GB1571990A - Process for the preparation of cyanoacetic acid anilide derivatives - Google Patents

Abstract

Hydroxyethylidenecyanoacetanilides of the formula Ia or their tautomeric form Ib are prepared by reacting cyanoacetone with an appropriately substituted isocyanate. The reaction is carried out at a temperature between -70 and +140 DEG C. The symbols in the formulae Ia and Ib have the meaning stated in the claim. The compounds of the formula Ia and Ib as well as their physiologically tolerated salts have potent anti-inflammatory and analgesic as well as anthelmintic, antimycotic and fungicidal activity. <IMAGE>

Description

(54) PROCESS FOR THE PREPARATION OF CYANOACETIC ACID ANILIDE DERIVATIVES (71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to a process for the preparation of hydroxyethylidene cyanoacetic acid anilide derivatives.

The hydroxyethylidene cyanoacetic acid anilide derivatives prepared are of the general formulae la and ib

in which Rl represents a halogen atom; a methyl or ethyl group which may be substituted by 1 to 3 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; a methoxy or ethoxy group which may be substituted by 1 to 4 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; or a methylthio or ethylthio group; and R2 represents a hydrogen or halogen atom; or a methyl, ethyl, trifluoromethyl or methoxy group; or Rl and R2 together represent the -OH2-O-group; and RS represents a hydrogen or chlorine atom or a methoxy group.

The preferred compounds of the general formulae Ia and 1b are those in which R1 represents a halogen atom, a methyl, ethyl or trifluoromethyl group, a methoxy. or ethoxy group, or an ethoxy group substituted by 3 fluorine atoms and a chlorine atom or by 4 fluorine atoms; R2 represents a hydrogen or halogen atom, or a trifluoromethyl or methoxy group; or R1 and R2 togther represent a -O-CH2-O- group in the 3,4-position; and R3 represents a hydrogen atom.

Especially preferred are those compounds of formula I in which R1 represents a fluorine, chlorine or bromine atom, or a methyl, trifluoromethyl or methoxy group; R2 represents a hydrogen, chlorine or bromine atom or a trifluoromethyl group; or R1 and R2 together represent a O-CH2-O- group in the 3,4-position; and R represents a hydrogen atom.

The physiologically tolerable salts of the compounds of the invention are especially alkali metal salts, for example, lithium, sodium, and potassium salts; ammonium salts; alkaline earth metal salts, for example, magnesium and calcium salts; zinc salts and iron salts; and salts with organic bases, for example, amines and tetraalkyl- ammonium hydroxides.

Preferred salts are sodium, potassium, ammonium, magnesium and calcium salts and salts with amines having from 2 to 8 carbon atoms, for example, piperidine, triethylamine, N-ethyl-piperidine, N-methylmorpholine, cyclohexylamine and diethanolamine.

In addition to the compounds of the invention described in the Examples, the following are also preferred compounds: 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,S-di- chloro, -2,6dichloro-, -3-chloro-2-methyl-, -5-chloro-2-methyl-, -3,4-dioçymethylene-, 3-ethoxy-, -3,5-bistrifluoromethyl-, 2,4,6-trichloro-, -2-chloro-4-methoy-, -2-trifluoro methyl-4-chloro, -3-methylthio and -4-ethylthiò-anilide).

The present invention provides a process for the preparation of a hydroxyethylidene-cyanoacetic acid anilide of the general formula Ia and/or its tautomeric form Ib

in which R1 represents a halogen atom; a methyl or ethyl group which may be substi- tuted by 1 to 3 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; a methoxy or ethoxy group which may substituted by 1 to 4 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; or a methylthio or ethylthio group; and R2 represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl or methoxy group; or Rl and R2 together represent the vCH2O-group; and R represents a hydrogen or chlorine atom or a methoxy group; or a salt thereof, which comprises al) reacting a cyanoacetic acid anilide of the general formula II

in which R1, R and R8 are defined as in the above formulae Ia and Ib, with an orthoacetic acid ester of the general formula III CH,---C( OR4) III in which R4 represents an alkyl radical having from one to four carbon atoms, in the presence of an anhydride of a lower fatty acid, preferably in the presence of acetic anhydride, advantageously by adding a catalytic amount. of a Lewis acid and optionally by adding a solvent, suitably at a temperature the range of from + 200 C and At180" C to yield an alkoxyethylidine-cyanoacetic acid anilide of the general formula IV

in which R1, R2, R3 and R4 are defined as above, and subsequently hydrolysing the isolated alkoxyethylidine-cyanoacetic acid anilide of the formula IV, preferably in an alkaline aqueous solution or suitably in an acid aqueous solution, optionally with the additional use of an organic solvent totally or partially miscible with water, at a temperature in the range of from 300 to +1500 C.

The term " lower " when used herein in connection with fatty acids indicates those fatty acids having from 1 to 6 carbon atoms and when used herein in connection with alcohols indicates those alcohols having from 1 to 4 carbon atoms.

In the reaction of the cyanoacetic acid anilide of formula II with an orthoacetic acid ester of formula III, the reaction temperature is preferably in the range of from +600 C to +1500 C, especially from +850 C to +1400 C. In this step, any low-boiling point compounds which may have been formed can be separated at least partially from the reaction mixture by distillation. When the reaction is carried out at the boiling temperature of the reaction mixture, the temperature can be varied, especially raised, during the reaction, depending on whether or in what amounts the lowboiling points compounds, which have been formed during the reaction, are distilled off.

The reaction is generally carried out under normal pressure, but lower or higher pressures may be used, for example, the autogenous pressure of the reaction mixture in the vessel. The reaction time is generally in the range of from 0.5 to 48 hours, preferably from 1 to 12 hours.

In a variant a2 of this process of the invention the alkoxy-ethylidene-cyanoacetic acid anilide of the formula IV obtained as an intermediate in process a1 is reacted, advantageously in a solvent and at a temperature in the range of from - 400 C to +1600 C, with a secondary amine of general formula V RB HNj < R" V in which each of R2 and R4, which may be identical or different, represents an alkyl radical having from 1 to 4 carbon atoms, or in which R5 and R0 together represent an alkylene chain having from 2 to 5 carbon atoms, a -CH2CH2-O-CH2CH2- or R7 CH2CH2M < CH2CH2-group, in which R' represents an alkyl radical having from 1 to 4 carbon atoms or a benzyl radical, to give the dialkylaminoethylidene-cyanoacetic acid anilide derivative of the general formula VI

(for bE nomenclature J.Org.Chemistry, Vol. 35, 2849 (1970), esp. page 2852). in which R1, R2 and R3 are as defined above and R5 and Rs are as defined in the formula V, and then hydrolising the compound of the general formula VI under acid or alkaline conditions, preferably under acid conditions optionally with the use of an organic solvent miscible with water.

The combined processes al) and a2) of the invention follow the reaction scheme

As the orthoacetic acid ester of general formula III, the methyl or ethyl ester is preferred.

The Lewis acid preferably used as a catalyst in process al) is, for example, an anhydrous salt of boron, aluminum, zinc, cadmium, mercury, thallium, titanium, zirconium, tin, lead, phosphorus, arsenic, antimony, iron, cobalt or nickel preferably borontrifluoride, borontrichloride, All2, ZnCl2, ZnBr2, ZnI2, Zn(CH3CO2)2, Zn2P2O7, ZnSO4, HgCl2, Hg(CH,CO2)2, HgSO4, Tic4, SnCl4, Pal3, PCls, SbBr3, SbCl2, SbCl.s, SHOCK, (SbO)2SO4, FeCI2, FeCOg or Fe2(SO4)2. The catalyst is generally used in an amount of from 0.005 to 5 mols % or more, calculated on the compound of the general formula II.

If the reaction is carried out in a solvent, this may be a hydrocarbon, halogenohydrocarbon, ether or nitrile, provided that the solvent is inert under the reaction conditions, i.e. does not contain any further functional groups which may lead to side reactions. There may be mentioned, for example, petroleum ether, n-hexane, toluene, xylenes, benzene, 1,2-dichloroethane, carbon tetrachloride, tetracbloroethylene, diiso propyl ether, dioxane, tetrahydrofuran, glycol, diglycoldimethyl ether and acetonitrile.

A mixture of two or more solvents may be used; however the reaction of the anilide II with the compound of the general formula III is preferably effected without a solvent.

In the reaction of the cyanoaceranilide of general formula II with an orthoacetic acid ester of the general formula III in the presence of an anhydride of a lower fatty acid, for example, in the presence of acetic anhydride, the reaction conditions and the quantitative ratios in respect of the reactants and, optionally, the catalysts, may vary to a great extent. This means that the cyanoacetanilide of the general formula II may be used in an excess of up to 35%, the orthoacetic acid ester of the general formula III in an excess of, for example, up to 200% or more, advantageously from 20 to 100%, calculated on the other reaction component, respectively but may also be used in a stoichiometric ratio. The same is true for the amount of carboxylic acid inhydride to be used, preferably acetic anhydride. Advantageously, the carboxylic acid anhydride is used in an excess, preferably from 20 to 170%, calculated on that of the two components which is used in excess, i.e. either the anilide of the general formula II or the ortho ester of the general formula III. Besides, the orthoacetic acid ester and the carboxyilc acid anhydride need not be added at once at the beginning of the reaction, but these reaction components may rather be added to the reaction batch in portions or continuously during the course of the reaction. It is also possible to distill off during the reaction, in portions or continuously, the different quantities of the slightly volatile compounds formed, at normal pressure, overpressure or underpressure. By operaring in this manner, the reaction temperature can be influenced in a desired manner.

The alkoxyethylidene-cyanoacetic acid anilides obtained of the general formula IV may be isoluated in different ways. When they form crystalline compounds in the reaction, they may be isolated and, if required, purified by recrystallisation from suitable solvent(s), for example, diethyl ether, isopropyl ether, benzene, toluene, ethyl acetate, dimethoxyethane, tetrahydrofuran, chloroform or carbon tetrachloride, or by column chromatography. Purification is essentially a separation from the non-reacted starting cyanoacetanilide which frequently crystallises with the reaction product in varying proportions.

If there are no crystalline compounds formed after the reaction is terminated, the reaction products may be crystallised, for example by distilling off easily boiling components. On the other hand, components which are easily soluble in a nonpolar solvents, for example saturated acyclic or cyclic hydrocarbons, e.g. n-hexane or -cyclohexane, are washed off by using suitable solvents, for example, diethyl ether, isopropyl ether, benzene, toluene, ethyl acetate, dimethoxy ethane, tetrahydrofuran, chloroform or carbon tetrachloride thus permitting the products to crystallise from the residue.

After recrystallisation the compound of the general formula IV may optionally be further purified in the usual manner.

Depending on the reaction conditions and the choice of radicals R1 to R4, the alkoxyethylidene-cyanoacetanilides of the general formula IV are either in the form of a E/Z stereoisomer mixture, in which case the ratio of the stereoisomers may differ greatly or sometimes are in the pure E or Z form. One of the two stereoisomers or even both stereoisomers may be obtained from the stereoisomer mixtures in pure form by separating the mixture by conventional methods, for example fractional crystallisation or column chromatography.

Alkoxyethylidene-cyanoacetanilides of the general formula IV, are for example: ethoxyethylidene-cyanoacet-(3-trifluoromethyl-, -3 -chloro-, -3-bromo-, -3 -iodo-, -4bromo-, -3,4-dichloro-, -3,4-dioxymethylene-, -2-methyl-3 -chloro-, -2-methyl-5-chloro-, A-methoxy-, -4-fluoro-, -4-chloro-, 3,5-dichloro-, -3,5-bis-(trifluoromethyl)-, -4chloro-2-trifluoromethyl-, -2,4-dichioro-, -2-ethoxy-, -3 - (tetrafluoroethoxy) -3-(1,1,2- trifluoro-2-chloroethoxy) -, -3-methylthio-, -3 -chloro-4-methyl- and -3,4-dimethoxy) - anilide.

The hydrolysis of the alkoxyethylidene-cyanoacetic acid anilide of the general formula IV to the corresponding enol of the general formula Ia or the tautomeric keto form Ib may be effected under alkaline or acid conditions within a wide temperature range in homogeneous or heterogeneous systems. The conditions of the hydrolysis in respect of the concentration of the acid or alkali used and of the composition of the reaction medium may also be varied within a wide range. For example, it is pos sible to work in water alone or in water containing different quantities of solvent(s) miscible with water. Examples of such solvents are: (C1 to Cs)alkanols and alkanediols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, acetonitrile, glycolmonomethyl or diethyl ether, dimethyl formamide, dimethylsulphoxide and/or (C, to C4)ketones.

The reaction time may be up to 25 hours. The time is, as is known, inversely proportional to the reaction temperature, i.e. higher temperatures require shorter reaction times.

Furthermore, the hydrolysis may also be carried out in a 2 or 3 phase system.

The 3-phese system generally implies that the cyanoacetanilide derivative of the general formula IV to be hydrolised or the hydrolysis product of the general formula- Ia and Ib or both substances are in the solid phase. Therefore it is possible that a solid phase is permanently present in the hydrolysis batch which may consist at the beginning of the reaction of a compound of the general formula IV and at the end of the reaction of the pure hydrolysis product of the general formula Ia and/or Ib, or of a mixture of the starting substance and the hydrolysis product.

The alkaline hydrolysis is preferably carried out in an aqueous medium, optionally with the additional use of a solvent as mentioned above, with an alkali concentration of from 0.2 to 8 N and at a temperature in the range of from 200 C to 1000 C. Preferred alkalis are sodium hydroxide or potassium hydroxide solutions, or sodium carbonate or potassium carbonate solutions. The alkali is generally used in at least equimolar quantity, preferably in an excess of 20% or more.

(The term " alkali" when used herein refers to alkali metal or ammonium compounds unless otherwise stated).

Using this mode of carrying out the hydrolysis, the total or part of the hydrolysis products are in the form of solutions of the sodium salt or the potassium salt. After acidifying, the corresponding hydroxyethylidene-cyanoacetanilide of the general formula la and/or tautomeric form Ib generally precipitates in crystalline form.

The acid hydrolysis is preferably carried out in an aqueous medium, which additionally contains the above-mentioned solvent(s) miscible with water, using a concentration of acid of from 1 N to 12 N at the temperature in the range of from 20 C to 1000 C. The solvent(s) advantageously added are (C1-C3)alkanols, tetrahydrofuran, l,2-dimethoxyethane, dioxane, glycolmonomethyl ether, acetone and/or acetonitrile. The hydroxyethylidene-cyanoacetic acid anilides of the general formula Ia and/or Ib may be obtained by hydrolysis precipitate in the form of crystals directly or after the total or partial evaporation of the organic solvent used.

In the varient a2) of the process of the invention, in which the alkoxyethylidenecyanoacetic acid anilides of the general formula IV are first converted into a compound of the general formula VI by reaction with a secondary amine V, the presence of a neutral organic solvent and a temperature within the range of from 200 C to 100" C being preferred. The preferred solvents are 1,2-dimethoxyethane, diethyl ether, dioxane, tetrahydrofuran, (C1-C3)alkanols, carbon tetrachloride, tetrachloroethylene and acetonitrile. A mixture of two or more solvents may be used. The reaction time is generally up to 8 hours.

The hydrolysis of the dialkylaminoethylidene-cyanoacetic acid anilide derivatives of the general formula may be effected in an acid or alkaline medium. Organic solvents totally or partially miscible with water may be used as described above in relation to the hydrolysis of the enol ethers of the general formula IV. The composition of the reaction medium, the concentration of the acid or base and the temperature may be varied to a large extent and the reaction time, which may be up to 8 hours, very much depends on the reaction conditions.

In the acid hydrolysis, which is generally preferred at this stage of the reaction, acid concentrations of N/100 to 6 N and temperatures in the range of from 0 C to 70" C are preferred. Compounds of the general formulae Ia and/or Ib are obtained.

Alkaline hydrolysis is generally effected by means of an alkali hydroxide solution or alkali carbonate solution having a concentration of from 0.2 N to 8 N. After the reaction, the resulting alkali metal salt of the compounds of the general formulae Ia and/or Ib may be totally or partially dissolved, and crystalline hydroxyethylidenecyanoacetanilides of the general formulae Ia and/or Ib may be obtained from the solution by acidification. In the alkaline hydrolysis of the compounds of the general formulae IV or VI at least equimolar quantities of alkali are generally used and excess amounts of from 30 to 500%, especially from 100 to 300%, are preferred.

Examples of dialkylaminoethylidene-cyanoacetic acid anilide derivatives of the general formula VI, which are prepared according to the invention as intermediates of the hydroxyethylidene-cyanoacetanilides Ia and/or Ib, are: (I-dimethylamino-, 1-diethylamino-, 1 -dipropylamino-, 1-dibutylamino-, 1-pyrro- lidino-, l-piperidino-, 1 -morpholino, 1-N-methylpiperazinoethylidene) -cyanoacetic acid-(3-trifiuoromethyl-, -3-chloro-, -3-bromo-, -3-iodo-, 4-iodo-, -3,4dichloro, -3,4-dioxymethylene-, -2-methyl-3 -chloro-, -2-methyl-5-chloro-, -4-methoxy-, -4fluoro-, -3,4-dioxymethylene-, -2-methyl-3 -chloro-, -2-methyl-5-chloro-, -4-methoxy-, -4-fluoro-, -2,4-dichloro-, -2-ethoxy-, -3- (tetrafluoroethoxy) -, -3- ( 1,1,2-trifluoro-2- chloro-ethoxy)-, -3 -methylthio-, -3 -chloro-4-methyl- and -3,4-dimethoxy-anilide).

Mcreover, it is also possible to prepare further (1 -:lialkylaminoethylidene) -cyanoacetic acid anilides by the process of the invention.

It is surprising in this variant of the process that the substituted (1-dialkylaminoethylidene)-cyanoacetic acid anilides of the general formula VI are hydrolised easily under acid conditions. The compounds of the general formula VI may be hydrolised under acid conditions at a pH of more than zero much more rapidly than the enol ethers of the general formula IV. Therefore, this variant of the process is preferred for the preparation of the compounds of the general formulae Ia and/or Ib, if these compounds contain acid or alkali sensitive substituents, especially if a modification of the substituents would be expxted in an alkaline hydrolysis.

It is also surprising that compounds of the general formula IV are hydrolysed much more rapidly under alkaline conditions than under acid conditions as it is generally known that enol ethers, the class of compounds to which the compounds of the general formula IV belong, are easily split under acid conditions in the presence of water.

-Ihe cyanoacetanilides of the general formula II needed as starting substances may be prepared by the process described in British Patent Specification No. 930,808 and the orthoacetic acid ester of the general formula III may be prepared by known methods (cf. Houben-Weyl-Miilier, Methoden der Organischen Chemie, IVth edition, Stuttgart 1965, vol. 6, part 3, page 295).

The invention also provides process b) for the preparation of a compound of the general formulae Ia and/or Ib, or a salt thereof, which comprises reacting a dialkylaminoethylidene-acetic acid anilide of the general formula VII

wherein each of Ri and R6, which may be identical or different, preferably identical, represents a (C1 to C4)alkyl radical or, together, represent an alkylene chain having from 2 to 5 carbon atoms, while Rt, R2 and RS are as defined in the general formulae Ia and Ib, in the presence of an aprotic solvent inert to this reactant, generally at a temperature within the range of from 700 C to + 500 C, with chloro- or fluoro sulphonyl isocyanate and subsequently with a tertiary amine of the general formula VIII

wherein each of R8, R9 and R1", which may be identical or different, represents an alkyl radical having from 3 to 12 carbon atoms and wherein two of these radicals together optionally represent an alkylene chain having from 2 to 5 carbon atoms, and/or with an N,N-dimethyl- and/or -diethyl amide of a (C1 to C)carboxylic acid and/or an N-methyl- and/or N-ethyl-2-pyrrolidone, generally at a temperature within the range of from --300 C to 250 C, and then adjusting the pH of the reaction mixture, optionally after evaporating the solvent, to a slightly alkaline range, i.e. having a pH in the range of from 7.5 to 12.0, preferably using an excess of dilute aqueous alkali bicarbonate solution, and then isolating from the lipophilic phase the dialkylaminoethylidene-cyanoacetic acid anilide of the general formula VI, suitably by crystallisation or by column chromatography and hydrolysing the compound thus obtained to yield the compound of the general formula Ia and/or Ib in the manner described above.

(1-Dialkylaminoethylidene) -cyanoacetic acid anilides of the general formula VI thus prepared being present in the Z- and/or E-form, may be converted as indicated in the first process described to yield the corresponding compounds of the general formulae Ia and/or Ib by acid or alkaline hydrolysis:

CHc /R5 /NNRb ')) X502 NCO (x-c6 xsqJco or F) ~~~~~~ c0 / R2 + H; R2 2) N-R YNR3 R'0 ndftr I cor & aatn,Ve (vii) R1 (vat V, vt (z form and/er E-4orm)/a,/.

Suitable inert aprotic solvents are, for example, methylene chloride, chloroform, carbon tetrachloride, tetrachloroethylene, and 1,2-dichloroethane.

Preferred starting materials for this process are substituted anilides of the general formula VII, in which R and K represents a methyl or ethyl radical or, together, a tetra- or penta-methylene radical, and R, R2 and KS have the especially preferred meanings given in the general formulae Ia and Ib. As the sulphonylisocyanate, chlorosulphonylisocyanate is generally used. As tertiary amines of the general formula VIII, triethyl-, tripropyl- and/or tributyl amine and/or N-methylpiperidine are preferred.

As carbonamides, N,N-dimethylformamide or -acetamide may be used.

A preferred embodiment of the process of the invention b) consists in combining homogeneously equimolar amounts of dilute solutions of an anilide of the general formula VII and of chlorosulphonylisocyanate in CH2Cl2, CHIC13 and/or ClCH2CH2CI, at a temperature in the range of from - 40 to - 50 C.

The degree of dilution of the anilide solution is about 12-33 parts by weight of solvent per part by weight of anilide. The isocyanate solutions contain about 10 to 20 parts by weight of solvent per part by weight of isocyanate.

To complete the reaction, the mixture may be stored at from 100 C to 100 C for 0.25 to 2 hours. Then, dimethylformamide or dimethylacetamide and/or one of the above-mentioned tertiary amines, optionally diluted with one of the abovementioned chloro alkanes, are advantageously added simultaneously or successively at a temperature in the range of from --25" C and +10 C, the sum of carbonamide and tertiary amines preferably being from about 2 to 4 mols per mol of chlorosulphonylisocyanate.

After total or partial evaporation the reaction mixture may be mixed with a dilute aqueous sodium or potassium carbonate solution containing from 1 to 2.5 equivalents of bicarbonate per mol of chlorosulphonylisocyanate. The undissolved lipophilic parts of the mixture may be extracted with CHsC12, CHCls and/or ether.

The extracted residue is usually chromatographed on a silica gel column, the crystalline cyanoacetic acid anilide derivatives of the general formula VI being obtained from the eluates.

The (1-dialkylaminoethylidene)-cyanoacetic acid anilide derivatives of the general formula VII used as starting material may be prepared by known methods, for example, by reacting corresponding acetoacetic acid anilides with secondary amines (cf. for example Ber. dtsch. chem. Ges. 25 (1892), 776; German Patent 967,642).

Chloro- and fluoro-sulphonylisocyanate may also be prepared by known met ethane or tetrachloroethylene and, if a tertiary amine is used as the base, also a lower polychloroalkane, for example, methylene chloride, chloroform or carbon tetrachloride.

A mixture of two or more solvents may be used.

As the basic compound, which is advantageously used in equimolar amounts or in an excess amount of up to 20%, there may be used, for example, a tertiary amine, an alkali metal alcoholate of a lower alcohol, sodium hydride, an alkali metal hydroxide or an alkali metal or alkaline earth metal carbonate. Tertiary amines, sodium and potassium alcoholates and sodium hydride are preferred.

The compounds Ia and/or Ib obtained by the reaction are in the form of salts from which the free acid is advantageously freed in the presence of water by the addition of an equivalent amount or a slight excess of an acid, preferably a mineral acid. The compounds Ia and/or Ib are often obtained in crystalline form and may be isolated by filtration. Sometimes, it is advantageous to add a solvent miscible with water, preferably a lower alcohol, 1,2-dimethyoxyethane or acetonitrile or a mixture of two or more solvents, keeping the impurities dissolved. Thus the cyanoacetic acid anilide derivatives of the general formulae Ia and/or Ib may be obtained in a more suitable form for filtration.

The cyanoacetone used as starting material may be prepared according to the process described by Dahn and Hauth, Helv. Chim. Acta 47, 1424 (1964). As described in this process and in several other publications (cf. Beilsteins Handbuch d. organ. Chimie IVth edition, vol. 3, page 659), the cyanoacetone may be easily polymerised, especially under alkaline and acid conditions. However, for the process of the invention, the cyanoacetone need not be isolated in pure form. As the byproducts are readily separated after the reaction with the isocyanate of the general formula X, the cyanoacetate may be used in the impure state in which it is obtained.

For example if in the acid cleavage of the 2-cyanoacetic acid-tert. -butyl ester toluene suIphonic acid has been used as a catalyst (cf. Helv. chim. Acta 47, 1424, (1964), it is not necessary to eliminate this acid before the reaction with the isocyanate. The cyanoacetic acid anilide derivatives of the general formulae Ia and/or Ib which have been set free from their salts by acidification generally exhibit such a good crystallisation behaviour that they can readily be separated from accompanying substances.

The invention further provides a process d) for the preparation of (1-hydroxy- ethylidene)-cyanoacetic acid anilides of the general formulae Ia and/or Ib, or a salt thereof, which process comprises reacting a cyanoacetic acid anilide of the general formula II, in which Rt, R2 and R3 are defined as in the general formulae Ia and Ib above, in the presence of a basic compound at a temperature in the range of from - 800 C to +200 C with an acetic acid halide of the general formula XI (CHSCO)^,X XI in which X represents a chlorine or bromine atom and n is 1, or with an acetic anhydride of the above general formula XI, in which X represents an oxygen atom and n is 2, or with an acetic acid ester of the general formula XII CH1-COOR11 XII in which K11 represents a (C1 to C4)alkyl, a benzyl, or phenyl radical or a phenyl radical substituted by one or two chlorine atoms or nitro groups, or a carbomethoxy or carboethoxy group, or with ketene. The reaction is advantageously carried out in a solvent or diluent.

Acetic acid esters of the general formula XII are, for example, methyl acetate and ethyl acetate, and the propyl, isopropyl, butyl, isobutyl, phenyl and benzyl esters of acetic acid may also be used.

The methyl, ethyl or phenyl ester of acetic acid is preferred.

As basic compounds, there may be used for example, alkali metal or alkaline earth metal hydrides, sodium or potassium alcoholates of lower alcohols, alkali metal amides, sodium or potassium carbonate or bicarbonate alkali metal hydroxides, lithium butyl and/or tertiary amines.

Preferred basic compounds are sodium hydride, sodium or potassium amide, potassium tertiary butylate, sodium methylate or ethylate and/or potassium carbonate.

The basic compounds are advantageously used in amounts of from 1 to 4 equivalents, preferably from 1.1 to 3.3 equivalents, calculated on a cyanoacetanilide of the general formula II.

This reaction of the invention is preferably carried out with the additional use of solvents or diluents.

As solvents or diluents for this process of the invention, all knows solvents sufficiently inert to the respective reactant, for example, aromatic hydrocarbons, mono- or dichlorobenzenes, nitrobenzene, anisol, dimethoxyethane, ether, tetrahydrofuran, dioxane, acetonitrile, tetrachloroethylene, acetone, lower alcohols, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or dimethylformamide may be used. Acetic acid esters may also serve as diluents. If the acetylation is effected with an acetic acid ester, the latter may also be used at the same time in excess as a diluent Preferred solvents or diluents are 1,2-dimethoxyethane, tetrahydrofuran, ether, dioxane, acetonitrile, anisol, toluene, chloro- and dichlorobenzene, acetone, tertiary butanol and chloroform, the basic compound used influencing the choice of the solvent or diluent optionally to be used additionally in the reaction of the invention. This means that when a strong base, for example, a hydride, alkali metal amide, butyl lithium or potassium tert.butylate is used, it is advantageous not to use a protic solvent or a halogenoalkane. On the other hand, when a weaker base, for example, potassium bicarbonate or an alcoholate is used, a protic solvent or halogenoalkane may readily be used as the solvent or diluent.

According to this process of the invention, the acetylation agent may be used in amounts of up to 4 equivalents, calculated on the cyanoacetanilide of the general formula II, except for the cases in which an acetic acid ester is used for the acetylation and at the same time serves as a solvent or diluent. In such cases, the ester is used in a molar excess of up to 50. Advantageously, 1 to 2 equivalents, calculated on a cyanoacetanilide, of one of the above acetylation agents is used.

In this reaction, the (1-hydroxyethylidene).cyanoacetic acid anilides of the general formula Ia and/or Ib are obtained in the form of their salts. Usually, the free acids are liberated from these salts by treating the reaction product, optionally after evaporating any solvents used, with water and/or a dilute aqueous alkali and/or aqueous ammonia, and, optionally after extracting the aqueous phase with diethyl ether, isopropyl ether or a hydrocarbon boiling at 40 to 1200 C, setting free the (1-hydroxy- ethylidene)-cyanoacetic acid anilide of the general formula Ia and/or Ib from the aqueous solution thereof by acidification. The acid is generally obtained in crystalline form.

Especially preferred embodiments of process d) of the invention are the following: a) When a strongly basic compound is used, for example sodium hydride, sodium or potassium amide, n-butyl-lithium or potassium tertiary butylate, it is advan tageous to work in the presence of from 0.5 to 80 parts by weight per part of cyanoacetanilide of one or several of the above preferred solvents. If acetic acid chloride, bromide, anhydride or ester are used as acetylation agent, from 2.0 to 2.2 equivalents of the base are added to the solution of the cyanoacetanilide of the general formula II, at a temperature in the range of from 5 C to + 300 C; if ketene is used as acetylation agent, from 1.0 to 1.3 equivalents of the base are added, and subsequently from 1.0 to 1.2 equivalents of the acetylation agent, optionally diluted with the above solvents, are added at a temperature in the range of from - 50 C to 60 C. After a reaction time of up to 5 hours, in which the temperature may optionally be raised to 125 C, the solvents or diluents are evaporated completely or partially and water is then added to the residue.

Subsequently, the compounds of the general formula I formed are isolated as des cribed above.

) When a weaker basic compound is used, for example sodium or potassium carbonate or a tertiary amine, for example triethyl amine, from 1.0 to 1.4 equi valents (calculated on the cyanoacetanilide) of the acetylation agent, optionally diluted by the above solvent(s), are added to a mixture of one part of cyano acetanilide of the general formula II and from 2 to 40 parts by weight of one or several of the above preferred solvents and from 2.0 to 3.3 equivalents of said weaker basic compound, if acetic acid chloride, bromide or ester are used as acetylation agent, or from 1.0 to 1.2 equivalents of said weaker basic compound if ketene is used as acetylation agent.

After a reaction time of up to 24 hours, during which the temperature may be in the range of from 20 to 1200 C, the process may be continued as described under a1) or a2) above to isolate the (l-hydroxyethylidene)-cyanoacetic acid anilides formed respectively.

In carrying out the reaction according to the invention, care must be taken that part of the reaction products or, depending on the amount of the acetylation agent used, the greatest part thereof, are obtained in the form of their 0- and/or N-acetyl products, if the respective acetylation product is used in an amount of more than about 1.3 equivalents per gramme equivalent of the cyanoacetanilide. The O-acetyl compounds of the general formula XII I, in which R1 to R3 are as defined above, are hardly soluble in water and are, if the extraction occurs in organic solvents, in the organic phase, but they may already be split hydrolytically by dilute alkalis and converted into the corresponding alkali metal salts of the compounds of the general formula Ia and/or Ib. The hydroxyethylidene compounds of the general formula Ia and/or Ib.

The hydroxyethylidene compounds of the general formula Ia and/or Ib may be set free from aqueous solutions or suspensions of these salts by acidifying with mineral acid.

When proceeding in this manner, it is possible also to convert that portion! of the reaction products which is optionally first obtained as O-acylated compound, into the respectively desired end product of the general formula Ia and/or Ib. But the formation of O-acetyl derivatives of the ( l-hydroxyethylidene) -cyanoacetanilides of the formula I may be avoided when a ratio of about 2 equivalents of base to one equivalent of acetylation agent is used in this process of the invention.

The a-acetylation of cyanoacetic acid-tertiary-butyl esters with acetyl chloride to yield O-acetyl-cyanoacetic acid tertiary butyl ester has been described by Dahn and Hauth, Helvetica chim. Acta 42, 1214 (1959). Furthermore, a-acyl-cyanoacetic acid esters have been described in German Auslegeschrift No. 1,194,630 without mentioning, however, methods for their preparation. The application of the reaction to the preparation of cyanoacetic acid anilides however, was by no means a matter of course, because in this case, i.e. process d), the -CONH grouping represents, as is known, a further deprotonisable and thus acylatable function which could lead to undesired products or to the failure of the a-acetylation.

The smooth course of the acylation of cyanoacetanilides in the presence of such relatively weak basic compounds as sodium and potassium carbonate as well as tertiary amines IS especially surprising. In reactions of a comparable type with H- acid compounds, only strong bases are used for the deprotonisation.

A further process of the invention is a process e) which comprises reacting an acetoacetic acid anilide of the general XIV, in which Rt, R2 and R8 are as defined is the general formulae Ia and Ib, in the presence of a basic compound, advantageously with the additional use of a solvent or diluent and at a temperature in the range of from 400 C to + 300 C, with chlorocyane or bromocyane and subsequently optionally heating the reaction mixture to a temperature of up to + 150 C.

The reaction time may comprise up to 25 hours. The reaction of the invention is preferably carried out with the additional use of a solvent or diluent at a tempera ture the range of from - 10 to +25 C and afterwards heating to a temperature of upto+80 C.

Suitable solvents or diluents are any known solvents sufficiently inert to the reactants, for example the solvents mentioned in the preceding process. Besides the preferred solvents mentioned in that process, still further preferred solvents or diluents are (C1 to C4)alcohols, such as methanol, ethanol, propanol, isopropanol or butanol.

As basic compounds, there may be used the same ones as in the said process. The same is true for the bases to be used by preference.

In the reaction e) of the invention, the hydroxyethylidene-cyanoacetanilides of the general formula Ia and/or Ib are obtained in the form of their salts.

The acid compounds of the general formula Ia and/or Ib may be then isolated therefrom as described in the preceding process.

The acetoacetic acid anilides of the general formula XIV required as starting materials may be prepared by known methods, for example by the reaction of acetoacetic acid esters with correspondingly substituted anilines at elevated temperatures (cf. Ullmanns Encyklopkdie der technischen Chemie, IInd edition, 1953, vol. 3, page 35). Moreover, acetoacetic acid anilides acid anilides may be very easily accessible by reacting, in known manner, correspondingly substituted anilines with diketene.

The following acetoacetic acid anilides may be used as starting materials.

Actoacetic a d-4-chloro-, -4-methoxy-, -4-fluoro-, -3 -methoxy-, -3 - (1', 1 ',2'-tri- fluoro-2'-chloro-ethoxy) -, -3 - (1', 1',2',2'-tetrafiuoroethoxy) -, -3,5-dichloro-, -2,4-di chloro, -3-chloro-6-methyl-, -3,5bis-(trifluoromethyl)-, -2,4,6-trichloro-, -2-chloro4-methoxy-, -2-trifluoromethyl-4-chloro- -3-methylthio-, -4-ethoxy-, -2,3 -dichloro-, -2,6-dichloro-, -4-bromo-2-methyl-, 2,6-dimethyl-, -2-bromo-4-ethoxy-, -2-methoxy-4- bromo- or -4-ethylthio-analide.

A further process of the invention is a process f) which comprises reacting a 2cyanoacetoacetic acid ester of the general formula XVa or XVb

in which K12 represents a (C1 to C4)alkyi radical or a phenyl or naphthyl radical all of which radicals may be optionally substituted by methyl, nitro or cyano and/or by 1 or 2 chlorine or bromine atoms, generally at a temperature within the range of from 0 to +250 C, preferably with the additional use of a solvent and optionally with the addition of a catalytic amount of a base, with a substituted aniline of the general formula XVI

in which Rl, R2 and Rs are as defined in the general formula Ia and Ib.

The preferred 2-cyano-acetoacetic acid esters of the general formula XVa or their tautomeric form XVb are those in which Rt2 represents a methyl, ethyl or phenyl radical. Esters of the general formula XVa or XVb in which K12 represents a methyl group are especially used.

Preferred anilines of the general formula XVI are those in which R1 represents a methol, ethyl or trifluoromethyl group, a halogen atom, a methoxy or ethoxy group, an ethoxy group substituted by 3 fluorine atoms and one chlorine atom, or by 4 fluorine atoms, or a methylthio group, R2 represents a hydrogen atom, a trifluoromethyl group, a halogen atom or a methoxy group and R3 represents a hydrogen atom or R2 and Rl together represent a -O-CH2-O-group in the 3,4-position. The anilines of the general formula XVI are advantageously used in amounts of from 0.8 to 1.5 mols per mol of cyanoacetoacetic acid ester.

The process f) of the invention is preferably carried out using a solvent sufficiently inert to the reactants in the presence of catalytic amounts of a base, preferably as organic base, in a temperature range of from 500 C to 1600 C.

A preferred embodiment of the process f) of the invention comprises slowly adding, dropwise, to a boiling solution of a 2-cyano-acetoacetic acid ester of the general formula XVa or XVb in an inert solvent boiling at a temperature of more than 1090 C, for example5 xylene or chlorobenzene, optionally in the presence of a catalytic amount of a base, the corresponding aniline of the general formula XVI, optionally in diluted form. The rate of addition is suitably the rate at which the alcohol formed in the reaction, especially, for example, methanol, is distilled off from the reaction mixture, advantageously over a distillation column, and, after the addition of the aniline, optionally heating the mixture at its boiling point for a while.

Suitable solvents for the process f) are, for example, aromatic hydrocarbons, e.g. benzene, toluene, xylene, or cumene, or chlorobenzene, dioxane, 1,2-dimethoxyethane, acetonitrile, nitrobenzene, tetrachloroethylene, dichlorobenzene, anisol and/or tert.butanol.

If bases are additionally used in this process of the invention, they are advantageously applied in amounts of from 0.1 to 5.0 mol %, calculated on the 2-cyanoacetoacetic acid ester. Suitable bases are, for example, tertiary amines, e.g. triethyl amine, tripropyl amine, N-methylpyrrolidine, N-ethyl-piperidine, triethanolamine, 1,4 diazobicyclo[2,2,2] octane, or pyridine, picolines, quinoline and N,N-dimethyl aniline.

After evaporating solvent(s) used the (1-hydroxyethylidene) cyanoacetanilides of the general formula Ia and/or Ib are isolated, advantageously, by treating the crude reaction product with dilute aqueous alkali, thus converting the compounds of the general formula Ia and/or Ib into the corresponding alkali metal salts. - In this state5 neutral or basic by-products, as well as excess starting materials may be eliminated by the extraction with nonpolar organic solvents, for example diethyl ether, isopropyl ether, carbon tetrachloride, tetrachloroethylene, benzene, toluene, hexane or cyclohexane, as well as benzene. The (1-hydroxyethylidene)-cyanoacetanilides may be precipitated, mostly in crystalline form, by acidification of the aqueousalkaline solution.

The 2-cyano-acetoacetic acid esters of the general formula XVa or XVb required as starting materials are mainly known compounds and may be prepared according to the processes described by Haller and Held, Annales de Chimie [9], 9, 80, (1918), and by Dahn and Hauth, Helvetica chim. Acta 42, 1214 (1959). Moreover, these starting substances are by acetylation, given analogously to the process d) described hereinbefore, .e. by the same method as the acylation of the cyanoacetanilides. Here cyanoacetic acid esters are advantageously acetylated with acetyl chloride or acetanhydride advantageously in the presence of 2 equivalents of a base.

The hydroxyalkylidene-cyanoacetic acid anilides of the general formulae Ia and Ib are acid compounds5 which according to their NMR spectra, are present mainly in the enol form Ia. The addition of Fecal3 produces a brown-red to claret coloured reaction.

If in one of the above processes the compounds Ia and/or Ib are first obtained in the form of their alkali metal, alkaline-earth metal or ammonium salts or as salts of organic bases and are in solution, these salts of the compounds I may optionally be purified by recrystallisation after evaporating the solvent(s) used. Moreover, salts of these compounds may be prepared by the addition of equimolar amount of a suitable base, advantageously with the additional use of solvent(s) inert to the base to a compound of the general formula Ia or Ib. These salts may be isolated after the evaporation of the solvent or by the addition of other solvents which lead to salt separation. As bases, there may be considered sodium, potassium, calcium, magnesium alcoholates of low alcohols, sodium, potassium, calcium, magnesium or ammonium hydroxides, sodium, potassium, calcium, magnesium or ammonium carbonate or bicarbonates as well as sodium amide, or organic bases, for example tertiary amines. When alkali metal or alkaline earth metal alcoholates are used, it is advantageous to work in the presence of a lower alcohol, while optionally using solvents. If the above-mentioned hydroxides, carbonates and/or bicarbonates are used as bases, it is advantageous to work in the presence of water and/or of lower alcohols, while optionally also using other organic solvents.

Preferred bases are sodium or potassium methylate or ethylate, potassium tertiary butylate, sodium, potassium or ammonium hydroxide, sodium or potassium carbonate or bicarbonate, ammonia or sodium hydride.

The compounds of the general formulae Ia and Ib of the invention exhibit strong anti-inflammatory and analgesic effects. The anti-inflammatory effects were demonstrated by means of the Carrageenin paw edema test (Winter, C. A. et al.,Proc.Soc.Exp.

Biol.Med. 111, 544 (1962) and an adjuvant arthritics in rats (Pearson, C. M., Wood, F. D.-Arthrit Rheumat. 2, 440 (1959)).

The analgesic effects were demonstrated by means of the writhing test in mice (Siegmund, E. et al.-Proc.Soc.Exp.Biol.Med. 95, 729 (1957) and by means of the Randall-Selitto test in rats (Randall, L. O. Selitto, J. J.-Arch. int. Pharmacodyn.

111,409(1957)).

A hydroxyethylidene-cyanoacetic acid anilide of the general formula Ia and/or Ib and/or a physiologically tolerable salt thereof preferably a sodium, potassium, magnesium, calcium or ammonium salt, may be the active ingredient of anti-inflammatory as well as analgesic compositions which may be used for the treatment of inflammations and pain in humans and vertebrates. Such an active ingredient is generally in the form of a pharmaceutical preparation e.g. in admixture or conjunction with a pharmaceutically suitable carrier, for example, solid preparations, for example, tablets, dragees, capsules and suppositories, and liquid preparations, for example, solutions in water, and sterile injection solutions. Such preparations may comprise 390% of the active ingredient.

The intermediate products of the general formulae IV and VI obtained in the process of the invention also exhibit anti-inflammatory and analgesic effects to various degrees. As both these compounds are the directly preceding stage of the preparation the compounds of the general formula Ia or Ib of rhe invention which have a strong anti-inflammatory and/or analgesic effect, i.e. they are the esters and amines respectively, their effects is identifiable in connection with that of the latter compounds.

Moreover, the compounds of the general formula Ia or Ib also exhibit anthelmintic, antimycotic and fungicidal effects.

The compounds of the general formula Ia or Ib of the invention may also serve as intermediates for the preparation of other pharmacologically and/or chemotherapeutically active compounds. The same is also true for the compounds of the general formula IV and VI.

The following Examples illustrate the invention. The term "DC" used herein refers to this layer chromatography.

EXAMPLE 1.

Hydroxyethylidene- cyanoacetic acid 3 -chloroanilide. a) Ethoxyethylidene-cyanoacetic acid 3-chloroanilide.

A mixture of 117 g (0.6 mol) of cyanoacetic acid 3-chloroanilide, 150 g (0.93 mol) of orthoacetic acid triethyl ester, 190 g (1.86 mols) of acetonhydride and 60 mg of anhydrous zinc chloride were boiled under reflux for 3 hours, whilst stirring. Then the most volatile moieties were distilled off in the course of 2.5 hours at a bath tem- perature of 1200 C over a 13 cm high Vigreux column. After cooling and standing overnight, the separated crystalline substance was isolated by suction-filtration. After washing with diethyl ether and drying 100 g of crystalline substance were obtained.

After diluting with diethyl ether a further 11 g of crystals were obtained from the filtrate. These crystalline products still contained proportions of the cyanoacetic acid 3-chloroanilide and were therefore boiled with 300 ml of CHols. The CHCI3 extract was then separated from the undissolved solid substance whilst hot. While cooling, 32 g of pure ethoxyethylidene-cyanoacetic acid 3-chloroanilide precipitated as uniform compound (Z- or E-form) from the extract in the form of crystals. The proportion remaining undissolved in CHCl,, was extracted twice in the same manner with CHIC1, (300 ml or 150 ml). A further 30 g of the above compound were obtained from the CHCIs extracts, whilst cooling. 4 g thereof remained undissolved and represented, according to the DC, almost pure ethoxyethylidene-cyanoacetic acid 3-chloroanilide which also contained traces of the starting material. The combined CHCl8 mother lyes were concentrated to about 300 ml, and the precipitate formed as a result was suction filtered. The precipitate represented a mixture of reaction product and starting anilide. About 100 ml of diethyl ether were added to the filtrate, whereafter 26 g of almost pure ethoxyethylidenecyanoacetic acid 3-chloro anilide precipitated as crystals in the form of the stereoisomer mixture. This proportion was purified by recrystallisation from CHCls. A total of 66 g (# 41.5% yield) of ethoxyethylidene-cyanoacetic acid 3-chloroanilide were obtained in the form of the pure Z- or E-stereoisomer (melting point 165 C to 1660 C) and 22 g (1 14% yield) as stereoisomer mixture (melting point 121" C to 123 C).

Analysis: C13111,ClN2O2 Calculated: C 59.0%; H 4.9%; Cl 13.4%; MW 264.7 Found: C 59.0%; H 4.9%; Cl 13.7%; MW 264; 266 (by mass spectroscopy). b) Hydroxyethylidene-cyanoacetic acid 3 -chloroanilide.

150 ml of 4 N sodium hydroxide solution were added to 26.5 g (0.1 mol) of the ethoxyethylidene compound prepared under (a) and the mixture was heated at 759 C for 10 minutes, whilst stirring. After adding 400 ml of water, the mixture was allowed to cool to 200 C, it was filtered over kieselguhr and the filtrate acidified to a pH of 1. The crystalline precipitate was suction filtered, washed with water until it was free of the salt and was neutral, it was then dried. 22.5 g ( 95 /O yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloroanilide (melting point 1690 C to 1700 C) were obtained.

The IR spectrum of this compound was identical w

EXAMPLE 3.

Hydroxyethylidene-cyanoacetic acid 3,4-dichioroanilide. a) Ethoxyethylidene-cyanoacetic acid 3 A-dichloroanilide.

A mixture of 115 g (0.5 mol) of cyanoacetic acid 3,4-dichloroanilide, 110 g (0.675 mol) of orthoacetic acid triethyl ester, 128 g (1.25 mols) of acetanhydride and 50 mg of zinc chloride were boiled under reflux at a bath temperature of 1150 C for 2.5 hours. The most volatile components were distilled off over a 20 cm Vigreux column, whilst stirring over a period of time of 2 hours at a bath temperature of 118 C to 1200 C. The reaction mixture entirely crystallised after cooling and standing for 10 hours, was diluted with isopropyl ether and then suction filtered.

The solid substance (134 g) washed out with the ether represented according to the DC, a mixture of both stereoisomers of the ethoxyethylidene compound and non-reacted starting anilide. The product was dissolved in 650 ml of boiling CHCl,, 200 ml of ether were added and the product which had precipitated as crystals, was suction filtered. 61 g of a pure stereoisomer (Z- or E-form) of the ethoxyethylidenecyanoacetic acid 3,4-dichloroanilide [3-ethoxy-2-cyano-crotonic acid 3,4-dichloro- anilide] (=A 41% yield and a melting point of 1550 C to 1570 C) were obtained.

Analysis: Ct3Hl2C12N202 Calculated: C 52.0%; H 4.4%; Cl 23.6%; N 9.4%; MW 299.2 Found: C 52.0%; H 3.9%; C124.0%; N 9.4%; MW 298; 302 (by mass spectroscopy).

The CHCl,/ether mother lye was evaporated and the residue was boiled out with 700 ml of CCl4. 26 g of cyanoacetic acid 3,4-dichloroanilide remained in the undissolved state. The CCl4-extract was evaporated. The residue was dissolved in 200 ml of CHCI,, amounts of undissolved matter were filtered off and 50 ml of ether were added to the filtrate. Thereupon 9 g of the other pure stereoisomer (E- or Z-form: the stereoisomer in question has the greater R-value in the DC; eluent CH2CI2/C2H5OH 10:1, silica gel prefabricated plates-Merck F 254), having a melt- ing point of 159 to 161" C (= 6% yield), precipitated as crystals. The compound showed the correct values on analysis to correspond to the molecular formula. b) Hydroxyethylidene-cyanoacetic acid 3,4-dichloroanilide 25.5 g (94% yield) of hydroxyethylidene-cyanoacetic acid 3,4-dichioroanilide (melting point: 208 to 2100 C) were obtained from 30 g (0.1 mol) of the ethoxyethylidene compound when proceeding in the manner analogous to that described in Example (1b).

EXAMPLES 4 to 8.

According to the method described in Examples 2a and 3a respectively the following compounds were obtained: Ethoxyethylidene-cyanoacetic acid [3-(1,1,2-trifluoro-2-chloro-ethoxy)-anilide], C1,H14ClF,N2Os, melting point: 102" C to 103 C (Z- or E-form), yield: 21%.

Ethoxyethylidene-cyanoacetic acid 3-bromoanilide, C13H13BrN2O2, melting point 1960 C to 1970 C, (Z- or E-form), yield: 50%.

Ethoxyethylidene-cyanoacetic acid 4-methoxyanilide, Cl,Hl6N203 melting point: 166 C to 1670 C (Z- or E-form), yield: 30%.

Ethoxyethylidenesyanoacenc acid 3-chloro-2-methylanilfde, CuH1ClN2O2, melting point: 171" Cto 173 C (Z- or B-form), yield: 42%.

EthGxyethylidene-cyanoacetic acid 5 -chloro-2-methylanilide, C14H15ClN2O2, melting point: 208 to 2100 C, (Z- or E-form), yield: 72%.

Methoxyethylidene-cyanoacetic acid 3-chloronilide (as the additional preliminary compound for the hydroxyethylidene compound to be prepared according to Example lb) C12H12C1H2O2, melting point: 118 to 1200 C (E- or Z-form), yield: 7%.

Melting point 1570 to 1580 C (Z- or E-form), yield: 10%.

The separation of the two stereoisomers and of minor portions of the cyanoacetic acid 3-chloroanilide was advantageously effected by means of column chromatography on silica gel (Merck) using methylene chloride/benzene in a ratio of 1:1, in which case the column is then eluted with CH2CI2. The composition of the eluted fractions has been determined by thin-layer chromatography. The compounds were eluted in a) sterecisomer having a low melting point b) stereoisomer having a higher melting point c) cyanoacetic acid 3-chloroanilide.

The ethoxyethylidene compounds above were converted into the corresponding 2hydroxyethylidene-cyanoacetanilides according to the method described in Example ( lob) i.e. gave Hydroxyethylidene - cyanoacetic acid [3 - (1,1,2 - trifluoro - 2 - chloro ethoxy) - anilide], melting point: 1400 to 1410 C.

Hydroxyethylidene - cyanoacetic acid 3 - bromoanilide, melting point: 1780 to 1790 C.

Hydroxyethylidene - cyanoacetic acid 4 - methoxyanilide, melting point: 151 to 152" C.

Hydroxyethylidene - cyanoacetic acid 3 - chloro - 2 - methylanilide, melting point: 1640 Coo 1650 C.

Hydroxyethylidene - cyanoacetic acid 5 - chloro - 2 - methylanalide, melting point: 127 to 129 C.

EXAMPLE 9.

8 ml of methanol and 70 ml of 0.5 N sodium hydroxide solution were added to 560 mg (2 mmols) of ethoxyethylidene-cyanoacetic acid 5-chloro-2-methylanilide and the mixture was stirred for 30 minutes at 650 C. After filtering the solution over kieselguhr, the filtrate was acidified with sulphuric acid, the precipitate was suctionfiltered, it was then washed with water until free of salt and was dried. 465 mg ( 93% yield) of hydroxyethylidene-cyanoacetic acid 5-chloro-2-methylanilide (melting point: 128 to 129 C) were obtained.

EXAMPLE 10.

Dimethylaminoethylidene-cyanoacetic acid 3-trifluoromethylanilide.

A gas stream of dimethylamine was introduced while stirring until oversaturation at 30 to 46" C into a mixture of 20.0 g (0.07 mol) of ethoxyethylidene-cyano- acetic acid 3-trifluoromethylanilide and 80 ml of 1,2-dimethoxyethane. The solution obtained was stirred for 1 hour while allowing a weak dimethylamine stream to pass through and was then evaporated in vacuo. The remaining residue was suspended in diethyl ether, suction filtered and washed with diethyl ether. After drying, 16 g ( ~ 80% yield) of dimethylaminoethylidene-cyanoacetic acid 3-trifluoromethyl- anilide [2-cyano-3-dimethylamino-crotonic acid 3-trifiuoromethylanilide] (melting point 127 to 1280 C) were obtained.

Analysis: C14H14F,N8O Calculated: C 56.6%; H 4.7%; F 19.2%; N 14.1%; MW 297.3 Found: C 56.3%; H 4.7%; F 19.5%; N 14.2%; MW 297 (by mass spectroscopy).

By this method, the following compounds were prepared: Dimethylaminoethylidine - cyanoacetic acid 3 - chloronilide, C1,H14ClN,O (MW 263.7), melting point: 146 to 1480 C.

Dimethylaminoethylidene - cyanoacetic acid 3 - bromoanilide, C1,H14BrN,O (MW 308.2), melting point: 141 to 142" C (from ethyl acetate).

Dimethylaminoethylidene - cyanoacetic acid 3 - chloro - 2 - methylanilide C,4H16ClN,O (MW 277.8), melting point: 142" to 143 C (from 1,2-dimethoxyethane).

EXAMPLE 11.

(4-Methyl-piperazinoethylidene) -cyanoacetic acid 3-trifluoromethylanilide.

A solution of 5.3 g (0.053 mol) of N-methylpiperazine in 10 ml of 1,2-dimethoxy- ethane was added dropwise within 15 minutes, at 300 C, to a mixture of 15 g (0.05 mol) of 2-ethoxyethylidinecyanoacetic acid 3-trifiuoromethylanilide and 100 ml of 1,2dimethoxyethane and the mixture was stirred at 450 C for 1 hour, whereby a solution was obtained. This solution was evaporated in nacuo. The residue crystallised by adding diethyl ether. The mixture was boiled and the crystals (11 g) were suction filtered.

After concentration and the addition of isopropyl ether, a further 4.5 g of crystalline compounds were isolated from the filtrate. The crystals were recrystallised from CC14.

12.4 g (70.5% yield) of pure (4-methyl^piperazinoethylidene)-cyanoacetic add 3- trifluoromethylanilide (melting point: 1290 to 1300 C) were obtained.

Analysis: Cl7Hl9F3N4O Calculated: C 58.0%; H 5.4%; F 16.2%; N 15.9%; MW 352.4 Found: C 58.0%; H 5.2%; F 15.8%; N 15.6%; MW 352 (by mass spectroscopy).

By this method the following were also prepared: Piperidinoethylidene-cyanoacetic acid 3-chloroanilide, C16H1sCIN3O (MW 303.8), melting point: 1380 to 1390 C (from ethyl acetate).

Piperidinoethylidene-cyanoacetic acid 5-chloro-2-methylanilide C1'H20ClN,O (MW 317.8), melting point: 133 to 134" C (from ethyl acetate).

EXAMPLE 12.

A mixture of 9 g (0.03 mol) of dimethylaminoethylidene-cyanoacetic acid 3trifluoromethylanilide, 60 ml of ethanol and 200 ml of 2 N hydrochloric acid was stirred at35" C for 4.5 hours. Then, the solid matter was suction filtered, washed with water until free of salt and until neutral and then dried.

8.0 g ( 99% yield) of hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point: 179 to 1800 C) were obtained.

By this method the following were prepared: a) from piperidinoethylidene - cyanoacetic acid 3 - chloronilide the hydroxyethylidene cyanoacetic acid 3 - chloroanilide, melting point: 1700 to 1710 C (94% yield), b) from (4 - methylpiperazinoethylidene) - cyanoacetic acid 3 - trifluoromethylanilide the hydroxyethylidene - cyanoacetic acid 3 - trifluoromethylanilide, melting point: 179 to 1810 C (98% yield), c) from dimethylaminoethylidene - cyanoacetic acid 3 - bromoanilide the hydroxyethylidene - cyanoacetic acid 3 - bromoanilide, melting point: 1780 to 1790 C (96% yield).

EXAMPLE 13.

A mixture of 4.5 g (0.015 mol) of dimethylarninoethylidene - cyanoacetic acid 3-trifluoromethylanilide, 70 ml of etnanol and 400 ml of 0.1 N hydrochloric acxel was stirred at 300 C for 10 hours it was then suction filtered. The crystalline sub stance, which was washed with water until neutral and dried, had a weight of 3.7 g ( 91.5% yield) and was pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl anilide (melting point: 1790 to 1810 C).

EXAMPLE 14.

A solution heated to 380 C, which had been obtained by dissolving 56 g (0.2 mol) of piperidinoetliylidene-acetic acid 3-chloroanilide with CH2Cl2 and making up to a volume of 1600 ml, also with CH2Cl2 and a solution which had been obtained by dissolving 28.3 g (0.2 mol, 17.36 ml) of chlorosulphonylisocyanate with CH2C12 and making up to 400 ml, also with CH2Cl2, were added regularly dropwise; at 300 to 200 C to 50 ml of CH2CI2 whilst stirring, over 2.5 hours with an exclusion of humidity in a drop ratio of 4:1. Then, the mixture was stirred for 20 minutes at --20" C, for 20 minutes at .290 C to 0 C and for 1 hour at 0 to +2 C. After cooling the solution to 100 C, a solution of 42 ml of dimethylformamide in 40 ml of CH2C12 was added dropwise and at that temperature and then the whole solution was stirred at 0 C for 30 minutes. 11 g of Triethyl amine were added dropwise, at --20" C, to the reaction solution. The mixture was heated to room temperature whilst stirring and then, at that temperature, it was evaporated in vacuo. The viscous oily residue (about 96 g) was introduced dropwise, at room temperature, into a solution of 34 g of sodium bicarbonate in 2 1 of water. After stirring for 30 minutes, the aqueous solution was drawn off from the separated, viscous, hydrophobic mass and was taken up in CH2Cl,. The methylene chloride solution was shaken three times with about 100 ml of water and dried with Na2SO4. After filtration, the solution was evaporated in vacuo and the residue (53 g) was dissolved in ethylacetate/benzene (3:1) to give a concentrated solution. The solution was filled in a silica gel column (Merck) (height: 55 cm, 4.7 cm); the column was eluted with that mixture and 100 ml fractions were collected at its outlet The first 4 fractions contained only oily byproducts. In the 5th to 8th fraction crystalline residues (24 g in total) were obtained after evaporating the solvents. They were recrystallised from an ethylacetate/diethyl ether/isopropyl ether mixture, whereby 12.8 g of pure piperidino-cyanoacetic acid 3-chloroanilide (melting point 138 to 1390 C) were obtained. The 9th and 10th fraction of the chromatography contained 4 g of partially crystalline product, which was dissolved in the mother lyes of the recrystallisation process and yielded, after concentration and further recrystallisation, another 2.2 g of the anilide (melting point 137 to 1380 C). The anilide was obtained in a yield of 25%.

In the same manner, starting from 5,8.6 g (0.2 mol) of piperidino-ethylideneacetic acid 5-chloro-2-methylanilide, 18.2 g (= 29% yield) of piperidinoethylidene-cyanoacetic acid 5-chloro-2-methylanilide (melting point 133 to 134" C) and starting from 48 g (0.2 mol) of dimethylaminoethylidene-acetic acid 3-chloroanalide, 5.8 g ( & 11% yield) of dimethylaminoethylidene-cyanoacetic acid 3-chloroanilide (melting point 146 to 1480 C) were obtained. In the latter case, there was also obtained a crystalline by-product in a remarkable quantity, which in the chromatography described, was detected shortly before the desired anilide. The first fractions of the chromatography were mixtures of both compounds and these fractions which were subjected to a second column chromatography, whereby a partial separation of the substances was achieved, these substances being then further purified by recrystallisation. The by-product had a melting point of 1600 to 161" C. Because of the difficulties mentioned, the yield of the desired anilide was considerably reduced in this synthesis.

EXAMPLE 15.

190 mg (1 mmol) of p-toluene-sulphonic acid-hydrate was added to a solution of 5.5 g (30 mmols) of 2-cyanoacetic acid-tert.-butyl ester in 60 ml of benzene and the mixture was stirred under reflux for 1 hour. After the addition of 3 drops of water, the mixture was heated for a further 2.5 hours under reflux. Small portions of crystalline substance (2-cyano-acetoacetic acid) were filtered off and the filtrate was evaporated in vacuo at a bath temperature of 300 C. A colourless oil resulted therefrom which contained crude cyanoacetone (87% according to GC). To this product, 4.67 g (25 mmols) of 3-trifiuoromethylphenylisocyanate and 50 ml of CH2Cl2 were added. 2.74 g (27 mmols) of triethylamine were added dropwise to the solution, whilst stirring within 6 minutes. The solution which was heated so as to nearly reach the boiling point, was boiled under reflux for 1 hour and then evaporated in vacua 40 ml of water and 10 ml of methanol were added to the residue, the mixture was thoroughly shaken and then acidified with 6 N hydrochloric acid. A precipitate was produced which turned to a crystalline mass in a short time. The admixture of ethanol gave a suspension which was suction filtered. The filter residue was washed with a water/methanol mixture having a ratio of 3:1 and then with a little amount of methanol and was finally dried. 5.65 g ( 70% yield, calculated on cyanoacetic acid fert.-butyl ester) of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 181" to 182" C) were obtained.

EXAMPLE 16.

By the method described in Example 15 and starting from 5.5 g (30 mmols) of cyanoacetic acid-tert.-butyl ester, 3.2 g of crude, benzene-containing cyanoacetone were obtained, which also contained about 1 mmol of p-toluene-sulphonic acid. This product was dissolved in 25 ml of anhydrous tetrahydrofuran and introduced dropwise, at +5 C to + 120 C, whilst stirring, and an exclusion of humidity, into a mixture of 900 mg of 80% sodium hydride-oil-suspension (30 30 mmols of NaH) in 40 ml of absolute tetrahydrofuran. Then, a solution of 5.8 g (29 mmols) of 3-bromophenylisocyanate in 40 ml of tetrahydrofuran, was added to the mixture at 0 to +5 C, while stirring and the mixture was stirred for 30 minutes at 50 C. After exaporating the reaction mixture in vacuo, 40 ml of ice water and 10 ml of methanol were added to the residue and the mixture was shaken, then 5.5 ml of 6 N hydrochloric acid were added. The precipitate was recrystallised. The addition of ethanol brought the precipitate, which was first in a partially oily state, into a form suitable for being suction filtered. After suction-filtering, the filter residue was washed with ethanol/ water (1:1) and recrystallised from methanol. 4.3 g (51% yield, calculated on cyanoacetic acid-tert.-butyl ester) of pure hydroxyethylidene-cyanoacetic acid 3-bromoanilide (melting point 178 to 1800 C) were obtained.

EXAMPLE 17.

As described in Example 15 and starting from 5.5 g (30 mmols) of cyanoacetic acid-tert.-butyl ester, 3.1 g of crude - cyanoacetone were prepared. It was dissolved in 20 ml of anhydrous acetonitrile and introduced dropwise into a mixture ot 850 mg of 80% NaH-oil-suspension and 50 ml of acetonitrile at about 0 C whilst stirring.

Then, a solution of 3.7 g (27 mmols) of 4-fluorophenylisocyanate in 20 ml of absolute acetonitrile was added dropwise to the mixture at room temperature, whilst stirring.

The temperature was allowed to rise to 35 C, the mixture was further stirred at 350 C for 1 hour and then evaporated in vacuo. The residue was worked up as described in Example 16. After recrystallising the crude product, from ethanol and a little water, 3.60 g ( ^- 55% yield) of pure hydroxyethylidene-cyanoacetic acid 4-fluoroanilide (melting point 1700 to 1710 C) were obtained.

EXAMPLE 18 to 22.

By the methods described in Examples 15 and 16, the following were prepared: Hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point 2070 to 2090 C) yield 55%.

Hydroxyethylidene-cyanoacetic acid 3,4-dichloroanilide (melting point 209 to 2100 C) yield 57%.

Hydroxyethylidene-cyanoacetic acid 2-ethoxyanilide (melting point 110 to 1110 C) yield 32%.

Hydroxyethylidene-cyanoacetic acid 2,4-dichioroanilide (melting point 140 to 141" C) yield 56%.

Hydroxyethylidene-cyanoacetic acid 4-chloro-2-trifiuoromethylanilide (melting point 1310 to 133 C) yield 51%.

EXAMPLE 23.

Hydroxyethylidene-cyanoacetic add 3-trifluoromethylanilide.

A solution of 11.4 g (0.05 mol) of cyanoacetic acid-(3-trifluoromethylanilide) in 50 ml of absolute dimethoxyethane was added dropwise whilst stirring at 10 to 250 C, to a mixture of 3.31 g of 80% sodium hydride-oil-suspension (0.11 mol of NaH) and 5 ml of dry 1,2-dimethoxyethane. After the gas evolution had ceased, a solution of 4.33 g (0.055 mol) of acetyl chloride in 15 ml of absolute dimethoxyethane was added dropwise at -5 to 0 C. The reaction mixture was stirred for 30 minutes ar 0 to +270 C and at 25 to 330 C and 62 to 65" C for 1 hour respectively and then evaporated in vacuo. 300 ml of water were added to the residue and the soludon was shaken for 30 minutes at room temperature. The product was dissolved except for a small portion. The product was then filtered over kieselguhr and the filtrate was acidified with dilute hydrochloric acid. The crystalline precipitate was suction filtered, washed with water until free of salt and until neutral, washed with a 2:1 methanol/water mixture and dried. 9.7 g (= 727 yield) of hydroxyethylidenecyanoacetic acid 3-uifluoromethylanilide (melting point 1790 to 1810 C) were obtained. 9 g of pure compound (melting point 1810 to 1820 C) were obtained from this product by recrystallisation from methanol.

When proceeding according to the method described in Example 23, the hydroxy ethlidene-cyanvacetic acid anilides listed in the following Table 1 were obtained in the yield indicated.

TABLE 1 Hydroxyethylidene-cyanoacetic acid anilides

No. R' R2 Mp. ( C) Yield in Ck 1 3-Cl H 168-169 73 2 3-1 H 198-200 64 3 4-Br H 208-209 73 4 4-F H 170-171 69 5 4-OCH3 H 150-152 57 6 2-oc2Hs H 109-111 43 7 3-C1 4-Cl 209-210 74 8 2-Cl 4-Cl 140-141 65 9 2-CH3 3-C1 164165 71 10 3-SCH3 H 135-136 62 11 2-CH3 3-Cl 127-128 73 12 3,4-O-CH2O 166-167 40 13 3-1 H 207-208 70 EXAMPLE 24.

Hydroxyethylidene-cyanoacetic acid 3-bromoanilide.

A solution of 12 g (0.05 mol) of cyanoacetic acid 3-bromoanilide in 100 ml of absolute tetrahydrofuran was added dropwise, whilst stirring at 100 to 25 C, to a mixture of 3.6 g of 80% sodium hydride-oil suspension (= 0.12 mol of NaH) and 10 ml of dry acetonitrile. After the hydrogen evolution had ceased, 4.35 g (about 0.055 mol) of acetylchloride were added dropwise at 100 to 0 C and the mixture was stirred at 0 to +280 C, at 28 to 250 C and at 620 to 650 C for 1 hour respectively.

Then, the reaction mixture was evaporated in vacuo, and the residue was worked up as described in Example 23. 10.1 g (# 72% yield) of pure hydroxyethylidenecyanoacetic acid 3-bromoanilide (melting point 1780 to 179 C) were obtained.

EXAMPLE 25.

9.45 g (0.12 mol) of acetyl chloride were added dropwise, while stirring at 2700C, to a mixture of 23.9 g (0.1 mol) of cyano-acetic acid 2-bromoanilide, 16.6 g (0.12 mol) of dry, pulverised K2CO3 and 100 ml of dry acetone. After stirring for 1 hour at 27 to 300 C and for 2.5 hours under reflux, the acetone was eliminated in vacuo and the residue was extracted with water. About 15 g ( (h-- 63%) of start- ing analide remained in an undissolved state. The aqueous extract was filtered and slightly acidified with dilute sulphuric acid. A crystalline precipitate was obtained which was recrystallised from methanol after suction filtering and washing with a 1:2 water/methanol mixture. After drying, 8.4 g ( 30% yield) of pure hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point 208 to 2090 C) were obtained.

EXAMPLE 26.

A solution of 4.1 g (0.052 mol) of acetyl chloride in 10 ml of toluene was added dropwise to a mixture of 11.4 g (0.or mol) of cyanoacetic acid 3-trifluoromethylanilide, 7.6 g (0.035 mol) of K2CO, and 150 ml of toluene whilst stirring at 700 C.

Then, the mixture was stirred for 1 hour at 900 C, cooled and the solid substance suction filtered and washed with 100 ml of toluene. The dried product was then extracted with water. The filtered aqueous extract was slightly acidified with dilute hydrochloric acid and the precipitate was suction filtered. After washing with water, it was recrystallised from methanol. 5.3 g ( 39% yield) of pure hydroxyethylidenecyanoacetic acid 3-trifluoromethylanilide (melting point 180 to 1820 C) were obtained.

The portion of solid substance (5.2 g) which had not been dissolved in water, mainly contained starting anilide according to DC.

EXAMPLE 27.

Hydroxyethylidene-cyanoacetic acid 5-chloro-2-methylanilide.

A solution of 4.35 g (0.55 mol) of acetyl chloride in 5 ml of 1,2-dimethoxyethane was added dropwise, at 35" C, over 25 minutes, to a mixture of 10.5 g (0.05 mol) of cyanoacetic acid S-chloro-2-methylanilide, 12.3 g (0.11 mol) of potassiumtert.-butylate and 150 ml of dry dioxane and the mixture was stirred at 900 C for 2 hours. After evaporating the solvent in vacuo, the residue was extracted with 300 ml of water. A crystalline precipitate was separated from the filtered aqueous extract upon being acidified with dilute hydrochloric acid. It was suction filtered, washed out and dried as described in Example 23. 6.4 g (51% yield) of hydroxyethylidenecyanoacetic acid 5-chloro-2-methylanilide (melting point 127 to 1280 C) were obtained.

EXAMPLE 28.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide.

At 10 to 200 C in 25 minutes, a solution of 11.4 g (0.05 mol) of cyanoacetic acid 3-trifluoromethylanilide in 50 ml of absolute dimethoxyethane and after the hydrogen evolution had ceased ID

*TABLE 2

No. R R Yield in % 1 3-Cl H 72 2 3-I H 63 3 4-F H 73 4 2-Cl 4-Cl 71 5 3CH, H 52 6 2-CH3 5-Cl 72 7 3,4-O-CH2-O- 35 8 4-OCH, H 40 9 2-CF, 4-Cl 51 EXAMPLE 30.

Hydroxyethylidene-cyanoacetic acid 3 -trifluoromethyl anilide.

Using the method described in Example 29 with the difference that 16.6 g (0.16 mol) of anhydrous sodium carbonate solution are used instead of 16.6 g of K2C08, 10.0 g (= 37 % yield) of hydroxyethylidene-cyanoacetic acid 3-trifluoro methylanilide (melting point 175 to 176 C) were obtained. In this method, the extraction of the reaction product with water left a considerable portion (13.5 g) in the undissolved state, which consisted according to the DC, to a large extent of nonreacted starting material.

EXAMPLE 31.

Hydroxyethylidene-cyanoacetic acid 3 -trifluoromethylanilide.

Following the method described in Example 29, 0.1 mol of cyanoacetic acid 3 trifluorcmethylanilide in dimethoxyethane were reacted in the presence of 16.6 g of K2CO3 with 14.3 g (0.14 mol) of acetanhydride and the mixture was further stirred at 90" C for 1 hour. After evaporating the mixture so obtained, the residue was mixed with water, the solution was filtered over kieselguhr and the filtrate acidified.

After suction filtering, the precipitate was washed successively with water, a 1:3 water/ methanol mixture and methanol and dried. 19.8 g (= 73% yield) of practically pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide- (melting point 178 to 1790 C) were obtained.

EXAMPLE 32.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide.

10.2 g (0.1 mol) of acetanhydride were introduced dropwise, at room temperature, whilst stirring, in a mixture of 22.8 g (0.1 mol) of cyanoacetic acid 3-trifluoro- methylanilide, 15.2 g (0.11 mol) of K2CO, and 100 ml of ethyl acetate and the mixture was stirred for 1 hour at room temperature and for 2 hours under reflux.

After evaporating the mixture in vacuo, the residue was worked up as described in Example 29. After recrystallisation of the crude product from methanol, 1.7 g ( 6.3 % yield) of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl- anilide (melting point 181 to 1820 C) were obtained.

EXAMPLE 33.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl anilide.

10.2 g (0.10 mol) of acetanhydride were added dropwise, at 700 C, whilst stirring thoroughly, to a mixture of 22.8 g (0.10 mol) of cyanoacetic acid 3-trifluoromethylanilide, 15.2 g (0.11 mol) of K2CO3 and 200 ml of toluene. Then the mixture was stirred for 1 hour at 90" C, it was cooled to about 15 C and the solid substance was suction filtered. It was washed out with ethyl acetate and a small amount of water.

The portion that remained in the undissolved state (9 g) consisted of the potassium salt of the hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 215 to 2170 C and a yield of 29%). 3 g of free hydroxy compound (melting point 166 to 1680 C and an = 11% yield) were precipitated from the washing water with dilute hydrochloric acid.

EXAMPLE 34.

Hydroxyethylidene-cyanoacetic acid 4-bromoanilide.

10.5 g (0.104 mol) of triethylamine were added dropwise at room temperature, whilst stirring, to a mixture of 12 g (0.050 mol) of cyanoacetic acid 4-bromoanilide, 5.2 g (0.051 mol) of acetanhydride and 50 ml of absolute 1,2-dimethoxyethane, the temperature slowly rising to 300 C. The mixture was stirred for 2 hours at 30 C and for 2 hours at 80" C and the mixture was evaporated in vacuo. The residue was a dark oil which was mixed with ethyl acetate. The solution formed was shaken successively 8 times with water and dilute sodium carbonate solution, respectively. All of the aqueous extracts were combined and slightly acidified with hydrochloric acid.

The precipitate was suction filtered, successively washed with water and a 3:1 methanol/water mixture and recrystallised from methanol, whereby 5.9 g (= 42% yield) of pure hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point 208 to 2090 C) were obtained.

EXAMPLE 35.

Hydroxyethylidene-cyanoacetic acid 3-chloroanilide.

A solution of 9.73 g (0.05 mol) of cyanoacetic acid 3-chloroanilide in 80 ml of absolute dimethoxyethane was added dropwise at 10 to 200 C to a mixture of 3.31 g of 80% sodium hydride-oil-suspension ( / 0.11 mol of NaH) and 10 ml of dry 1,2-dintethoxy ethane. After the hydrogen evolution has ceased, a solution of 5.3 g (0.06 mol) of ethyl acetate in 100 ml of dimethoxyethane was added dropwise, at 0 C to 5 C, whilst stirring, and the mixture was further stirred for 20 minutes at 5 to 280 C and for 1.25 hours at 700 to 750 C. Then. the mixture was evaporated in vacuo, and to the residue were added 150 ml of water; then the mixture was shaken.

The solution was extracted with; 100 ml of diethyl ether. After separating the phases, the aqueous phase was slightly acidified with dilute hydrochloric add and the precipitate was suction filtered and washed with a 6:1 methanol/water mixture and dried. 9.7 g ( . 82% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloro- anilide (melting point 168 to 1690 C) were obtained.

After concentration 1 g (8.5 yield) of product (melting point 165 to 167 C) was isolated from the washing water. When, instead of 5.3 g of ethyl acetate, 7.5 g (0.55 mol) of phenyl acetate were used, 9.3 g (A 79% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloroanilide were obtained by the same method.

EXAMPLE 36.

Hydroxyethylidene-cyanoacetic acid 3 -chloroanilide.

A solution of 9.73 g (0.05 mol) of cyanoacetic acid 3-chloroanilide in 50 ml of absolute dimethoxyethane was added dropwise, at room temperature, to a mixture of 6.0 g (0.11 mol) of sodium methylate and 25 ml of absolute 1,2-dimethoxyethane.

To the mixture so obtained, a solution of 5.6 g (0.ops mool) of acetanhydride in 10 ml of absolute dimethoxyethane was added dropwise, at 70 to 0 C, whilst stirring, and the total mixture was stirred for 30 minutes at 0 C and then at 30 to 350 C and at 65 to 70" C for 1 hour respectively. Then, the reaction mixture was evaporated in vacuo, and the residue was taken up in a mixture of 150 ml of water and 25 ml of 2 N sodium hydroxide solution. The portion that remained in the undissolved state, was suction filtered, and washed with about 200 ml of slightly alkaline water (pH of 11 to 12). The combined, alkaline filtrates were slightly acidified with hydrochloric acid. The precipite was suction filtered and successively washed with water, a 4:1 methanol/water mixture and a litttle methanol and dried.

3.1 g (-^- 26% yield) of hydroxyethylidene-cyanoacetic acid 3-chloroanalide (melting point 167 to 168 C) were obtained.

EXAMPLE 37.

Hydroxyethylidene-cyanoacetic acid 3-chloroanilide.

A solution of 9.73 g (0.or mol) of cyanoacetic acid 3-chloroanilide in 80 ml of methanol was added dropwise, within 5 minutes, at room temperature, to a solution of 2.5 g of sodium in 30 ml of methanol. The mixture was cooled to 0 C and a solution of 4.5 g (0.061 mol) of methyl acetate in 10 ml of methanol was added dropwise, at 0 C for 15 minutes. The reaction mixture was stirred at 0 C to 260 C for 30 minutes and then at 38"--40" C and under reflux (61 C) for 1 hour respectively. Again, 4.5 g (0.061 mol) of methyl acetate were added to the reaction mixture. The mixture was further stirred for 1 hour under reflux. The reaction solution was evaporated in vacuo and a mixture of 150 ml of water and 7 ml of 4 N hydrochloric acid was added to the residue. The solution so obtained, which had a pH value of about 1, was adjusted to a pH of 8 using 6 ml of 2 N acetic acid, whereby a precipitate was formed. This precipitate was suction filtered and washed out with dilute sodium carbonate solution, the portion that remained in the undissolved state was shaken for 1 hour with. 2 N sodium carbonate solution. The suspension so obtained was suction-filtered and the solid substance was washed out successively and thoroughly with 1 N 10 sodium carbonate solution and with water. The sodium carbonate extracts and the washing water as well as the original aqueous filtrate (pH 8) were combined and slightly acidified with hydrochloric acid. The precipitate was suction-filtered and successively washed with water, a 5:1 methanol/water mixture and a little methanol.

After drying, 6.7 g (n 57% yield) of pour hydroxyethylidene-cyanoacetic acid 3chloroanilide were obtained.

EXAMPLE 38.

Hydroxyethylidene-cyanoacetic acid 3 -chloroanilide.

A solution of 9.73 g (0.050 mol) of cyanoacetic acid 3-chloroanilide in 50 ml of absolute dimethoxyethane were introduced at room temperature, whilst stirring, into a mixture of 4.05 g (0.075 mol) of sodium methylate and 10 ml of dry 1,2dimethoxyethane. Then, a solution of 4.5 g (0.060 mol) of methyl acetate in 10 ml of absolute dimethoxyethane was added dropwise, at5 C to 0 C, whilst stirring. The mixture obtained was stirred at 700 C for 15 minutes, at 0 to 25" C for 30 minutes and at 40 C for 1.5 hours and then it was evaporated in vacuo. The residue was taken up in a mixture of 150 ml of water and 2 ml of 4 N hydrochloric acid. The portion that remained in the undissolved state, was suction filtered, and it represented 8.5 g of practically pure starting anilide. 0.5 ml of 4 N hydrochloric acid was added to the filtrate, and the precipitate was suction filtered. This substance was also pure starting anilide (0.4 g). The aqueous filtrate was then slightly acidified with 8.2 ml of 4 N hydrochloric acid, the crystalline precipitate was suction filtered and washed successively with water, a 5:1 methanol/water mixture and a small amount of methanol. After drying, 0.47 g (4% 4% yield) of pure hydroxyethylidene-cyanoacetic acid (3-chloro-anilide (melting point 168 to 1690 C) was obtained.

EXAMPLE 39.

Hydroxyethylidene-cyanoacetic acid 3 -trifluoromethylanilide.

A solution of 22.8 g (0.10 mol) of cyanoacetic acid 3-trifluoromethylanilide in 100 ml of absolute 1,2-dimethoxyethane was added dropwise, at 20 to 25" C to a mixture of 3.3 g (0.11 mol) of 80% sodium hydride-oil-suspension and 10 ml of absolute dimethoxyethane. After the hydrogen evolution had ceased 5+0.5 g of gaseous ketene were introduced at 24 to 270 C, whilst stirring, the apparatus being provided with a reflux cooler filled with dry ice. The mixture was further stirred for 30 minutes at room temperature, then the solvent was evaporated in vacuo. The residue was extracted with water. The filtered, alkaline extract was acidified with dilute sulphuric acid. The precipitate was suction filtered and washed with water, a 4:1 methanol/water mixture and a litttle methanol. After drying, 17:6 g (S 65% yield) of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 180 to 1810 C) were obtained.

EXAMPLE 40.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide.

5+0.5 g (- 0.12 mol) of gaseous ketene were introduced into a mixture of 22.8 g (0.10 mol) of cyanoacetic acid 3-trifluoroanilide, 100 ml of absolute dimethoxyethane and 7.6 g (0.055 mol) of potassium carbonate at room temperature, whilst stirring; and with the use of a reflux cooler filled with dry ice. The mixture was stirred for 1 hour at 250 C and 900 C respectively and then evaporated in vacuo. The residue was worked up as described in Example 39. 17.3 g (=" 64% yield) of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 180 to 1810 C) were obtained.

Hydroxyethylidene-cyanoacetic acid 4-fluoroanilide (yield 65%) and 3-bromoanilide (yield 67%), were prepared in an analogous manner.

EXAMPLE 41.

Hydroxyethylidene-cyanoacetic acid 4-fluoroanilide.

At 18 to 220 C, a solution of 5.85 g (0.030 mol) of acetoacetic acid 4-fluoro- anilide in 40 ml of absolute dimethoxyethane and, after the hydrogen evolution has ceased, at 0 C, a solution of 3.20 g (0.30 mol) of bromocyane in 15 ml of absolute dimethoxyethane, were introduced dropwise, whilst stirring, into a mixture of 190 g (0.063 mol) of 80% sodium hydride-oil-suspension and 15 ml of absolute 1,2dimethoxyethane. Then, the reaction mixture was stirred for 30 minutes at 0 C and at 0 to 28 C respectively and for 1 hour at 56 to 600 C. Then, the solvent was evaporated in vacuo, the residue was thoroughly shaken with a mixture of 100 ml of water and 1.5 ml of concentrated hydrochloric acid and the aqueous phase was separated from the undissolved, resinic mass. Upon acidifying with hydrochloric add, a crystalline precipitate was obtained from the filtered aqueous solution, which was suction filtered and successively washed out with 4:1 methanol/water mixture and a litde methanol. After recrystallisation of the filter residue from methanol, 1.97 g ( .30% yield) of pure hydroxyethylidene-cyanoacetic acid 4-fluoroanilide (melting point 170 to 1710 C) were obtained.

EXAMPLE 42.

Hydroxyethylidene-cyanoacetic acid 3 -bromoanilide.

At 22 to 280 C, a solution of 12.81 g (0.05 mol) of acetoacetic add 3-bromoanilide in 70 ml of absolute dimethoxyethane, and, after the hydrogen evolution has ceased, at -10 to --5" C, a solution of 4.0 g (0.065 mol) of chlorocyane in 15 ml of absolute dimethoxyethane, were added dropwise, whilst stirring, to a mixture of 3.3 g (0.11 mol) of 80% sodium hydride-oil-suspension and 1S ml of absolute 1,2-dimethoxy-ethane. The brown suspension obtained was stirred for 30 minutes at 0 C and for 1 hour at 54 to 560 C and then evaporated in vacuo. The remaining solid residue was thoroughly shaken *ith 150 ml of water. The substance that remained in the undissolved state, was suction filtered, successively washed out with water and diethyl ether and dissolved in a mixture of 160 ml of 1 N sodium hydroxide solution, 250 ml of water and 60 ml of ethanol. After filtration over kieselguhr, the solution was acidified with conc. hydrochloric acid and the precipitate was then suction filtered. After washing out with water and methanol and after drying, it had a weight of 5.35 g (38% yield) and represented pure hydroxyethylidene-cyanoacetic acid 3-bromo-anilide (melting point 179 to 1790 C). The acid aqueous filtrate was extracted three times with methylene chloride. The combined CH2Cl2 extracts were dried with Na2SO4, filtered and evaporated in vacuo. 10 ml of methanol were added to the residue (1.90 g) and the undissolved crystalline material was suction filtered. After drying, this product had a weight of 1.40 g (melting point 178 to 1790 C; 10% yield) and represented pure hydroxyethylidene-compound.

The originally aqueous filtrate was precipitated with diethyl ether and then acidified with hydrochloric add. The precipitate was suction filtered, successively washed out with water and methanol and dried. 4.5 g (=4 32% yield) of pure hydroxyethylidene-cyanoacetic acid 3-bromoanilide (melting point 178 to 1790 C) were obtained. The total yield was 80%.

Hydroxyethylidene-cyanoacetic acid 4-fluoroanilide (yield 73%), 3-trifluoro- methylanilide (yield 71%), 3-chloroanilide (yield 81%) and 3,4-dimethoxyethyleneanilide (yield 22%) were prepared in an analogous manner.

EXAMPLE 43.

Hydroxyethylidene-cyanoacetic acid 3 -chloroanilide.

A solution of 3.20 g (0.030 mol) of bromocyane in 30 ml of absolute dimethoxyethane was added dropwise to a mixture of 6.36 g (0.03 mol) of acetoacetic acid 3-chloroanilide 4.85 g (0.035 mol) of K2CO3 and 60 ml of absolute 1,2-dimethoxy ethane, for 35 minutes, at 18 to 25 C, whilst stirring. After the mixture had been stirred at 27 C and at 40 C for 30 minutes respectively, and at 600 C for 2 hours, the solvent was evaporated in vacuo and the residue was shaken with 100 ml of water.

The aqueous solution was filtered off from a resinous mass which had remained in the undissolved state and was slightly acidified with hydrochloric acid. After working up the precipitate as usual, 60 mg of the pure hydroxyethylidene compound (melting point 168 to 169 C) were obtained. 60 ml of N Sodium hydroxide solution and diethyl either were added to the resinous mass and the mixture was shaken thoroughly. After separating the phases, the aqueous-alkaline phase was slightly acidified with conc. hydrochloric acid, the precipitate was suction filtered and then washed out with methanol. After drying, 0.95 g ( 13.4% yield) of pure hydroxyethylidenecvanoacetic acid 3-chloroanilide (melting point 168 to 169 C) were obtained.

EXAMPLE 44.

Hydroxyethylidene-cyanoacetic acid 4-chloro-2-trifluoromethylanilide.

A solution of 5.6 g (0.090 mol) of chlorocyane in 60 ml of absolute dimethoxyethane was added dropwise, at 5 to 100 C, for 40 minutes, whilst stirring, to a mixture of 23.3 g (0.083 mol) of acetoacetic acid 4-chloro-2-trifiuoromethylamiide, 12.4 g (0.090 mol) of K2CO3 and 100 ml of absolute 1,2-dimethoxyethane. Then the mixture was stirred at 10 to 250 C, at 28 to 30 C and at 44 to 460 C and, for 1.5 hours, at 600 C. After evaporating the solvent in vacuo 400 ml of water were added to the residue. The portion that had remained undissolved was suction filtered, washed out with a little water and then shaken with 100 ml of 0.5 N sodium hydroxide solution for 30 minutes. The portion that had remained in the undissolved state (12.6 g) during this treatment, was successively washed out with methylene chloride and diethyl ether and then dissolved in a mixture of 50 ml of 1 N sodium hydroxide solution, 100 ml of water and 100 ml of methanol. After filtration over kieselguhr, the solution was slightly acidified with conc. hydrochloric acid. The precipitate was suction filtered and washed with water and a small amount of methanol. After drying, 9.9 g (^ 39% yield) of pure hydroxyethylidene-cyanoacetic acid 4-chloro-2-trifluoromethyl- anilide (melting point 132 to 133 C) were obtained.

EXAMPLE 45.

Hydroxyethylidene-cyanoacetic acid 3 -chloroanilide.

A solution of 7.05 g (0.05 mol) of 2-cyanoacetic acid methyl ester and 14 g (0.11 mol) of 3-chloroaniline in 30 ml of dioxane was boiled under reflux for 10 hours and then evaporated in vacuo. 20 ml of methanol and 50 ml of water were added to the residue, the mixture so obtained was thoroughly shaken and the two-phase mixture was slightly acidified with hydrochloric acid. The organic phase was separated and evaporated in vacua 80 ml of 1 N sodium hydroxide solution and diethyl ether were added to the residue and the mixture was shaken. After separating the phases, the alkaline aqueous phase was slightly acidified with hydrochloric acid. The crystalline precipitate was suction filtered, successively washed out with water, a 5:1 methanol/ water mixture and a small amount of methanol and was then dried. After drying, 1.40 g ( 12% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloroanilide (melting point: 168 to 1690 C) were obtained.

EXAMPLE 46.

Hydroxyethylidene-cyanoacetic acid 4-bromoanilide.

A mixture of 9.6 g (0.04 mol) of cyanoacetic acid 4-bromoanilide, 80 g (about 1.1 mol) of methyl acetate, 13.6 g )0.10 mol) of phenyl acetate and 6.1 g (0.044 mol) of K2CO3 was stirred for 8 hours under reflux and then evaporated in vacua 300 ml of water were added to the residue and the mixture was thoroughly shaken.

The aqueous phase was separated from the solid substance impregnated with oil by filtration and adjusted to a pH of 9 with 1 N hydrochloric acid. The precipitate formed was suction filtered and the filtrate was slightly acidified with hydrochloric acid, whereby a further crystalline substance was precipitated. It was suction-filtered and successively washed with water, a 4:1 water/methanol mixture and a small amount of methanol. After drying, 0.83 g (4 7.5% yield) of pure hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point: 207 to 208 C) were obtained.

EXAMPLE 47.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilidecyclohexylammonium salt.

27 g (0.1 mol) of 2-hydroxyethylidene-cyanoacetic a d-3-trifluoromethylanilide were suspended in 100 ml of methylene chloride, the suspension was stirred and 11 g (0.11 mol) of cyclohexylamine were added dropwise at room temperature. Then, the mixture obtained was evaporated to give a solid product which could be washed out with cyclohexane. After drying, 27 g (=" 73 % yield) of hydroxyethylidenecyanoacetic acid 3-trifluoromethyl-anilide cyclohexylammonium salt (melting point: 157 to 1590 C) were obtained.

Analysis: ClsH22FsNso2 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-trifluoromethylanilide diethanolammonium salt.

30 g (0.11 mol) of 2-hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide were suspended in 100 ml of ethyl acetate, the suspension was stirred and 11.5 g (0.11 mol) of diethanolamine were added dropwise at room temperature to make the mixture homogeneous. On evaporating the clear, brown solution, a solid residue remained which yielded, after washing out with cyclohexane, 32 g (= 76% yield), of pure hydroxyethylidene cyanoacetic acid 3-trifluoromethylanilide diethanolammonium salt hemlhydrate (melting point: 96 to 980 C).

Analysis: Cl6H20FsNsO4 Calculated with H20: C 50.0%; H 5.5%; N 10.9%; MW 375.4 Found: C 50.3%; H 5.8%; N 11.0% WHAT WE CLAIM IS:- 1. A process for the manufacture of a hydroxyethylidene-cyanoacetic acid anilide of the general formula Ia or the tautomeric form Ib,

in which R1 represents a halogen atom; a methyl or ethyl group which may be substituted by 1 to 3 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; a methoxy or ethoxy group which may be substituted by 1 to 4 halogen atoms, which may be the same or different, selected from fluorine and chlorine atoms; or a methylthio or ethylthio group; and R2 represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl or methoxy group; or R1 and R2 together represents the -O-CH2----O-group; and Rt represents a hydrogen or chlorine atom or a methoxy group, or a salt thereof, which comprises al) reacting a cyanoacetic acid anilide of the general formula II

in which R1, R2 and R3 are as defined above, with an orthoacetic acid ester of the general formula III CH3"C(0R4)s III in which R' represents an alkyl radical having from 1 to 4 carbon atoms, in the presence of an anhydride of a lower fatty acid to give an alkoxyethylidene-cyanoacetic acid anilide of the general formula IV

in which Rl, R2, R3 and R4 have the meanings given above, and subsequently hydrolising the alkoxyethylidene-cyanoacetic acid anilide of the general formula IV at a temperature in the range of from --300 to +150 C, or a2) reacting a compound of the general formula IV at a temperature with a secondary amiite of the general formula V

in which each of R5 and R", which may be identical or different, represents an alkyl radical having from 1 to 4 carbon atoms, or together represent an alkylene chain having 2 to 5 carbon atoms, a -CH2CH2-O-CH2CH2 group or a

in which R7 represents an alkyl radical having from 1 to 4 carbon atoms or a benzyl radical and hydrolising the dialkylaminoethylidene-cyanoacetic acid anilide derivative of the general formula VI so obtained

in which R1, R2 and Ra have the meanings given above and R3 and R6 have the meanings given for the general formula V, b) reacting a dialkylaminoethylidene-acetic acid anilide of the general formula VII

in which each of R5 and K6, which may be identical or different, represents an alkyl radical having from 1 to 4 carbon atoms or together represent an alkylene chain having from 2 to 5 carbon atoms, and R1, R2 and R3 have the meanings given for the general formulae Ia and Ib, in the presence of an aprotic solvent inert to this reactant first with chloro or fluoro-sulphonyl isocyanate; and then with a tertiary amine of the general formula VIII

in which each of R8, R9 and R10 which may be identical or different represents an alkyl radical having from 3 to 12 carbon atoms and in which two of these radicals may together represent an alkylene chain of from 2 to 5 carbon atoms, and/or with an N,N-dimethyi and/or -diethyl-amide of a (Cl to C4)carboxylic acid and/or an Nmethyl- and/or N-ethyl-2-pyrrolidone and then adjusting the pH of the reaction mixture to a valve in the range of from 7.5 to 12.0 and isolating thereafter the dialkylaminoethylidene-cyanoacetic acid anilide of the general formula VI from the lipophilic phase and hydrolising it, c) reacting cyanoacetone of formula IX

in the presence of a basic compound with an isocyanate of the general formula X

in which Rl, K2 and R3 have the meanings given above and RS and Re have the meand) reacting a cyanoacetic acid anilide of the general formula II

in which R1, K2 and Rs have the meanings given in the general formulae Ia and Ib, in the presence of a

Claims (25)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   in which each of R8, R9 and R10 which may be identical or different represents an alkyl radical having from 3 to 12 carbon atoms and in which two of these radicals may together represent an alkylene chain of from 2 to 5 carbon atoms, and/or with an N,N-dimethyi and/or -diethyl-amide of a (Cl to C4)carboxylic acid and/or an Nmethyl- and/or N-ethyl-2-pyrrolidone and then adjusting the pH of the reaction mixture to a valve in the range of from 7.5 to 12.0 and isolating thereafter the dialkylaminoethylidene-cyanoacetic acid anilide of the general formula VI from the lipophilic phase and hydrolising it, c) reacting cyanoacetone of formula IX

   in the presence of a basic compound with an isocyanate of the general formula X

   in which Rl, K2 and R3 have the meanings given above and RS and Re have the meand) reacting a cyanoacetic acid anilide of the general formula II

   in which R1, K2 and Rs have the meanings given in the general formulae Ia and Ib, in the presence of a basic compound at a temperature in the range of from 800 to +2000 C, with an acetic acid halide of the general formula XI (CH3co)=x XI in which X represents a chlorine or bromine atom and n is 1, or with an acetic anhydride of the general formula XI in which X represents an oxygen atom and n is 2, or with ar. acetic acid ester of the general formula XII CH,----COOK11 XII in which K11 represents an alkyl radical having from 1 to 4 carbon atoms, a benzyl or phenyl radical or a phenyl radical substituted by one or two chlorine atoms, nitro groups, a carbomethoxy group or a carboethoxy group, or with ketene, e) reacting an acetoacetic acid anilide of the general formula XIV

   in which R1, R2 and Rs have the meanings given for the general formulae Ia and Ib, in the presence of a basic compound with chlorocyane or bromocyane. f) reacting a 2-cyanoacetoacetic acid ester of the general formula XVa or XVb

   in which Rl2 represents alkyl radical having from 1 to 4 carbon atoms or a phenyl or naphthyl radical which aromatic radical may be substituted by a methyl, nitro or cyano group and/or by 1 to 2 chlorine or bromine atoms with a substituted aniline of the general formula XVI

   in which R, R2 and R" have the meanings given for the general formulae Ia and Ib, and, if desired, converting a resulting salt of a hydroxyethylidene-cyanoacetic acid anilide of the general formulae Ia and/or Ib into the free acid or another salt, or con- verting an acid of the general formula Ia and/or Ib so obtained into a salt thereof.
2. 2. A process as claimed in claim 1, wherein, in process a1), the methyl or ethyl ester of orthoacetic acid is used.
3. 3. A process as claimed in claim 1 or claim 2, wherein, in process al), the anhydride is acetic anhydride.
4. 4. A process as claimed in any one of claims 1 to 3, wherein, in process al), an amount of a Lewis acid in the range of from 0.005 to 5 moles %, based on the compound of the general formula II, is present
5. 5. A process as claimed in any one of claims 1 to 4, wherein, in process al), the compounds of the general formula IV are subjected to alkaline hydrolysis.
6. 6. A process as claimed in claim 5, wherein a sodium or potassium hydroxide or carbonate solution is used.
7. 7. A process as claimed in claim 1, wherein, in process a2), the reaction of a compound of the general formula IV with an amine of the general formula V is carried out in a neutral, organic solvent.
8. 8. A process as claimed in claim 1 or claim 7, wherein, in process a2), the compounds of the general formula VI are subjected to acid hydrolysis.
9. 9. A process as claimed in claim 1, wherein, in process b), the anilide and the sulphonylisocyanate are used in equimolar amounts, and a total of 2 to 4 mols of tertiary amines and/or carbonamides is used per mol of sulphonylisocyanate.
10. 10. A process as claimed in claim 1, wherein process c), is carried out in the presence of an aprotic solvent and a basic compound and at a temperature in the range of from 700 C to 1400 C.
11. 11. A process as claimed in claim 1 or claim 10, wherein process c), is carried out at a temperature in the range of from 0 to 1100 C.
12. 12. A process as claimed in claim 11, wherein process c), is carried out at a temperature in the range of from 10 to 85" C.
13. 13. A process as claimed in any one of claims 1 or 10 to 12, wherein in process c), the basic compound used is a tertiary amine, a sodium alcoholate, a potassium alcoholate or sodium hydride.
14. 14. A process as claimed in claim 1, wherein, in process d), 2 equivalents of the base are used per equivalent of acetylating agent.
15. 15. A process as claimed in claim 1 or claim 14, wherein process d), is carried out in a solvent or diluent.
16. 16. A process as claimed in any one of claims 1, 14 and 15, wherein, in process d), the methyl, ethyl or phenyl ester of acetic acid is used.
17. 17. A process as claimed in any one of claims 1 and 14 to 16, wherein, in process d), the basic compound is sodium hydride, sodium or potassium amide, potassium tertiary butylate, sodium methylate or ethylate and/or potassium carbonate.
18. 18. A process as claimed in claim 1, wherein, in process f), R12 represents a methyl group.
19. 19. A process as claimed in claim 1 or claim 18, wherein, in process f), R1 represents a methyl, ethyl or trifluoromethyl group, a halogen atom, a methoxy or ethoxy group, an ethoxy group substituted by 3 fluorine atoms and one chlorine atom, or by 4 fluorine atoms, or a methylthio group, R2 represents a hydrogen atom, a trifluoromethyl group, a halogen atom or a methoxy group and R3 represents a hydrogen atom or R2 and Rl together represents a -O-CH2-O-group in the 3,4-position.
20. 20. A process as claimed in claim 1, carried out substantially as described in any one of Examples 1 to 9, 12, 13 and 15 to 48.
21. 21. A process as claimed in claim 1, carried out substantially as described herein.
22. 22. A process as claimed in claim 1, wherein process d) is carried out substantially as described in process a) or s) herein.
23. 23. A compound of formula Ia and/or Ib as in claim 1 or a salt thereof, whenever prepared by a process as claimed in any one of claims 1 to 22.
24. 24. A compound of the general formula (XVII) and its tautomer.

    in which R, R2 and R3 are as defined in claim 1 and Y represents a alkoxy group or an

    group, in which Rs and R6, which may be identical or different, each represents an alkyl group having 1 to 4 carbon atoms, or together form an alkylene chain having 2 to 5 carbon atoms, a ---CH',CH2(H2CH2-group or a

    in which R7 represents an alkyl group haviing 1 to 4 carbon atoms or a benzyl group.
25. 25. A pharmaceutical preparation which comprises a compound as claimed in claim 24 or its tautomer, in admixture or conjunction with a pharmaceutically suitable carrier.