CS195255B2 - Process for preparing alpha-anilinocarbonitriles - Google Patents

Abstract

1327294 Preparation of alpha-anilino carboxylic esters and nitriles SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ NV 30 April 1971 12410/71 Heading C2C Alpha-anilino carboxylic esters of the general formula in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> each individually represent a halogen atom or an alkyl, haloalkyl or alkoxy group, while R<SP>1</SP> and/or R<SP>2</SP> may also be hydrogen atoms, and R<SP>2</SP> may also be a group -NH-CH(R<SP>4</SP>)-X or a group -(A) n - C @ H 2 (R<SP>1</SP>,R<SP>3</SP>)-NH-CH(R<SP>4</SP>)-X, in which A=CH 2 ), S or NH and n=zero or 1; R<SP>4</SP> is a hydrogen atom or an alkyl group and X is a carboxylic ester group are prepared by reacting a nitrile of the general formula with a primary or secondary alcohol in the presence of hydrogen chloride or bromide, first (a) at a temperature ranging from - 20‹ C. to + 70‹ C. for a time not exceeding that necessary for the conversion of at least 70% of the nitrile, and subsequently (b) at a temperature ranging from 55‹ to 150‹ C.-with the proviso that at least during the time interval (a) the amount of HC1 or HBr present should be greater than 3À5 equivalents, based on the nitrile, while the concentration of the said hydrohalide in the reaction medium should be at least 4 mole per litre. The ester may be converted to the alpha- (N-acylanilino) carboxylic ester by reacting with an acylating agent, e.g. benzoyl chloride. Alpha-anilino carbonitriles of the general Formula II above may be prepared by reacting in an alcoholic medium an aniline compound of the general formula with either (a) hydrogen cyanide and an aldehyde R<SP>4</SP>-CHO or (b) a cyanohydrin R<SP>4</SP>-CH(OH)-CN, in the additional presence in the case being of a strong base. Compounds claimed per se are alpha-(4-fluoroanilino) propiononitrile, alpha - (4 - chloro - 3 - fluoroanilino) propiononitrile.

Description

The invention relates to a process for the preparation of α-anilinocarbonitriles from the corresponding anilines. These substances have generally useful herbicidal properties. α-Anilinocarbonitriles are in part novel compounds not yet described.

The α-anilinocarbonitriles of the invention can also be converted into α-anilinocarboxylic acid esters in high yields by reacting the α-anilinocarbonitriles with an alcohol in the presence of hydrogen chloride or hydrogen bromide.

The esters produced from α-aminocarbonitriles also have significant herbicidal properties.

The invention relates to a process for the preparation of α-anilinocarbonitriles of the general formula II, (S) -NH-CH-CN (ID where the symbols

R1, R2 and R3 each represent a halogen atom, wherein

R ¹ and / or R ² may also be hydrogen, and

R ⁴ represents a hydrogen atom or an alkyl group of up to 4 carbon atoms.

According to the invention, the aniline of formula III is

where

R ^1, R ² and R ³ have the above meanings, is reacted in an alcohol at a temperature of -20 to - | - 100 ° C, either a) with hydrogen cyanide and an aldehyde of formula

R ^{4 =} CHO or b) with a cyanohydrin of the formula

R ^{4 -} CH (OH) - CN 'in the presence of a strong base, in which R ⁴ is as defined above.

Particularly preferred anilines of the formula III are those in which R @ ¹ is hydrogen, R @ ² is hydrogen or chlorine, and R @ ³ is chlorine or fluorine. Examples of suitable anilines are various isomeric mono- and dichlorodi-19525S rivates, fluoro and fluorochloro derivatives and methyl chloro derivatives and (trifluoromethyl) chloro derivatives, particularly preferred are 4-chloroaniline, 4-fluoroaniline, 4-chloro-3-fluoroaniline, 3-chloro-4-fluoroaniline , and in particular 3,4-dichloroaniline.

The aniline of formula III is preferably reacted with hydrogen cyanide and an aldehyde of formula R ⁴ -HCO, wherein R ⁴ is hydrogen or C 1 -C 4 alkyl, such as methyl, ethyl, propyl or n-butyl. Particularly suitable aldehydes are formaldehyde where R 4 is hydrogen, and especially acetaldehyde where R 4 is methyl. As a rule, favorable results are obtained when hydrogen cyanide and% aldehyde are used in a molar excess, preferably of 3 to 10 and in particular of 4 to 7 mol%, calculated on the aniline.

Most preferably, the aldehyde is added to a mixture of hydrogen cyanide and aniline in an alcohol medium, although other methods may be used, such as the simultaneous addition of aldehyde and hydrogen cyanide to aniline.

The alcohol used as the reaction medium is preferably a straight or branched chain aliphatic mono- or polyhydric alcohol, which may contain substituents if desired. Alcohols containing no more than 6 carbon atoms are usually most preferred. Particularly preferred are methanol, ethanol, isopropyl alcohol, 2-chloroethanol and ethylene glycol. Of course, mixtures of two or more alcohols and / or solvents or diluents may also be used.

The reaction is generally carried out at a temperature in the range of from -20 to -60 ° C, preferably from 10 to 25 ° C and in particular from 15 to 20 ° C and at atmospheric pressure. However, pressures higher than atmospheric pressure may also be used if desired.

Alternatively, the aniline of formula (III) is reacted with a cyanohydrin of formula R ⁴ -CH (OH (-CN, derivative of the above-mentioned aldehyde R ⁴ -CHO). It is preferred that the cyanohydride is used in molar excess, preferably 10 to 50 mol%, in particular 20 to 40 mol%, based on aniline.

In this case too, it is necessary to carry out the reaction in an alcoholic medium, the alcohols suitable for this purpose being the same as mentioned above and most preferably ethanol. In addition, a salt base such as a base having a pKa of at least 9 must be present in the reaction. Examples are alcoholates such as sodium ethyl alcoholate, alkaline earth metal hydroxides such as sodium and potassium hydroxide, preferably used on a solid support such as silica or alumina; in particular γ-alumina, a basic anion exchanger, for example of the tertiary amine or quaternary ammonium type, in particular an anion exchanger containing trlalkylammonium or dialkylhydroxyalkylammonium groups, for example "Amberlite" such as IRA-400 and IRA-904, "Amber lyst" such as · A —26 and A — 29, “Deacodote FF,“ Dowex ”1,“ Duolite ”A — 42, ·“ Nalcite ”SBR,“ Permutit ”ESB,“ Wofatit ”L — 165, and“ Lewatit ”MN. Organic bases, in particular tertiary nitrogen bases, are most preferred, with favorable results being obtained in particular with an aliphatic tertiary amine in which two or more alkyl groups may be the same or different and in which each alkyl group preferably has no more than 6 carbon atoms . Examples are triethylamine, triisopropylamine, tri-n-butylamine and triethanolamine. Excellent results are achieved especially with triethylamine. The amount of tertiary nitrogenous base is usually in the range of 0.3 to 10 mol. %, preferably 2 to 6 mol. % using cyanohydrin.

Suitable temperatures for the reaction of cyanohydrin with aniline are generally in the range from 50 to 100 ° C and preferably from 60 to 80 ° C. When a low boiling alcohol such as ethanol is used as the reaction medium, it is particularly advantageous to carry out the reaction at the boiling point of the reaction mixture.

An important feature of the process according to the invention is the use of an alcoholic reaction medium in both reaction processes (aj and (b)), thereby achieving excellent yields of the nitrile produced, while using other types of solvents such as diethyl ester, dimethylformamide, toluene or xylene As a rule, by-products and yields of the nitrile of the general formula (II) are far from satisfactory in considerable amounts, moreover, if the process (bj strong base) is not used, negligible, if any, nitrile amounts are formed.

The tritium of the formula II obtained by the process according to the invention is - as already mentioned - particularly suitable starting material for the preparation of the .alpha.-anilinocarboxylic acid esters of the formula I;

R ³ wherein * R ^X , R ² and R 3 are each a halogen atom or an alkyl, haloalkyl or alkoxy group, wherein:

R1 and / or ^R2 may also be hydrogen and

R2 may also denote a group -NH-CH (R ⁴ j -X or - (A) _n -C61 ^: (R ¹ R 3 -NH-CH (R 4 (-X wherein

A is CH2, oxygen, sulfur or NH and n is zero or 1,

R4 represents a hydrogen atom or an alkyl group;

WITH

X represents a carboxylic acid ester group.

. In many cases, alcohol solutions of nitrile can be used directly in the synthesis of said carboxylic acid esters. Many of these nitriles were obtained for the first time. Novel compounds are, for example, α- (4-fluoroanilino) propionitrile and α- (4-chloro-3-fluoroanilino) propiononitrile.

Some of the nitriles of formula II exhibit herbicidal properties.

An interesting use of the invention is to produce valuable herbicides by reacting the aniline of formula III with hydrogen cyanide and an aldehyde of formula R ⁴ -CHO or alternatively with a cyanohydrin of formula R ⁴ -CH (OH) -CN followed by alcoholysis of the formed nitrile of formula II and acylating the obtained carboxylic acid ester. This process can either be carried out in whole or in part in a continuous, continuous or semi-continuous manner. Ethyl esters of N- (N-benzoyl-3,4-dichloroanilino) propionic acid can thus be produced in high yields, for example from 3,4-dichloroaniline, hydrogen cyanide and acetaldehyde to the resulting α- (3,4-dichloroanilino) propiononitrile and ethyl ester of the corresponding carboxylic acid. .

Example 1

Production of α- (3,4-dichloroanilino) propiononitrile from 3,4-dichloroaniline, acetaldehyde and hydrogen cyanide

91.5 kg (3.389 mol) of hydrogen cyanide are introduced into a 5-liter four-necked round-bottomed flask equipped with stirrer, addition funnel, reflux condenser and thermometer with cooling to 0-10 ° C and then 521.5 g are added. (3.22 mol) of 3,4-dichloroaniline and 2.3 liters of 96% ethanol. The temperature is then allowed to rise to 15 [deg.] C. and 149.1 g (3.389 mol) of acetaldehyde are gradually added over 1 hour at this temperature with stirring. After stirring for an additional half hour at room temperature, the mixture was warmed to 160 ° C and left at this temperature for 1/2 hour to dissolve the crystalline precipitate formed and then allowed to cool to room temperature. The reaction product separated as a crystalline mass, which is filtered off and dried under vacuum at a temperature of about 70 ^° C and at a pressure of 1.6 to 2.66 kPa, contains 542 g (2.52 mol) of α- (3,4-dichloroanilino) propiononitrile. m.p. 118-119 ° C and a purity of 99%, which corresponds to a yield of 78.3 mol% based on the amount of 3,4-dichloroaniline used.

An additional amount of product is obtained from the filtrate by removing the volatiles in a thin-layer evaporator at 40-50 ° C (bath temperature) and a pressure of 1.6-2.0 kPa followed by crystallization from ethanol, increasing the overall yield to 98%. The combined product thus obtained is used in the reactions described in Examples 5 and 6.

By comparison, when the process is carried out in an alcohol-free environment under otherwise analogous conditions, substantially lower yields, such as 75 to 80 moles, are obtained. % in diethyl ether, 50 to 60 mol. % in dimethylformamide and 40 to 50 mol. % in toluene.

Instead of isolating the solubilized product from the filtrate, it has proven advantageous to let the filtrate pass the reaction flask again for further reaction with fresh starting material under the same conditions as described above. The same yield is obtained directly and the new filtrate obtained can then be reacted in the same manner.

Example 2

Production of α- (4-chloroanilino) propiononitrile

4-Chloranylin (25.5 g, 0.2 mol) and hydrogen cyanide (39 mL) in 96% ethanol (300 mL) were stirred at 15 ° C and acetaldehyde (56 mL) was added to the solution over 1 h. The mixture was stirred at 15 ° C for an additional hour and then at 60 ° C for 2 hours. The mixture was allowed to stand for 16 hours at room temperature and then poured into water (500 mL). The product which crystallizes from the solution and which is filtered off has a melting point of 113-115 ° C. (Yield 33 g, 91% based on 4-chloroaniline).

Example 3

The following (new) compounds were obtained in a manner analogous to Example 2:

a) α- (4-fluoroanilino) propiononitrile

This compound, m.p. 71-73 ° C, was obtained with a yield of 91% based on 4-fluoroaniline.

Analysis: C9H9FN2 found:

66.3% C, 5.6% H, 17.0% N;

calculated:

H, 5.5; N, 17.1.

b) α- (4-chloro-4-fluoroanilino) propiononitrile

This compound, m.p. 130 DEG-132 DEG C., is obtained with a yield of 91% based on the 4-chloro-3-fluoroaniline used.

Analysis: C9H8CIFN2 found:

C, 54.7; H, 4.1; N, 14.2;

calculated:

C, 54.4; H, 4.0; N, 14.1.

Example 4

Preparation of α- (3,4-dichloroanilino) propionitrile from

3,4-dichloroanilm and α-hydroxyproplonitrile.

g (0.5 mol) of 3,4-dichloroaniline, 46.1 g (0.65 mol) of .alpha.-hydroxypropiononitrile, 100 ml of ethanol (96%) and 2.6 g (0.025 mol) of triethylamine were added. add to a 500 ml reaction flask,. with a stirrer and a reflux condenser, and refluxed for 3 hours. Complete conversion of 3,4-dichloroaniline is then achieved. Ethanol (150 ml) was added and the mixture was allowed to cool to room temperature. The crystalline precipitate thus formed is filtered off, washed with 25 ml of cold ethanol, freed from ethanol at 50 DEG C. (2.66 kPa) in vacuo to give .alpha .- (3,4-dichloroanilino) proplonone lithium having a melting point of 118; to 119 ° C.

When the mother liquor was concentrated to about 25 mL and cooled to 10 ° C, an additional amount of crystals was obtained, which were washed and dried as described above. way. The total yield obtained is increased to 86 g, corresponding to 80 mol. calculated on 3,4-dichloroaniline.

Example 1 a d 5

Claims (11)

Example 1 a d 5 Preparation of α- (3,4-dichloroanilino) -propionic acid ethyl ester (a) 21.5 g (0.1 mol) of α- (3,4-dichloroanilino) propiononitrile (from the experiment described in Example 1) and 50 ml of anhydrous ethanol are placed in a 250 ml three-necked round-bottomed flask equipped with with a stirrer, a forging funnel and a reflux condenser. A solution of 29 g (0.8 mol) of hydrochloric acid in 50 ml of anhydrous ethanol is then added in one portion to the suspension while stirring, and the resulting solution is then heated to 50 DEG C. (oil bath temperature) and maintained. at this temperature. 3 hours. The conversion of the starting material reaches 981%. Then the suspension is heated to reflux for a further 3 ¥ 2 hours. Excess ethanol was then evaporated in vacuo and the residue was evaporated. add 100 milliliters of water and. 100 ml toluene. After phase separation, the upper organic layer was washed twice with 100 ml of saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The 22.5 g residue thus obtained contains α- (3,4-dichloroanilino) -propionic acid ethyl ester. Crystallization from. of n-hexane, 19.1 g of product are obtained in the form of white crystals, m.p. 83-39 ° C (96% purity), corresponding to a yield of 73 · mol. %, based on the starting material used. b) In experiments carried out under the same conditions as described under (a) above, but using lower temperatures in the first heating phase, it appeared that additional reaction times at these temperatures were required to achieve analogous results. Table I shows the conversion of α- (3,4-dichloroanilino) -propiononitrile achieved at different time intervals at temperatures of 30, 40 and 50 ° C. Table I Temperature ° C 1 h2 h 30 —— 40 —65 50 7995 c) The effect of increasing concentrations of hydrogen halide is shown by experiments in which 0.1 mol of α- (3,4-dichloroanilino) propionitrile and 100 ml of anhydrous ethanol are used. Heat at 55 ° C for 2 hours, maintain at this temperature for 1 hour, then heat to reflux for 1 hour and finally boil for 2 hours. When the amounts of hydrogen chloride used are 0.8 moles, 1.0 moles and 1.2 moles, these amounts correspond to a yield of 87.5%, 79.6% and 69.1% of the ethyl ester of α- (3,4-dichloroanilino) propionic acid, the yield loss resulting mainly from the subsequent hydrolysis of the ester formed. If, on the other hand, less than 0.8 moles of hydrogen chloride is used, otherwise. In analogous conditions, there is a tendency to cleave 3,4-dichloroaniline. conversion (%) after 4 h 5 h6 h - 60 ·. 7585 87 96 98— 98 - '—— Example 6. The following comparative experiments show that, if one or more reaction conditions, such as the concentration or amount of hydrogen chloride and / or temperature, are not in accordance with the requirements imposed on them, unsatisfactory results are obtained. a). 0.01 mol of α- (3,4-dichloroanilino) propionitrile was heated with 0.04. mol of hydrogen chloride and 30 ml of anhydrous ethanol. to 50-55 ° C. Even though. the mixture is heated for 20 ¥ 2 hours, almost no conversion occurs due to the low amount and concentration of hydrogen chloride present. (b) If test (a) is carried out using 0.08 mol of hydrogen chloride and 40 ml of anhydrous ethanol, also at a temperature of 50 to 55 ° C, part of the starting material is converted after 20 hours. However, subsequent heating to boiling yields no more than 40% of the corresponding ester. Although the correct amount of hydrogen chloride was used in this case, its concentration was again too low. In subsequent experiments, 0.01 mol of α- (3,4-dichloroanilino) propiononitrile and 10 ml of anhydrous ethanol in the presence of varying amounts of hydrogen chloride as shown in Table II were heated to reflux until complete conversion of the starting material. The results show that decomposition occurs to a very high extent if the concentration of hydrogen chloride is too low, but if the mixture is heated at a lower temperature before heating to reflux, only very little, if any, 3,4 -dichloroaniline (DCA). Table II HCl, mol 0,025 0,035 ⁺ 0.10 Reflux time h The resulting dichloraniline, mol. % calculated on nitrile 2.5 0.5 ⁺ Hydrogen chloride gas was introduced into the boiling mixture Example 7 Production of ethyl .alpha .- (N-benzoyl-3,4-dichloroanilino) propionate A mixture of 263.4 g (1.005 mol) of ethyl .alpha .- (3,4-dichloroanilino) propionate, prepared according to Example 4 and having a purity of 98.5%, and 100 ml of toluene is heated to reflux at 130 DEG C. 162 g (1.15 mol) of benzoyl chloride are added at this temperature over 45 minutes. After refluxing for an additional 4 hours, the mixture was cooled to 90 ° C and stirred for 15 minutes at this temperature. 250 ml of a 10% aqueous solution of sodium bicarbonate. After phase separation, the toluene layer is washed with 50 ml of water, the toluene is evaporated in vacuo (at 1 mmHg) to give 361.2 g of .alpha .- (N-benzoyl-3,4-dichloroanilino) propionic acid ethyl ester as an oil of purity. 92%. Yield 91.7 mol. %, based on the ester used. 245 g of the crude product are dissolved by heating with 25 ml of toluene and the warm solution is poured into 500 ml of petroleum ether, b.p. 60-80 ° C. The product is then separated as a light gray solid, which is filtered off and dried under vacuum at 40-50 ° C to give 208.9 g of purified product with a purity of 96%, corresponding to a yield of 89%. WHO HAVE VYNALEZU A process for the preparation of α-anilino carbonitriles of the general formula II, R ¹ ff \ -NH-CH-CN (Ю _R 2> _R 3 & £ wherein the symbols R @ ¹ , R @ ² and R @ ³ each represent a halogen atom, wherein R @ ¹ and / or R @ ² can also be hydrogen atoms and represent a hydrogen atom or an alkyl group of up to 4 carbon atoms, characterized in that the aniline of the formula III, wherein R ^1, R ² and R ³ have the above meanings, is reacted in an alcohol at a temperature of -20 to +100 ° C with either hydrogen cyanide and an aldehyde of formula R ^{4 =} CHO or with a cyanohydrin of the general formula R ⁴ —CH (OH) —CN in the presence of a strong base, in which formulas R ⁴ is as defined above. 2. The process according to claim 1, wherein the aniline compound of the formula III is 4-chloroaniline, 4-fluoroaniline, 4-chloro-3-fluoroaniline, 3-chloro-4-fluoroaniline or especially 3,4-dichloroaniline. . 3. A process according to claim 1, wherein acetaldehyde is used when an aldehyde is used, and [alpha] -hydroxypropiononitrile is used when cyanohydrin is used. 19S2SS 4. A process according to any one of claims 1 to 3, wherein the alcohol is ethanol. Process according to Claims 1 to 4, characterized in that the hydrogen cyanide and the aldehyde are used in a molar excess of 3 to 10%, in particular 4 to 7%, based on the aniline. 6. A process according to claim 1, wherein the aldehyde is added to a mixture of hydrogen cyanide and aniline in an alcoholic medium. 7. Process according to claim 1, characterized in that the cyanohydrin is used in a molar excess of 10 to 50%, in particular 20 to 40%, based on the aniline compound. 8. The process of claims 1 to 4 and 7, wherein the strong base used in the reaction with cyanohydrin is a tertiary nitrogen base. 9. The process of claim 8 wherein the tertiary amine is triethylamine. Process according to claim 8 or 9, characterized in that the tertiary nitrogen base is used in an amount of 0.3 to 10%, based on cyanohydrin. 11. The process of claim 1 wherein the ethanol reaction is carried out at the boiling point of the reaction mixture.