CH630342A5 - Process for the preparation of novel cyanoacetic acid anilide derivatives. - Google Patents

Abstract

Novel hydroxyethylidene-cyanoacetic acid anilides of the formula Ia or their tautomeric form Ib are prepared by reacting a corresponding cyanoacetic acid anilide with an acetic acid chloride, acetic acid bromide, acetic anhydride or acetic acid ester. The reaction is carried out in the presence of a basic compound at a temperature between -80 and +200 DEG C. The symbols in formulae Ia and Ib have the meaning given in the patent claim. The compounds of formula Ia and Ib and their physiologically tolerated salts exhibit a powerful antiphlogistic and analgesic, as well as anthelminthic, antimycotic and fungicidal action. <IMAGE>

Description

630342

2nd

PATENT CLAIM Process for the preparation of new hydroxyethylidene-cyanoacetic anilides of the formula Ia or their tautomeric form Ib

(Ia)

(Ib)

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

0 II

NC-CH -C-NH

Compound at a temperature between -80 and + 200 ° C with an acetic acid halide of formula III

(CHrCO) nX

(HI),

30th

(II),

in which X is chlorine or bromine and n = 1, or with acetic anhydride or with an acetic acid ester of the formula IV

CH3-COOR11 (IV),

35

in the R11 a Cr to C4 alkyl group, a benzyl group,

represents a phenyl group or a phenyl group substituted by one or two chlorine atoms or nitro groups or by a carbomethoxy or carboethoxy group, reacted with 40 or with ketene and optionally a salt of a hydroxyethylidene-cyanoacetic anilide of the formula Ia or Ib obtained in this way by adding a strong acid to one Transfer compound of formula Ia or Ib

45

in which R1, R2 and R3 have the meaning given above for the formula Ia or Ib, in the presence of a basic

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

0

NC

s \\ _ S

0

H

(la)

(Ib)

3rd

630342

in which R1 is a halogen atom, a methyl or ethyl group which can be substituted by 1 to 3 fluorine and / or chlorine atoms, a methoxy or ethoxy group which can be substituted by 1 to 4 fluorine and / or chlorine atoms,

or a methyl or ethyl mercapto group; R2 represents a hydrogen atom, a halogen atom, a methyl or ethyl group, a trifluoromethyl group or a methoxy group and R3 represents a hydrogen atom, a chlorine atom or a methoxy group, or R1 and R2 together represent the -0-CH2 - O grouping, and of their salts.

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

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

R3 is a hydrogen atom;

and R1 and R2 together form a 3,4 -0-CH2-0 grouping.

The radicals R1 particularly preferably denote a fluorine, chlorine or bromine atom or a methyl, tri

fluoromethyl or methoxy group;

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

R3 is a hydrogen atom;

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

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

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

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

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

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

NC-CHL-C-NH

in which R1, R2 and R3 have the meaning given above for the formula Ia or Ib, advantageously with the use of solvents or diluents, in the presence of a basic compound at a temperature between

—80 and + 200 ° C with an acetic acid halide of the formula III

(CH3-CO) nX (III),

in which X is chlorine or bromine and n = 1, or with acetic anhydride or with an acetic acid ester of the formula IV

CH3-COORu (IV),

in the R11 a Cx to C4 alkyl group, a benzyl group,

represents a phenyl group or a phenyl group substituted by one or two chlorine atoms or nitro groups or by a carbomethoxy or carboethoxy group, or reacted with ketene.

As acetic acid esters of the formula IV, methyl or ethyl acetate can be used for the acetylation of the anilides of the formula II by the process according to the invention; in addition, for example, the propyl, isopropyl, butyl, isobutyl, phenyl or benzyl ester of acetic acid can also be used.

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

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0 II

NC-CH -C-NH

(II)

3 + (CH3-CO) nX

(III)

/

0

TT II

3 O-C-CH.

OHH O

(V)

NC

0

C I

HN

R

R-

R "

respectively.

(II) + CH ^ -COOR11> 7 ^

(III) 1v) • x ^ OH® / H 0

respectively.

(II) + CH2 = C = 0 "> -7 (I)

J (v) - ^^ 0H® / H20

Alkaline or alkaline earth metal hydrides, sodium or potassium alcoholates of lower alcohols, alkali amides, sodium or potassium carbonate or bicarbonate, alkali metal hydroxides, lithium butyl and / or tertiary amines can be used as basic compounds.

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

The reaction according to the invention is preferably carried out using solvents or diluents.

Suitable solvents or diluents for the process according to the invention are all known solvents which are sufficiently inert to the respective reactants, such as, for example, aromatic hydrocarbons, mono- or dichlorobenzenes, nitrobenzene, anisole, dimethoxyethane, ether, tetrahydrofuran, dioxane, acetonitrile, tetrachlorethylene, Acetone, lower alcohols, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or dimethylformamide are considered. In addition, vinegar

30th

acid esters serve as diluents. If the acetylene is carried out with an acetic acid ester, this can of course also be used in excess as a diluent. Preferred solvents or diluents are 1,2-dimethoxyethane, tetrahydrofuran, ether, dioxane, acetonitrile, anisole, toluene, chloro- and di-chlorobenzene, acetone, tertiary butanol and chloroform, the choice of which may be used in the process according to the invention Reaction to be used with the solvent or diluent is influenced by the basic compound used. This means that when using strong bases such as hydrides, alkali amides, lithium butyl or potassium tert-butoxide, for example, no protic solvents or haloalkanes are expediently used, but the latter when using a weaker basic compound such as potassium carbonate or Alcohol can be used without further ado.

According to the process of the invention, the above-mentioned acetylating agents can be used in amounts of up to 4 equiva-50 lents, based on a cyanoacetanilide of the formula II, an exception to this are the cases in which acylation is carried out with acetic acid esters if these are simultaneously used as a solution or diluents. In such cases, the esters are used in an up to 50-fold 55 equimolar excess. 1 to 2 equivalents of one of the above acetylating agents, based on a cyanoacetanilide, are preferably used.

In this reaction, the (1-hydroxyethylidene) -cyanoacetic anilides of the formula I formed are in the form of their 60 salts.

The acidic compounds of the formula I are usually isolated therefrom in such a way that, if appropriate after evaporation of the solvents used, the reaction product is treated with water and / or dilute aqueous alkalis and / or aqueous ammonia and, if appropriate after extraction of the aqueous phase, with Ether, isopropyl ether or a hydrocarbon boiling range 40 to 120 ° C, from the aqueous solution by An

5

630342

acidifies the (l-hydroxyethylidene) -cyanoacetic anilide of the formula I, which usually precipitates out as a crystalline precipitate.

Particularly preferred embodiments of the method according to the invention are as follows:

a) When using a strongly basic compound, such as sodium hydride, sodium or potassium amide, lithium n-butyl or potassium tert-butoxide, the procedure is expedient in the presence of 0.5 to 80 parts by weight per part of cyanoacetanilide one or more of the solvents indicated above as preferred. 2.0 to 2.2 equivalents of the base are added to the solution of the cyanoacetanilide of the formula II at a temperature between -5 and + 30 ° C., if acetic acid chloride, bromide, anhydride or ester are used as the acylating agent, or 1.0 to 1.3 equivalents of the base, if ketene is used as the acetylating agent, and then adds 1.0 to 1.2 equivalents of the acetylating agent, if appropriate with the above, at a temperature between -5 and + 60 ° C. Diluted solvents. After a reaction time of up to 5 hours, in which the temperature can optionally be increased temporarily up to 125 ° C., most or all of the solvents or diluents are evaporated off and water is added to the residue. The compounds of formula I formed in each case are then isolated as described above.

b) When using a weaker basic compound such as sodium or potassium carbonate or a tertiary amine such as triethylamine, at a temperature between +20 and + 120 ° C to a mixture of a part of cyanoacetanilide of the formula II and 2 to 20 Parts by weight of one or more of the solvents indicated above as preferred and 2.0 to 3.3 equivalents of such a compound if acetic acid chloride, bromide, anhydride or ester are used as acylating agents, or 1.0 to 1.2 Equivalents of such a basic compound, if ketene is used as the acetylating agent, 1.0 to 1.4 equivalents, based on the cyanoacetanilide, of the acetylating agent, optionally in the form diluted by the above solvents. After a reaction time of up to 24 hours, within which the temperature can be between +20 and + 120 ° C, the procedure is analogous to that described under a) or earlier, in order to produce the (l-hydroxyethylidene) -cyanoacetic acid anilides formed in each case isolate.

When carrying out the reaction according to the invention, it must be taken into account that if the respective acetylating agent is used in amounts of more than about 1.3 equivalents per val of the cyanoacetanilide, then the reaction products partly or, depending on the amount of the acetylating agent used, largely in the form of their O- and / or N-aectyl products. The O-acetyl compounds of formula V

0 II

O-C-CH.

c

II

c

10th

15

NC

0

(V),

20 in which R1, R2 and R3 have the meaning given above are hardly soluble in water and, if extracted with organic solvents, are in the organic phase, but they are already hydrolytically cleaved by dilute alkalis and thereby go into the corresponding ones 25 alkali salts of the compounds I on. The hydroxyethylidene compounds of the formula I can be released from aqueous solutions or suspensions of these salts by acidification with mineral acid. If this procedure is followed, the proportion of the reaction products which may initially be obtained as an O-acylated compound is also recorded and converted into the desired end product of the formula I. The formation of O-acetyl derivatives of the (l-hydroxyethylidene) -cyanacetanilides of the formula 1 can, however, be largely avoided if a ratio of about 2 equivalents of base to one equivalent of acetylating agent is used in the process according to the invention.

The a-acylation of tert-butyl cyanoacetate with acetyl chloride to form tert-butyl acid tert-butyl O-acetyl-cyano was carried out by Dahn and Hauth, Helvetica Chim. Acta 42, 1214 (1959). In addition, a-acylcyanoacetic acid esters were mentioned in DE-AS 1 194 630.

Manufacturing methods were not described there, however. However, the transfer of the reaction to cyanoacetic acid-45 anilides was by no means a matter of course, since it is known that the -CONH group has another deprotonable and thus acylatable function which could lead to undesired products or to failure of the a-acylation.

50 The smooth course of the acylation of cyanoacetanilides in the presence of relatively weakly basic compounds, such as sodium and potassium carbonate and tertiary amines, is particularly surprising. In reactions comparable in type with C-H-acidic 55 compounds, only extremely strong bases are generally used for deprotonation.

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

If the compounds I are first formed in the form of their alkali metal, alkaline earth metal or ammonium salts or as salts of organic bases and are present as such in solution in one of the types of preparation, these salts of the compounds I can optionally be purified by recrystallization by evaporating off the solvents used . On the other hand, by adding an equimolar amount

630342

6

a suitable base, advantageously with the use of solvents which are inert to the bases, to give a compound of the formula Ia or Ib salts of these compounds, and isolated after evaporation of the solvent or by addition of other solvents which lead to the separation of the salts . As bases, sodium, potassium, calcium or magnesium alcoholates of lower alcohols, sodium, potassium, calcium, magnesium or ammonium hydroxide, sodium, potassium, calcium, magnesium or ammonium carbonate or bicar- bonate and sodium, magnesium or calcium hydride, ammonia or sodium amide or organic bases, such as tertiary amines, are used. When using alkali or alkaline earth alcoholates, it is advantageous to work in the presence of a lower alcohol in addition to any solvents that may be used. If the above-mentioned hydroxides, carbonates and / or bicarbonates are used as bases, it is advantageous to work in the presence of water and / or lower alcohols, where appropriate other organic solvents can also be used.

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

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

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

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

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

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

example 1

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

In a mixture of 3.31 g of 80% sodium hydride - oil suspension 0.11 mol NaH) and 5 ml of dry 1,2-dimethoxyethane, a solution of 11.4 g (0 , 05 mol) of cyanoacetic acid (3-tri-fluoromethylanilide) in 50 ml of absolute dimethoxyethane. After the evolution of hydrogen had subsided, 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.degree. The reaction mixture was stirred for 30 minutes at 0 to + 27 ° C and for 1 hour at 25 to 33 ° C and 62 to 65 ° C and then evaporated in vacuo. 300 ml of water were added to the residue and shaken at room temperature for 30 minutes. The product went into solution except for a small amount. The mixture was filtered through diatomaceous earth and the filtrate was acidified with dilute hydrochloric acid. The resulting crystalline precipitate was filtered off, washed with water until salt-free and neutral, washed with methanol / water (2: 1) and dried. 9.7 g (^ 72% yield) of hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide) were obtained, mp 179-181 ° C. From this product, 9 g of pure compound of mp 181 ° to 182 ° C. were obtained by recrystallization from methanol.

Analogously to the procedure described in Example 1, the hydroxyethylidene-cyanoacetic anilides listed in Table 1 below were prepared in the indicated yields.

TABLE 1 Hydroxyethylidene cyanoacetic anilides

0H

CH

NC-C-CONH

No.

R1

R2

Mp (° C)

Yield in%

1

3-C1

H

168-169

73

2nd

3-year

H

198-200

64

3rd

4-Br

H

208-209

73

4th

4-F

H

170-171

69

5

4-OCH3

H

150-152

57

6

2-OC2H5

H

109-111

43

7

3-C1

4-C1

209-210

74

8th

2-C1

4-C1

140-141

65

9

2-CH3

3-C1

164-165

71

10th

3-SCH3

H

135-136

62

11

2-CH3

5-C1

127-128

73

12th

3,4-0-CH20-

3,4-0-CH20-

166-167

40

13

4-y

H

207-208

70

Example 2

Hydroxyethylidene-cyanoacetic acid- (3-bromoanilide)

A solution of 12 g (0.05 mol) was stirred into a mixture of 3.6 g of 80% sodium hydride oil suspension (^ 0.12 mol NaH) and 10 ml of dry acetonitrile at 10 to 25 ° C. with stirring. Cyanacetic acid (3-bromoanilide) added dropwise in 100 ml of absolute tetrahydrofuran. After the ablining 5

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630342

In order to develop hydrogen, 4.35 g (approx. 0.055 mol) of acetyl chloride were added dropwise at −10 to 0 ° C. and the mixture was subsequently stirred at 0 to + 28 ° C. for 30 minutes and at 28 to 35 ° C. and 62 to 65 ° C. for 1 hour each continue.

The reaction mixture was then evaporated in vacuo and the remaining residue was further processed as described in Example 1. 10.1 g (A 72% yield) of pure hydroxyethylidene-cyanoacetic acid (3-bromani-lid) with an mp of 178 to 179 ° C. were obtained.

Example 3

Hydroxyethylidene-cyanoacetic acid- (4-bromoanilide)

A mixture of 23.9 g (0.1 mol) of cyanoacetic acid - (4-bromoanilide), 16.6 g (0.12 mol) of dry, powdered K2C03 and 100 ml of dry acetone was added dropwise with stirring at 27 ° C. 9.45 g (0.12 mol) of acetyl chloride. After stirring at 27 to 30 ° C. for 1 hour and stirring under reflux for 2.5 hours, the acetone was removed in vacuo and the residue was extracted with water. About 15 g (A 63%) of starting anilide remained undissolved. The aqueous extract was filtered and weakly acidified with dilute sulfuric acid. A crystalline precipitate formed, which was recrystallized from methanol after suction, washing with water / methanol (1: 2). After drying, 8.4 g (A 30% yield) of pure hydroxyethylidene-cyanoacetic acid (4-bromoanilide) of mp. 208 to 209 ° C. were obtained.

Example 4

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

A solution was added to a mixture of 11.4 g (0.05 mol) of cyanoacetic acid - (3-trifluoromethylanilide), 7.6 g (0.055 mol) of K ^ COj and 150 ml of toluene at 70 ° C. with stirring in 30 minutes 4.1 g (0.052 mol) of acetyl chloride in 10 ml of toluene was added dropwise. The mixture was then stirred at 90 ° C. for 1 hour, then cooled, the solid present was suctioned off and washed with 100 ml of toluene. The dried product was extracted with water. The filtered aqueous extract was acidified slightly with dilute hydrochloric acid and then the precipitate formed was suction filtered. After washing with water, this was recrystallized from methanol. 5.3 g (A 39% yield) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethylanilide) of mp 180 ° to 182 ° C. were obtained. According to the result of thin-layer chromatography, the proportion (5.2 g) of the solid which was not dissolved in water was predominantly starting anilide.

Example 5

Hydroxyethylidene-cyanoacetic acid- (5-chloro-2-methylanilide)

To a mixture of 10.5 g (0.05 mol) of cyanoacetic acid - (5-chloro-2-methylanilide), 12.3 g (0.11 mol) of potassium tert-butylate and 150 ml of dry dioxane a solution of 4.35 g (0.055 mol) of acetyl chloride in 5 ml of 1,2-dimethoxyethane was added dropwise at 35 ° C. in 25 minutes and the mixture was then stirred at 90 ° C. for 2 hours. After evaporating the solvents in vacuo, the residue was extracted with 300 ml of water. The filtered aqueous extract separated out a crystalline precipitate on acidification with dilute hydrochloric acid. This was suctioned off, washed as described in Example 1 and dried. 6.4 g (A 51% yield) of hydroxyethylidene-cyanoacetic acid (5-chloro-2-methylanilide) were obtained, mp. 127 to 128 ° C.

Example 6

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

With stirring, a mixture of 11.4 g was added to a mixture of 3.40 g (0.113 mol) of 80% sodium hydride oil suspension and 5 ml of dry 1,2-dimethoxyethane at 10 to 20 ° C. in 25 minutes (0.05 mol) of cyanoacetic acid- (3-tri-fluoromethylanilide) in 50 ml of absolute dimethoxyethane and after the evolution of hydrogen has ceased at -10 to -5 ° C. in 25 minutes a solution of 5.6 g (0.055 mol) of acetic anhydride in 100 ml of absolute dimethoxyethane was added dropwise. The mixture was then stirred for a further 30 minutes at −5 ° C. to room temperature and for 1 hour each at 25 to 30 ° C. and 65 to 70 ° C., and the reaction mixture was then evaporated in vacuo. The residue was dissolved in 300 ml of water and the solution was shaken out with 80 ml of ether. The aqueous phase was slightly acidified after filtering with hydrochloric acid. The precipitate was washed successively with water, methanol / water (2: 1) and a little methanol and then dried. This gave 12.8 g (A 95% yield) of pure hydroxyethylidene-cyanoacetic acid - (3-trifluoromethylanilide), mp. 181 to 182 ° C.

In an analogous manner, 2-hydroxyethylidene-cyanoacetic acid- (3-bromoanilide) (yield: 93%) and- (3,4-dichloroanilide) (yield: 94%) were prepared.

Example 7

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

16.6 g (0.12 mol) of potassium carbonate were suspended in a solution of 22.8 g (0.1 mol) of cyanoacetic acid- (3-trifluoromethylanilide) in 100 ml of 1,2-dimethoxyethane. With stirring, 14.3 g (0.14 mol) of acetic anhydride were then added dropwise at room temperature. After 4 hours of stirring at room temperature, the mixture was evaporated in vacuo and the remaining residue was extracted with water. After filtration through kieselguhr, the aqueous extract was precipitated into 3-trifluoromethylanilide (hydroxyethyl-iden-cyanoacetic acid) by acidification with dilute sulfuric acid. After suction, washing and drying, 19 g (A 70% yield) of product mp 172-173 ° C were obtained, from which after recrystallization from methanol 17.3 g (A 64% yield) of pure compound (mp 181-182 ° C) were isolated.

Analogously to the procedure described in Example 7, the hydroxyethylidene-cyanoacetic anilides listed in Table 2 below were prepared in the indicated yields.

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TABLE 2

No.

R1

R2

Yield in%

1

3-C1

H

72

2nd

3-year

H

63

3rd

4-F

H

73

4th

2-CI

4-cl

71

5

3-SCHa

H

52

6

2-CH3

5-cl

72

7

3,4-0-CH2-0-

3,4-0-CH2-0-

35

8th

4-OCH3

H

40

9

2-CF3

4-cl

51

Example 8

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

If the procedure is as in Example 7, but instead of 16.6 g of K2CO316.6 g (0.16 mol) of anhydrous soda, 10.0 g (A 37% yield) of hydroxyethylidene-cyanoacetic acid (3-trifluoromethylanilide) obtained from mp 175 to 176 ° C. In this procedure, a considerable part (13.5 g) remained undissolved in the extraction of the reaction product with water, which, according to the result of thin-layer chromatography, consisted largely of unreacted starting material.

Example 9

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

As described in Example 7, 0.1 mol of cyanoacetic acid- (3-trifluoromethylanilide) in dimethoxyethane was reacted with 14.3 g (0.14 mol) of acetic anhydride in the presence of 16.6 g of K2CO3 and the mixture was stirred, after this was added, continue at 90 ° C for 1 hour. After the mixture obtained had been evaporated, the residue was taken up in water, the solution was filtered through diatomaceous earth and the filtrate was acidified. The precipitate which had separated off was washed with water, water / methanol (1: 3) and methanol in succession and dried. 18.8 g (A 73% yield) of practically pure hydroxyethylidene-cyanoacetic acid - (3-trifluoromethylanilide) of mp 178 ° to 179 ° C. were obtained.

Example 10

Hydroxy'thylidene-cyanoacetic acid- (3-trìfluoromethylanilide)

With stirring, it was added dropwise at room temperature to a mixture of 22.8 g (0.1 mol) of cyanoacetic acid- (3-trifluoromethylanilide), 15.2 g (0.11 mol) of K2C03 and 100 ml of ethyl acetate 10.2 g (0.1 mol) of acetic anhydride and stirring was continued at room temperature for 1 hour and under reflux for 2 hours. After evaporating the mixture in vacuo, the remaining residue was worked up as described in Example 7. After recrystallization of the crude product from methanol, 1.7 g (A 6.3% yield) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl-s anilide) of mp. 181 to 182 ° C.

Example 11

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

io A mixture of 22.8 g (0.10 mol) of cyanoacetic acid- (3-trifluoromethylanilide), 15.2 g (0.11 mol) of KjSC ^ and 200 ml of toluene was mixed with vigorous stirring at 70 ° C 10 , 2 g (0.10 mol) of acetic anhydride was added dropwise. The mixture was then stirred at 90 ° C for 1 hour, Hess cool to about 15 ° C and the solid was suctioned off. This was washed out with ethyl acetate and a little water.

The undissolved portion (9 g) was found to be the potassium salt of hydroxyethylidene-cyanoacetic acid (3-trifluoromethylanilide), mp. 215 to 217 ° C (yield: 29%). 3 g of free hydroxy compound, mp 166 ° to 168 ° C. (A 11% yield), were precipitated from the wash water with dilute hydrochloric acid.

Example 12

25 hydroxyethylidene-cyanoacetic acid- (4-bromoanilide)

A mixture of 12 g (0.050 mol) of cyanoacetic acid (4-bromoanilide), 5.2 g (0.051 mol) of acetic anhydride and 50 ml of absolute 1,2-dimethoxyethane was added dropwise to 10.5 g with stirring at room temperature (0.104 mol) of triethylamine were added, the temperature slowly rising to 30 ° C. The mixture was stirred at 30 ° C and 2 hours at 80 ° C for 2 hours and then the mixture was evaporated in vacuo. This gave a dark-colored oil as a residue, which was taken up in 35 ethyl acetate. The solution formed was shaken 8 times in succession with water and dilute soda solution. All aqueous extracts were then combined and weakly acidified with hydrochloric acid. The precipitate which had separated out was filtered off with suction, washed successively with water and water / methanol / water (3: 1) and recrystallized from methanol, 5.9 g (A 42% yield) of pure hydroxyethylidene-cyanoacetic acid (4-bromoanilide), mp 208 to 209 ° C were obtained.

45 Example 13

Hydroxyethylidene-cyanoacetic acid- (3-chloroanilide)

To a mixture of 3.31 g of 80% sodium hydride oil suspension (A 0.11 mol NaH) and 10 ml of dry 1,2-dimethoxyethane at 10 to 20 ° C a solution of 9.73 g ( 0.05 mol) of cyanoacetic acid (3-chloroanilide) in 80 ml of absolute dimethoxyethane. After the evolution of hydrogen had subsided, the mixture was added dropwise with stirring

0 to 5 ° C a solution of 5.3 g (0.06 mol) of ethyl acetate

55 in 100 ml of dimethoxyethane and stirred for 20 minutes at 5 to 28 ° C and 1.25 hours at 70 to 75 ° C. The mixture was then evaporated in vacuo and the remaining residue was mixed with 150 ml of water and shaken. The resulting solution was extracted with 100 ml of ether 60. After the phases had been separated, the aqueous phase was weakly acidified with dilute hydrochloric acid and the precipitate which had separated out was filtered off with suction and washed with methanol / water (6: 1) and dried. 9.7 g of t (A 82% yield) of pure hydroxyethylidene-cyanoacetic acid 65 - (3-chloroanilide) of melting point 168 to 169 ° C. were obtained.

After the concentration, the wash liquor became still

1 g (8.5% yield) product of mp. 165 to 167 ° C isolated.

Instead of 5.3 g of ethyl acetate, 7.5 g (0.055 mol)

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Using phenylacetate, 9.3 g (A 79% yield) of pure hydroxyethyl-iden-cyanoacetic acid (3-chloroanilide) were obtained by the same procedure.

Example 14

Hydroxyethylidene-cyanoacetic acid- (3-chloroanilide)

A mixture of 6.0 g (0.11 mol) of sodium methylate and 25 ml of absolute 1,2-dimethoxyethane was added dropwise at room temperature with a solution of 9.77 g (0.05 mol) of cyanoacetic acid (3-chloroanilide) in 50 ml of absolute dimethoxyethane added. A solution of 5.6 g (0.055 mol) of acetic anhydride in 10 ml of absolute dimethoxyethane was then added dropwise to the resulting mixture at −7 to 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes and at 30 to 35 ° for 1 hour each C and 65 to 70 ° C further. The reaction mixture was then evaporated in vacuo and the residue was taken up in a mixture of 150 ml of water and 25 ml of 2N sodium hydroxide solution. The undissolved portion was suctioned off and washed out with about 200 ml of weakly alkaline water (pH 11 to 12). The combined alkaline filtrates were weakly acidified with hydrochloric acid. The precipitate was filtered off and washed successively with water, methanol / water (4: 1) and a little methanol and dried. 3.1 g (A 26% yield) of hydroxyethylidene-cyanoacetic acid (3-chloroanilide) of mp 167-168C were obtained.

Example 15

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 to a solution of 2.5 g of sodium in 30 ml of methanol at room temperature in 5 minutes. The mixture was then cooled to 0 ° C. and a solution of 4.50 g (0.061 mol) of methyl acetate in 10 ml of methanol was added dropwise at 0 ° C. in 15 minutes. The reaction mixture was then stirred for 30 minutes at 0 to 26 ° C. and for 1 hour each at 38 to 40 ° C. and under reflux (61 ° C.). Another 4.5 g (0.061 mol) of methyl acetate were then added to the reaction mixture. The mixture was stirred under reflux for a further hour. The reaction solution was then evaporated in vacuo and the remaining residue was treated with a mixture of 150 ml of water and 7 ml of 4N hydrochloric acid. The solution thus obtained with a pH of about 10 was adjusted to pH 8 with 6 ml of 2N acetic acid, a precipitate being formed. This was suctioned off and washed out with dilute soda solution; the undissolved portion was shaken with 2N soda solution for 1 hour. The resulting suspension was again sucked off and n

washed the solid one after the other intensively with soda oil

10th

solution and with water. The soda extracts and the wash water and the original aqueous (pH 8) filtrate were combined and weakly acidified with hydrochloric acid. The precipitate was filtered off and washed successively with water, methanol / water (5: 1) and a little methanol. After drying, 6.7 g (A 57% yield) of pure hydroxyethylidene-cyanoacetic acid (3-chloroanilide) were obtained.

Example 16

Hydroxyethylidene-cyanoacetic acid- (3-chloroanilide)

A solution of 9.73 g (0.050 mol) of cyanoacetic acid (3-chloroanilide) in 50 ml of absolute solution was added to a mixture of 4.05 g (0.075 mol) of sodium methylate and 10 ml of dry 1,2-dimethoxyethane with stirring at room temperature Add dimethoxyethane. A solution of 4.5 g (0.060 mol) of methyl acetate in 10 ml of absolute dimethoxyethane was then added dropwise at -5 to 0 ° C. with stirring. The resulting mixture was then stirred at 0 to 25 ° C for 15 minutes, at 40 ° C for 30 minutes and at 70 ° C for 1.5 hours and then evaporated in vacuo. The residue was taken up in a mixture of 150 ml of water and 2 ml of 4N hydrochloric acid. The portion that remained undissolved was suctioned off; it was 8.5 g of practically pure starting anilide. The filtrate was mixed with 0.5 ml of 4N hydrochloric acid and the precipitate which had separated out was filtered off with suction. This substance was also pure starting anilide (0.4 g). The aqueous filtrate was then acidified slightly with 8.2 ml of 4N hydrochloric acid, the crystalline precipitate formed was filtered off with suction and washed successively with water, methanol / water (5: 1) and a little methanol. After drying, 0.47 g (A 4% yield) of pure hydroxyethylidene-cyanoacetic acid (3-chloroanilide) of mp 168 to 169C were obtained.

Example 17

Hydroxy'ethyUden cyanoacetic acid- (3-trifluoromethylanilide)

A mixture of 3.3 g (0.11 mol) of 80% sodium hydride oil suspension and 10 ml of absolute dimethoxyethane was added dropwise at 20 to 25 ° C. with a solution of 22.8 g (0.10 mol) Cyanoacetic acid (3-trifluoromethyl anilide) in 100 ml of absolute 1,2-dimethoxyethane. After the evolution of hydrogen had subsided, 5 ± 0.5 g of ketene were gassed in at 24 to 27 ° C. while stirring, the apparatus being equipped with a reflux condenser filled with dry ice. The mixture was then stirred for a further 30 minutes at room temperature and the solvent was then evaporated in vacuo. The residue was extracted with water. The filtered alkaline extract was acidified with dilute sulfuric acid. The precipitate was filtered off and washed with water, methanol / water (4: 1) and a little methanol. After drying, 17.6 g (A 65% yield) of pure hydroxyethylidene-cyanoacetic acid (3-trifluoromethylanilide) of mp 180 ° to 181 ° C. were obtained.

Example 18

Hydroxyethylidene-cyanoacetic acid- (3-trifluoromethylanilide)

Into a mixture of 22.8 g (0.10 mol) of cyanoacetic acid - (3-trifluoromethylanilide), 100 ml of absolute dimethoxyethane and 7.6 g (0.055 mol) of potassium carbonate were 5 ± with stirring at room temperature using a dry ice reflux condenser 0.5 g (about 0.12 mol) of ketene gasified. The mixture was subsequently stirred at 25 and 90 ° C. for 1 hour each, and the mixture was then evaporated in vacuo. The residue was worked up as described in Example 17. 17.3 g (A 64% yield) of pure hydroxy-ethylidene-cyanoacetic acid (3-trifluoromethylanilide) of mp 180 ° to 181 ° C. were obtained.

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

Example 19

Hydroxyethylidene-cyanoacetic acid- (4-bromoanilide)

A mixture of 9.6 g (0.04 mol) of cyanoacetic acid (4-bromoanilide), 80 g (approx. 1.1 mol) of methyl acetate, 13.6 g (0.10 mol) of phenylacetate and 6.1 g (0.044 mol) of K2CO3

5

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8 hours, stirred under reflux and then evaporated in vacuo. The residue was mixed with 300 ml of water and then the mixture was shaken vigorously. The aqueous phase was filtered off from the oil-permeated solid and adjusted to pH 9 with 1N hydrochloric acid. The precipitate was filtered off and the filtrate was slightly acidified with hydrochloric acid, whereby further crystalline material precipitated. This was suctioned off and washed successively with water, water / methanol (4: 1) and a little methanol. After drying, 0.83 g (A 7.5% yield) of pure hydroxyethylidene-cyanoacetic acid (4-bromoanilide) of mp. 207 to 208 ° C. was obtained.

Example 20

Hydroxyethylidene cyanoacetic acid (3-trifluoromethyl anilide) cyclohexylammonium salt

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

Yield) hydroxyethylidene-cyanoacetic acid- (3-trifluoromethyl-anilide) -cyclohexylammonium salt of mp. 157 to 159 ° C obtained.

Analysis: C ^ H ^ F3NgOjj 5 calculated: C 58.5 H 6.0 N 11.4 MG 369.4 found: C 58.5 H 6.0 N 11.1

Example 21

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

10th

30 g (0.11 mol) of 2-hydroxyethylidene-cyanoacetic acid (3-trifluoromethyl anilide) were suspended in 100 ml of ethyl acetate, stirred and 15 11.5 g (0.11 mol) of diethanolamine were added dropwise at room temperature. The mixture became homogeneous during the dropping. When the clear brown solution was evaporated, a solid residue remained which, after washing with cyclohexane, 32 g (A 76% yield) of pure hydroxyethylidene-cyanoacetic acid- (3-trifluoro-2o methyl-anilide) -diethanolammonium salt hemihydrate, mp 96 to 98 ° C delivered.

Analysis: C16H20FsN3O4

calculated: *) C 50.0 H 5.5 N 10.9 MG 375.4 found: C 50.3 H 5.8 N 11.0 25 *) with H H, 0

v