IE44047B1 - 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> [GB1571990A]

Description

- 2 - 4 4 0-17 The present invention relates to a process for the preparation of hydroxyethylidene cyanoacetic acid anilide derivatives.

The hydroxyethylidene cyanoacetic acid anilide 5 derivatives prepared are of the general formulae la and lb CH. OH CH O <(/ _- 'V' I! -c- I CO CO NC C NC ' C I E2 H I .2 "v* , "vx 3 CH-» O—E (la) R (lb) R in which R^" represents a halogen atom; a methyl or ethyl group which may be substituted by 1 to 3 halogen 10 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 ethyl-2 15 thio group; and R represents a hydrogen or halogen ί* . Μ';=«· ' ':fk V if ' 4404 7 - 3 - atom ; or a methyl, ethyl, trifluoromethyl or methoxy group; or 1 2 R and R together represent the -O-CH -0- group; and 3 2 R represents a hydrogen or chlorine atom or a methoxy 5 group.

The preferred compounds of the general formulae la and lb 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 10 by 3 fluorine atoms and a chlorine atom or by 4 fluorine atoms; 2 R represents a hydrogen or halogen atom, or a tri“ fluoromethyl or methoxy group; or 1 2 R and R together represent a -O-CH^-O- group in the 15 3,4-position; and 3 R represents a hydrogen atom.

Especially preferred are those compounds of formula I in which 20 R^ represents a fluorine, chlorine or bromine atom, or a methyl, trifluoromethyl or methoxy group; 2 R represents a hydrogen, chlorine or bromine atom or a trifluoromethyl group; or 1 2 R and R together represent a-O-CH^-O- group in the 25 3,4-position; and 3 R represents a hydrogen atom.

The physiologically tolerable salts of the compounds of the invention are especially alkali metal 30 salts, for example, lithium, sodium, and potassium salts; ammonium salts; alkaline earth metal salts, for example, magnesium and calcium salts; zinc salts - 4 .- ·Ύ t . . ι';/ ,. • ''" . ;:ϊ-Γ-4/τ.;' . ; /ΐ;χΧ^χν. , '. Γ · and iron salts; and salts with organic bases, for example, amines and tetraalkylammonium hydroxides.

Preferred salts are sodium, potassium, ammonium, magnesium and calcium salts and salts with amines having 5 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 10 preferred compounds: hydroxyethylidene-cyanoacetic acid-(3-bromo, -3-fluoro-, -3-iodo-, -3-(11,11,21 -trifluoro-21-chloro-ethoxy)-, -3-(tetrafluoroethoxy)-, -4-bromo-, -<4-methoxy, -4-chloro-, -4-fluoro-, -3,4-dichloro-, -2,3-dichloro-, 3,S-dichloro-, -2,6-dichloro-, 15 -3-chloro-2-methyl-, -5-chloro-2-methyl-, -3,4-dioxy-methylene-, '3-ethoxy-, -3,5-bistrifluoromethyl-, 2,4,6-trichloro-, -2-chloro-4-methoxy-, -2-trifluoro-methyl-4-chloro-, -3-methylthio- and -4-ethylthio-anilide).

The present invention provides a process for the preparation of a hydroxyethylidene-cyanoacetic acid anilide of the general formula la and/or its tautomeric form lb CH OH CH, .0 i i CO CO HC C NC 1 C I r2 h ! r2 (la) (Bb) R1 R1 _ 5 - 4 4047 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 5 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 ethyl-2 thio group; and R represents a hydrogen or halogen atom, or a methyl, ethyl, trifluoromethyl or methoxy 10 group; or 1 2 R and R together represent the -0-CEL-0- group; and 2 “ R represents a hydrogen or chlorine atom or a methoxy group; or a salt thereof, which comprises 15 a^) reacting a cyanoacetic acid anilide of the general formula II 0 R2 11 NC-CH -C-NH - · 3 II 2 ( -7—!— R 12 3 in which R , R and R are defined as in the above formulae la and lb, with an orthoacetic acid ester 20 of the general formula III ch3-c(or4)3 III 4 in which R 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 25 presence of acetic anhydride, advantageously by adding ί! ';--Μ ' - 1 4.40'ΐ1*1 .· · g _· a catalytic amount of a Lewis acid and optionally by adding a solvent, suitably at a temperature in the range offrom +20°C· and +180°C to yield an alkoxyethyl-idine-cyanoacetic acid anilide of the general formula IV CH OR4 R40 CH„ C ,0 CO / \ S / \ / NC C r2 NC C m-, HH- Q—E 2~ \>C 1 E“ >Oc R /3 2 R R 12 3 4 in which R , R , R and R are defined as above, and subsequently hydrolysing the isolated alkoxyethylidine-cyanoacetic acid anilide of the formula IV, preferably 10 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 -30°C to +150°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 ; ,-, · ,^ί· .., ., ,. . ” ... ·'. 'Γ -7- 440 4 7 in the range of from +60°C to +150°C, especially from +85°C to +140°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 dis-5 filiation. 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 low-boiling point compounds, which have been 10 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 15 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 20 is reacted, advantageously in a solvent and at a temperature in the range of from -40°C to +160°C, with a secondary amine of general formula V Θ in which each of R3 and R , which may be identical or 25 different, represents an alkyl radical having from 1 to 4 carbon atoms, or in which R^ and R^ together represent an alkylene chain having from 2 to 5 carbon atoms, a -C^CH^-O-CE^CH^- or R7 -CH2CH2N cH2CH2-group. - : · ' ·.; - \ · - 8 - ' '' ·" - ' Λ 7 - - ! in which R represents an alkyl radical having from 1 to 4 carbon atoms or a benzyl radical, to give the dialkylaminoethylidehe-cyanoacetic acid anilide derivative of the general formula VI _ 5 -- Z*5 R CH_ N c \ · ^ / \r6 , N CH X C / N/ 'i »a/or J „ (vtl I / \ ✓ 2 CO NC C R / \ S 2 I NC ° 3 E- 1 · Z- R (for Z-E nomenclature J. Org. Chemistry, Vol. 35, 2849 (1970), esp. page 2852). 12 3 5 in which R , R and R are as defined above and R and R^ are as defined in the formula V, and then hydrolysing 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 a^) and a2) of the invention follow the reaction scheme -9- 4 40 17 CH, Ο + CH -C (OR4)-- /s? / 3 3 NC ^ C „2 \ R HN X , i (xi) Xj (in) VAr 4 4 CEL OR R 0 CH, •v3. / \ X 3 13 and/or ^ CO (IV) CO \ / ' \ /' -- NC C / NC C l *> / . 2 R“- / 1 HN . /^y / HN /'^^x : k^r3 / 5 T gh-r3 ί z- vyi / /* E- CVi ; XX'· r / + fflsr κ \As I / x» / (v) | 5 5 1 ,R R j, CII, N N CH, ' X r6X 3 c R and/or R ^ C 0 (VI) C 0 / \ X X \ x NC C NC C 2 · i „2 „,X ^ ^ ίή-"3\ z_ 'xSS E~ ^Xr1 \ la—Xb 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 5 process ) is, for example, an anhydrous salt of boron, aluminium, zinc, cadmium, mercury, thallium, titanium, zirconium, tin, lead, phosphorus, arsenic, antimony. . , v rt * 3 4?: : · .-: - ίο - iron, cobalt or nickel preferably borontrifluoride, borontrichloride, A'1C13, ZnCl2, ZnBr2, Znl2, Zn(CH3C02.)^, Zn2P20?, ZnS04, HgCI2, Hg(CH3C02)2, HgS04, TiCl4, SnCl4, PCI,, PCI,, SbBr,; SbCl,, SbCl.., SbOCl, (SbO),SO., PeCl,, : 3 5 3 3 b 2 4 3 FeCO^ or Fe2(SO^)3. The catalyst is generally used in an amount of from O.OOS to 5 mols % or more, calculated on the compound: of· the general formula II. Γ · - - * 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, tetrachloroethylene, diisopropyl 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 cyanoacetanilide 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 L00%, calculated on the other reaction component, 1 _ 11 _ 440 47 respectively but may also be used in a stoichiometric ratio. The same is true for the amount of carboxylic acid anhydride to be used, preferably acetic anhydride. Advantageously, the carboxylic acid anhydride is used 5 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 carboxylic acid 10 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 15 or continuously, the different quantities of the slightly volatile compounds formed, at normal pressure, overpressure or underpressure. By operating 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 isolated 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), 25 for example, diethyl ether, isopropyl ether, benzene, toluene, ethyl acetate, dimethoxyethane, tetrahydro-furan, chloroform or carbon tetrachloride, or by column chromatography. Purification is essentially a separation from the non-reacted starting cyanoacet-30 anilide which frequently crystallises with the reaction product in varying proportions. 4 0 47 .12 - . \ If there are np 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 solvent, 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 1 λ choice of radicals R to R', the alkoxyethylidene-cyanoacetanilides of the general formula IV are either in the form of an 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-; -4-bromo-, -3,4-dichloro-, -3,4-dioxy-methylene-, -2-methyl-3-chloro-, -2-methyl-5-chloro-, -4-methoxy-, -4-fluoro-, -4-chloro-, 3,5-dichloro-, -3,5-bis-(trifluoromethyl)-, -4-chloro-2-trifluoro- 44 0 47 - 13 - methyl-, -2,4-d.i.chloro-, -2-ethoxy-, -3-(tetra£luoro~ ethoxy)-, -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 la or the tautomeric keto form lb may be effected under alkaline or acid conditions within a wide temperature range in homogeneous 10 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 possible to work in water alone or in 15 water containing different quantities of solvent(s) miscible with water. Examples of such solvents are: (C^ to Cg)alkanols and alkanediols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, acetonitrile, glycolmono-methyl or diethyl ether, dimethyl formamide, dimethyl-20 sulphoxide and/or (C^ to 0^)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-phase system generally implies that the cyanoacetanilide derivative of the general formula IV to be hydrolysed or the hydrolysis product of the general formula la and lb or 30 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 ·' · ' .·- 14 '- - . ' · ,047 ' - · 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 la 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 H and at a temperature in the range of from 20°C to 100°G. 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 lb 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 100°C. The solvent(s) advantageously added are (C^-C^) alkanols, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, glycolmonomethyl ether, acetone and/or - 15 - / 4 4 0 4 7 acetonitrile. The hydroxyethylidene-cyanoacetic acid anilides of the general formula la and/or lb may be obtained by hydrolysis and participate in the form of crystals directly or after the total or partial evapor-5 ation of the organic solvent used.

In the variant a^) of the process of the invention, in which the alkoxyethylidene-cyanoacetic acid anilides of the general formula XV are first converted into a compound of the general formula VI by reaction with a 10 secondary amine V, the presence of a neutral organic solvent and a temperature within the range of from 20°C to 100°C being preferred. The preferred solvents are 1,2-dimethoxyethane, diethyl ethers, dioxane, tetra-hydrofuran, (C^-Cgjalkanols, carbon tetrachloride, 15 tetraehloroethylene 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 20 formula VI 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 25 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 30 preferred at this stage of the reaction, acid concentrations of N/100 to 6 N and temperatures in the range of from 0° to 70°C are preferred. Compounds " ' - v-. .- *, - ^ ' Ί. • · it? 440-i7 ; _ _ i6 ·χ . . of the general formulae la and/or lb 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 la and/or lb may be totally or partially dissolved, and crystalline hydroxyethylidene-cyanoacetanilides of the general formulae la and/or lb 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-cyanoacet-anilides la and/or lb, are: (1-dimethylamino-, 1-diethylamino-, 1-dipropylamino-, 1-dibutylamino-, Ι-pyrrolidino-, 1-piperidino-, 1-morpholino-, 1-N-methylpiperazino-ethylidene)-cyanoacetic acid-(3-trifluoromethyl-, -3-chloro-, ‘ -3-bromo-, -3-iodo-, 4-iodo-, -3,4-dichloro-, -3,4-dioxymethylene-, -2-methyl-3-chloro-, -2-methyl-5-chloro-, -4-methoxy-, -4-fluoro-, -3,4-dioxymethylene-, -2-methyl-3-chloro-, -2-methyl-5-chloro-, -4-methoxy-, -4-fluoro-, -2,4-dichloro-, -2-ethoxy-, -3-(tetra-fluoroethoxy)-, -3-(1,1,2-trifluoro-2-chloro-ethoxy) -, -3-methylthio-, -3-chloro-4-methyl- and -3,4-dimethoxy-anilide). Moreover, it is also possible to prepare further (1-dialkylaminoethylidene)-cyanoacetic acid - 17 - 44047 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 5 are hydrolysed easily under acid conditions. The compounds of the general formula VI may be hydrolysed 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 10 is preferred for the preparation of the compounds of the general formulae la and/or lb, if these compounds contain acid or alkali sensitive substituents, especially if a modification of the substituents would be expected 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 20 formula IV belong, are easily split under acid conditions in the presence of water .

The cyanoacetanilides of the general formula II needed as starting substances may be prepared by the process described in British Patent Specification 25 No. 930,808 and the orthoacetic acid ester of the general formula III may be prepared by known methods (cf. Houben-Weyl-Muller, 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 la and/or lb, or a salt thereof, which comprises 10 4V; ‘ ! .. .. .· . . ' . . - 18 ^ . ’’ . reacting a dialkylaminoethylidene-acetic acid anilide of the general formula VII . . >:r5 ;: Λ - CI-I, N , i! . r,·· ,. - 5 6 wherein each of R and R , which may be identical or different, preferably identical, represents a (C^ to -.)alkyl radical or, together, represent an alkylene 4 12 rhain having from 2 to 5 carbon atoms, while R , R and R9 are as defined in the general formulae la and lb, in the presence of an aprotic solvent inert to bhis reactant, generally at a temperature within the range of from -70°C to +50°C, with chloro- or fluoro- aulphonyl isocyanate and subsequently with a tertiary mine of the general formula VIII /RS N-R9 VIII ^R10 wherein each of R*3, R9 and R10, which may be identical sr different, represents an alkyl radical having from 3 to 12 carbon atoms and wherein two of these radicals :ogether optionally represent an alkylene chain 44047 - 19 - having from 2 to 5 carbon atoms, and/or with an N,N- dimethyl- and/or -diethyl amide of a (C. to C.)carboxylic X 4· acid and/or an N-methyl- and/or N-ethyl-2-pyrrolidone, generally at a temperature within the range of from -30°C 5 to 25°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 10 isolating from the lipophilic phase the dialkylamino-ethylidene-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 15 la and/or lb in the manner described above. (1-Dialkylaminoethylidene)-cyanoacetic acid anilides of the general formula VI thus prepared being present in the 2- and/or E-form, may be converted as indicated in the first process described to yield the 20 corresponding compounds of the general formulae la and/or lb by acid or alkaline hydrolysis: ^ R5 CH. N .- / n3 / \R6 ( ^ CX j 1) XS02NC0 L ,/ —- 1 .° \ ^r8q ., c' „ 2) n'-R9 and/or i n2 v , carbonamide 1 ,R \ Ri0 (VII) R (VIII) __> VI (Z- form and/or E-form)--5, la, lb. (14047. . ' · / . - 20· - 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 It5 and R6 each represents a methyl or ethyl radical or, together, a tetra- or penta-methylene radical, and 12 3 R , R and R have the especially preferred meanings given in the general' formulae la and lb. As the sulphonylisocyanate, chlorosulphonylisocyanate is generally used. As the 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, CHCl3 and/or ClCH2CH2Cl, at a temperature in the range of from -40 to -5°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 -10°C to 10°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 above-mentioned chloro alkanes, are advantageously added simultaneously or 44047 - 21 - successively at a temperature in the range of from -25°C to +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 10 mixture may be extracted with CI^Cl^, CHCi^ and/or ether . The extracted residue is usually chromatographed on a silica gel column, the crystalline cyano-acetic 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 20 Ber. dtsch. chem. Ges. 25_ (1892), 776; German Patent 967,642). Chloro- and fluoro-sulphonylisocyanate may also be prepared by known methods (cf. Graf, Angew. Chem. 80, (1968), 179).

A further process of the invention is process c) which comprises reacting the cyanoacetone of formula IX CH_ 0 X* X C IX CH CN « * ; · . - ' ' · • ; · -:. - 22 - ίη the presence of a basic compound advantageously in :he presence of an aprotic solvent and in the presence yf a basic compound and at a temperature in the range sf from -70 to +140°C, with an isocyanate of formula X 0C“~f^l_R3 VXr1 12 3 /herein R , R and R are as defined in the general formulae la and Xb, and optionally setting the :ompounds of the general formulae la and/or lb free from the salts thus obtained, by adding an equivalent >r excess amount of a mineral acid or a strong irganic acid.

CH .0 2 r* "—“ (XX) (X) The reaction is preferably carried out in the resence of an aprotic solvent, at a temperature in :he range of from 0°C to 110°C, especially of from 10°C :o 85°G. Suitable solvents are, for example, hydro-arbons, e.g. pentane, hexane, isooctane, petroleum ther, benzene, toluene, xylenes and cyclohexane and/or .iethvl ether, isopropyl ether, 1,2-dimethoxyethane, ioxane, tetrahydrofuran, acetonitrile, dichloroethane r tetrachloroethylene and, if a tertiary amine is sed as the base, also a lower polychlor©alkane, for 44047 - 23 - example, methylene chloride, chloroform or carbon tetrachloride. A mixture of two or more solvents may be used.

As the basic compound, which is advantageously 5 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 10 amines, sodium and potassium alcoholates and sodium hydride are preferred.

The compounds la and/or lb obtained by the reaction are in the form of salts from which the free acid is advantageously freed in the presence of water 15 by the addition of an equivalent amount or a slight excess of an acid, preferably a mineral acid. The compounds Xa and/or lb are often obtained in crystalline form and may be isolated by filtration. Sometimes, it is advantageous to add a solvent miscible 20 with water, preferably a lower alcohol, 1,2-dimethoxy-ethane or acetonitrile or a mixture of two or more solvents, keeping the impurities dissolved. Thus the cyanoacetic acid anilide derivatives of the general formulae la and/or lb may be obtained in a more 25 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 30 publications (cf. Beilsteins Handbuch d. organ.

Chimie IVth edition, vol. 3, page 659), the cyanoacetone may be easily polymerised, especially under ,1 & Ο '17 / ' ; ί ··· ; ' . - · - id -- alkaline and acid conditions. However, for the process .· of the invention, the cyanoacetone need not be isolated in pure form. As the by-products 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 toluenesulphonic 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 la and/or lb 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-hydroxyethylidene)-cyanoacetic acid anilides of the general formulae la and/or lb, or a salt thereof, which process comprises reacting a cyanoacetic acid anilide of the general formula IX, 12 3 in which R , R and R are defined as in the general formulae la and lb above, in the presence of a basic compound at a temperature in the range of from -80°C to +200°C with an acetic acid halide of the general formula XI (CH,-CO) X XI j n 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 44047 - 25 - atom and n is 2, or with an acetic acid ester of the general formula XII ch3— coop.11 XII 11 in which R represents a (C^ to )alkyl, a benzyl, or 5 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, 10 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. 4404^- _____ . ' ; - 26 ;τ · ο J(^LR3 + (CH3-CO)nX -^ (I) NC-CH R1 (XI) \ f H \ (H) II (z, CH O-C-CH. / OH' /H O 3 / 2 (XIII) || / .c ^ o / ^ \ ^ / NC C / II + CH -COOR11 ^ I \ O (XII) (XIII) 0H^ /H20 II + CH2=C=0 --pr X ^ (XIII) -^^0hO/H20 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. - 27 - 44047 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 known solvents sufficiently inert to the 10 respective reactants, for example, aromatic hydrocarbons, mono- or dichlorobenzenes, nitrobenzene, anisole, dimcthoxyethane, - ether, tetrahydrofuran, dioxane, acetonitrile, tetrachloroethylene, acetone, lower alcohols, methylene chloride, chloroform, carbon 15 tetrachloride, 1,2-dichloroethane or dimethylformamide may be used. Acetic acid esters may also serve as diluents. If the acylation is effected with an acetic acid ester, the latter may also be used at the same time in excess as a diluent. Preferred solvents 20 or diluents are 1,2-dimethoxyethane, tetrahydrofuran, ether, dioxane, acetonitrile, anisole, 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 25 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 30 hand, when a weaker base, for example, potassium carbonate or an alcoholate is used, a protic solvent or halogenoalkane may readily be used as the solvent or diluent. 44047 . • - 28 - According to this process of the invention, the acetylation agent may be used in amounts of up to 4 aquivalents, calculated on the cyanoacetanilide of the jeneral 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 uases, the ester is used in a molar excess of up to 50. Advantageously, 1 to 2 equivalents, calculated on a ayanoacetanilide, of one of the above acetylation agents Ls used.

In this reaction, the (1-hydroxyethylidene)-ayanoacetic acid anilides of the general formula la ind/or lb are obtained in the form of their salts. Jsually, the free acids are liberated from these salts ay treating the reaction product, optionally after svaporating any solvents used, with water and/or a iilute aqueous alkali and/or aqueous ammonia, and, aptionally after extracting the aqueous phase with iiethyl ether, isopropyl ether or a hydrocarbon boiling it 40 to 120°C, setting free the (1-hydroxyethylidene)-ayanoacetic acid anilide of the general formula la md/or lb from the aqueous solution thereof by acidification. The acid is generally obtained in crystalline form.

Especially preferred embodiments of process d) >f the invention are the following: x) When a strongly basic compound is used, for example sodium hydride, sodium or potassium amide, n-butyl-lithium or potassium tertiary butylate, it is advantageous to work in the presence of from 0.5 to 80 parts by weight per part of cyanoacetanilide of one or - 29 - 4 4 0 4 7 several of the above preferred solvents. If acetic acid chloride, bromide, anhydride or ester are used as acetylation agents, from 2.0 to 2.2 equivalents of the base are added to 5 the solution of the cyanoacetanilide of the general formula II, at a temperature in the range of from -5°C to +30°C; if ketene is used as acetylation agent, from 1.0 to 1.3 equivalents of the base are added, and subsequently 10 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 -5°C to 60°C. After a reaction time of up to 5 hours, in which the temperature 15 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 described above. p) 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 equivalents (calculated on the cyanoacetanilide) of the acetylation agent, 25 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 30 equivalents of said weaker basic compound, if acetic acid chloride, bromide or ester are 440 47 -:30 - C _ 1 . s 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 L20°C, the process may be continued as described under a^) or a2) above to isolate the (1-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 tiore than about 1.3 equivalents per gramme equivalent af the cyanoacetanilide. The 0-acetyl compounds of the general formula XIII, in which to 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 la and/or lb. The hydroxyethylidene compounds of the general formula la and/or lb 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 aptionally first obtained as O-acylated compound, into the respectively desired end product of the general formula I and/or lb. But the formation of 0-acetyl Serivatives of the (l-hydroxyethylidene)-cyanoacet- - 31 - 440 4? anilides of the formula X 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 α-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 (1955) . Furthermore, α-acyl-cyanoacetic acid 10 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 15 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-acetyl-ation.

The smooth course of the acylation of cyano- acetanilides 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 C-H-acid 25 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 1 2 anilide of the general formula XIV, in which R , R 30 and R^ are as defined in the general formulae la and lb, in the presence of a basic compound, advantageously with the additional use of a solvent or diluent 40 Ί7 - 32 - and at a temperature in the range of from -40°C to +30°C, with cyanogenchloride or cyanogenbromide and subsequently optionally heating the reaction mixture to a temperature of up to +150°C.

C^3 /? 1.) Base +ΛΙ ---^ 1 | 2.] HO Ii~C 0 2 V/ i r2 HN —s X X—Lr (XIV) ^ Ά (X1 = Cl or Br) 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 temperature in the range of from -10 to +-25°C and afterwards heating to a temperature of up to +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 (C^ to C^)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. - 33 - 4 4 0-17 In the reaction e) of the invention, the hydroxy-ethylidene-cyanoacetanilides of the general formula la and/or lb are obtained in the form of their salts.

The acid compounds of the general formula la 5 and/or lb may be then isolated therefrom as described in the preceding process.

The acetoacetic acid anilides of the general formula XIV required as starting material may be prepared by known methods, for example by the reaction 10 of acetoacetic acid esters with correspondingly substituted anilines at elevated temperatures (cf.

II Ullmanns Encyklopadie der technischen Chemie, Ilnd edition, 1953, vol. 3., page 35). Moreover, acetoacetic acid anilides may be very easily accessible by 15 reacting, in known manner, correspondingly substituted anilines with diketene. The following acetoacetic acid anilides may be used as starting materials.

Acetoacetic acid-4-chloro-, -4-methoxy-, -4-fluoro-, -3-methoxy-, -3-(11,1',2'-trifluoro-21-chloro-ethoxy)-, 20 -3-(11,1',21,21-tetrafluoroethoxy)-, -3,5-dichloro-, -2,4-dichloro-, -3-chloro-6-methyl-, -3,5bis-(trifluoro-methyl)-, -2,4,6-trichloro-, -2-chloro-4-methoxy-, 2-trifluoromethyl-4-chloro-, -3-methylthio-, -4-ethoxy-, -2,3-dichloro-, -2,6-dichloro-, -4-bromo-2-methyl-, 25 -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 2-cyanoacetoacetic acid ester of the general formula XVa or XVb - 34 - · 1 -. ' ' . CH, 0 CH_ OH "V I 12 I NC-C —COOR C.

I / \ 12 ' NC COOR H (»a) (XVb) • 12 in which R represents a (C^ to C^) alkyl radical or a phenyl or naphthyl radical all of which radicals may be optionally substituted by methyl, nitro or cyano 5 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 10 formula XVI —f 'X Q---R3 (XVI) XXr1 12 3 in which R , R and R are as defined m the general formula la and lb.

The preferred 2-cyano-acetoacetic acid esters 15 of the general formula XVa or their tautomeric form 12 XVb are those in which R represents a methyl, ethyl or phenyl radical. Esters of the general formula 12 XVa or XVb in which R represents a methyl group are especially used.

Preferred anilines of the general formula XVI are those in which R represents a methyl, ethyl or trifluoromethyl group, a halogen atom, a methoxy or ethoxy group, an ethoxy group substituted by 3 fluorine \ - 35 - 440 47 atoms and one chlorine atom, or by 4 fluorine atoms, or 2 a methylthio group, R represents a hydrogen atom, a trifluoromethyl group, a halogen atom or a methoxy 3 2 1 group and R represents a hydrogen atom or R and R together represent a -0-CH2-0- 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 10 carried out using a solvent sufficiently inert to the reactants in the presence of catalytic amounts of a base, preferably an organic base, in a temperature range of from 50°C to 160°C.

A preferred embodiment of the process f) of the 15 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 109°C, for example, xylene or chlorobenzene, optionally in the 20 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 25 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 30 example, aromatic hydrocarbons, e.g. benzene, toluene, xylene, or cumene, or chlorobenzene, dioxane, 1,2-dimethoxyethane, acetonitrile, nitrobenzene, tetra- !/;· | i : - i 4(,4, -36- chloroethylene, dichlorobenzene, anisoleand/or fcert. 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-eyano-acetoacetic acid ester. Suitable bases are, for example, tertiary amines, e.g. triethyl amine, tripropyl amine, N-methylpyrrolidine, N-ethyl-piperidine, triethanolamine, l,4-diazobicyclo[2,2,2]octane, or pyridine, picolines, quinoline and N,N-dimethyl aniline.

After evaporating solvent(s) used the (l-hydrdxy-ethylidene) eyanoacetanilides of the general formula la and/or lb are isolated, advantageously, by treating the crude reaction product with dilute aqueous alkali, thus converting the compounds of the general formula la and/or lb into the corresponding alkali metal salts.

In this state, 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 • j { cyclohexane, as well as benzene. The (1-hydroxyethyl-idene)-eyanoacetanilides may be precipitated, mostly in crystalline form, by acidification of the aqueous-alkaline 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 - 37 - 44047 (1959). Moreover, these starting substances are by acetylation, given analogously to the process <3) described hereinbefore, i.e. by the same method as the acylation of the cyanoacetanilides. Here cyano-5 acetic acid esters are advantageously acetylated with acetyl chloride or aceticanhydride advantageously in the presence of 2 equivalents of a base.

The hydroxyalkylidene-cyanoacetic acid anilides of the general formulae la and lb are acid compounds, 10 which according to their NMR spectra, are present mainly in the enol form la. The addition of FeCl^ produces a brown-red to claret coloured reaction.

If in one of the above processes the compounds la and/or lb are first obtained in the form of their 15 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 20 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 la or lb. These salts may be isolated after the evaporation of the solvent or by 25 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, 30 magnesium or ammonium carbonate or bicarbonates as well as sodium amide, or organic bases, for example tertiary amines. When alkali metal or alkaline <40 4? -38- 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 la and lb 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. Ill, 544 (1962) and an adjuvant arthritis 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. Ill, 409 (1957)).

A hydroxyethylidene-cyanoacetic acid anilide of the general formula la and/or lb 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 - 39 - 4‘10 4 7 t i 1 * 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 5 example tablets, dragees, capsules and suppositories, and liquid preparations, for example, solutions in water, and sterile injection solutions. Such preparations may comprise 3-90% of the active ingredient.

The intermediate products of the general formulae 10 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 of the compounds of the general formula la or lb of the 15 invention Which have a strong anti-inflammatory and/or analgesic effect, i.e. they are the esters and amines respectively, their effect is identifiable in connection with that of the latter compounds.

Moreover, the compounds of the general formula 20 la or lb also exhibit anthelmintic, antimycotic and fungicidal effects.

The compounds of the general formula la or lb of the invention may also serve as intermediates for the preparation of other pharmacologically and/or 25 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 thin layer chromatography. 14047 -40- EXAMPLE 1.

Hydroxyethylidene-cyanoacetic acid 3-chloro-anilide. 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 aceticanhydride 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 temperature of 120°C over a 15 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 CHCl^. The CHClg 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 CHCl^ (300 ml or 150 ml).

R further 30 g of the above compound were obtained from the CHCl^ 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 - 41 - 4 4 0 4 7 starting material. The combined CHCl^ 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 5 anilide. About 100 ml of diethyl ether were added to the filtrate, whereafter 26 g of almost pure ethoxyethyl-idenecyanoacetic acid 3-chloroanilide precipitated as crystals in the form of the stereoisomer mixture. This proportion was purified by recrystallisation from CHCl^.

A total of 66 g (= 41.5% yield) of ethoxyethylidene-cyanoacetic acid 3-chloroanilide were obtained in the form of the pure 2- or E-stereoisomer (melting point 165°C to 166°C) and 22 g (= 14% yield) as stereoisomer mixture (melting point 121°C to 123°C).

Analysis: ci3HjL3C'*'N202 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 20 (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 25 at 75°C for 10 minutes, whilst stirring. After adding 400 ml of water, the mixture was allowed to cool to 20°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 30 free of the salt and was neutral, it was then dried. 440 47 ,--42-- ; - ' 22.5 g (= 95¾ yield) of pure hydroxyethyliderie-cyano- i acetic acid 3-chloroanilide (melting point 169°C to 170°C) were obtained.

The IR spectrum of this compound was identical with that of the same compound obtained in a different manner according to German Offenlegungschrift No. 24 929.0 (Patent Specification No. 43004).

EXAMPLE 2.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide. a) Ethoxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide.

A mixture of 68.5 g (0.3 mol) of cyanoacetic acid 3-trifluoromethylanilide, 66 g (0.41 mol) of ortho-acetic acid triethyl ester, 77 g (0.75 mol) of acetican-hydride and 40 mg of zinc chloride were boiled under reflux at a bath temperature of 110°C for 3 hours.

Then the most volatile moieties were slowly distilled off over a 20 cm high Vigreux column over 2.5 hours at a bath temperature of 120°C, the distillation pressure having been reduced to 350 torrs during the last 5 minutes.

After cooling and standing for 16 hours, the reaction mixture was entirely crystallised. The mixture was diluted with 200 ml mixture of diethyl ether and isopropyl ether in a 1:1 ratio. The crystals were then suction filtered and washed with isopropyl ether. After drying, 49.5 g of a stereoisomer mixture (according to DC and NMR spectrum) of ethoxyethylidene-cyanoacetic acid 3-trifluoromethylanilide [3-ethoxy-2-cyano-crotonic acid 3-trifluoro- _43- *4 0 47 methylanilide] (melting point 135 to 137°C) were obtained (55.5% yield).

Analysis: Calculated: 5 C 56.4%; H 4.4%; F 19.2%; N 9.4%; MW 298.3 Found: C 56.4%; H 4.5%; F 19.3%; N 9.2%; MW 298 (by mass spectroscopy).

A reaction carried out in analogous manner but 10 where no 2inc chloride had been added, yielded 41.5 g of a stereoisomer mixture of the ethoxyethylidene-cyanoacetic acid 3-tri£luoromethylanilide (melting point: 125°C to 127°C), in which a form (either Z or E) had been enriched to a large extent. b) Hydroxyethylidene-cyanoacetic acid 3-trifluoro- methylanilide.

A mixture of 30 g (0.1 mol) of ethoxyethylidene-cyano-acetic acid 3-trifluoromethylanilide, 1.3 litre of ethanol and 750 ml of 6 N hydrochloric acid was 20 heated to 64°C to 65°C for 12 hours whilst stirring, and then suction filtered while hot. The filter residue was washed with water until neutral and dried. 21 g of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide [2-cyano-3-hydroxy-crotonic 25 acid 3-trifluoromethylanilide] (melting point 181°C to 182°C, (- a 78% yield), were obtained).

This product has a melting point and an IR spectrum identical with that of the same compound prepared in a different manner according to German 30 Offenlegungschrift No. 25 24 929.0 (Patent Specification No. 430Q4). 4 4 0 4^ “ 44 - EXAMPLE 3.

Hydroxyethylidene-cyanoacetic acid 3,4-dichloro-anilide. a) Ethoxyethylidene-cyanoacetic acid 3,4-dichloroanilide.

A mixture of 115 g (0.5 mol) of cyanoacetic acid 3,4-dichloroanilide, 110 g (0.675 mol) of orthoacetic acid triethyl ester, 128 g (1.25 mols) of aceticanhydride and 50 mg of zinc chloride were boiled under reflux at a bath temperature of 115°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 120°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 ethoxyethylidene-cyanoacetic acid 3,4-dichloroanilide [3-ethoxy-2-eyano-crotonic acid 3,4-dichloroanilide (= 41% yield and a melting point of 155°C to 157°C) were obtained.

Analysis: ci3Hi2Cl2W2°2 Calculated: C 52.0%; H 4.4%; Cl 23.6%; N 9.4%; MW 299.2 Pound: C 52.0%; H 3.9%; Cl 24.0%; N 9.4%; MW 298; 302 (by mass spectroscopy). 44047 - 45 - The CHClg/ether mother lye was evaporated and the residue was boiled out with 700 ml of CCl^. 26 g of cyanoacetic acid 3,4-dichloroanilide remained in the undissolved state. The CCl^-extract was evaporated.

The residue was dissolved in 200 ml of CHC13< 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 10 the DC? eluent CH^Cl^/C^HgOH 10:1, silica gel prefabricated plates - Merck F 254), having a melting 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. .5 g (94% yield) of hydroxyethylidene-cyanoacetic acid 3,4-dichloroanilide (melting points 208 to 210°C) were obtained from 30 g (0.1 mol) of the ethoxy-20 ethylidene compound when proceeding in the manner analogous to that described in Example (lb) .

EXAMPLES 4 to 8.

According to the method described in Examples 2a and 3a respectively the following compounds were 25 obtained: Ethoxyethylidene-cyanoacetic acid [3-(1,1,2-trifluoro-2-chloro-ethoxy) -anilide], ΟΙχςΗ^ΟΐΡ,^Ο^, melting point: 102° C to 103° C (Z- or E-form), yield: 21%. 44047 _46~ Ethoxyethylidene-cyanoacetic acid 3-bromoanilide, C13H13Br^2°2' point 196°C to 197°C, (2- or E-form); yield: 50%.

Ethoxyethylidene-cyanoacetic acid 4-methoxyanilide, melting point: 166°C to 167°C (Z- or E-form); yield: 30%.

Ethoxyethylidene-cyanoacetic acid 3-chloro-2-methylanilide, C^H^gCl^Og, melting point: 171°C to 173°C (Z- or E-form), yield: 42%.

Ethoxyethylidene-cyanoacetic acid 5-chloro-2-mefchylanilide, C^H^ClNgOg, melting point: 208°C to 210°C, (Z- or E-form), yield: 72%,.

Methoxyethylidene-cyanoacetie acid 3-chloroanilide (as the additional preliminary compound for the hydroxy-ethylidene compound to be prepared according to Example lb) C12H12C1m 202, melting point: 118° to 120°C (E- or Z-form), yield; 7%.

Melting point 157° to 158°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 chrom- : " atography on silica gel (Merck) using methylene chloride/ benzene in a ratio of 1:1, in which case the column is then eluted with CHgClj. The composition of the eluted fractions has been determined by thin-layer chromatography. The compounds were eluted in the following order: a) stereoisomer having a low melting point b) stereoisomer having a higher melting point c) cyanoacetic acid 3-chloroanilide. _ 47 - 4 4 0 4 7 The ethoxyethylidene compounds above were converted into the corresponding 2-hydroxyethylidene-cyanoacet-anilides according to the method described in Example (lb) i.e. gave 5 Hydroxyethylidene-cyanoacetic acid [3-(1,1,2- trifluoro-2-chloroethoxy)-anilide], melting point: 140° to 141°C.

Hydroxyethylidene-cyanoacetic acid 3-bromoanilide, melting point: 178° to 179°C.

Hydroxyethylidene-cyanoacetic acid 4-methoxy- anilide, melting point: 151° to 152°C.

Hydroxyethylidene-cyanoacetic acid 3-chloro-2-methylanilide, melting point: 164°C to 165°C.

Hydroxyethylidene-cyanoacetic acid 5-chloro-2-15 methylanilide, 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 ethoxyethyl-idene-cyanoacetic acid 5-chloro-2-methylanilide and the 20 mixture was stirred for 30 minutes at 65°C. After filtering the solution over kieselguhr, the filtrate was acidified with sulphuric acid, the precipitate was suction-filtered, it was then washed with water until free of salt and was dried. 465 mg (= 93% yield) of 25 hydroxyethylidene-cyanoacetic acid 5-chloro-2-methyl-anilide (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 -48- a mixture of 20.0 g (0.07 mol) of ethoxyethylidene-cyanoacetic acid 3-trifluoromethylanilide and 80 ml of 1,2-dimethoxyethane. The solution obtained was stirred for 1 hour while allowing a weak dimethylarnine 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-trifluoromethylanilide [2-cyano-3-dimethylamino-crotonic acid 3-trifluoromethylanilide] (melting point 127 to 128°C) were obtained.

Analysis: C^H^F^O 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%; I®* 297 (by mass spectroscopy).

By this method, the following compounds were prepared: Dimethylaminoethylidene-cyanoacetic acid 3-chloroanilide, (MW 263.7), melting point: 146° to 148°C.

Dimethylaminoethylidene-cyanoacetie acid 3-bromo-anilide, C^^H^^rN^O (MW 308.2), melting point: 141 to 142°C (from ethyl acetate).

Dimethylaminoethylidene-cyanoacetic acid 3-chloro-2-methylanilide C^H^gClM^O (MW 277.8), melting point: 142° to 143°C (from 1,2-dimethoxyethane). - 49 - 440 4? EXAMPLE 11. (4-Methyl-piperazinoethylidene)-cyanoacetic acid 3-trifluoromethylanilide.

A solution of 5.3 g (0.053 mol) of N-methylpiper-5 azine in 10 ml of 1,2-dimethoxyethane was added dropwise within 15 minutes at 30°C, to a mixture of 15 g (0.05 mol) of 2-ethoxyethylidinecyanoacetic acid 3-trifluoro-methylanilide and 100 ml of l,2-dimethoxyethane and the mixture was stirred at 45°C for 1 hour, whereby a solution 10 was obtained. This solution was evaporated in. vacuo .

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 15 compounds were isolated from the filtrate. The crystals were recrystallised from CCl^. 12.4 g (70.5% yield) of pure (4-methyl-piperazinoethylidene)-cyanoacetic acid 3-trifluoromethylanilide (melting point: 129° to 130°C) were obtained.

Analysis: C^H^gF^N^O 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 25 (by mass spectroscopy).

By this method the following were also prepared: Piperidinoethylidene-cyanoacetic acid 3-chloro-anilide, C^IL^ClNgO (MW 303.8), melting point: 138° to 139°C (from ethyl acetate). ‘ίΊ - - 50 - Piperidinoethylidene-cyanoacetic acid 5-chloro-2-ithylanilide C^^HjqCIN 0 (MW 317.8), melting point: 3° to 134°C (from ethyl acetate).

EXAMPLE 12.

A mixture of 9 g (0.03 mol) of dimethylaminoethyl-ene-cyanoacetic acid 3-trifluoromethylanilide, 60 ml ethanol and 200 ml of 2 N hydrochloric acid was irred at 35°C for 4.5 hours. Then, the solid matter s suction filtered, washed with water until free of It and until neutral and then dried. 8.0 g (= 99% yield) of hydroxyethylidene-cyano-etic acid 3-trifluoromethylanilide (melting points 9° to 180°C) were obtained.

By this method the following were prepared* from piperidinoethylidene-cyanoacetic acid 3-Loroanilide the hydroxyethylidene-cyanoacetic acid ::hloroanilide, melting point: 170° to 171°C (94% aid), from (4-methylpiperazinoethylidene)-cyanoacetic id 3-trifluoromethylanilide the hydroxyethylidene-moacetic acid 3-trifluoromethylanilide, melting Lnt: 179° to 181°C (98% yield), from dimethylaminoethylidene-cyanoacetic acid nromoanilide the hydroxyethylidene-cyanoacetic acid Dromoanilide, melting point: 178° to 179°C (96% sld) .

EXAMPLE 13.

A mixture of 4.5 g (0.015 mol) of dimethylamino-lylidene-cyanoacetic acid 3-trifluoromethylanilide, ml of ethanol and 400 ml of 0.1 N hydrochloric acid s stirred at 30°C for 10 hours, it was then suction _ 51 - 44047 \ , 1 filtered· The crystalline substance, 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-trifluoromethylanilide (melting 5 point: 179° to 181°C).

EXAMPLE 14.

A solution heated to 38°C, which had been obtained by dissolving 56 g (0.2 mol) of piperidinoethylidene-aeetic acid 3-chloroanilide with and making up 10 to a volume of 1600 ml, also with CH2Ci2 and a solution which had been obtained by dissolving 2S.3 g (0.2 mol, 17.36 ml) of chlorosulphonylisocyanate with CH2C12 and making up to 400 ml, also with CH2C12, were added regularly dropwise, at -30° to -20°C to 50 ml of CH2C12 15 whilst stirring, over 2.5 hours with ar. 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 -29°C to 0°C and for 1 hour at 0° to +2°C. After cooling the solution to -10°C, a solution of 42 ml of 20 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 25 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 30 aqueous solution was drawn off from the separated, viscous, hydrophobic mass and was taken up in CH^Cl^. -52- · he methylene chloride solution was shaken three times ith about 100 ml of water and dried with Na^SO^. fter filtration, the solution was evaporated in vacuo nd the residue (53 g) was dissolved in ethylacetate/ enzene (3:1) to give a concentrated solution. The olution was filled in a silica gel column (Merck) height: 55 cm, 4.7 cm)j the column was eluted with hat mixture and 100 ml fractions were collected at its utlet. The first 4 fractions contained only oily y-products. In the 5th to 8th fraction crystalline esidues (24 g in total) were obtained after evaporating he solvents. They were recrystallised from an ethyl-cetate/diethyl ether/isopropyl ether mixture, whereby 2.8 g of pure piperidino-cyanoacetic acid 3-chloro-nilide (melting point 138° to 139°C) were obtained, he 9th and 10th fraction of the chromatography ontained 4 g of partially crystalline product, which as dissolved in the mother lyes of the recrystallis-tion process and yielded, after concentration and urther recrystallisation, another 2.2 g of the nilide (melting point 137° to 138°C) . The anilide as obtained in a yield of 25%.

In the same manner, starting from 58.6 g (0.2 mol) f piperidino-ethylideneacetic acid 5-chloro~2-methyl-nilide, 18.2 g (= 29% yield) of piperidinoethylidene-yanoacetic acid 5-chloro-2-methylanilide (melting oint 133° to 134°C) and starting from 48 g (0.2 mol) f dimethylaminoethylidene-acetic acid 3-chloro-nilide, 5.8 g (= 11% yield) of dimethylaminoethyl-dene-cyanoacetic acid 3-chloroanilide (melting point 46° to 148°c) were obtained. In the latter case, here was also obtained a crystalline by-product in - 53 - 4 4 0 4 7 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 5 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 160° to 161°C. Because of the difficulties 10 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) 15 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 20 (2-cyano-acetoacetic acid) were filtered off and the filtrate was evaporated iri vacuo at a bath temperature of 30°C. A colourless oil resulted therefrom which contained crude cyanoacetone (87% according to GC).

To this product, 4.67 g (25 mmols) of 3-trifluoromethyl-25 phenylisocyanate and 50 ml of CH^Cl^ 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 30 and then evaporated in vacuo. 40 ml of water and 10 ml of methanol were added to the residue, the ι 4 Ο 4 Τ' _ 54 - ixture was thoroughly shaken and then acidified with N hydrochloric acid. A precipitate was produced hich turned to a crystalline mass in a short time, he admixture of ethanol gave a suspension which was uction filtered. The filter residue was washed with water/methanol mixture having a ratio of 3:1 and hen with a little amount of methanol and was finally ried. 5.65 g (= 70% yield, calculated on cyano-cetic acid-tert.-butyl ester) of pure hydroxyethyli-ene-cyanoacetic acid 3-trifluoromethylanilide melting point 181° to 182°C) were obtained.

EXAMPLE 16.

By the method described in Example 12 and start-ng from 5.5 g (30 mmols) of cyanoacetic acid-tert.-utyl ester, 3.2 g of crude, benzene-containing cyano-cetone were obtained, which also contained about 1 mol of p-toluene-sulphonic acid. This product was issolved in 25 ml of anhydrous tetrahydrofuran and ntroduced dropwise, at +5°C to +12°C, whilst stirring, nder exclusion of humidity, into a mixture of 900 and g of 80% sodium hydride-oil-suspension (= 30 mmols f NaH) in 40 ml of absolute tetrahydrofuran. Then, solution of 5.8 g (29 mmols) of 3-bromophenyliso-yanate in 40 ml of tetrahydrofuran, was added to the ixture at 0° to +5°C, whilst stirring and the mixture as stirred for 30 minutes at 50°C. After evaporat-ng the reaction mixture in vacuo, 40 ml of ice water nd 10 ml of methanol were added to the residue and he mixture was shaken, then 5.5 ml of 6 H hydro-hloric acid were added. The precipitate was ecrystallised. The addition of ethanol brought - 55 - 440 47 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 si) and recrystallised from 5 methanol. 4.3 g (51% yield, calculated on cyano- acetic acid-terjfc.-butyl ester) of pure hydroxyethyli-dene-cyanoacetic acid 3-bromoanilide (melting point 173° to 180°C) were obtained.

EXAMPLE 17.

As described in Example 15 and starting from 5.5 g (30 mmols) of cyanoacetic acid-tart.-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 of 850 mg of 80% NaH-15 oi3-suspension and 50 ml of acetonitrile at about 0°C whilst stirring. Then, a solution of 3.7 g (27 mmols) of 4-£luorophenylisocyanate in 20 ml of absolute acetonitrile was added dropwise to the mixture at room temperature, whilst stirring. The temperature 20 was allowed to rise to 35°C, the mixture was further stirred at 35°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 25 hydroxyethylidene-cyanoacetic acid 4-fluoroanilide (melting point 170° to 171°C) were obtained.

EXAMPLES 18 to 22.

By the methods described in Examples 15 and 16, the following were prepared! ' - 56 - Hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point 207° to 209°C) yield 55%.

Hydroxyethylidene-cyanoacetic acid 3,4-dichloro-anilide (melting point 209° to 21o°C) yield 57%.

Hydroxyethylidene-cyanoacetic acid 2-ethoxyanilide (melting point 110° to 114°C) yield 32%.

Hydroxyethylidene-cyanoacetic acid 2,4-dichloro-anilide (melting point 140° to 141°C) yield 56%.

Hydroxyethylidene-cyanoacetic acid 4-chloro-2-trifluoromethylanilide (melting point 131° to 133°C) yield 51%.

EXAMPLE 23.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide.

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 25°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 at 0 to +27°C and at 25 to 33°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 solution 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 - 57 - 4 4047 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 (= 72% yield) of hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl-5 anilide (melting point 179° to 181°C) were obtained. 9 g of pure compound (melting point 181° to 182°c) were obtained from this product by recrystallisation from methanol.

When proceeding according to the method described 10 in Example 23, the hydroxyethilidene-cyanoacetic acid anilides listed in the following Table 1 were obtained in the yield indicated. 0 47 - 58 -TABLE 1 Hydroxyethylidene-cyanoacetic acid anilides CS OH 11 fzX NC—C—CONH-' ft \ R No. R1 R2 Mp. (°C) Yield in % 1 3-Cl H 168-169 73 23-1 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 2-0C2H5 H 109-111 43 7 3-Cl 4-Cl 209-210 74 8 2-Cl 4-Cl 140-141 65 9 2-CH3 3-Cl 164-165 71 10 3-SCH3 H 135-136 62 11 2-CH3 5-Cl 127-128 73 12 3,4-0-CEL,0 166-167 40 13 3-1 H 207-208 70 ! * -59- 44047 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 5 was added dropwise, whilst stirring at 10° 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 -10° 10 to 0°C and the mixture was stirred at 0° to +28°C, at 28° to 25°C and at 62° to 65°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 hydroxyethyl- 15 idene-cyanoacetic acid 3-bromoanilide (melting point 178° to 179°C) were obtained.

EXAMPLE 25. 9.45 g (0.12 mol) of acetyl chloride were added dropwise, while stirring at 270°C, to a mixture of 20 23.9 g (0.1 mol) of cyano-acetic acid 2-bromoanilide, 16.6 g (0.12 mol) of dry, pulverised K^CO^ and 100 ml of dry acetone. After stirring for 1 hour at 27 to 30°C and for 2.5 hours under reflux, the acetone was eliminated in vacuo, and the residue was extracted with 25 water. About 15 g (= 63%) of starting anilide 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 30 after suction filtering and washing with a 1:2 water/ methanol mixture. After drying, 8.4 g (= 30% yield) 4°47 _60_ if pure hydroxyethylidene-cyanoacetic acid 4-bromo-inilide (melting point 208 to 209°c) were obtained.

EXAMPLE 26.

A solution of 4.1 g (0.052 mol) of acetyl chloride .n 10 ml of toluene was added dropwise to a mixture of .1.4 g (0.05 mol) of cyanoacetie acid 3-trifluoromethyl-milide, 7.6 g (0.055 mol) of ^00^ and 150 ml of :oluene whilst stirring at 70°C. Then, the mixture 'as stirred for 1 hour at 90°C, cooled and the solid lubstance suction filtered and washed with 100 ml of :oluene. The dried product was then extracted with ater. The filtered aqueous extract was slightly cidified with dilute hydrochloric acid and the precipi-ate was suction filtered. After washing with water, t was recrystallised from methanol. 5.3 g (= 39% ield) of pure hydroxyethylidene-cyanoacetic acid -trifluoromethylanilide (melting point 180 to 182°C) ere obtained. The portion of solid substance (5.2 g) hich had not been dissolved in water, mainly contained tarting 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 n 5 ml of 1,2-dimethoxyethane was added dropwise, at 5°C, over 25 minutes, to a mixture of 10.5 g (0.05 mol) f cyanoacetie acid 5-chloro-2-methylanilide, 12.3 g 0.11 mol) of potassium-tert.-butylate and 150 ml of ry dioxane and the mixture was stirred at 90°C for 2 ours. After evaporating the solvent in vacuo, the esidue was extracted with 300 ml of water. A -61- 44047 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% 5 yield) of hvdroxyethylidene-cyanoacetic acid 5-chloro-2-methylanilide (melting point 127 to 128°C) were obtained.

EXAMPLE 28.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide.

At 10 to 20°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 at -10° to -5°C in 25 minutes, a solution of 5.6 g ¢0.055 mol) of acetiear.-15 hydride in 100 ml of absolute dimethoxyethane were added dropwise, whilst stirring,to a mixture of 3.40 g (0.113 mol) of 80% sodium hvdride-oil-suspension and 5 ml of dry 1,2-dimethoxyethane. Then, the mixture was stirred at -5°C to room temperature for 30 minutes 20 at 25 to 30°C and at 65°-70°C for 1 hour respectively and then, the reaction mixture was evaporated in vacuo.

The residue was dissolved in 300 ml of water and the solution was shaken with 80 ml of diethyl ether.

After filtration, the aqueous phase was slightly acid-25 ified with hydrochloric acid. The precipitate was washed successively with water, a 2:1 methanol/water mixture and a small amount of methanol and then dried. 12.8 g (= 95% yield) of pure hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 181 30 to 182°c) were obtained. Ο 4 7 - 62 - In an analogous manner, 2-hydroxyethylidene-cyano-icetic acid 3-bromoanilide (yield 93%) and 3,4-dichloro-milide (yield 94%) were prepared.

EXAMPLE 29.

In a solution of 22.8 g (0.1 mol) of cyanoacetic icid 3-trifluoromethylanilide in 100 ml of 1,2-dimethoxy-;thane, there were suspended 16.6 g (0.12 mol) of (Otassium carbonate. 14.3 g (0.14 mol) of acetican-lydride were added dropwise, at room temperature, whilst itirring. After stirring for 4 hours at room tempera-:ure, the mixture was evaporated in vacuo and the esidue was extracted with water. After filtration -ver kieselguhr, the hydroxyethylidene-eyanoacetic acid -trifluoromethylanilide was precipitated from the queous extract by acidification with dilute sulphuric cid. After suction filtering, washing and drying 9 g (= 70% yield) of product (melting point 172° to 73°C) were obtained, wherefrom 17.3 g (= 64% yield) f pure compound (melting point 181 to 182°C) were solated after recrystallisation from methanol.

The hydroxyethylidene-eyanoacetic acid anilides s listed in the following Table 2 were prepared ccording to the method described in Example 29 in he yields indicated. - i 44047 - '63 - TABLE 2 CEL OH 11 /7^ NC — C — CONH / \ ν:χ R2 _ - No. R R Yield in % 1 3-Cl H 72 2 3-1 H 63 3 4-F H 73 4 2-Cl 4-Cl 71 5 3-SCH3 II 52 6 2“CH3 5-Cl 72 7 3,4-0-CH2-0- 35 8 4-OCH3 H 40 9 2-CF3 4-C1 51 EXAMPLE 30.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methyl anilide.

Using the method described in Example 29 with the 5 difference that 16.6 g (0.16 mol) of anhydrous sodium carbonate solution are used instead of 16.6 g of ^00^ 10.0 g (= 37¾ yield) of hydroxyethylidene-cyanoacetic acid 3-trifluoromethylanilide (melting point 175 to 176°c) were obtained. In this method, the extraction , & Ο 4 ί1 _ 64 - 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 non-reacted starting material.

EXAMPLE 31.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide.

Following the method described in Example 29, 0.1 mol of cyanoacetic acid 3-trifluoromethylanilide in dimethoxyethane were reacted in the presence of 16.6 g of &2C03 14.3 g (0.14 mol) of aceticatihydride 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 179°C) were obtained.

EXAMPLE 32.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide. .2 g (0.1 mol) of aceticatihydride were introduced dropwise, at room temperature, whilst stirring, in a mixture of 22.8 g (0.1 mol) of cyanoacetic acid 3-trifluoromethylanilide, 15.2 g (0.11 mol) of J^CO^ 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 iri vacuo, the residue 44047 - 65 - was worked up as described in Example 29. After recrystallisation of the crude product from methanol, 1.7 g (= 6.3¾ yield) of pure hydroxyethylidene-cyano-acetic acid 3-trifluoromethylanilide (melting point 5 181 to 182°C) were obtained.

EXAMPLE 33.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methyl anilide. .2 g (0.10 mol) of acetieanhydride were added drop-10 wise, at 70°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 K^CO^ 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 15 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-trifluoromethyl-20 anilide (melting point 215 to 217°C and a yield of 29¾) . 3 g of free hydroxy compound (melting point 166 to 168°C and an = 11¾ yield) were precipitated from the washing water with dilute hydrochloric acid.

EXAMPLE 34.

Hydroxyethylidene-cyanoacetic acid 4-bromo- anilide. .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 30 4-bromoanilide, 5.2 g (0.051 mol) of aceticanhydride - 66 - and 50 ml of absolute 1,2-dimethoxyethane, the temperature slowly rising to '30°C. The mixture was stirred for 2 hours at 30°C .and for 2 hours at 80°C and the mixture was evaporated in vaouo. 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 209°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 dimethoxy-ethane was added dropwise at 10 to 20°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-dimethoxy ethane.

After the hydrogen evolution had 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 20minutes at 5° to 28°C and for 1.25 hours at 70° to 75°C. Then, the mixture was evaporated in vacuo, and to the residue were added 150 ml of water; then the mixture was shaken. - 67 - *404? The solution was extracted with 100 ml of diethyl ether. After separating the phases, the aqueous phase was slightly acidified with dilute hydrochloric acid and the precipitate was suction filtered and washed with 5 a 6:1 methanol/water mixture and dried. 9.7 g (= 82% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloroanilide (melting point 168 to 169°C) were obtained.

After concentration 1 g (8.5% yield) of product (melting point 165 to 167°C) was isolated from the 10 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 (= 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 dimethoxy- ethane was added dropwise, at room temperature, to a 20 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 (0.055 mol) of acetican- hydride in 10 ml of absolute dimethoxyethane was added dropwise, at -7° to 0°C, whilst stirring, and the o 25 total mixture was stirred for 30 minutes at 0 C and then at 30 to 35°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 30 solution. The portion that remained in the undissolved state, was suction filtered, and washed with about 4 40 47 - 68-- ' .. 200 ml of slightly alkaline water (pH of 11 to 12) .

The combined, alkaline filtrates were slightly acidified with hydrochloric acid. The precipitate was suction filtered and successively washed with water, a 4:1 methanol/water mixture and a little methanol and dried. 3.1 g (= 26% yield) of hydroxyethylidene-cyano-acetic acid 3-chloroanilide (melting point 167 to 168°C) were obtained, EXAMPLE; 37.

Hydroxyethylidene-cyanoacetic acid 3-chloroanilide.

A solution of 9.73 g (0.05 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 26°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 - 69 ~ 44047 solution. The suspension so obtained was suction-filtered and the solid substance was washed out successively and thoroughly with 1 N 10 5 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 10 washed with water, a 5:1 methanol/water mixture and a little methanol. After drying, 6.7 g (= 57% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloro-anilide 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 dimethoxy-ethane were introduced at room temperature, whilst stirring, into a mixture of 4.05 g (0.075 mol) of 20 sodium methylate and 10 ml of dry 1,2-dimethoxyethane.

Then, a solution of 4.5 g (0.060 mol) of methyl acetate in 10 ml of absolute dimethoxyethane was added dropwise, at ~5°C to 0°C, whilst stirring. The mixture obtained was stirred at 70°C for 15 minutes, 25 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 H hydrochloric acid. The portion that remained in the undissolved state, was suction filtered, and 30 it represented 8.5 g of practically pure starting 440 47 - 70 - anilide. 0.5 ml of 4 H 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 5 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% yield) of pure hydroxyethylidene-lO cyanoacetic acid 3-chloro-anilide (melting point 168 to 169°C) was obtained.

EXAMPLE 39.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-methylanilide.

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 dimethoxy-20 ethane. After the hydrogen evolution had ceased 5+0.5 g of gaseous ketene were introduced at 24 to 27°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 25 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 30 a little methanol. After drying, 17.6 g (= 65% yield) of pure hydroxyethylidene-cyanoacetic acid _ 7i 440 47 3-trifluoromethylanilide (melting point 180 to 181°C) were obtained.

EXAMPLE 40.

Hydroxyethylidene-cyanoacetic acid 3-trifluoro-5 methylanilide. - 0.5 g (/>j0.12 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 10 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 25°C and 90°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-cyano acetic acid 3-trifluoromeuhylanilide (melting point 180 to 181°C) were obtained.

Hydroxyethylidene-cyanoacetic acid 4-fluoro-anilide (yield 65%) and 3-bromoanilide (yield 67%), 20 were prepared in an analogous manner .

EXAMPLE 41.

Hydroxyethylidene-cyanoacetic acid 4-fluoro-anilide.

At 18 to 22°C, a solution of 5.85 g (0.030 mol) 25 of acetoacetic acid 4-fluoroanilide in 40 ml of absolute dimethoxyethane and, after the hydrogen evolution had ceased, at 0°C, a solution of 3.20 g (0.30 mol) of cyanogen bromide in 15 ml of absolute dimethoxy ethane, were introduced dropwise, whilst stirring, 30 into a mixture of 190 g (0.063 mol) of 80% sodium - 72 - 4 40 Ί'· —. · . . hydride-oil-suspension and 15 ml of absolute 1,2-dimeth-oxyethane. 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 60°C. Then, the solvent was evaporated 5 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 acid, a crystalline precipitate was : 10 obtained from the filtered aqueous solution, which was suction filtered and successively washed out with 4:1 methanol/water mixture and a little methanol.

After recrystallisation of the filter residue from methanol, 1.97 g (= 30% yield) of pure hydroxyethyl-15 idene-cyanoacetic acid 4-fluoroanilide (melting point 170 to 171°C) were obtained.

EXAMPLE 42.

Hydroxyethylidene-cyanoacetic acid 3-bromo-anilide.

At 22 to 28°C, a solution of 12.81 g (0.05 mol) of acetoaeetic acid 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 cyanogen chloride in 15 ml of absolute dimethoxyethane, 25 were added dropwise, whilst stirring, to a mixture Of 3.3 g (0.11 mol) of 80% sodium hydride-oil-suspension and 15 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 56°C and then evaporated 30 in vacuo. The remaining solid residue was thoroughly shaken with 150 ml of water . The substance that _73— 44047 • · » > remained in the undissolved state, was suction filtered, successively washed 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 5 filtration over kieselguhr, the solution was acidified with cone. 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-10 cyanoacetic acid 3-bromo-anilide (melting point 173 to 179°C). The acid aqueous filtrate was extracted three times with methylene chloride. The combined CH^Cl^ extracts were dried with Na^SO^, filtered, and evaporated in vacuo. 10 ml of methanol were added 15 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 179°C; 10% yield) and represented pure hydroxyethyl- idene-compound.

The original aqueous filtrate was precipitated with diethyl ether and then acidified with hydrochloric acid. The precipitate was suction filtered, successively washed out with water and methanol and dried. 4.5 g (= 32% yield) of pure hydroxyethyli-25 dene-cyanoacetic acid 3-bromoanilide (melting point 178 to 179°c) were obtained. The total yield was 80%.

Hydroxyethylidene-cyanoacetic acid 4-fluoro-anilide (yield 73%), 3-trifluoromethylanilide (yield 71%), 3-chloroanilide (yield 81%) and 3,4-dimethoxy-30 ethyleneanilide (yield 22%) were prepared in an analogous manner. 4 40-17 - 74 - EXAMPLE 43.

Hydroxyethylidene-cyanoacetic acid 3-chloroanilide .

A solution of 3.20 g (0.030 mol) of cyanogen bromide* 5 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 K^CO^ and 60 ml of absolute 1,2-dimethoxyethane, for 35 minutes, at 18 to 25°C, whilst stirring. After the mixture had been 10 stirred at 27°C and at 40°C for 30 minutes respectively, and at 60°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 15 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 ether were added to 20 the resinous mass and the mixture was shaken thoroughly. After separating the phases, the aqueous-alkaline phase was slightly acidif ied with cone. hydrochloric acid, the precipitate was suction filtered and then washed out with methanol. After drying, 0.95 g 25 (= 13.4% yield) of pure hydroxyethylidene-cyanoacetic acid 3-chloroanilide (melting point 168 to 169°C) were obtained.

EXAMPLE 44.

Hydroxyethylidene-cyanoacetic acid 4-chloro~2-30 trifluoromethylanilide.

A solution of 5.6 g (0.090 mol) of oy.-niofyii chloride in 60 ml of absolute dimethoxyethane was added - 75 - 4 40 47 dropwise, at 5 to 10°C, for 40 minutes, whilst stirring, to a mixture of 23,3 g (0.083 mol) of acetoacetic acid 4-chloro-2-trifluoromethylanilide, 12.4 g (0.090 mol) of ί^ΟΟ^ and 100 ml of absolute 1,2-dimethoxyethane.

Then the mixture was stirred at 10 to 25°C, at 28 to 30°C and at 44 to 46°C and, for 1.5 hours, at 60°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 10 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 15 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 cone, hydrochloric acid.

The precipitate was suction filtered and washed with 20 water and a small amount of methanol. After drying, 9.9 g (= 39% yield) of pure hydroxyethylidene-cyano-acetic acid 4-chloro-2-trifluoromethylanilide (melting point 132 to 133°C) were obtained.

EXAMPLE 45.

Hydroxyethylidene-cyanoacetic acid 3-chloro- anilide.

A solution of 7.05 g (0.05 mol) of 2-cyanoacetic acid methyl ester and 14 g (0.11 mol) of 3-chloro-anilina in 30 ml of dioxane was boiled under reflux 30 for 10 hours and then evaporated in vacuo. 20 ml of methanol and 50 ml of water were added to the 440 - 76 - 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 vacuo. 80 ml of 1 H sodium hydroxide solution and diethyl ether were 5 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 10 mixture and a small amount of methanol and was then dried. After drying, 1.40 g (= 12% yield) of pure hydroxvethylidene-cyanoacetic acid 3-chloroanilide (melting point: 168 to 169°C) were obtained.

EXAMPLE 46.

Hydroxyethylidene-cyanoacetic acid 4-bromo- anilide.

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 20 mol) of K2C03 was stirre4 for 8 hours under reflux and then evaporated in vacuo. 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 25 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 30 washed with water, a 4:1 water/methanol mixture and a small amount of methanol. After drying, 0.83 g ' ! 1 - 77 - 440 47 ( = 7.5¾ yield) of pure hydroxyethylidene-cyanoacetic acid 4-bromoanilide (melting point: 207 to 208°C) were obtained.

EXAMPLE 47.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl-anilidecyclohexylammonium salt 27 g (0.1 mol) of 2-hydroxyethylidene-cyanoacetic acid-3-trifluoromethylanilide ware suspended in 100 ml of methylene chloride, the suspension was stirred and 10 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 hydroxyethylidene-cyanoacetic acid 15 3-trifluoromethyl-anilide cyclohexylammonium salt (melting point: 157° to 159°C) were obtained.

Analysis: cigH22F3N302 Calculated: C 58.5%; H 6.0%; N 11.4%; MW 369.4 20 Found: C 58.5%; H 6.0%; IT 11.1% EXAMPLE 48.

Hydroxyethylidene-cyanoacetic acid 3-trifluoromethyl-anilide diethanolammonium salt 30 g (0.11 mol) of 2-hydroxyethylidene-cyanoacetic 25 acid 3-trifluoromethylanilide were suspended in 100 ml of ethyl acetate,the suspension was stirred and 11.5 g (O.il mol) of diethanolamine were added dropwise at room temperature to make the mixture homogeneous.

On evaporating the clear, brown solution, a solid 30 residue remained which yielded, after washing out with 4404*? “ 78 - cyclohexane, 32 g ( = 76% yield) of pure hydroxyethyl-idcne cyanoacetic acid 3-trifluoromethylanilide diethanolammonium salt hemihydrate (melting point: 96 to 98°C).

Analysis: Calculated with H^O: C 50.0%; H 5.5%; N 10.9%; MW 375.4 Found: C 50.3%; H 5.8%; N 11.0%

Claims (25)

1. A process for the manufacture of a hydroxy-ethylidene-cyanoacetic acid anilide of the general formula la or the tautomeric form lb, CH0 OH CH, 0 X. / c II 0 /c\./ -/·-.«/ NC C NC ' „ I

2. H 1 ΪΓ > r*£\ R3 (4A- R n—I— A 1 5 (E) XSo 2 > R m \ R3 k$

3. A process as claimed in claim 1 or claim 2, wherein, in process a^), the anhydride is acetic 20 anhydride.

4. A process as claimed in any one of claims 1 to 3, wherein, in process a^), 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. 25 5. A process as claimed in any one of claims 1 to 4, wherein, in process a^), the compounds of the general formula IV are subjected to alkaline hydrolysis. 4404” -86- 5. C^-COOR11 XII in which R"^ represents an alkyl radical having from 1 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 10 group, or with ketene, e) reacting an acetoacetic acid anilide of the general formula XIV OH, Ό 'V H„C 0 (XIV) 2 \ / Οζχ 12 3 in which R , R and R have the meanings given for the general formulae la and lb, in the presence of a basic J5 compound with cyanogen chloride or cyanogen broinide f) reacting a 2-cyanoacetoacetic acid ester of the general formula XVa or XVb CEL 0 CH_ OH -I y -- / XC ^- XC NC-C—C00R12 1 12 H NC C00R (XVa) (XVb) 12 - 85 - 440*1? in which R represents an 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 5 atoms with a substituted aniline of the general formula XVI H2SY > 3 (XVI> 12 3 in which R , R and R have the meanings given for the general formulae la and lb, and, if desired, converting 10. resulting salt of a hydroxyethylidene-cyanoacetic acid anilide of the general formulae la and/or lb into the free acid or another salt, or converting an acid of the general formula la and/or lb so obtained into a salt thereof. 15 2. A process as claimed in claim 1, wherein, in process a^), the methyl or ethyl ester of orthoacetic acid is used.

5. IX CH2 CN in the presence of a basic compound with an isocyanate of the general formula X /-v “2 12 3 in which R , R and R have the meanings given above, 10 d) reacting a cyanoacetic acid anilide of the general formula II 0 11 ~X NC-CH2-C-NH-^ ^ r3 II 12 3 in which R , R and R have the meanings given in the general formulae la and lb, in the presence of a basic 15 compound at a temperature in the range of from -80° to +200°C, with an acetic acid halide of the general formula XI (CEL-CO) X XI 3 n 44047 - 84 - in which X represents a chlorine or bromine atom and n is 1, or with an acetic anhydride of the general formula XX in which X represents an oxygen atom and n is 2, or with an acetic acid ester of the general formula XXI

6. A process as claimed in claim 5, wherein a sodium or potassium hydroxide or carbonate solution is used.

7. A process as claimed in claim 1, wherein, in 5 process ’ the reaction of a compound of the general formula XV with an amine of the general formula V is carried out in a neutral, organic solvent.

8. A process as claimed in claim 1 or claim 7, wherein, in process ), the compounds of the general 10 formula VI are subjected to acid hydrolysis.

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 15 per mol of sulphonylisocyanate.

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 -70°C to 140°C. 20

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 110°C.

12. A process as claimed in claim 11, wherein process c), is carried out at a temperature in the 25 range of from 10 to 85°C.

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. 30

14. A process as claimed in claim 1, wherein, in process d), 2 equivalents of the base are used per equivalent of acetylating agent. — 87 — 44047 I , 15. -CH CH N group, \οη2οη2- 7 in which R represents an alkyl group having 1 to 4 carbon atoms or a benzyl group. - 89 - 44047 I , ’

15. A process as claimed in claim 1 or claim 14, wherein process d), is carried out in a solvent or diluent.

16. A process as claimed in any one of claims 1, 5 14 and 15, wherein, in process d), the methyl, ethyl or phenyl ester of acetic acid is used.

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 10 tertiary butylate, sodium methylate or ethylate and/or potassium carbonate.

18. A process as claimed in claim 1, wherein, 12 in process f), R represents a methyl group.

19. A process as claimed in claim 1 or claim 18, 15 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 2 atoms, or a methylthio group, R represents a hydrogen 20 atom, a trifluoromethyl group, a halogen atom or a 3 2 methoxy group and R represents a hydrogen atom or R and R1 together represent a -O-CH^-0-group in the 3,4-position.

20. A process as claimed in claim 1, carried 25 out substantially as described in any one of Examples 1 to 9, 12, 13 and 15 to 48.

21. A process as claimed in claim 1, carried out substantially as described herein.

22. A process as claimed in claim 1, wherein 30 process d) is carried out substantially as described in process a) or β) herein. 4404? _s8_

23. A compound of formula la- and/or Xb as in claim 1 or a salt thereof, whenever prepared by a process as claimed in any one of claims 1 to 22.

24. A compound of the general formula (XVII) and 5 its tautomer. CH- Y II C y0 (XVII) / \ s NC C 12 3 in which R , R and R are as defined in claim 1 and Y represents a (C^-C^alkoxy group or an 10 group, in which R5 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^CH^-0-CH^CH^- group or a ^ R7

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. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS.