CH632236A5 - Process for preparing novel substituted phenylacetonitriles - Google Patents

Description

The present invention relates to a process for the preparation of new substituted phenylacetonitriles of the formula I.

cooa

20th

COOB I

C - CN

(I)

wherein X is sodium or potassium and R has the same meaning as in formula I, with the remainder R 'introducing agents at temperatures between 70 and 150 ° C.

2. The method according to claim 1, characterized in that compounds are prepared in which R 'is a methyl-substituted C5-C7 cycloalkyl group.

3. The method according to claim 1, characterized in that compounds are prepared in which R represents the methyl or ethyl group and R 'has the meaning given in claim 1.

4. The method according to claim 1, characterized in that the temperature is 120 to 130 ° C.

5. Use of the compound of the formula I obtained by the process according to claim 1 for the preparation of compounds of the formula in which R is different or the same and denotes a straight-chain 25 or branched alkyl group having 1 to 4 carbon atoms, preferably the methyl group and in particular the ethyl group , and in which R 'is a straight-chain or branched alkyl group having 1 to 4 C atoms, a cycloalkyl group having 5 to 7 C ring atoms which is optionally substituted by a straight-chain or branched alkyl group having 1 30 to 4 C atoms, and in particular the methyl group, the benzyl group or a benzyl group 35 which is substituted by bromine or chlorine, preferably chlorine, or the group -COORj, where R ^ has the meaning given for R above.

The compounds of the formula I obtained according to the invention can be used to prepare compounds of the following formula

40

CH-CN I

B *

f »)

(II)

wherein R 'is defined in claim 1, by subjecting said compounds of formula I to partial saponification and then partial decarboxylation, characterized in that the solid or oily substance obtained after saponification with aqueous alkali and subsequent acidification after the separation of the aqueous phase heated to the boiling point with xylene.

wherein R 'is a straight-chain or branched alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 5 to 7 C-ring atoms optionally substituted by a straight-chain or branched alkyl group with 1 to 4 carbon atoms, and in particular the methyl group, the benzyl group or a benzyl group substituted by chlorine or bromine, preferably chlorine, or 55 the carboxyl group.

Starting from the compounds of the formula I, the compounds of the formula II can be used to obtain pharmacologically highly active compounds of the phenylacetic acid series, e.g. to the 3-benzoylphenylacetic acid-6o derivatives of DE-OS 2 258 985 or, by saponification of the nitrile group, to new 3-carboxyphenylacetic acid derivatives with anti-inflammatory, anti-rheumatic, anti-microbial and anti-arthritic effects (cf. the German patent application of Rütgerswerke AG by the same Filing date).

Since a high degree of purity must be sought for the pharmaceutical utility of these compounds, the problem arose, even the compounds of the formula II

as pure and isomer-free as possible in a technically simple and economically advantageous manner.

It has now been shown that, if one starts from the compounds of the formula I according to the invention, the compounds of the formula II in the high purity required for further processing into pharmaceuticals and, moreover, in very good yields (80 to 98%) receives.

According to the process for the preparation of the compounds II known from the literature (ER Biehl, HM Li, J. Org. Chem. 31, 1966, 602), o-chlorobenzoic acid is dissolved in liquid ammonia in the presence of freshly prepared sodium amide with corresponding a-active hydrogen components, e.g. Propionitrile, butyronitrile, etc. implemented. In addition to the fact that this process is far too complex, cumbersome and expensive for technical batch sizes and gives highly unsatisfactory results in terms of yield (49-71%), the reaction proceeding through the aryne stage does not provide uniform products, but rather analogously to those in Biehl and Li , Ie, aminobenzoic acid isomer mixtures mentioned. This can be seen e.g. in a difference in the melting points: the compound II with R '= CH3 produced according to the Biehl and Li method melts at 134-135 ° C, the same compound produced according to the method according to the invention from I at 146-147 ° C, so significantly higher. The purity of the compounds prepared from I by the process according to the invention was verified by thin layer chromatography.

The compounds of formula I are therefore new, valuable intermediates for the synthesis of partly known and partly new pharmacologically active compounds. The synthesis starting from the new intermediate I proceeds via the compounds of the formula II, from which the active compounds can then be obtained in a manner known per se, e.g. Ketoprofen from II (with R '= CH3) by the process of DE-OS 2 258 985, or new 3-carboxyphenylacetic acid derivatives of the formula A.

E '

with anti-inflammatory, anti-rheumatic, anti-microbial and anti-arthritic effects (cf. the German patent application of Rütgerswerke AG from the same filing date) from II by saponification of the nitrile group.

The compounds II can be obtained from the compounds of the formula I which can be prepared according to the invention by partial saponification and decarboxylation. The solid or oily substance obtained after saponification with aqueous lye and subsequent acidification is usually heated to the boiling point after the aqueous phase has been separated off with xylene. Pure x-, m- or p-xylene or else a mixture of the isomers can be used as the xylene. It has been found to be particularly advantageous to suspend the substance to be saponified in a water / methanol mixture = 1: 1 and to drop in the sufficient amount of about 10-15% aqueous sodium hydroxide solution at 20 to 25 ° C. and to add it completely Stir clarity of the mixture. In principle, another lye can also be selected, e.g. Potash lye. The mixture can then be mixed with acid, e.g. Hydrochloric acid adjusted to pH 1 632 236

the. The resulting solid or oily substance after separation from the aqueous phase is preferably washed with water and then heated to boiling temperature with stirring with xylene.

With such a procedure, three effects can be achieved simultaneously: the product is drained within a very short time, decarboxylated at the same time and, before crystallization from the solvent, freed of inorganic (e.g. common salt) and organic impurities by filtration. The yields are good and are 80-98% of theory. There is also no annoying foaming of the reaction mixture, as can usually be observed when using aromatic solvents, which has a disruptive effect, especially in the case of larger batches. In addition, the nitrile group is not saponified when heated in xylene, which was actually to be expected due to the still high water content of the crude saponification product. It is therefore possible, even without complex intermediate drying of the saponification product, to decarboxylate the compounds I selectively and in very high yields to give the compounds II.

Alkali-3-carbalkoxyphenylcyanoacetic acid esters of the formula III are used to prepare the compounds of the formula I according to the invention

COOE

COOE C-CN

wherein X is sodium or potassium and R has the same meaning as in formula I, with the remainder R 'introducing agents at temperatures between 70 and 150 ° C, preferably at 120 to 130 ° C. Such agents are preferably dialkyl sulfate type agents, e.g. Dimethyl and diethyl sulfate, alkyl and cycloalkyl halides, e.g. Butyl bromide and cyclohexyl bromide, the benzyl halides and the halogen-substituted benzyl halides, e.g. Benzyl chloride and 4-chlorobenzyl chloride, or the halomethylbenzoic acid ester, e.g. 3-chloro-methylbenzoic acid ethyl ester. Suitable solvents to be used preferably are substances which do not interfere with the course of the reaction and which have a boiling point which is sufficiently high for the reaction to proceed, e.g. Ethanol, butanol, xylene, mesitylene, pseudocumene, diethyl carbonate, dimethylformamide (DMF), hexamethylphosphoric acid triamide. After preferred treatment with water and removal of the solvent, the reaction products can be purified by distillation.

The alkali-3-carbalkoxyphenylcyanoacetic acid esters of the formula III, in which X and R have the meaning given there, can be obtained from methyl 3-cyanomethylbenzoate or. ethyl ester of the general formula

OOE

in which R has the same meaning as in formula III, according to the customary methods of carbalkoxylation of nitriles,

3rd

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632236

which have an active hydrogen atom. This reaction is preferably carried out using dimethyl or diethyl carbonate in the presence of an alkaline condensing agent, in particular sodium or. Potassium methylate or ethylate performed. The C-alkali salt of the compounds of the formula III is obtained as insoluble, yellow crystals, it can be filtered off and washed by washing with e.g. Diethyl carbonate can be cleaned. In this way, the compounds III are obtained completely free of the starting material IV, which could contaminate the later end products.

The compounds of formula IV are obtained e.g. from the corresponding 3-carbalkoxybenzyl chlorides of the general formula

COOB

wherein R has the meaning given in formula I, by conversion with sodium or potassium cyanide in a lower alcohol. Nitrilation is particularly advantageously carried out in an alcohol of which the radicals R corresponds to the R of the formula V, e.g. nitrating carbethoxy-benzyl chloride preferably in ethanol and the carbomethoxy-benzyl chloride in methanol. In this way, transesterification and the formation of mixtures can be avoided. In principle, however, one can also proceed in reverse, without the quality of the subsequent end product being reduced.

The compounds of the formula V, in which R has the meaning given there, can be prepared by the processes known from the literature (cf. CT Morgan, Ch. R. Porter, J. Chem. Soc. (London) 1926, 1256-62 , DRP 234 913 or AF Titley, J. Chem. Soc. 1928, 2571-2583).

The following examples are intended to illustrate the invention without limiting it.

Preliminary note The thin layer chromatograms are carried out on F 254/366 silica gel plates from Woelm.

Lsm: methanol; Running meter: benzene: dioxane: glacial acetic acid = 90: 25: 4

Amount of substance applied: approx. 200 y.

Preparation 1 Methyl 3-cyanomethylbenzoate 108 g (2.2 mol) of sodium cyanide and 1000 ml of methanol are heated to reflux with stirring. 369 g (2 mol) of methyl 3-chloromethylbenzoate are added dropwise at this temperature over the course of 1 hour. The mixture is stirred at reflux temperature for 20 hours (vigorous dark coloring and saline separation), the excess methanol is distilled off to such an extent that the residue is barely stirrable, 500 ml of toluene and 11 water are added, the mixture is stirred well, the phases are separated and the mixture is stirred the organic with cyanide-free water, dries with anhydrous sodium sulfate, the solvent evaporates, lastly in a water jet vacuum at a bath temperature of around 150 ° C. Now the residue is distilled on the high vacuum pump. Kp0.067mbar: 126-128 ° C Yield: 297-308 g = 85-88% of theory

Purity: 95-96% (gas chromatography)

Preparation 2 3-cyanomethylbenzoic acid ethyl ester 324 g (6.6 mol) of sodium cyanide and 1200 ml of ethanol are heated to reflux with stirring. 1191 g (6 mol) of 3-chloro-methylbenzoic acid ethyl ester are added dropwise over 5 hours. After the addition has ended, the mixture is refluxed for 15 hours, during which the table salt separates out with a slight brown color. Now the alcohol is distilled off until the mixture can still be stirred (the alcohol can be used again in the next batch), the residue is taken up in 11 toluene and 31 water, the phases are separated and the organic is washed with water cyanide free. Nim is dried with sodium sulfate, the solvent is distilled off, lastly in a water jet vacuum at 150 ° C. bath temperature. The residue is distilled in a high vacuum.

Kp0,039nrt) ar: 122-126 ° C Yield: 1020-1055g = 90-93% of theory

Water-clear, somewhat viscous liquid, which solidifies to a solid with a melting point of 34-35 PC.

Content determined by gas chromatography: 97-98%.

Preparation 3

Sodium compound des (3-carbäthoxyphenyl) -25 ethyl cyanoacetate

35 g (1.5 GA) of sodium are dissolved in 700 ml of ethanol and alcohol is distilled off until a temperature of 110 ° C. is reached in the bottom. A mixture of 30,900 ml of diethyl carbonate and 189 g (1 mol) of 3-cyanomethyl-benzoic acid ethyl ester is now added dropwise, while ethanol is continuously distilled off. A yellow solid soon begins to separate, the amount of which increases with the duration of the reaction. After the addition of the mixture has ended, the solvent is distilled off until 35 is reached in the bottom and at the distillation transition 123-125 ° C .; it is necessary to add about 500 ml of diethyl carbonate in the meantime in order to keep the mixture stirrable. It is now cooled to room temperature, suction filtered and washed first with 250 ml of diethyl carbonate, which is displaced by washing with about 500 ml of xylene. The result is the light yellow, crystalline and air-resistant C-sodium salt of the (3-carbäthoxyphenyl) -cyanoacetic acid ethyl ester, which is used wet for xylene for further processing.

45 Example 1

2-cyano-2- (3-carbäthoxyphenyl) propionic acid ethyl ester The sodium salt prepared according to preparation 3 is slurried in 500 ml xylene and with stirring at 120-125 ° C with 189 g (146 ml) (1.5 mol) dimethyl sulfate so ( you can also use the equivalent amount of methyl iodide) added dropwise. The mixture is stirred for 10 hours at the stated temperature, cooled to room temperature, 500 ml of water are added and the phases are separated. The organic is stirred once with 500 ml of water. 55 The solvent is then distilled off, lastly in a water jet vacuum at a bath temperature of about 160 ° C.

Crude yield: 245-250 g = 90-91% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used in Example 3.

6o The cleaning is done by distillation on the high vacuum pump:

Kp0.04 mbar * 138-140 ° C

Yield: 237-243 g = 86-88.5% of theory, based on the 3-cyanomethylbenzoic acid 65-ethyl ester used in preparation 3.

The 2-cyano-2- (3-carbäthoxyphenyl) propionic acid ethyl ester is a water-clear to slightly yellowish liquid, the content of which was determined by gas chromatography

is 98%. After some time, the product solidifies to a solid mass with a melting point of 40-41 ° C.

Example 2 Ethyl 2- (3-carboxyphenyl) propionitrile 275 g (1 mol) of ethyl 2-cyano-2- (3-carboxyphenyl) propionate are suspended in 275 ml of water and 275 ml of methanol. At 20-25 ° C (external cooling), a solution of 88 g (2.2 mol) caustic soda in 500 ml water is added dropwise and the mixture is stirred at the stated temperature until the solution is completely clear (about 15 hours). The reaction solution is treated with 20 g of activated carbon and is made at 20-40 ° C with conc. Hydrochloric acid to pH 1, small amounts of carbon dioxide escape. The initially oily product crystallizes soon, it is suctioned off, washed with 250-500 ml of water, poured over with 300 ml of xylene and the water is removed with stirring, the organic part of the solid goes into solution with slight evolution of carbon dioxide, while table salt is present remains unsolved. When the water circulation has ended, a further 400 ml of xylene are added, the mixture is briefly heated to reflux, allowed to come to 120-125 ° C., filtered and the filtrate is allowed to cool to room temperature while stirring; the 2- (3-carboxyphenyl) propionitrile crystallizes out. It is suctioned off, washed with 300 ml of xylene and 500 ml of hexane and dried at about 80 ° C in a vacuum. Yield: 163-166.5 g = 93-95% of theory

M.p .: 146-147 ° C SZ: 308.5; calculated: 310 DC: 1 comp.

Color: white to very light beige.

Example 3 2- (3-carboxyphenyl) propionic acid 175 g (1 mol) of 2- (3-carboxyphenyl) propionitrile are refluxed with a solution of 140 g {2.5 mol) of KOH in 600 ml of water for 24 hours. A lively stream of ammonia escapes. The mixture is cooled to room temperature, treated with 20 g of activated charcoal and concentrated with stirring by adding about 300 ml. Hydrochloric acid to pH 1, suction filtered, washed with distilled water, chloride-free and dried at 80 ° C in a vacuum.

Yield: 183-185 g = 94.3-95.3% of theory

M.p. 157-158 ° C

Acid number: found: 577.8; calculated: 578 DC: 1 comp.

Color white

Example 4

2-cyano-2- (3-carbäthoxyphenyl) butyric acid ethyl ester The sodium salt of the (3-carbäthoxyphenyl) cyanoacetic acid ethyl ester prepared according to preparation 3 is reacted according to example 1 instead of dimethyl sulfate with 231 g = 197 ml (1.5 mol) diethyl sulfate and how described worked up. Crude yield: 274 g = 94.8% of theory After distillation on a high vacuum pump: 260 g = 90% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

KPcuMmbar-- 142-144 ° C

Colorless to slightly yellowish oil.

Example 5 2- (3-carboxyphenyl) butyronitrile 289 g (1 mol) of the ester prepared according to Example 4 are saponified and worked up under the conditions of Example 2. 176-179.5 g = 93-95% of theory are obtained. 2- (3-carboxyphenyl) butyronitrile.

5 632236

Mp: 128-129 ° C DC: 1 comp.

Color: white to very light beige.

5 Example 6

2- (3-carboxyphenyl) butyric acid 189 g (1 mol) of the 2- (3-carboxyphenyl) butyronitrile prepared according to Example 5 are saponified and worked up according to Example 3. 200 g = 96% of theory are obtained 2- (3-carboxy-lo phenyl) butyric acid.

Mp 181-182 ° C

Acid number: found: 539.8; calculated: 539 DC: 1 comp.

Color white.

15

Example 7

2-Cyano-2- (3-Carbäthoxyphenyl) -valeriansäureäthylester The sodium salt of the (3-Carbäthoxyphenyl) -cyanessigsäureäthylester prepared according to preparation 3 is further processed analogously to 20 Example 1, but 184.5 g (1.5 mol) are used instead of dimethyl sulfate 1-bromopropane (you can also use the equivalent amount of 1-iodopropane); the subsequent stirring time at 120-125 ° C is 36 hours. Crude yield of 2-cyano-2- (3-carbäthoxyphenyl) -25 ethyl valerate: 257 g = 85% of theory, based on ethyl 3-cyanomethylbenzoate used according to Example 3.

KP0.0133 mbar: 132-135 ° C Colorless, slightly viscous liquid.

30th

Example 8 2- (3-carboxyphenyl) valeronitrile 303 g (1 mol) of the ester J5 prepared according to Example 7 are saponified and worked up under the conditions of Example 2. Finally, 182.5-186.5 g = 90-92% of theory 2- (3-carboxyphenyl) valeronitrile.

Mp: 134-135 ° C

Acid number: found: 281; calculated: 276 DC: 1 comp.

40 T-,. r

Color white.

Example 9 2- (3-carboxyphenyl) valeric acid 45 203 g (1 mol) of the 2- (3-carboxyphenyl) valeronitrile prepared according to Example 8 are saponified and worked up according to Example 3.

Yield: 200-204 g = 90-92% of theory

Mp: 158-159 ° C see acid number: found: 505; calculated: 502.5 DC: 1 comp.

Color white.

Example 10

55 2-Cyano-2- (3-carbäthoxyphenyl) -caproic acid ethyl ester The sodium salt of the (3-carbäthoxyphenyl) -cyanoacetic acid ethyl ester prepared according to preparation 3 is reacted according to the conditions of example 1, but instead of dimethyl sulfate, 206 g (1.5 Mol) butyl bromide. 6o The subsequent stirring time is 36 hours.

Crude yield: 286-289 g = 90-93% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

It is distilled on a high vacuum pump and the fraction is collected with the 65 K-P 0.0133 mbar * 137-140 ° C

Yield: 253-260 g = 80-82% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

Colorless, slightly viscous oil.

632236

Example 11 2- (3-carboxyphenyl) -capronitrile 317 g (1 mol) of ester prepared according to Example 10 are saponified and worked up according to the conditions of Example 2. 173.5-185 g = 80-85% of theory are obtained. 2- (3-carboxyphenyl) capronitrile.

Mp: 134-135 ° C

Acid number: found: 261; calculated: 258 DC: 1 comp.

Color white.

Example 12 2- (3-carboxyphenyl) -caproic acid 217 g (1 mol) of the nitrile prepared according to Example 11 are saponified under the conditions of Example 3. The work-up is changed in that the charcoal-treated saponification solution is introduced at room temperature with stirring into excess, half-concentrated hydrochloric acid. This significantly promotes the crystallization of the end product. If you work the other way round, the 2- (3-carboxyphenyl) -caproic acid first becomes lumpy and sticky and includes considerable amounts of inorganic salt, which is then difficult to wash out. It is washed chloride-free with distilled water and dried at 80 ° C in a vacuum.

Yield: 219-228 g = 93-95% of theory

Mp: 123 ° C

Acid number: found: 472; calculated: 474.25 DC: 1 comp.

Color white.

Example 13

2-cyano-2- (3-carbäthoxyphenyl) -3-methyl-butyric acid ethyl ester The sodium compound of the (3-carbäthoxyphenyl) -cyanoacetic acid ethyl ester prepared according to preparation 3 is, as described under example 1, with 184.5 g (1.5 mol) 2- Bromopropane implemented. Allow to stir for 36 hours and then work up as described.

Crude yield: 250-258 g = 82.5-85% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used. KPo, ûl33mbar: 137-140 ° C

Yield: 237-243 g = 78-80% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

Colorless, slightly viscous liquid.

Example 14

2- (3-carboxyphenyl) -3-methyl-butyronitrile 303 g (1 mol) of the ester prepared according to Example 11 are saponified and worked up under the conditions of Example 2, but the xylene solution of 2- (3-carboxyphenyl) -3-methyl-butyronitrile at about 60 ° C with stirring 500 ml of hexane and then only allowed to cool to room temperature while stirring, at which stirring is continued for 3 hours. Then the further work-up takes place as in Example 2, by washing here only with hexane.

Yield: 162.5-172.5 g = 80-85% of theory

Mp: 116-117 ° C DC: 1 comp.

Color: white to very light beige.

Example 15

2- (3-Carboxyphenyl) -3-methyl-butyric acid 203 g (1 mol) of the nitrile prepared according to Example 14 are saponified under the conditions of Example 6 and worked up according to the variation described in Example 12.

6

Yield: 204-211 g = 92-95% of theory

Acid number: 498.5; calculated: 502.5 DC: 1 comp.

Mp 178-179 ° C

5

Example 16

Cyano- (3-carbäthoxyphenyl) -cyclohexylacetic acid, ethyl ester The sodium compound of the (3-carbäthoxyphenyl) -cyanoacetic acid ethyl ester produced according to the instructions of preparation 3 is, under the conditions of example 1 and a subsequent stirring time of 48 hours, with 245 g ( 1.5 mol) of bromocyclohexane reacted and worked up.

Crude yield: 297-308 g = 86.7-90% of theory, based on i5 based on the 3-cyanomethylbenzoic acid ethyl ester used. Kp 0.0133 mbar: 175-180 ° C

Yield: 279-285 g = 80-83% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

Colorless, somewhat viscous oil.

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Example 17 (3-carboxyphenyl) cyclohexyl acetonitrile 343 g (1 mol) of ethyl cyano- (3-carboxyphenyl) cyclohexyl acetate are mixed with 350 ml of methanol 25 and with stirring in a solution of 88 g (2.2 mol) Caustic soda in 500 ml of water at 20-30 ° C. The mixture is stirred for 24 hours at the temperature indicated, 500 ml of water are added and the mixture is made up with conc. Hydrochloric acid to pH 1, thereby separating a viscous oil. The aqueous phase is poured off, the residue is stirred with 500 ml of water, the washing water is poured off and all of the water is removed from the residue with 500 ml of xylene. It is filtered hot (approx. 110-120 ° C.) of undissolved inorganic salts, stirred with cooling and 35 500 ml of hexane are added when crystallization begins. The mixture is stirred for 3 hours at room temperature, suction filtered, washed first with a xylene / He-xan mixture = 1: 1 (400 ml) and finally with hexane. It is dried at 60 ° C in a vacuum.

. Yield: 143-144 ° C (light sintering at 135 ° Q 40 DC: 1 comp.

Acid number: 235; calculated: 230.5

Example 18

45 (3-carboxyphenyl) cyclohexylacetic acid

243 g (1 mol) of (3-carboxyphenyl) cyclohexylacetonitrile are stirred under reflux for 72 hours with a solution of 224 g (4 mol) of potassium hydroxide in 700 ml of water. It is diluted with 250 ml of water, treated with 25 g of A-so coal and the solution is added dropwise with stirring at 20-25 ° C. in a mixture of 500 ml of conc. Hydrochloric acid and 500 ml of water. After the addition has ended, the mixture is stirred for a further 1 hour, filtered off with suction and washed free of chlorine ions with water. Drying takes place at 80-100 ° C in a vacuum.

55 Yield: 249-254 g = 95-97% of theory

Mp: 214-215 ° C DC: 1 comp.

Acid number: 425; calculated: 427.5 white crystals.

60

Example 19

2-cyano-2- (3-carbäthoxyphenyl) -3- (4-chlorophenyl) -

Ethyl propionate The sodium compound of ethyl 65 (3-carbäthoxyphenyl) -cyanoacetate prepared according to preparation 3 is reacted with 242 g (1.5 mol) of 4-chlorobenzyl chloride under the conditions of Example 1, the subsequent stirring time being extended to 48 hours. A raw yield is obtained

340-347 g = 88-90% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

Kpo, oi33mbar: 205-210 ° C

Distillate: 325-330 g = 84.5-85.5% of theory, based on the 3-cyanomethylbenzoic acid ethyl ester used.

Colorless, highly viscous substance at room temperature.

Example 20

2- (3-carboxyphenyl) -3- (4-chlorophenyl) propionitrile 385.5 g (1 mol) of the ester prepared according to Example 19 are dissolved in 400 ml of methanol and at about 25 ° C. in a solution of 88 g ( 2.2 mol) of caustic soda in 500 ml of water. The mixture is stirred for 24 hours to complete clarity and adjusted to pH 1 at room temperature. The aqueous phase which separates out is poured off, the residue is stirred again with 500 ml of water and then separated from the aqueous phase. 1000 ml of xylene are added, the mixture is heated to reflux, the insoluble constituents are filtered at 120-125 ° C., the mixture is stirred to a temperature of 55-60 ° C. and 750 ml of hexane are added. After stirring for about 12 hours at room temperature, the product is filtered off with suction, washed with 500 ml of hexane and dried at 80-100 ° C. in vacuo.

Yield: 243-252 g = 85-88% of theory

Mp: 173-174 ° C DC: 1 comp.

Acid number: 194; calculated: 196.2 white crystals.

Example 21

2- (3-carboxyphenyl) -3- (4-chlorophenyl) propionic acid 285.5 g (1 mol) of the nitrile prepared according to Example 10 is processed analogously to the conditions of Example 18 to 2- (3-carboxyphenyl) -3- (4-chlorophenyl) propionic acid. Yield: 258-274 g = 85-90% of theory

Mp: 213-214 ° C acid number: 365.8; calculated: 366.8 DC: 1 comp.

White crystals.

Example 22 2- (3-carboxyphenyl) propionitrile 35 g (1.5 GA) sodium are dissolved in 700 ml methanol and alcohol is distilled off until a temperature of 90 ° C. is reached in the bottom. A mixture of 800 ml of dimethyl carbonate and 175 g (1 mol) of 3-cyano-methylbenzoic acid methyl ester (see Example 1) is added dropwise with continued distillation of methanol. A yellow solid soon begins to separate. After the addition of the mixture has ended, the solvent is distilled off until 90 ° C. is reached in the bottom and at the distillation transition; it is necessary to add about 500 ml of dimethyl carbonate in the meantime in order to keep the mixture stirrable. It is now cooled to room temperature, filtered off, washed first with 250 ml of dimethyl carbonate, then with 500-600 ml of xylene. The result is a hell632 236

yellow, crystalline, air-resistant mass that is used for further processing when wet with xylene.

The C-sodium salt of the (3-carbmethoxyphenyl) -cyanoic-acetic acid methyl ester is slurried in 500 ml of xylene and 189 g = 146 ml (1.5 mol) of dimethyl sulfate are added dropwise with stirring at 120-125 ° C. The mixture is stirred for 10 hours at the stated temperature, cooled to room temperature, 500 ml of water are added and the phases are separated. The organic is extracted with 500 ml of water; then the solvent is distilled off, finally in a water jet vacuum at a bath temperature of about 160 ° C.

Crude yield: 210-215 g = 85-87% of theory

KP0.0133 mbar * 118-121 ° C

Yield: 205-210 g = 83-85% of theory, based on the 3-cyanomethylbenzoic acid methyl ester used.

The distilled ester is suspended in a mixture of 250 ml of methanol and 250 ml of water. A solution of 75 g (1.87 mol) caustic soda in 250 ml water is added dropwise at 20-25 ° C. The mixture is stirred at the stated temperature until completely clear (about 15 hours). The reaction solution is treated with 20 g of activated carbon and is made at 20-40 ° C with conc. Hydrochloric acid to pH 1, small amounts of carbon dioxide escape. The product separates oily at first, but soon becomes crystalline; it is suctioned off, washed with 250-500 ml of water, poured over with 300 ml of xylene and the water is removed with stirring. With a slight evolution of carbon dioxide, everything except solution of table salt is in solution. After the water has been removed from the circulation, a further 350 ml of xylene are added, the mixture is briefly heated to boiling, allowed to come to 120-125 ° C., filtered and the filtrate is allowed to cool to room temperature with stirring. 2- (3-Carboxyphenyl) propionitrile crystallizes out. It is suctioned off, washed with 400 ml each of xylene and hexane and dried at about 80 ° C. in vacuo.

Yield: 138.5-141.5 g = 79-81% of theory, based on the 3-cyanomethylbenzoic acid methyl ester used.

Mp: 146-147 ° C

DC: 1 comp.

Color: white to very light beige.

Example 23 2- (3-Carboxylphenyl) propionic acid

The 2- (3-carboxyphenyl) propionitrile obtained is heated under reflux with a solution of 112 g (2 mol) of caustic potash in 500 ml of water for 24 hours. A lively stream of ammonia escapes. It is cooled to room temperature, treated with 20 g of activated charcoal and concentrated with the addition of about 250 ml. Hydrochloric acid to pH 1, suction filtered, washed with distilled water, chloride-free and dried at 80 ° C in a vacuum.

Yield: 144-149 g = 74-77% of theory, based on the 3-cyanomethylbenzoic acid methyl ester used.

Mp: 157-158 ° C

Acid number: 577; calculated: 578

DC: 1 comp.

Color white.

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Claims (3)

632 236 PATENT CLAIMS 1. Process for the preparation of new substituted phenylacetonitriles of the formula COOB COOB (I) COOB (III) 6. Use according to claim 5 of the compound obtained according to the method of claim 2. 7. Use according to claim 5 of the compound obtained according to the method of claim 3. 10th in which R is different or identical and denotes a straight-chain or branched alkyl group having 1 to 4 carbon atoms and in which R 'is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, one optionally by a straight-chain or branched alkyl group having 1 to 4 carbon atoms -Atoms substituted cycloalkyl group having 5 to 7 C ring atoms, the benzyl group or a benzyl group substituted by bromine or chlorine or the group -COORj, in which Rx has the meaning given for R above, characterized in that alkali-3-carbalkoxyphenylcyan acetic acid esters of the formula