized in that cyanoacetone of the formula IX expediently in the presence of an aprotic solvent and in the presence of basic compounds at a temperature between -70 ° and + 140 ° C with an isocyanate of the general formula in which R1, R2 and R3 have the meanings given for formulas Ia and Ib, and optionally then converts the compounds of formula Ia or Ib by adding an equivalent amount or an excess of a mineral and / or a strong organic acid releases the salts formed in the reaction.

The reaction is preferred in the presence of an aprotic solvent at a temperature between 00 and 110 ° C, in particular between 100 and 85 ° C, executed. The solvents used are, for example, hydrocarbons such as pentane, Hexane, isooctane petroleum ether, benzene, toluene, xylenes and diethyl ether, isopropyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, acetonitrile, dichloroethane, tetrachlorethylene and, if tertiary amines are used as bases, also lower polychloroalkanes such as methylene chloride, chloroform and / or carbon tetrachloride in question.

As basic compounds, which are advantageous in equimolar amounts or can be used in an excess of up to 20, for example tertiary ones Amines, alkali alcoholates of lower alcohols, sodium hydride, alkali hydroxide or Alkali as well as alkaline earth carbonates can be used. Tert are preferred. Amines, Sodium or potassium alcoholates or sodium hydride are used.

After the reaction, the compounds Ia or

Ib in the form of salts, from which advantageous in the presence of Water by adding an equivalent amount or a slight excess of one Acid, preferably a mineral acid, the acidic compounds of the formula Ia or Ib are released, which then often occur already in crystalline form and can be isolated by filtration. Sometimes it is beneficial with this Process step a water-miscible solvent - preferred for this purpose lower alcohols, 1,2-dimethoxyethane and / or acetonitrile suitable - to be used, since this measure keeps Yerun clean lengths in solution and the cyanoacetic anilide derivatives of the formula Ia or Ib are obtained in a form that is easier to filter.

The cyanoacetone used as the starting material can be based on that of Dahn and Hauth Helv. Chim. Acta 47, 1424 (1964). As there and in some other publications (see Beilstein's handbook d organ. Chemistry IY. Ed.

Vol. 3, 5 g) described, the cyanoacetone polymerizes very easily, especially under alkaline and acidic conditions.

However, it is essential to carry out the method according to the invention not necessary to isolate the cyanoacetone in pure form. Since after Reaction with isocyanates of the formula X by-products can be easily separated off the cyanoacetone to be used is used as a starting material in the state As is the case with the acidic cleavage of 2-Cyneacetoacetic acid tert-butyl ester accrues. For example, toluenesulfonic acid is used as a catalyst for this cleavage (cf. Helv. chim. Acta 47, 1424 (1964), the removal of this acid must be carried out before the Reaction with isocyanate not necessary. Those released from their salts by acidification Cyanoacetic anilide derivatives of the general formula Ia or

Ib generally crystallize so well that they can easily be removed from accompanying substances can be separated.

Another object of the invention is a process d) for production of (1-Hydroxyäthyliden) -cyanessigsäureaniliden of the general formula Ia or their tautomeric form Ib, which is characterized in that one is a cyanoacetic anilide of the general formula II, in which R1, R2 and R3 are the above for the formula Ia or Ib have given meaning, expedient using Solvents or diluents, in the presence of a basic compound in a Temperature between -80 ° C and + 2000C with an acetic acid halide of the formula XI, in which X is chlorine or bromine and n = 1, or with acetic anhydride (formula XI, X = oxygen and n = 2) or with an acetic acid ester of the formula XII, in which R11 is a (C1-C4) -alkyl group, a benzyl group, a phenyl group or a through one or two chlorine atoms or nitro groups or by a carbomethoxy or carboethoxy group means substituted phenyl group, or reacts with ketene.

Acetic acid esters of the formula XII are used for acetylating the anilides of the formula II according to the process according to the invention, methyl or ethyl acetate usable; in addition, for example, the propyl, isopropyl, butyl, Isobutyl, phenyl or benzyl esters of acetic acid can be used.

The methyl, ethyl or phenyl esters of acetic acid are preferably used.

As basic compounds according to the invention, for example Alkali or alkaline earth hydrides, sodium or calcium alcoholates of lower alcohols, Alkali amides, sodium or potassium carbonate or bicarbonate, alkali hydroxides, lithium butyl and / or tertiary amines can be used.

Sodium hydride, sodium or potassium amide, potassium tert-butoxide are preferred, Sodium methylate or ethylate and / or sodium or potassium carbonate as basic Connections used. The basic compounds are expediently in amounts of 1-4 equivalents, preferably 1.1-3.3 equivalents, based on a cyanoacetanilide of formula II applied.

The reaction according to the invention with concomitant use is preferred carried out by solvents or diluents.

As a solvent or diluent for the process according to the invention are all known to be solvents which are sufficiently inert towards the respective reactants such as aromatic hydrocarbons, mono- or dichlorobenzenes, nitrobenzene, Anisole, dimethoxyethane, ether, tetrahydrofuran, dioxane, acetonitrile, tetrachlorethylene, Acetone, lower alcohols, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or dimethylformamide into consideration. Acetic acid esters can also be used as diluents to serve. If the acetylation is carried out with an acetic acid ester, can this can of course be used in excess at the same time as a diluent. Preferred solvents or diluents are 1,2-dimethoxyethane, tetrahydrofuran, Ether, dioxane, acetonitrile, anisole, toluene, chlorobenzene and dichlorobenzene, acetone, tert. Butanol and chloroform, the choice of which may be used in the case of the invention Reaction to be used Solvent or diluent of the basic compound used is influenced. That means that when applied of strong bases such as hydrides, alkali amides, lithium butyl or potassium tert-butylate For example, it is advisable not to use any protic solvents or haloalkanes be that the latter, however, when using a weak basic compound such as Potassium carbonate or, when using alcoholates, can be used without further ado can According to the method of the invention, the above acetylating agents in amounts of up to 4 equivalents, based on a cyanoacetanilide of the formula II are, an exception to this are the cases in which -with acetic acid esters is acylated if they also serve as a solvent or diluent. In such cases the esters are used in up to a 50-fold equimolar excess 1 - 2 equivalents of one of the above acetylating agents are preferred, based on a cyanoacetanilide applied.

In this reaction, the (1-hydroxyethylidene) -cyanoacetic anilides formed fall of formula I in the form of their salts.

Usually it becomes the acidic compounds of the general Formula I isolated in such a way that, if appropriate after evaporation of the related Solvent, the reaction product with water and / or dilute aqueous alkalis and / or treated with aqueous ammonia and, optionally after extraction of the aqueous Phase with ether, isopropyl ether or a hydrocarbon with a boiling point of 40 ° - 120? C, from the aqueous solution by acidification the (1-hydroxyethylidene) -cyanacetic anilide of the formula I is released, this mostly precipitating out as a crystalline precipitate.

Particularly preferred embodiments of the method according to the invention are as follows: When using a strongly basic compound such as sodium hydride, Sodium or potassium amide, lithium n-butyl or potassium tert-butylate are used expediently in the presence of 0.5 to 80 parts by weight per part of cyanoacetanilide one or more of the solvents indicated above as being preferred. One gives to the Solution of the cyanoacetanilide of the general formula II at a temperature between -50 and + 300C 2.0 - 2.2 equivalents of the base and then added at one Temperature between 50 and + 600C with 1.0 - 1.2 equivalents of the acetylating agent, optionally diluted with the above solvents.

After a reaction time of up to 5 hours, if necessary the temperature can be temporarily increased to up to 12500, one steams the Most or all of the solvents or diluents are removed and the Residue with water. Then the compounds formed in each case are the general formula I isolated as described above.

ß) When using a weaker basic compound, such as Sodium or potassium carbonate or a tertiary amine, such as triethylamine, become a mixture of one at a temperature between +20 and + 1200C Part of cyanoacetanilide of the formula II and 2 - 40 parts by weight of one or more of the solvents specified above as preferred and 2.0-3.3 equivalents of one such basic compound 1.0 - 1.4 equivalents (based on the cyanoacetanilide) of the acetylating agent, optionally in diluted by the above solvents Shape, added. After a reaction time of up to 24 hours, within which the Temperature can be between 20 and 12000, is carried out in the same way as under CL) or

described earlier worked to the respectively educated (1-Hydroxyäthyliden) -cyanessigsäureanilide to isolate.

When carrying out the reaction according to the invention, it must be ensured that that, if the respective acetylating agent in amounts of more than about 1.3 equivalents is used per val of cyanoacetanilide, then the reaction products in part or depending on the amount of acetylating agent used, largely in the form of their 0- and / or N-acetyl products are obtained. The O-acetyl compounds of the formula XIII, in the R1-R3 have the meaning given above, are hardly soluble in water and are located if extraction is carried out with organic solvents, in the organic phase, but they are hydrolytically split by dilute alkalis and leave at the same time in the corresponding alkali metal of the compounds I. From aqueous solutions or suspensions of these salts can be the Hydroxyäthyli.den compounds of the formula I can be released by acidification with mineral acid. If proceed in this way is, one also records the proportion of the reaction products, which may be initially is obtained as an O-acylated compound, and leads it into the desired end product of formula I over. The formation of O-acetyl derivatives of (1iydroxyäthyliden) -cyanacetanilide of the formula I can largely be avoided if a ratio of about 2 equivalents of bases to one equivalent planet of acetylating agent in the case of the invention Procedure applies.

The & 7Acylation of tert-butyl cyanoacetate with acetyl chloride with the formation of O-acetyl-cyanoacetoacetic acid tert.-butyl ester is used by Dahn and Hauth, Helvetica chim.

Acta 42, 1214 (1959). In addition, -Acylcyanessigsäureester Mentioned in DAS 1 194 630, but manufacturing methods were not mentioned there described. However, the transfer of the reaction to cyanoacetic anilides was by no means of course, as it is known here with the -CONH group one further deprotonatable and thus acylable function is present that are too undesirable Products or could lead to the failure of CC acylation.

The smooth course of the acylation is particularly surprising of cyanoacetanilides in the presence of such relatively weakly basic compounds as for example sodium and potassium carbonate and tertiary amines. With the type comparable reactions with C-H-acidic compounds are usually only expressed strong bases used for deprotonation.

The invention also relates to a process e) for the preparation of (1-Hydroxytäthyliden) -cyanessigsäureaniiden of the general formula I, which is characterized in that one - acetoacetic anilide of the general formula XIV, in which R1, R2 and R3 the above in the Formula I have given meaning, in the presence of a basic compound, expediently with the use of solvents or diluents, at a temperature between -40 ° and + 30 ° C. with cyanogen chloride or cyanogen bromide and then optionally the reaction mixture to a temperature of up to + 1500C warmed up.

The reaction times can be up to 24 hours. Is preferred the reaction according to the invention with the concomitant use of solvents or diluents at a temperature between -100 and + 250C with subsequent heating up to carried out a temperature of + 800C.

All known solvents or diluents are used as solvents or diluents The reactants are sufficiently inert solvents, such as those in the Description of the aforementioned method mentioned as examples in question. Preferred Solvents or diluents are preferred in addition to those in that process named solvents or lower (C1 "C4-) alcohols, such as methanol, ethanol, Propanol, isopropanol and / or butanol.

As the basic compounds, the same as those of that method can be used be used. The same applies to the bases to be used with preference.

In the reaction e) according to the invention, the hydroxyethylides formed fall -cyanacetanilide of the formula I in the form of their salts.

The acidic compounds of the formula I are made therefrom as in the above described method isolated.

cet The acetic acid anilides of the formula required as starting materials XIV can by known methods, for example by reacting acetoacetic acid esters : with appropriately substituted anilines at elevated temperatures (cf. Ullmanns Encyclopedia der Technische Chemie, II. Aufl., 1953, Vol. 3, p. 35). Acetoacetic anilides are also in a known manner by reacting appropriately substituted Anilines with diketene are very easily accessible. For example, the following acetoacetic anilides can be used can be used as starting materials.

Acetoacetic acid-4-chlpr-, -4-methoxy-, -4-fluoro-, -3-methoxy-, -3- (1 ', 1', 2'-trifluoro-2'-chloroethoxy) -, -3 (1 ', 1', 2 ', 2' tetrafluoroethoxy) -, -3,5-dichloro-, -2,4-dichloro-, -3-chloro-6-methyl-, -3,5-bis-trifluoromethyl-, -2.4.6-trichlor-, -2-chloro-4-methoxy-, -2-trifluoromethyl-4-chloro-, -3-methylthio-, -4-ethoxy-, -2.3-dichloro-, -2.6-dichloro-, -4-bromine-2-methyl-, -2. 6-dimethyl-, -2-bromo-4-ethoxy-, -2-methoxy-4-bromo- or -4-ethylthio-anilide.

The invention also relates to a method f) for production of Hydroxyäthyliden-cyanoacetic anilides of the general formula I, which thereby is characterized in that one has a 2-cyano-acetic acid ester of the general formula XVa or

XVb in which R12 denotes a C1-C4-alkyl group or a phenyl or naphthyl radical optionally substituted by a methyl, nitro or cyano group and / or 1-2 chlorine or bromine atoms, at a temperature between 0 ° and + 250 ° C, preferably with the use of solvents and optionally with the addition of catalytic amounts of a base with a substituted aniline of the formula XVI, in which R1, R2 and R3 have the meaning given above for formula I.

Such 2-cyano- acetic acid esters of the formula XVa or their tautomeric form XVb are used in where R12 is a methyl, ethyl or phenyl group. In particular, esters of the formula XVa or XVb is used, in which -.

R12 denotes the methyl group.

Preferred anilines of the general formula XVI are those in which R1 is a methyl, ethyl or trifluoromethyl group, a halogen atom, a methoxy, or ethoxy group, one substituted by 3 fluorine and one chlorine atoms or 4 fluorine atoms Ethoxy group or a methylthio group.

R2 is a hydrogen atom, a trifluoromethyl group, a halogen atom or a methoxy group.

and R3 is a hydrogen atom, and R2 and R1 together are in 3.4 position standing -O-CH2 - & - mean grouping. The anilines of Formula XVI become advantageous used in amounts of 0.8 to 1.5 mol per mole of 2-cyano-ac etessigsäureester.

The method f) according to the invention is preferably used of solvents which are sufficiently inert towards the reactants in the presence of catalytic ones Amounts of bases, preferably organic bases, in a temperature range of + 50 ° to + 1600C carried out.

A preferred embodiment of the method f) is that to a boiling solution of a 2-cyanoacetacetic acid ester of the general Formula XVa or XVb in an inert solvent boiling above 1090C, such as, for example Xylene or chlorobenzene, optionally in the presence of catalytic amounts of a base, the corresponding aniline of the general formula XVI, optionally in dilute Form slowly drips in to such an extent as that resulting from the implementation Alcohol, in particular, for example, methanol from the reaction mixture, expediently via a Distillation column distilled off and, optionally, after the addition of the aniline further heated for a while at the boiling point of the mixture.

Solvents suitable for process f) are, for example aromatic hydrocarbons such as benzene, toluene, xylene or cumene, chlorobenzene, Dioxane, 1,2-dimethoxyethane, acetonitrile, nitrobenzene, tetrachlorethylene, dichlorobenzenes, Anisole and / or tert. Butanol.

If bases are also used in the process according to the invention, these are advantageously used in amounts of 0.1-5.0 mol%, based on the 2-cyano-acetic acid ester Suitable bases are, for example, tertiary amines, such as triethylamine, Tripropylamine, N-methyl-pyrrolidine, N-ethyl-piperidine, triethanolamine, 1,4-diazabicyclo / 2.2.270ctane or pyridine, picolines, quinoline and N.N.-dimethylaniline.

The (1-HydroxyätWliden) -cyanacetanilide formed in the reaction according to the invention of the formula I are, after evaporation of the solvents advantageously used expediently isolated in such a way that the crude reaction products are diluted with Treated aqueous alkalis, wherein the compounds of formula I in the corresponding Pass over alkali salts. In this state you can then be neutral or basic By-products, such as also excess or not implemented Starting materials by extraction with non-polar organic solvents, such as ether, Isopropyl ether, carbon tetrachloride, tetrachlorethylene, benzene, toluene, hexane or remove cyclohexane and gasoline. By acidifying the aqueous-alkaline solution then the (1-Hydroxyäthyliden) -cyanacetanilide, mostly in crystalline form, failed.

The 2-cyano-acetic acid esters required as starting materials XVa and XVb are predominantly known compounds and can be traced to Haller's and Held, Annales de Chimie [6] 17, 222 (1889) and by Guinchant, Annales de Chimie [9] 9, 80 (1918) and by Dahn and Hauth, Helvetica chim. Acta 42, 1214 (1959) described method are produced. In addition, these starting materials are analogous the above on p. 22ff. listed process d) accessible by after the same method as there acylated cyanoacetanilides instead of the anilides Cyanoacetic acid esters advantageously with acetyl chloride or acetic anhydride in the presence acetylated by advantageously 2 equivalents of base.

The hydroxyalkylidene cyanoacetic anilides of the general formula Ia and Ib are acidic compounds which, according to their N spectra, are predominantly in the Enol form Ia are present. When FeCl3 is added, they give inen brown-red to wine-red Color reaction.

If, in one of the types of production, the connections T initially in the form of their alkali, alkaline earth or ammonium salts or as organic salts Bases are formed and as such in solution. can be present by evaporation of the solvents used, these salts of the compounds I, if appropriate, through Purify recrystallization. On the other hand, by adding an equimolar amount a suitable base, expediently with the concomitant use of those which are inert towards the bases Solvents to a compound of formula Ia or Ib salts of these compounds, manufactured and after evaporation of the solvent or by adding other solvents, which lead to the separation of the salts, are isolated. Sodium, Potassium, calcium or magnesium alcoholates of lower alcohols, sodium, potassium, Ca, magnesium or ammonium hydroxide, sodium, potassium, calcium, magnesium or Ammonium carbonate or bicarbonate as well as sodium, magnesium or calcium hydride, Ammonia or sodium amide, or organic bases, such as tertiary amines, to serve. When using alkali or alkaline earth metal alcoholates, it is advantageous to in addition to any solvents used in the presence of a lower alcohol to work.

Are the aforementioned hydroxides, carbonates and / or m- abonates Used as bases, it is advantageous in the presence of water and / or lower To work alcohols, where appropriate also other organic solvents can also be used.

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

The compounds of Foel Ia and Ib according to the invention are strong anti-inflammatory and analgesic effects.

The anti-inflammatory effects could be demonstrated in the carrageenin paw edema test (Winter, C.A. et al. - Proc. Soc. Exp. Biol.

Med. 111, 544 (1962) and on adjuvant arthritis of the rat (Pearson, C.M., Wood, F.D. - Arthrite. Rheumatism. 2, 440 (1959)).

The analgesic effects were measured in the mouse "writhing test" (Siegmund, E. et al. - Proc. Soc. Exp. Biol. I ea. 95, 729 (1957) and on the Randall-Selitto test the rat (Randall, L.

O., Selitto, J.J.'-Arch. Int. Pharmacodyn. -111, 409 (1957)).

The new HydroxySthyliden-c-vanessigsaureanilide of the formula Ia or Ib and their physiologically acceptable salts, preferably their * salts are as Medicinal usable. The compounds according to the invention can be used as anti-inflammatory drugs and analgesics used in admixture with the usual pharmaceutical excipients will. Solid preparations are used for this, e.g. as tablets, coated tablets, capsules or suppositories can be administered, or liquid preparations, which can be applied e.g. as drops, syrup or injection solutions, in Consideration. These anti-inflammatory and / or analgesic agents can preferably 3 - 90 4/0 of compounds of the general formula Ia or Ib contain.

The intermediate products obtained in the process according to the invention Formula IV and Formula VI also unfold with different strengths anti-inflammatory and analgesic effects. Since these connections are each the direct precursor of the invention, strongly anti-inflammatory and / or analgesic Acting compounds of the formula Ia or Ib represent, their action can be related with that of the latter connections.

In addition, anthelmintic ( Antimylrotic and fungicidal effects found.

The compounds according to the invention of the general formula Ia or Ib can also be used as intermediates for the preparation of pharmacological and / or Chemotherapeutically active compounds are used. The same goes for that too Compounds of the general formula IV and to be prepared as Zalischenprodukte VI.

*) Sodium, potassium, magnesium, calcium or ammonium EXAMPLES Example 1: hydroxyethylidene cyanoacetic acid (3-chloroanilide) ethoxyethylidene cyanoacetic acid (3-chloroanilide) A mixture of 117 g (0.6 mol) of cyanoacetic acid (3-chloroanilide), 150 g (0.93 mol) Triethyl orthoacetate, 190 g (1.86 mol) of acetic anhydride and 60 mg of anhydrous Zinc chloride was refluxed with stirring for 3 hours. Subsequently were low-boiling components through a 15 cm high Vigreux column at a bath temperature of 1200C distilled off over the course of 2.5 hours. After cooling down and standing overnight the precipitated crystalline substance was isolated by suction.

After washing with ether and drying, 100 g of crystals were obtained After dilution with ether, a further 11 g of crystals were obtained from the filtrate. These crystalline products still contained proportions of cyanoacetic acid (3-chloroanilide) and were therefore boiled with 300 ml of CHCl3. The CHCl3 "2xtrakt got hot from separated undissolved solid. 32 crystallized from the extract on cooling pure Aethoxyäthylidenidenidenessigsäure- (3-chloroanilide) as a single compound (Z or E shape). The portion undissolved in CHC13 was twice more in the same Extracted with CHCl3 (300 ml or 150 ml). Obtained from the CHCl3 extracts one more 30 g of the above-mentioned compound 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 CHCl3 mother liquors were concentrated to approx. 300 ml, the resulting precipitate was filtered off with suction, it was a mixture of reaction product and starting anilide. The filtrate about 100 ml of ether were added, after which a further 26 g of almost pure ethoxyethylidenecyanoacetic acid were added (3-chloroanilide) crystalline in the form of the mixture of stereoisomers failed.

This portion was purified by recrystallization from CHCl3.

A total of 66 g (# 41.5% yield) of ethoxyethylidenecyanoacetic acid (3-chloroanilide) were obtained in the form of the pure Z or E stereoisomer of m.p. 1650-1660C and 22 g (# 14 % Yield) as a mixture of stereoisomers with a melting point of 1210-1230C.

Analysis C1 3 H15 ClNz ° 2 calc .: C 59.0%; H 4.9%; Cl 13.4%; MG 264.7 Found: C, 59.0; H 4.9%; C1 13.7%; MW 264; 266 (mass spectroscopy) b) Hydroxyethylidene cyanoacetic acid (3-chloroanilide) 26.5 g (0.1 mol) of the ethoxyethylidene compound prepared under (a) were 150 ml of 4N sodium hydroxide solution are added and the mixture is heated to 750 ° C. for 10 minutes while stirring. After adding 400 ml of water, the mixture was allowed to cool to 200 ° C. and filtered through kieselguhr and acidified the filtrate to pH 1. The precipitated crystalline precipitate was Sucked off, washed salt-free and neutral with water and dried. One received 22.5 g (95% yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) from M.p. 1690-1700C.

The IR spectrum of this compound was identical to that of same connection made in a different way according to the German patent application P 25 24 929.0 had been received.

Example 2: hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) 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 triethyl orthoacetate, 77 g (0.75 mol) of acetic anhydride and 40 mg of zinc chloride were added for 3 hours at a bath temperature of 110.degree refluxed.

It was then distilled over a 20 cm high Vigreux column low-boiling components slowly in 2.5 hours at a bath temperature of 1200C, with finally the distillation pressure was reduced to 350 torr for 5 minutes.

After cooling and standing for 16 hours, the reaction mixture had completely crystallized. It was diluted with 200 ml of ether: isopropyl ether 1: 1, and the crystals were sucked and washed it off with isopropyl ether. After drying, 49.5 g of a mixture of steroids were obtained (according to TLC and NMR spectrum) of ethoxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) [4-ethoxy-2-cyano-crotonic acid- (3-trifluoromethyl-anilide)] with a melting point.

obtained from 135 ° - 137 ° C (55.5 °, 'yield).

Analyzer: C14H13F3N2O2 calc .: C 56.4%; H 4.4; F 19.2%; N 9.4%; MW 298.3 Measured values: C 56.4; H 4.5%; F 19.3; N 9.2; MG 298 (mass sp.) An analog The approach carried out, in which no zinc chloride was added, gave 41.5 g of one Stereoisomeric mixture of ethoxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) in which one form (Z- or E-) was highly enriched, with a m.p. of 1250-1270C.

b) Hydroxyäthyliden-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 kept at 64 ° -65 ° C. for 12 hours Stir heated and then sucked off warm. The filter residue became neutral with water washed and dried.

21 g of pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) were obtained [2-Cyano-3-hydroxy-crotonic acid- (3-trifluoromethyl-anilide)] with a melting point of 181 ° - 182 ° C (# 78% yield).

This product agrees in the melting point and IR spectrum with the same, produced in a different way according to the German patent application P 25 24 929.0 Connection match.

Example 3: hydroxyethylidene cyanoacetic acid (4,5-dichloroanilide) ethoxyethylidene cyanoacetic acid (3,4-dichloroanilide) A mixture of 115 g (0.5 mole) cyanoacetic acid (3,4-dichloroanilide), 110 g (0.675 Mol) triethyl orthoacetate, 128 g (1.25 mol) of acetic anhydride and 50 mg of zinc chloride was refluxed at a bath temperature of 115 ° C. for 2.5 hours. Then distilled one over a 20 cm Vigreux column with stirring over a period of 2 hours at 1180-1200C bath temperature low-boiling components from. The after cooling and Standing for 10 hours, the reaction mixture crystallized with isopropyl ether diluted and vacuumed. The one washed out with ether.

According to TLC, the solid (i34 g) was a mixture of the two stereoisomers the ethoxyethylidene compound and unreacted starting anilide. It was dissolved the product in 650 ml of boiling CHCl3, added 200 ml of ether and sucked the crystallized out Product. 61 g of a pure stereoisomer (Z or E form) of ethoxyethylidene cyanoacetic acid (3,4-dichloroanilide) were obtained [3-ethoxy-2-cyano-crotonic acid (3,4-dichloroanilidi7 (# 41% yield), melting point 155 ° - 57 ° C.

Analysis: C13H12Cl2N2O2 calcd .: C 52.0; H 4.4%; C1 23.6%; N 9.4%; MW 299.2 Measured values: C 52.0%; H 3.9; C1 24.0; N 9.4%; MW 298; 300; 302 (mass spectroscopy) The CHCl3 / ether mother liquor was evaporated and the residue with 700 ml CC14 boiled out. 26 g of cyanoacetic acid (3,4-dichloroanilide) remained undissolved. Of the CCl4 extract was evaporated. The remaining residue was dissolved in 200 ml CHCl3, filtered off small amounts of undissolved material and added 50 ml of ether to the filtrate. Then 9 g of the other pure stereoisomer (E or Z form; this is the stereo isomer with the larger RF value in the TLC; Solvent CH2Cl2 / C2H5OH 10: 1, silica gel prefabricated plates Merck F 254) with a melting point of 1590 - 1610C from (\ 6% yield).

The combination gave the correctness corresponding to the gross formula Analysis values.

b) Hydroxyäthyliden-cyanoacetic acid (3,4-dichloroanilide) analogous to in example (1) under (b) the method described, starting from 30 g (0.1 mol) the ethoxyethylidene compound 25.5 g (94% yield) hydroxyethylidene cyanoacetic acid (3,4-dichloroanilide) obtained from m.p. 2080-210 ° C.

EXAMPLES 4 - 8: According to the examples (2) and (3) below (a) procedure described were obtained: -AethOxyäthyliden-cyanoacetic acid- / 3- (1,1,2-trifluoro-2-chloroethoxy) anilide], C15H14ClF3N2O3, m.p. 102-103 ° C (Z or E form), yield: 21%.

Ethoxyethylidene cyanoacetic acid (3-bromanilide), C13H13BrN2O2, m.p. 1960-1970C (Z or E form), yield: 50.

Ethoxyethylidene cyanoacetic acid (4-methoxy-anilide), C14H16N2O3, m.p. 166 ° - 167 ° C (Z or E form), yield: 30%.

Ethoxyethylidene cyanoacetic acid (3-chloro-2-methyl-anilide), C14H15ClN2O2, Mp. 1710-1730C (Z or E form), yield: 42%, ethoxyethylidene cyanoacetic acid (5-chloro-2-methyl-anilide), C14H15ClN2O2, m.p. 2080-2100C (Z or E form), yield: 72%.

Methoxyethylidene cyanoacetic acid (3-chloroanilide), C12H11ClN2O2, m.p. 118 ° - 120 ° C (E or Z form), yield 7 r; Mp. 157 ° - 158 ° C (Z- or E-shape), Yield 10%.

+) as an additional precursor for the hydroxyethylidene compound to be prepared according to (1b) To the Separation of both stereoisomers and for the separation of small amounts of cyanoacetic acid (3-chloroanilide) in this case it is advisable to use column chromatography on silica gel (Merck) from methylene chloride / benzene 1: 1, the column then being eluted with CH2C12, to execute. The composition of the eluate fractions was checked by means of TLC. The compounds are in the order: a) low-melting stereoisomer, b) higher melting stereoisomer c) cyanoacetic acid (3-chloroanilide) eluted.

The above Aethoxyäthylidenverbindungen were according to the example (1) the procedure described under (b) into the corresponding 2-hydroxyethylidene-cyanacetanilide convicted; accordingly obtained: hydroxyethylidene cyanoacetic acid [3- (1,1,2-trifluoro-2-chloroethoxy) anilide7, M.p. 1400-1410C.

Hydroxyethylidene cyanoacetic acid (3-bromanilide), m.p. 1780-179 ° C.

Hydroxyethylidene cyanoacetic acid (4-methoxy anilide), melting point 151 ° -1520 ° C.

Bydroxyethylidene cyanoacetic acid (3-chloro-2-methyl-anilide), m.p. 1640-1650C.

Hydroxyethylidene cyanoacetic acid (5-chloro-2-methyl-anilide), m.p. 127 ° - 129 ° C.

Example 9: 560 mg (2 mmol) of ethoxyethylidene cyanoacetic acid (5-chloro-2-methyl-anilide) 8 ml of methanol and 70 ml of 0.5N sodium hydroxide solution were added and 30 minutes at 650C stirred. To Filtration of the solution through kieselguhr acidified Man-the filtrate with sulfuric acid, sucked off the precipitate, this was washed with Water free of salt and dried it. 465 mg (# 93% yield) of hydroxyethylidene cyanoacetic acid (5-chloro-2-methyl-anilide) were obtained of m.p. 1280-1290C.

Example 10: Dimethylaminoethylidene cyanoacetic acid (3-trifluoromethylanilide In a mixture of 20.9 g (0.07 mol) of Aethoxyäthylidenidenidenessigsäure- (3-trifluoromethyl-anilide) and 80 ml of 1,2-dimethoxyethane were passed in at 30 ° -46 ° C. with stirring to supersaturation a dimethylamine gas stream. The resulting solution was passed through for 1 hour a weak stream of dimethylamine and then evaporated in vacuo.

The remaining residue was suspended in ether, filtered off with suction and washed with ether. After drying, 16 g (# 80% yield) of dimethylaminoethylidene cyanoacetic acid (3-trifluoromethyl anilide) were obtained F2-cyano-3-dimethylaminocrotonic acid (3-trifluoromethyl-anilide)] of m.p. 1270-1280C.

Analysis: C14H14F3N3O calcd .: C 56.6%; H -4.7%; F 19.2%; N 14.1; MW 297.3 Measured values: C 56.3%; H 4.7; F 19.5%; N 14.2%; MG 297 (mass spectroscopy) According to this procedure were prepared: Dimethylaminoäthyliden-cyanoacetic acid (3-chloroanilide), C13H14ClN5O (MW 263.7), m.p. 1460-1480C.

Dimethylaminoethylidene cyanoacetic acid (5-bromanilide), C13H14BrN3O (MW 308.2), melting point 141-1420C (from ethyl acetate).

Dimethylaminoethylidene cyanoacetic acid (3-chloro-2-methylanilide), C14H16ClN3O (MW 277.8), melting point 134 ° -135 ° C. (from ethyl acetate).

Dimethylaminoethylidene cyanoacetic acid (5-chloro-2-methylanilide), C14H16ClN3O (MW 277.8), m.p. 1420-1430C (from 1,2-dimethoxyethane).

Example 11: (4-Methyl-piperazinoäthyliden) -cyanessffi-äure- (3-trifluor methyl anilide) To a mixture of 15 g (0.05 mol) of 2-ethoxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) and 100 ml of 1,2-dimethoxyethane were added dropwise in 15 minutes at 300C a solution of 5.3 g (0.053 mol) of N-methylpiperazine in 10 ml of 1,2-dimethoxyethane and stirred for 1 hour at 450C, a solution formed. This was evaporated in vacuo. The residue crystallized with the addition of ether. The mixture was boiled and vacuumed the crystals (11 g) from. After concentration and addition of Isopropyl ether isolated another 4.5 g of crystalline compound. The crystals were recrystallized from CC14. 12.4 g (70.5% yield) of pure (4-methyl-piperazinoethylidene) -cyanoacetic acid (3-tr1-fluoromethyl-anilide) were obtained, M.p. 1290-1300C.

Analysis: C17H19F3N4O calcd .: C 58.0%; H 5.4%; F 16.2%; N 15.9%; MW 352.4 Measured values: C58.0%; H 5.2%; F 1 ^ 5.8%; B 15.6%; MG 352 (mass spec.) Correspondingly This procedure also produced: Piperidinoæthyliden-cyanoacetic acid- (3-chloroanilide), C16H18C1N50 (MW 303.8), EP. 1380-1390C (from ethyl acetate).

Piperidinoethylidene cyanoacetic acid (5-chloro-2-methyl-anilide), C17H20ClN3O (MW 317.8), melting point 133 ° - 134 ° C (from ethyl acetate), Example 12: One Mixture of 9 g (0.03 mol) Dimethylaminoäthylidenidenidenessigsäure- (3-trifluoromethyl-anilid), 50 ml of ethanol and 200 ml of 2N hydrochloric acid were stirred at 350 ° C. for 4.5 hours. Afterward The solid was filtered off with suction, washed salt-free and neutral with water and dried him.

8.0 g (# 99% yield) of hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) are obtained of m.p. 1790-1800C.

The following were prepared according to this procedure: a) from piperidinoethylidene cyanoacetic acid (3-chloroanilide) Hydroxyethylidene cyanoacetic acid (3-chloroanilide), m.p. 1700-1710C (94% yield).

b) from (4-methylpiperazinoethylidene) cyanoacetic acid (3-fluoromethyl anilide) Hydroxyethylidene cyanoacetic acid (3-trifluoromethylanilide), melting point 179-181 ° C. (98% yield).

c) from dimethylaminoethylidene cyanoacetic acid (3-bromanilide) hydroxyethylidene cyanoacetic acid (3-bromanilide), m.p. 1780-1790C (96% yield).

Example 13: A mixture of 4.5 g (0.015 mol) of dimethylaminoethylidenecyanoacetic acid (3-trifluoromethyl anilide), 70 ml of ethanol and 400 ml of 0.1 N hydrochloric acid were stirred for 10 hours at 30 ° C., then was sucked off. The crystalline substance washed neutral with water and dried weighed 3.7 g (A 91.5% yield) and was pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) of m.p. 1790-1810C.

Example 14: At -300 to -200C became 50 ml of CH2C12 at the same time and evenly with stirring in 2.5 hours with moisture slip in one Drop ratio of 4: 1 a solution heated to 380C, which can be filled with 56 g (0.2 mol) of piperidinoethylidene cyanoacetic acid (3-chloroanilide) with CH2Cl2 a volume of 1600 ml was made, and a solution made up by filling up of 28.3 g (0.2 mol) (17.36 ml) of chlorosulfonyl isocyanate with CH2C12 to 400 ml was added dropwise. The mixture was then stirred at -200 ° C. for 20 minutes Minutes at 200 to 0 ° C and 1 hour at 0 ° to + 2 ° C. After cooling the reaction solution to -100C at this temperature was a solution of 42 ml of dimethylformamide in 40 ml of CH2Cl2 were added dropwise and the mixture was then stirred at 0 ° C. for 30 minutes. Thereupon 11 g of triethylamine were added dropwise to the reaction solution at -200C. The mixture was allowed to warm to room temperature with stirring and was then evaporated Room temperature in a vacuum. The viscous residue (approx. 96 g) was at room temperature added dropwise with stirring to a solution of 34 g of sodium bicarbonate in 2 liters of water. After stirring for 30 minutes, the aqueous solution of the deposited tooth, hydrophobic mass decreased, took it up in CH2C12, shook the methylene chloride solution three times with approx. 100 ml of water and dried them with Na2S04. After filtration the solution was evaporated in vacuo and the residue (53 g) concentrated in Ethyl acetate / benzene 3: 1 dissolved. The solution was applied to a silica gel (Merck) column (Height 55 cm, 6 4.7 cm) raised; the column was then eluted with it Mixture and collected 100 ml fractions at the drain. The first 4 fractions contained only oily by-products. In the 5th to 8th fractions, the solvents fell after evaporation crystalline residues (together 24 g). These were made from ethyl acetate / ether / isopropyl ether recrystallized, leaving 12.8 g of pure Piperidinoethylidene cyanoacetic acid (3-chloroanilide) with a m.p. of 138C-1390C. The 9th and 10th fractions of the chromatography contained 4 g of partially crystalline product in the mother liquors of the recrystallization was dissolved and after concentration and renewed recrystallization a further 2.2 g of des Anilide of m.p. 1370-1380C. Overall, the anilide was thus in one 25% yield obtained.

Following the same procedure, starting from 58.6 g (0.2 mol) of piperidinoethylidene-acetic acid (5-chloro-2-methyl-aiiilid) 18.2 g (d 29% yield) piperidinoethylidene cyanoacetic acid (5-chloro-2-methylanilide), Mp. 133 ° - 134 ° C and starting from 48 g (0.2 mol) of dimethylaminoethylidene-acetic acid (3-chloroanilide) 5.8 g (d 11% yield) dimethylaminoethylidene-cyaracetic acid (3-chloroanilide), m.p. Manufactured in 1460-1480C.

In the latter case, a likewise crystalline one is formed in appreciable quantities By-product that shortly before the described execution of the chromatography the desired anilide runs. The first chromatography fractions were mixtures from both compounds, which is expediently a second column chromatography were subjected to a partial separation of the substances, which then continues purified by recrystallization. The by-product had one Mp. From 160 ° -1610C. Because of the aforementioned complications, this synthesis was the yield of the desired anilide is considerably lower.

Example 15.

A solution of 5.5 g (30 mmol) of 2-cyanoacetoacetic acid tert-butyl ester 190 mg (1 rualol) of p-toluenesulfonic acid hydrate were added in 60 ml of benzene and refluxed for 1 hour.

After adding 3 drops of water, the mixture was refluxed for a further 2.5 hours heated. Small fractions were then filtered more crystalline Substance (2-cyano-acetic acid) and the filtrate evaporated at a bath temperature of 300C in a vacuum. A colorless oil remained, the crude cyanoacetone (according to GC 87 % ig) represented. This product was with 4.67 g (25 mmol)% tri-fluoromethyl-phenyl-isocyanate and 50 ml of CH2C12 are added. Into the resulting solution was added dropwise with stirring in 6 Minutes 2.74 g (27 mmol) of triethylamine. The one that warms up to close to the body Solution was refluxed for 1 hour and then evaporated in vacuo. 40 ml of water and 10 ml of methanol were added to the residue, and the mixture was intensive shaken and then acidified with 6N hydrochloric acid. A precipitate fell which turned into a crystal mass in a short time. By adding ethanol a suspension was formed which was suctioned off. The filter residue was washed with water / methanol 3: 1 and finally washed out with a little methanol and dried. 5.65 was obtained g (# 70% yield, based on cyanoacetoacetic acid tert-butyl ester) pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl-anilide), mp 181-182 ° C.

Example 16: Starting from 5.5 g (30 mmol) of tert-butyl cyanoacetoacetate were 3.2 g of crude, benzene-containing according to the procedure described in Example (15) Produced cyanoacetone, which still contained about 1 sol p-toluenesulfonic acid. This Product was dissolved in 25 ml of anhydrous tetrahydrofuran and stored at + 5 ° to + 12 ° C with stirring and with exclusion of moisture in a mixture of 900 mg of 80% strength Sodium hydride oil suspension (t 30 mmol NaH) in 40 ml of absolute tetrahydrofuran dripped in.

Then it was added dropwise to the mixture at 0 ° to + 50 ° C. with stirring a solution of 5.8 g (29 Slol) of 3-bromophenyl isocyanate in 40 ml of tetrahydrofuran and then stirred at 50 ° C. for 30 minutes. After evaporation of the reaction mixture in vacuum the residue was mixed with 40 ml of ice water and 10 ml of methanol added and shaken thoroughly, then 5.5 ml of 6N hydrochloric acid were added. The unusual one Precipitate crystallized. At the beginning, some of it was brought about by adding ethanol oily precipitate in a form that can be easily removed by suction. The filter residue was after the suction with ethanol / water 1: 1 and methanol and washed out of methanol recrystallized. 4.3 g were then obtained (51% yield, based on tert.-butyl cyanoacetoacetate) pure hydroxyethylidene cyanoacetic acid (3-bromanilide) with a melting point of 178 ° -180 ° C.

Example 17: As described in example (15) on the basis of 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 stored at about 0 ° C with stirring in a mixture of 850 mg of 80 pointer NaH oil suspension and 50 ml of absolute acetonitrile dripped in. Then a mixture was added at room temperature with stirring Solution of 3.7 g (27 mmol) of 4-fluorophenyl isocyanate in 20 ml of absolute acetonitrile dripped. The temperature was allowed to rise to 350 ° C. and the mixture was stirred for 1 hour 35PC further and the mixture evaporated in vacuo. The residue was as in the example (16) described worked up.

After recrystallization of the Ron product from ethanol and a little water 3.60 g (55% yield) of pure hydroxyethylidene cyanoacetic acid (4-fluoroanilide) of m.p. 1700-171CC.

Examples 18-22: According to that described in Examples (15) and (16), respectively AL-beitsweise were produced: Hydroxyäthyliden-cyanoacetic acid- (4-bromanilide), Mp. 2070-209 ° C, yield 55%.

Hydroxyethylidene cyanoacetic acid (3,4-dichoranilide), m.p. 2090-2100C, Yield 57%.

Hydroxyäthyliden-cyanoacetic acid- (2-ethoxy-anilide), mp. 110 ° -111 ° C, Yield 32.

Hydroxyethylidene cyanoacetic acid (2,4-dichloroanilide), melting point 140 ° -141 ° C, Yield 56%.

Hydroxyethylidene cyanoacetic acid (4-chloro-2-trifluoromethylanilide), Mp. 1310-133 ° C, yield 51%.

Example 23: Hydroxväthy1iden-cyanessisäure- (3-trifluoromethyl-anilid) In a mixture of 3.31 g of 80% sodium hydride oil suspension (# 0.11 mol NaH) and 5 ml of dry 1,2-dimethoxyethane became a solution at 10 ° -25 ° C. with stirring of 11.4 g (0.05 mol) of cyanoacetic acid (3-trifluoromethyl anilide) in 50 ml of abs.

Dimethoxyethane added dropwise. After the evolution of hydrogen has subsided one added dropwise at -5 ° to 0 ° C a solution of 4.33 g (0.055 mol) of acetyl chloride in 15 ml abs. Dimethoxyethane too. The reaction mixture was 30 min at 0 ° to + 270C and stirred for 1 hour each at 250-330C and 620-650C and then evaporated in vacuo. 300 ml of water were added to the residue and the mixture was shaken at room temperature for 30 minutes the product went into solution with the exception of a small residue. It was filtered through kieselguhr and acidified the filtrate with dilute hydrochloric acid. The precipitating crystalline Precipitate was filtered off with suction, washed salt-free and neutral with water, with methanol / water (2: 1) washed and dried. 9.7 g (# 72% yield) of hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) were obtained from fp.

179 ° -181 ° C. From this product were made by recrystallization Methanol 9 g of pure compound with a melting point of 181 ° -182 ° C. were obtained.

Analogous to the procedure described in Example (23) were the Hydroxyäthyliden-cyanoacetic anilides listed in Table 1 below produced in the indicated yields.

Table 1 Hydroxyäthyliden-Cyanoessigsäueanilide No. R¹ R² melting point (° C) Yield in% l 3-Cl H a 169 75 2 3-JH 198-200 64 3 4-Br H 208-209 73 4 4-FH 170-171 69 5 4-OCH3 H 150-152 57 6 2-OC2H5 H 109-111 43 7 3-Cl 4-Cl 209-210 74 8 2-C1 4-C1 140-141 65 9 2-CH3 3-Cl 164-165 71 10 3-SCH6 H 135-136 62 11 2-CH5 5-C1 127-128 73 12 3,4-O-CH2O 166-167 40 Example 24: Hydroxyethylidene cyanoacetic acid (3-bromanilide) a mixture of 3.6 g of 80% sodium hydride oil suspension (0.12 mol NaH) and 10 ml of dry acetonitrile was stirred at 10 ° -25 ° C a solution of 12 g (0.05 mol) of cyanoacetic acid (3-bromanilide) in 100 ml of abs. Added dropwise tetrahydrofuran. After the evolution of hydrogen had subsided, 4.35 g (about 0.055 mol) of acetyl chloride were added dropwise at -100 to 0 ° C. and the mixture was then stirred for 30 minutes at 0 ° to + 28 ° C. and at 28 ° -35 ° each time for 1 hour C and 62 ° -65 ° C further.

The reaction mixture was then evaporated in vacuo and the remaining one The residue is processed further as described in example (23). 10.1 g were obtained (# 72% yield) pure 3 hydroxyethylidene cyanoacetic acid (3-bromanilide) with a M.p. from 1780-1790C.

Example 25: Hydroxyäthyliden-cyanoacetic acid (4-bromanilide) to a Mixture of 23.9 g (0.1 mol) cyanoacetic acid (4-bromanilide), 16.6 g (0.12 mol) dry, Powdered K2CO3 and 100 ml of dry acetone were added dropwise with stirring at 270 ° C 9.45 g (0.12 mole) acetyl chloride. After stirring for one hour at 27 ° -30 ° C and 2.5 hours Stirring under reflux, the acetone was removed in vacuo and the residue with Water extracted. About 15 g (- ^ 63%) of the starting anilide remained undissolved. The aqueous extract was filtered and diluted with dil.

Sulfuric acid weakly acidified. A crystalline one formed in the process Precipitate, which after suction, washing out with water / methanol (1: 2) Methanol was recrystallized.

After drying, 8.4 g (# 30% yield) of pure hydroxyethylidn-cyanoacetic acid (4-bromanilide) were obtained from fp.

208 ° -209 ° C.

Example 26: Hydroxyäthyliden-cyanoacetic acid- (3-trifluoromethyl-anilidj To a mixture of 11.4 g (0.05 mol) of cyanoacetic acid (3-trifluoromethyl anilide), 7.6 g (0.055 mol) of K2CO5 and 150 ml of toluene were added at 70 ° C. with stirring in 30 min. a solution of 4.1 g (0.052 mol) of acetyl chloride in 10 ml of toluene was added dropwise. Afterward The mixture was stirred for 1 hour at 90 ° C., then allowed to cool and the solids present were sucked off and washed it off with 100 ml of toluo. The dried product was extracted with Water. The filtered aqueous extract was acidified weakly with dilute hydrochloric acid and then sucked off the precipitate formed.

This was recrystallized from methanol after washing with water. 5.3 g of 9 39 yield) of pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) were obtained from m.p. 180-182 ° C. The portion (5.2 g) of the solid not dissolved in water provided According to TLC mainly starting anilide aarS Example 27: Hydroxyethylidene-cyanoacetic acid- (5-chloro-2-methyl-anilide) To a mixture of 10.5 g (0.05 mol) of cyanoacetic acid (5-chloro-2-methyl-anilide), 12.3 g (0.11 mol) of potassium tert-butoxide and 150 ml of dry dioxane were added dropwise a solution of 4.35 g (0.055 mol) of acetyl chloride in 5 ml of 1,2-dimethoxyethane at 35 ° C. in 25 minutes and then stirred for 2 hours at 900C. 14 after evaporation of the solvents. the residue was extracted with 300 ml of water in vacuo. The filtered warm A crystalline precipitate separated out on acidification with dilute hydrochloric acid the end. This was suctioned off, as described in Example (23), washed out and dried. Obtain. 6.4 g (# 51% yield) of hydroxyethylidene cyanoacetic acid (5-chloro-2-methyl-anilide), M.p. 1270-128 ° C.

Example 28: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) ter stirring was added to a mixture of 3.40 g (0.013 mol) 80% sodium hydride oil suspension and 5 ml of dry 1,2-dimethoxyethane at 100-200C in 25 min. A solution of 11.4 g (0.05 mol) of cyanoacetic acid (3-trfluoromethyl anilide) in 50 ml of abs. Dimethoxyethane and after the evolution of hydrogen has subsided at -10 ° to -50C in 25 minutes Solution of 5.6 g (0.055 mol) of acetic anhydride in 100 ml of abs. Dimethoxyethane was added dropwise.

The mixture was then stirred for 30 minutes at -50C to room temperature and each 1 hour at 25 ° -30 ° C and 65 ° -70 ° C further and then the reaction mixture was evaporated in a vacuum. The residue @ was dissolved in 300 ml of water and the solution with 80 ml of ether out? shakes. The aqueous phase was acidified after filtration weak with hydrochloric acid. The precipitate which has separated out is sequentially with Washed water, methanol / water (2: 1) and a little methanol and then dried. 12.8 g (# 95% yield) of pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) were obtained of m.p. 1810-1820C.

In an analogous manner, 2-hydroxyethylidene cyanoacetic acid (3-bromanilide) (Yield: 93 0) and - (3,4-dichloro-anilide) (Yield: 94%).

Example 29: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) In a solution of 22.8 g (0.1 mol) of cyanoacetic acid (3-trifluoromethyl anilide) in 100 ml of 1,2-dimethoxyethane were suspended 16.6 g (0.12 mol) of potassium carbonate. Under Stirring, 14.3 g (0.14 mol) of acetic anhydride were then added dropwise at room temperature.

After stirring for 4 hours at room temperature, the mixture was evaporated in a vacuum and extracted the remaining residue with Water. After filtration through kieselguhr, the aqueous extract was acidified with diluted sulfuric acid, hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) pleases. After suctioning off, washing out and drying, 19 g (70% yield) Product of melting point 172 ° -173 ° C. was obtained, from which after recrystallization from methanol 17.3 g (64% yield) of pure compound (melting point 181 ° -182 ° C.) were isolated.

Analogous to the procedure described in Example (29) were the Hydroxyäthyliden-cyanoacetic anilides listed in Table 2 below produced in the indicated yields.

Table 2 Entry Ri R2 Yield in% 1 3-C1 H 72 2 3-JH 63 3 4-FH 73 4 2-Cl 4-C1 71 5 3-SCH5 H 52 6 2-CHz 5-C1 72 7 3,4-O-CH2-O- 35 8 4-OCH5 H 40 9 2-CF3 4-Cl 51 Example 30: Hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl-anilide) If you proceed as in Example (29), but instead of 16.6 g of K2CO5 16.6 g (0.16 mol) of anhydrous soda are used, then 10, 0 g (37% yield) of hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) with a melting point of 175 ° -176 ° C. In this procedure, a considerable part (13.5 g) remained undissolved during the extraction of the reaction product with water , which according to TLC largely consisted of unreacted starting material.

Example 31: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) As described in Example (29), 0.1 mol of cyanoacetic acid (3-trifluoromethyl anilide) in dimethoxyethane in the presence of 16.6 g of K2COz with 14.3 g (0.14 mol) of acetic anhydride and, after this had been added, continued stirring at 90 ° C. for 1 hour.

After evaporation of the mixture obtained, the residue was dissolved in Absorb water, filter the solution through kieselguhr and acidify the filtrate The precipitate which had separated out was after suctioning off successively with water, water / methanol (1: 3) and methanol and dried. 19.8 g (, \ - 73% yield) were obtained practically pure Hydroxyäthyliden-cyaness% g acid (3-trifluoromethyl-anilide) from Mp 178-179 ° C.

Example 32: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) While stirring, the mixture was added dropwise at room temperature to a mixture of 22.8 g (0.1 mol) Cyanoacetic acid (3-trifluoromethyl anilide) 15.2 g (0.11 moles) of K2CO3 and 100 ml of ethyl acetate and 10.2 g (0.1 mol) of acetic anhydride and stirred at room temperature 1 hour and further under reflux for 2 hours. After evaporating the mixture in The remaining residue was worked up in vacuo as described in Example (29). After recrystallization of the crude product from methanol, 1.7 g (# 6.3 % Yield) pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) from Mp 181-182 ° C.

Example 33: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) To a mixture of 22.8 g (0.10 l of cyanoacetic acid (3-trifluoromethylanilide, 15.2 g (0.11 mol) of K2CO3 and 200 ml of toluene were 10.2 with intensive stirring at 700C g (0.10 mol) of acetic anhydride were added dropwise. The mixture was then stirred at 90 ° C for 1 hour, Liep to about 150C and sucked off the solid, This was with ethyl acetate and washed out little water.

The remaining undissolved portion (9 g) turned out to be the potassium salt of Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) with a melting point of 215 ° -217 ° C (yield: 29%). 3 g of free hydroxy compound were obtained from the washing water with dilute hydrochloric acid of melting point 166 ° -168 ° C. (# 11% yield) precipitated.

Example 34: Hydroxyethylidene cyanoacetic acid (4-bromanilide) A mixture from 12 g (0.050 mol) cyanoacetic acid (4-bromanilide), 5.2 g (0.051 mol) acetic anhydride and 50 ml abs. 1,2-Dimethoxyethane was dripping with stirring at room temperature mixed with 10.5 g (0.104 mol) of triethylamine, the temperature slowly up to 300C rise. The mixture was stirred at 30 ° C. for 2 hours 2 hours at 800C further and then evaporated the mixture in vacuo. A dark colored one fell Oil as a residue, which was taken up in ethyl acetate. The formed solution was shaken out successively 8 times with water and dilute soda solution. All aqueous extracts were then combined and made weakly acidic with hydrochloric acid. The deposited precipitate was filtered off with suction, successively with water and methanol / Washed water (3: 1) and recrystallized from methanol, whereby 5.9 g (A42 42 % Yield) pure hydroxyethylidene cyanaacetic acid (4-bromanilide) with a melting point of .2080 - 2090C.

Example 35: Hydroxyäthyliden-cyanoacetic acid (3-chloroanilide) to one Mixture of 3.31 g of 80 pointer sodium hydride oil suspension (# 0.11 mol NaH) and 10 ml of dry 1,2-dimethoxyethane became a solution of 9.73 g at 100 to 200C (¢, 05 mol) cyanoacetic acid (3-chloroanilide) in 80 ml of abs. Dimethoxyethane dripped. After the evolution of hydrogen had subsided, the mixture was added dropwise with stirring at 0 ° bis 50C a solution of 5.3 g (0.06 mol of ethyl acetate in 100 ml of dimethoxyethane to and stirred for 20 minutes at 50 to 280C and 1.25 hours at 700 to 75 ° C. Subsequently was the mixture evaporated in vacuo and the remaining residue with 150 ml of water offset and shaken.

The resulting solution was extracted with 100 ml of ether. After separation of the phases, the aqueous phase was weakly acidified with dilute hydrochloric acid and the precipitated precipitate is suctioned off and washed with methanol / water (6: 1) and dried. rian received 9.7 g (# 82 r yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) of m.p. 168-169 ° C.

After concentration, the washing liquor was converted into 1 g (8.5% yield) Product isolated with a melting point of 165 ° -167 ° C.

Were instead of 5.3 g of ethyl acetate 7.5 g (0.055 mol) of I% enyI acetate used, 9.3 g (# 79% yield) of pure was obtained after the same A procedure Hydroxyethylidene cyanoacetic acid (3-chloroanilide).

Example 36: Hydroxyethylidene cyanoacetic acid (3-chloroanilide) one Mixture of 6.0 g (0.11 mol) of sodium methylate and 25 ml of abs. 1,2-dimethoxyethane was added dropwise at room temperature with a solution of 9.3 g (0.05 mol) of cyanoacetic acid (3-chloroanilide) in 50 ml abs. Dimethoxyethane added. Then it was added dropwise with stirring -7 ° to 0 ° C to the resulting mixture, a solution of 5.6 g (0.055 mol) of acetaldehyde in 10 ml abs. Dimethoxyethane and stirred for 30 minutes at 0 ° C and 1 hour each at 30 ° -35 ° C and 65 ° -70 ° C further. Then you vaporite the reaction mixture in 'vacuum and took the residue in a mixture of 150 ml of water and 25 ml of 2N sodium hydroxide solution on. The undissolved portion was sucked off and washed with about 200 ml weakly alkaline water (pH 11-12). The combined alkaline filtrates were made weakly acidic with hydrochloric acid. The deposited precipitate was filtered off with suction and washed out successively with water, methanol / water (4: 1) and a little methanol and dried.

3.1 g (A 26 26 ß yield) of hydroxyethylidene cyanoacetic acid (3-chloroanilide) were obtained of m.p. 1670-1680C.

Example 37: Hydroxyäthyliden-cyanoacetic acid (3-chloroanilide) to one A solution of 2.5 g of sodium in 30 ml of methanol became a solution at room temperature of 9.73 g (0.05 mol) of cyanoacetic acid (3-chloroanilide) in 80 ml of methanol in 5 min. added dropwise. The mixture was then cooled to 0 ° C. and added dropwise over 15 minutes. at 0 ° C., a solution of 4.50 g (0.061 mol) of methyl acetate in 10 ml of methanol is added. Man The reaction mixture was then stirred at 0 ° to 260 ° C. for 30 minutes and at 380 ° for 1 hour each time - 400C and under reflux (610C) further. Now became the reaction mixture again 4.5 g (0.061 mol) of methyl acetate were added. The mixture was stirred under reflux for a further hour after. The reaction solution was then evaporated in vacuo and the remaining solution was added Residue with a mixture of 150 ml of water and 7 ml of 4N hydrochloric acid. The thus obtained Solution with a pH of about 10 was adjusted to pH 8 with 6 ml of 2N acetic acid, whereby a precipitate formed. This was sucked off and ve.rt soda solution washed out, the undissolved portion was shaken with 2N soda solution for 1 hour. The resulting suspension was again filtered off with suction and the solid was washed one after the other intensively with ## soda solution and with water. The soda extracts and the wash water and the original aqueous (PH 8) filtrate were combined and weakly acidified with hydrochloric acid.

The deposited precipitate was filtered off with suction and washed together with water, methanol / water (5: 1) and a little methanol.

After drying, 6.7 g (57% yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) obtain.

Example 38: Hydroxyäthyliden-cyanoacetic acid (3-chloroanilide) to one Mixture of 4.05 g (0.075 mol) of sodium methylate and 10 ml of dry 1,2-dimethoxyethane a solution of 9.73 g (0.050 mol) of cyanoacetic acid (3-chloroanilide) was left with stirring at room temperature in 50 ml abs. Dimethoxyethane suflesser.

A solution of was then added dropwise at 5 ° to 0 ° C. with stirring 4.5 g (0.060 mol) of methyl acetate in 10 ml of abs. Dimethoxyethane too. After that, the The resulting mixture was stirred for 15 minutes at 70 ° C. and then evaporated in vacuo. The The residue was taken up in a mixture of 150 ml of water and 2 ml of 4N hydrochloric acid. The portion that remained undissolved was sucked off; it was with him by 8.5 g of practically pure starting anilide.

The filtrate was treated with 0.5 ml of 4N hydrochloric acid and the precipitated one Sucked off precipitate. This substance was also pure starting anilide (0.4 g). The aqueous filtrate was then acidified weakly with 8.2 ml of 4N hydrochloric acid on, sawed off the crystalline precipitate formed and washed it one after the other with water, methanol / water (5: 1) and a little methanol. After drying were 0.47 g (# 4% yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) from Mp. 168 ° 1690C.

at 0 ° to 25 ° C, 30 min. at 40 ° C and 1.5 hours Example 39: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) A mixture of 3.3 g (0.11 mol) of 80% sodium hydride cel suspension and 10 ml abs. Dimethoxyethane was at 200 to 2, R ° dropwise with a solution of 22.8 g (0.10 mol) of cyanoacetic acid (3-trifluoromethyl anilide) in 100 ml of abs. 1,2-dimetho; y ethane displaced. After the evolution of hydrogen had subsided, at 240 to 270C with stirring 5 # 0.5 g of ketene gassed, the apparatus with a with dry ice filled reflux condenser was provided. The mixture was then stirred for 30 min. continued at room temperature and then evaporated the solvent in vacuo. The residue was extracted with water. The filtered alkaline extract was acidified with dilute sulfuric acid.

The precipitate was sucked off and washed with water, Methanol / water (4: 1) and a little methanol. After drying, 17.6 was obtained g (# 65% yield) of pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) from fp.

1800-1810C.

Example 40: Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) In a mixture of 22.8 g (0.10 mol) of cyanoacetic acid (3-fluoromethyl anilide), 100 ml abs. Dimethoxyethane and 7.6; Potassium carbonate (0.055 mol) were added with stirring at room temperature using a dry ice reflux condenser 5 # 0.5 g (0.12 Mole) ketene gassed. The mixture was then stirred at 250 and 90 ° C. for 1 hour each and then evaporated the mixture in vacuo. You worked the backlog as in Example (39) described on. 17.3 g (464 çtn yield) of pure were obtained Hydroxyethylidene cyanoacetic acid (3-trifluoromethylanilide) with a melting point of 1800-1810C.

In an analogous manner were hydroxyethylidene cyanoacetic acid (4-fluoroanilide) (Yield 65,) and - (3-bromanilide) (Yield 67 d;).

Example 41 * Hydroxyäthyliden-cyanoacetic acid (4-fluoroanilide) In a Mixture of 1.90 g (0.063 mol) 80 pointer sodium hydride oil suspension and 15 ml Section. 1,2-Dimethoxyethane was stirred into a solution of 5.85 g (0.030 Moles) acetone acetic acid (4-fluoroanilide) in 40 ml abs. Dimethoryethane and after the evolution of hydrogen has subsided, a solution of 3.20 g at 0 ° C (0.030 mol) cyanogen bromide in 15 ml of abs. Dimethoxyethane dripped. The reaction mixture was stirred then 30 min. at 0 ° C and at 0 ° to 280 ° C and 1 hour at 560 - 60 ° C. Thereafter if the solvent was evaporated in vacuo, the residue was shaken with a mixture from 100 ml of water and 1.5 ml of conc. Hydrochloric acid through intensively and separated the aqueous Phase from the undissolved resinous mass. From the filtered aqueous solution a crystalline precipitate was obtained on acidification with hydrochloric acid, which one sucked off and washed out successively with methanol / water (4: 1) and a little methanol, After recrystallizing the filter residue from methanol, 1.97 g were obtained (t 307 yield) pure hydroxyethylidene cyanoacetic acid (4-fluoroanilide) of m.p. 170 ° -171 ° C.

Example for 42: Hydroxyethylidene cyanoacetic acid (3-bromanilide) In a mixture of 3.3 g (0.11 mol) of 80% sodium hydride oil suspension and 15 ml abs. 1,2-Dimethoxyethane became a solution of 12.81 at 22 ° to 280C with stirring g (0.05 mol) of tcetZ acetic acid (3-bromanilide) in 70 ml of abs. Dimethoxyethane and after when the evolution of hydrogen subsides at 100 to -50C a solution of 4.0 g (0.065'Mol) cyanogen chloride in 15 ml of abs. Dimethoxyethane dripped. The resulting brown Suspension was SjG Min.

stirred at 0 ° C and 1 hour at 540-560C and then in vacuo evaporated. The remaining solid residue .. earth shaken vigorously with 150 ml of water. The undissolved substance was sucked off, one after the other with water and ether washed out and in a mixture of 160 ml of ln sodium hydroxide solution, 250 ml of water and 60 ml of ethanol dissolved. After filtration through kieselguhr, the solution was acidified conc. Hydrochloric acid and then sucked off the deposited precipitate. This weighed after washing with water and methanol and drying for 5s35 g (38% yield) and made pure hydroxyethylidene cyanoacetic acid (3-bromanilide) dar (m.p. 1780-1790C). The acidic aqueous filtrate was washed three times with methylene chloride extracted. The. Purified CH2Cl2 extracts were dried with Na2SO4, filtered and evaporated in vacuo. 10 μl of methanol were added to the residue (1.90 g) and the mixture was filtered off with suction the undissolved crystalline material.

After drying, this product weighed 1.40 g (melting point 178 ° -179 ° C; 10% Yield) and was a pure hydroxyethylidene compound.

The original aqueous filtrate was etherified once and then acidified with hydrochloric acid. The deposited precipitate was filtered off with suction, one after the other washed with water and methanol and dried. At this point, 4.5 g (# 32% yield) of pure hydroxyethylidene cyanoacetic acid (3-bromoanilide) of melting point. Obtained 1780-1790C. The overall yield ar of this compound was accordingly 80%.

In an analogous manner were hydroxyethylidene cyanoacetic acid (4 fluoroanilide) (Yield 73%), - (3-trifluoromethyl-anilide) (yield 71%), - (3-chloroanilide) (yield 81%) and (3,4-dioxy methylene-anilide) (yield 22%).

Example 43.

Hydroxyäthyliden-cyanoacetic acid (3-chloroanilide) to a mixture from 6.36 g (0.03 mol) acetoacetic acid (3 chloranilide), and 4.85 g (0.035 mol) K2CO3 and 60 ml abs.

1,2-Dimethoxyethane was stirred at 180-250C in 35 min.

a solution of 3.20 g (0.030 mol) of cyanogen bromide in 30 ml of abs. Dimethoxyethane dripped, after the mixture then 30 min. at 270C and 400C and 2 hours at 600C had been stirred, the solvent was evaporated in vacuo and shaken the residue was washed through the aqueous solution with 100 ml of water from an undissolved resinous liquid filtered off and weakly with hydrochloric acid acidified. After the usual work-up of the precipitate, 60 mg were obtained pure hydroxyethylidene compound with a melting point of 168 ° -169 ° C. The resinous mass was made with 60 ml each of sodium hydroxide solution and ether are added and shaken vigorously. After this Separating the phases, the aqueous alkaline phase was acidified with conc. Hydrochloric acid weak on, sucked off the precipitate and washed it with methanol. One received after drying 0.95 g (- 13.4% yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) from fp.

168 ° -169 ° C.

Example 44: Hydroxyethylidene cyanoacetic acid (4-chloro-2-trifluoromethylanilide A mixture of 23.2 g (0.083 mol) of acetoacetic acid (4-chloro-2-trifluoromethyl anilide), 12.4 g (0.090 mol) K2CO3 and 100 ml abs. 1,2-Dimethovyethane was at 50 to 100C with stirring in 4.0 min. dropwise with a solution of 5.6 g (0.090 mol) of cyanogen chloride in 60 ml abs. Dimethoxyethane added and then oil each 30 min. At 100 to 25 ° C, at 28 ° -30 ° C and at 44 ° -46 ° C and 1.5 hours at 600C. After the subsequent Evaporation of the solvent in vacuo, 400 ml of water were added to the residue. The undissolved portion was filtered off with suction, washed out with a little water and then shaken together 100 ml of 0.5N sodium hydroxide solution for 30 minutes. The one in this treatment The undissolved portion (12.6 g) was successively treated with methylene chloride and ether washed out and then in a mixture of 50 ml of ln sodium hydroxide solution, 100 ml of water and 100 ml of methanol dissolved. After filtration through kieselguhr, the solution was acidified with conc. Hydrochloric acid weakly. The precipitated precipitate was filtered off with suction and with water and little Methanol washed. After drying were 9.9 g (4 39?, O yield) of pure hydroxyethylidene cyanoacetic acid (4-chloro-2-trifluoromethyl anilide) obtained from m.p. 1320-1330C.

Example 45: Hydroxyethylidene cyanoacetic acid (3-chloroanilide) one Solution of 7.05 g (0.05 mol) of methyl 2-cyanoacetacetate and 14 g (0.11 mol) 5-chloroaniline in 30 ml of dioxane was refluxed for 10 hours and then im Evaporated in vacuo. The residue was mixed with 20 ml of methanol and 50 ml of water, shook the resulting mixture and then acidified the two-phase mixture weak with hydrochloric acid.

The organic phase was separated off and evaporated in vacuo.

80 ml of 1N sodium hydroxide solution were added to the remaining residue and ether and shook this mixture through.

After the phases had separated, the alkaline aqueous phase became with Hydrochloric acid weakly acidified. he precipitated crystalline precipitate was sucked off, washed out successively with water, methanol / water (5: 1) and a little methanol and dried.

After drying, 1.40 g (# 12% yield) of pure hydroxyethylidene cyanoacetic acid (3-chloroanilide) were obtained from fp.

168 ° -169 ° C.

Example 6.

Hydroxyäthyliden-cyanoacetic acid (4-bromanilide) A mixture of 9.6 g (0.04 mol) cyanoacetic acid (4-bromanilide), 80 g (ca 1.1 mol) methyl acetate, 13.6 g (0.10 mol) phenyl acetate and 6.1 g (0.044 mol) K2CO3 were refluxed for 8 hours stirred and then evaporated in vacuo. The residue was mixed with 300 ml of water and then shook the mixture vigorously. the aqueous phase was filtered off from the solid soaked with oil and dissolved in hydrochloric acid pH adjusted to 9. The resulting precipitate was filtered off with suction and the filtrate weakly acidified with hydrochloric acid, further crystalline material precipitated. This one one sucked off and washed it successively with water, water / methanol (4: 1) and little methanol. After drying, 0.83 g (# 7.5% yield) of pure hydroxyethylidene cyanoacetic acid (4-bromanilide) obtained from m.p. 207-208 ° C.

Example 47: 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 added dropwise at room temperature mixed with 11 g (0.11 mol) of cyclohexylamine. Then the resulting The mixture was evaporated, leaving a solid product that turned out to be cyclohexane washed out. After drying, 27 g (# 73% yield) of hydroxyethylide cyanoacetic acid (3-trifluoromethyl anilide) cyclohexylammonium salt were obtained obtained from m.p. 157 ° -1590C.

Analysis: C18H22F3N5O2 Calculated: C 58.5%; H 6.0%; N 11.4%; MW 369.4 Found: C 58.5; H 6.0%; N 11.1% Example 48: 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 dropwise at room temperature mixed with 11.5 g (0.11 mol) of diethanolamine. The mixture became during the dropping homogeneous. When the clear brown solution was evaporated, a solid residue remained, after washing with cyclohexane 32 g (# 76% yield) of pure hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) diethanolammonium salt hemihydrate of m.p. 96 ° -98 ° C.

Analysis: C16H20F3N3O4 calc .: +) C 50.0%; H 5.5%; N 10.9%; MW 375.4 found0: C 50> 3%; H 5.8% N 11.0% +) with 1/2 H2O

Claims (5)

Patent claims 1. Hydroxyäthyliden-cyanoacetic anilide of the general formula Ia or its tautomeric form Ib in which a halogen atom, a methyl or ethyl group which can be substituted by 1-3 fluorine and / or chlorine atoms, a methoxy or ethoxy group which can be substituted by 1-4 fluorine and / or chlorine atoms, or an ethyl - or ethyl mercapto group, a hydrogen atom, a halogen atom, a methyl or ethyl group, a trifluoromethyl group or a methoxy group and R3 denotes a hydrogen, a chlorine atom, a dietiloxy group, or where R2 and R¹ together denote the -O-CH2-O grouping, and their physiologically compatible salts. 2. A process for the preparation of hydroxythylidene-cyanoacetic anilides of the formula Ia or its tautomeric form Ib in claim 1 and its salts, characterized in that a1) a cyanoacetic anilide of the formula II in which R1, R2 and R3 have the meaning given above for the FormeSnla and Ib, with an orthoacetic acid ester of the formula III CH3-C (0) 3 (III) in de.r R4 is an alkyl radical with 1 to 4 carbon atoms, in the presence of an anhydride of a lower fatty acid, at a temperature between +200 and + 180 ° C to form an alkoxyethylidene cyanoacetic anilide of the formula IV in which R1 - R4 have the meanings given above, and then the alkoxyethylidene cyanoacetic anilide of the formula IV is hydrolyzed at a temperature between ~ 30 ° and + 150 ° C, or a2) at a temperature between -400 and + 1600C with eie secondary amine of formula V in which R and R, which can be the same or different, each represent an alkyl radical with 1 to 4 carbon atoms or together an alkylene chain with 2 to 5 carbon atoms, a -CH2GH2-O-CH2CH2- or a -Group in which R7 is alkyl with 1 to 4 carbon atoms or benzyl, means 1 and the resulting dialkylaminoethylidene cyanoacetic anilide derivative of the formula VI in which R¹ - R³ have the meanings given above and R5 and R6 have the meanings given for formula V, hyd lysed; b) a dialkylaminoethylidene cyanoacetic anilide of the formula In the presence of basic compounds at a temperature between -70 ° and + 140 ° C with an isocyanate of the general formula in which R¹, R² and R³ have the meaning given in the formulas Ia and Ib, respectively, d) a cyanoacetic anilide of the general formula II in which R¹, R2 and R3 have the meanings given above for the formula Ia and Ib in the presence of a basic compound at a temperature between -80 ° and + 200 ° C with an acetic acid halide of the formula XI (CH3 -CO) nx XI in X is chlorine or bromine and n = 1, or with acetic anhydride (formula XI, X = oxygen and n = 2) or with an acetic ester of the formula XII CH3-COOR11 XII in R5 and R6, which can be identical or different , in each case a (C1-C4) -alkyl radical or together an alkylene chain with 2-5 carbon atoms and R¹, R² and R³ have the meaning given for formula Ia and Ib, in the presence of an inert, aprotic solvent initially at a Temperature between -70 ° and + 50 ° C with chloro- or fluorosulfonyl isocyanate and then with a tertiary amine of the formula in which R8, R9 and R10, which can be the same or different, denote alkyl radicals with a total carbon number between 3 and 12, and two of these radicals together can denote an alkylene chain with 2 - 5 carbon atoms and / or an NN-dimethyl- and / or diethylamide of a lower (C1-C4) carboxylic acid and / or N-methyl- and / or N-ethyl-2-pyrrolidone, at a temperature between 30 and -25 ° C and then making the reaction mixture alkaline, and then the dialkylaminoethylidene cyanoacetic anilide of the general formula VI isolated and hydrolyzed from the lipophilic phase, c) cyanoacetone of the formula IX, r in which R11 is a (C1-C4) -alkyl group, a benzyl group, a phenyl group or a phenyl group substituted by one or two chlorine atoms or nitro groups or by a carbomethoxy or carboethoxy group, or reacts with ketene. e) an acetoacetic anilide of the general formula XIV in which R1, R2 and R3 have the meanings given above for formula I, in the presence of a basic compound at a temperature between -40 ° and + 5C ° C with cyanogen chloride or cyanogen bromide, acet .f) a 2-cyanoacetic acid ester of general formula XVa or XVb in which R12 means a C1-C4-alkyl group or a phenyl or naphthyl radical, optionally substituted by a methyl, nitro or cyano group and / or - 1-2 chlorine or bromine atoms, at a temperature between 00 and + 250 ° C, with a substituted aniline of the formula XVI, in which R1, R2 and R3 have the meaning given above for the formula I converts, and optionally converts a salt of a hydroxyethylidene-cyanoacetic anilide of the formula I obtained in this way into a compound of the formula I by adding a strong acid, or optionally one obtained in this way The compound of the formula I is converted into its salt by adding a base. 3. Salts of hydroxyethylidene cyanoacetic anilides of the formula I. with organic bases. 4. Means consisting of a compound of the formula I in claim 1 and a pharmaceutically customary carrier and / or excipient. 5. Combat inflammation and pain through a compound of formula I in claim 1.