DK143446B - PROCESS FOR THE PREPARATION OF ALFA-ANILINOCARBOXYLIC ACIDS AND / OR DERIVATIVES THEREOF - Google Patents

Description

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(19) DENMARK yp.aJ

(12) PRESENTATION WRITING ου 143446 B;

Dl The Patent and Trademark Office

(21) Application No. 519 ^ / 71 (51) IntCi.3 C 07 C 101/18 (22) Filing Day 26 Oct. 1971 0 07 C 99/00 (24) Race day 2β. October 1971 (41) Aim. available Apr 29 1972 (44) Posted Aug 24 1981 (86) International Application No. “(86) International Filing Day - (85) Continuation Day” (62) Master Application No. “

(30) Priority Oct 28 1 97Ο, 7015842, NL

(71) Applicant SHELL INTERNATIONAL RESEARCH MAATSCHAFPIJ N.V., The Hague, NL.

(72) Inventor Dirk Everard Poel, NL: Hendrik Cornells Keldertnan, NL.

(74) Plougmann & Vlngtoft Patent Office.

(54) Process for the preparation of alpha-anillinocarboxylic acids and / or derivatives thereof.

The present invention relates to a process for the preparation of o-anilinocarboxylic acids and / or derivatives thereof in which thaw process aniline or a nucleus substituted aniline is reacted Φ with an α-halo carboxylic acid or a derivative thereof.

-rf · rt (V) Examples of such transformations are already known. Normally, the alpha-halogenearboxylic acid or e.g. an ester thereof reacts with an excess of the relevant aniline to bind the hydrogen halide formed by the reaction.

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However, this process has the disadvantage that the reaction usually proceeds very slowly and that unsatisfactory yields are obtained. Therefore, attempts have already been made to improve the method. According to Dutch Patent Application No. 6,717,715, Example II, the excess amount of the aniline in question is thus replaced with sodium bicarbonate. Also, in this case, however, the time required for the reaction described, namely the reaction of 3,4-dichloroaniline with α-chloropropionic acid, is very long and the yield leaves much to be desired. This is especially the case in the direct preparation of compounds which can be easily hydrolyzed, especially esters of α-anilinocarboxylic acids. Other bases, e.g. calcium = cesium oxide and magnesium oxide, give rise to partial saponification.

Of course, in these cases it is possible to use a two-step process, first preparing the carboxylic acid and then preparing the desired corresponding ester from the carboxylic acid. Finally, it can be mentioned that the applicants have obtained low yields by using as a base, part of a side reaction with the α-halo atom to form the α-aminocarboxylic acid or a derivative thereof.

It has now been found that the above disadvantages are avoided and that the desired compounds are obtained in high yield by a smooth and generally applicable reaction when using a tertiary amine as a base.

The invention thus relates to a process for the preparation of α-ani-linocarboxylic acids and / or derivatives thereof of the general formula I

R1 A_i

<v,) - KH-CH-T I

14 K3 K4 12 3 wherein each of the symbols R, R and R represents a hydrogen or halogen atom or an alkyl, haloalkyl or alkoxy group, R4 represents a hydrogen atom or an alkyl group, Y represents a carboxyl group or a corresponding salt or a corresponding ester group or a corresponding carboxamide group which may be substituted on the nitrogen atom by one or two hydrocarbon groups or if the nitrogen atom is part of a cyclic system and X represents a

hydrogen atom or an acyl group, by which process a compound of the general formula II

R1 EX> -ffi2 12 3

wherein R, R and R are as defined above, reacted with a compound of general formula III

Hal-CH-Y

III

R4 4 wherein Hal represents a halogen atom and R and Y have the meanings set forth above, characterized in that the reaction components of the general formulas II and III, respectively, are heated in the presence of a tertiary amine to form a compound of formula I, wherein X represents a hydrogen atom wherein the crude product of the general formula I obtained is optionally subjected to an acylation reaction after removal of the hydrohalide of the tertiary amine to form a compound of formula I wherein X represents an acyl group.

3 In formulas I and II shown above, the symbols R, R and R can have the same or different meaning. Very good results are obtained when at least one of these symbols represents a halogen or hydrogen = 1 2 3 atom. Preferably, R is hydrogen, R is halogen and R is hydrogen, halogen, alkyl, haloalkyl or alkoxy. The halogen atoms are e.g. chlorine, bromine or fluorine; as a rule, chlorine and fluorine are preferred. In the case of the alkyl or alkoxy groups, such groups which contain no more than 10 carbon atoms are generally preferred, and especially those which do not contain more than 6 carbon atoms, while the halogen = alkyl group preferably contains no more than 6 carbon atoms and which have one halogen. or more chlorine and / or fluorine atoms. The alkyl, halogen = alkyl and alkoxy groups may have branched or straight chain structure. Examples of particularly suitable radicals are H, Cl, F, methyl, ethyl, propyl, n-butyl, octyl, methoxy and trifluoromethyl. Among the alkyl = groups, the methyl group is particularly preferred.

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Examples of anilines of general formula II which are particularly suitable for use as starting compounds are the various isomeric monochloro and dichloro anilines, e.g. 2-, 3- and 4-chloro = aniline and 3,4- and 2,5-dichloroaniline; fluoro- and fluoro-chloro anilines, especially 4-fluoro-aniline and 3-chloro-4-fluoro-aniline; as well as methyl chloro, (trifluoromethyl) chloro and methoxychlor anilines, e.g. 2-methyl = -4-ehloro, 4-methyl-3-chloro, 3-trifluoromethyl-4-chloro and 2-methoxy-4-chloro aniline (R 2 = H; R 2 = Cl or E; R ^ = H, Cl, CH ^, CE ^ or OCH ^). Examples of other anilines that may also be used include the isomeric monomethyl and dimethylanilines as well as the unsubstituted aniline (R R = H; R ^ = H or CH CH; R ^ = H or CH ^). Particularly preferred are 4-chloro and 4-fluoro-aniline, 2-methyl-4-chloro-aniline, 3-chloro-4-fluoro-aniline and, in particular, 3,4-dichloro-aniline.

By the process of the invention, the aniline of general formula II is reacted with an α-halo carboxylic acid or with a salt derived therefrom, a derivative ester or a derivative carboxamide of the general formula III wherein Hal represents a halogen atom, f. eg. fluorine, chlorine or bromine. Particularly good results are obtained when Hal is Cl or Br, among which chlorine is preferred. With respect to the other symbols, R 1 and T, in general formula III (and in general formula i), R 1 is a hydrogen atom or an alkyl group - with straight or branched chain - preferably containing at most 5 carbon atoms. As a rule, the preferred compounds in which R 1 is hydrogen or methyl are preferred and the latter (R 2 = methyl) has been found to be particularly advantageous.

As the starting compound of the general formula III, the relevant α-halo carboxylic acid or a salt derived therefrom is used, e.g. a metal salt such as the sodium salt or an ammonium salt; an ester of a carboxylic acid, wherein T preferably represents a branched or straight chain alkoxycarbonyl group having 1-10 carbon atoms in the alkoxy moiety; or a carboxamide wherein the nitrogen atom, if desired, carries one or two hydrocarbon groups as substituents, preferably one or two alkyl groups, which may be the same or different, which may have branched or straight chain and containing not more than 6 carbon atoms, or = For example, a carboxamide wherein the nitrogen atom is part of a cyclic system.

As starting compounds, the esters and carboxamides are generally preferred over the corresponding free acids and their salts, and the esters are particularly preferred. It is particularly convenient to proceed from an ester of the general formula III wherein Y is an alkoxycarbonyl group 5 143AA 6 with a maximum of 4 carbon atoms in the alkoxy moiety, e.g. methoxy, ethoxy, isopropoxy or n-butoxycarbonyl; preferred to use the carboxamides, it is particularly convenient to use the appropriate H-methyl or N, T-dimethyl derivative (Y = COMCH 2 or CO (CH 2) 2).

Examples of suitable α-halo carboxylic acids and derivatives thereof are the cc-chloro and α-bromopropionic acids, the corresponding chloro and bromoacetic acids and their salts, esters and amides, in particular the ethyl esters and the N-me = methyl and Ν, dim-dimethylamides. . In particular, the ethyl ester of α = -chloropropionic acid is preferred.

The starting compounds II and III can be used in approximate amounts of metric amounts, but it is generally preferred to use an excess of the compound of the general formula III. Suitable mole ratios of the carboxylic acid or derivative thereof and the aniline are usually between 1.2: 1 and 3: 1, preferably between 1.3: 1 and 2.5: 1 and most preferably between 1.8: 1 and 2.1: 1. Higher mole ratios, e.g.

4: 1 or more are also possible, but may in some cases lead to undesirable side reactions and will require longer reaction times. The excess amount used, e.g. of an ester can often advantageously serve as a solvent. If desired, other solvents having a suitable boiling point may also be used, preferably polar and aprotic solvents and diluents, e.g. dimethylformamide or the dimethyl or diethyl ester of diethylene glycol. Said solvents and diluents and / or the reactant used in excess, e.g. an ester of formula III may be removed from the reaction mixture in the usual manner, e.g. by distillation, and used again.

According to the invention, the reaction between compounds II and III to form the α-anilinocarboxylic acid and / or the derivative thereof (I) is to be carried out in the presence of a tertiary amine. Thus, the hydrohalide released during this condensation, HHal, binds to the tertiary amine to form the corresponding hydrogen halide. Lower tertiary amines are e.g. aliphatic, aromatic and heterocyclic tertiary amines where the substituents on the nitrogen atom may be the same or different, as well as acyclic and / or cyclic tertiary amines. Suitable substituents on the nitrogen atom are e.g. alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, aralkyl, alkaryl and alkylene.

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In addition, the nitrogen atom is also part of a heteroaromatic system and, if desired, inert substituents and / or heteroatoms may also be present. Examples of substituents on the nitrogen atom are ethyl, isopropyl, n-butyl, cyclohexyl, allyl, phenyl, benzyl, tolyl, pentamethylene and oxyethylene. Thus, as suitable tertiary amines, e.g. mention is made of the relevant trialkyl and triallylamines, ϋΓ, dial-dialkylanilines, N-alkylpiperidines and morpholines, and hetero-aromatic amines such as pyridine, picolines and quinoline.

The processing of the reaction mixture becomes easy when aliphatic amines are used in which each of the substituents on the nitrogen atom contains no more than 6 carbon atoms, since hydrohalide salts of aliphatic amines with no more than 6 carbon atoms in each substituent can be easily removed from the reaction mixture and are readily obtained. get rid of it without polluting the environment. Among aliphatic amines have tert.al = cooling and allylamines with a maximum of 4 carbon atoms per minute. substituent has been found to give particularly good results. It is advantageous to use an amine in which the substituents on the nitrogen atom are the same. Preliminary results have been obtained with e.g. triethylamine and especially tri = -n-butylamine and triallylamine. In particular, tri-n-butylamine is preferred.

It has been found that the rate at which the reaction proceeds is generally the higher, the more basic the amine, and vice versa. When less basic amines are used, the rate of reaction may be increased, if desired, by raising the temperature.

Therefore, it is recommended to select the amine and the reaction temperature in such a way that the conversion proceeds at a reasonable rate. Generally = the reaction temperature is at least 100 ° C and at most 175 ° C. However, the use of lower temperatures, e.g. using particularly reactive reaction participants, or higher temperatures. It is preferred to operate at temperatures of 120 to 160 ° C, especially at temperatures of 130 to 150 ° C. The reaction usually proceeds easily at atmospheric pressure. In special cases, e.g. when a low boiling amine such as triethylamine is used, it is preferred to use over-atmospheric pressure. However, it is also possible to use lower pressure.

It is preferred that no more than the stoichiometric amount of the tertiary amine is used. An amount which is approximately equal to or slightly less than (e.g., 5 mole percent less than) the amount of the aniline of the general formula II has generally been found to be sufficient. Generally speaking, when using larger quantities, no benefits are obtained. However, if the free carboxylic acid (Y = COOH) is used as reaction participant III, it is recommended to use a correspondingly greater amount of the tertiary amine.

According to a preferred embodiment of the process according to the invention, the tertiary amine, or at least part thereof, is added little by little to the reaction mixture during the reaction. Namely, it has been found that in this way a higher degree of conversion of the aniline of the general formula II can be obtained. Thus, it is possible to start from a reaction mixture containing 10 - 30 $ of the calculated amount of the tertiary amine and to add the residue later, ie. during the reaction, either continuously or portionwise.

Furthermore, it has been found that the reaction proceeds substantially faster if a salt of a tertiary amine is present already at the beginning of the reaction; the salt then acts as a catalyst. In three steps, a hydrohalide, especially a hydrohalide, which is also formed during the reaction, e.g. the hydrochloride of tri-n-butylamine, if starting material is used as an α-ehlorocarboxylic acid or a derivative thereof, and tri-n-butylamine as tertiary amine. An amount of e.g. 2-60 mole percent, calculated on the aniline of the general formula II, has generally been found to be very suitable. If desired, larger amounts may also be used, e.g. up to 300 mole percent or more, calculated on the aniline. The fact that a salt of a tertiary amine is present already at the beginning of the reaction, which can also be advantageously used in combination with the above gradual addition of the amine, leads especially to a significantly higher conversion of the aniline at the beginning of the reaction. Eg. For example, as much as $ 80 of the aniline has been converted in half the time that would be required to achieve the same conversion under otherwise the same conditions.

To prevent oxidation of the aniline, it may be convenient to operate under the exclusion of oxygen, e.g. in that the reaction is carried out in an atmosphere of nitrogen or another inert gas.

The method according to the invention can e.g. is performed batchwise, continuous or semi-continuous.

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The reaction product obtained can be reprocessed in the usual manner. Almin = partially, the hydrohalide of the tertiary amine is first removed by washing with water, and then component III, which is normally used in excess, is removed. by distillation. Any amounts of unreacted aniline (II) present may, after dilution with e.g. toluene, precipitates in the form of the hydrochloride (by introducing the required amount of hydrogen chloride), which can then be removed by filtration. The solution thus obtained of the desired compound of general formula I may, if desired, be used as such for further conversions or for direct use; the product can also be easily separated from the solution, e.g. by removing the solvent by distillation.

The α-anilinocarboxylic acids and / or derivatives thereof which can be prepared by the process of the invention are, inter alia, important intermediates for the preparation of pharmaceutical products and especially for the manufacture of chemicals for controlling undesirable plant growth, or the compounds themselves may have valuable herbicidal properties.

Thus, e.g. α-Anilinocarboxamides of general formula I, wherein Γ is a carboxamide group with or without a substituent, are particularly suitable as active ingredients in herbicides (cf. Dutch Patent Application No. 6,707,890).

By acylating the α-anilinocarboxylic acids and / or derivatives thereof of general formula I prepared by the process of the invention, the corresponding E-acyl derivatives are obtained with the acyl substituent on the aniline nitrogen atom. These derivatives have excellent herbicidal activity, as described in Dutch Patent Application No. 6,717,715. Because of their selective herbicidal properties, they have proved particularly suitable for the control of oats. For use, such a compound is usually mixed with a carrier and / or a surfactant. Excellent results are obtained when the active ingredient e.g. is the ethyl ester of α- (N-ben = zoyl-3,4-dichloro anilino) propionic acid, which is attractively obtained by reaction of 3,4-dichloroaniline with the ethyl ester of α-chloro propionic acid in the presence of tri-IT-butylamine by the process of the present invention and subsequent benzoylation with benzyl chloride.

9 14344 $

The process according to the invention is further illustrated by the following examples:

Example 1.

Preparation of ethyl α- (3,4-dichloroanilino) propionate using tri-n-benzylamine).

In a 250 ml * s three-necked round bottom flask equipped with mechanical stirrer, gas supply tube, thermometer and reflux chamber, a mixture of 54.6 g (0.4 mole) of ethyl a-chloropropionate, 32.4 g, is heated. g (0.2 mole) of 3,4-diehloroaniline and 35.3 g (0.19 mole) of tri-n-butylamine at 145 ° C for 12.75 hours.

The mixture is then cooled and, after dilution with 100 ml of toluene, it is washed three times with 50 ml of water each time to remove the resulting tri-n-butylamine hydrochloride. Finally, the mixture is dried over sodium sulfate and the toluene is removed by distillation.

An analysis of the reaction product thus obtained by gas-liquid chromatography shows that 97.7 mole percent of the 3,4-dichloroaniline is converted to the desired ethyl α- (3,4-dichloroanilino) -propionate with selectivity of 86.7 mole percent. The yield is therefore $ 84.7, calculated on the aniline.

Examples 2-6.

Table 1 below sets forth the results of a series of experiments which differ in certain respects from the procedure described in Example 1. Further details can be found in the table.

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Table A

A = ethyl oc-chloropropionate B = 3,4-dichloroaniline C = tri-n-butylamine

Example Mole Ratio Reaction = Temp = 0mg = Selection = Yield, No. ABC time, hours rature, see (B), white calculated ° C mole percent (B), mole = on B, mole percent = cent 2 1.2 1 1 6 155 89.9 78.6 70.6 5 1.38 11 6 155 93.7 87.9 82.4 4 2 1 1 8 145 92.9 90.1 83.7 5 2 1 la) 8. 145 96 0 89.7 86.1 6 2 1 lb) 6 145 94.4 90.0 85.0 a) 1/4 thereof added at the beginning and 3/4 continuously over 7 hours.

b) 1/4 of it added initially and 3/4 continuously over 4 hours; the test was also carried out in the presence of 5 mole percent added hydrohloride of C (calculated on B).

Thus, e.g. a comparison between Example 2 and Example 3 that a higher molar ratio A: B increases the yield. Furthermore, the gradual addition of a portion of the amine C during the reaction results in an increase in the conversion and yield, as will be seen in a comparison between Example 5 and Example 4. Example 6 wherein the hydrochloride of the amine C is added to the starting mixture. further shows that, in just 6 hours, approximately the same result as in Example 5 is obtained.

Example 7 ·

Preparation of ethyl cc- (3,4-dichloroaniliro) propionate (using tri-n-butylamine).

In a 100 ml * s three-necked, round-mouthed flask equipped with magnetic stirrer, gas conduit, thermometer and reflux condenser, a mixture of 13.66 g (100 millimoles) of ethyl-a-chloropropio = night, 8.10 g (50 millimoles) of 3,4-dichloroaniline, 5.55 g (25 millimoles) of tri-n-butylamine hydrochloride and 8.80 g (47.5 millimoles) of tri-n-butyl = amine for 4 hours at 135 ° C under nitrogen atmosphere. The mixture is then cooled and, after dilution with 25 ml of toluene, it is washed with 25 ml of water to remove the resulting tri-n-butylamine hydrochloride.

Finally, the mixture is dried over sodium sulfate.

An analysis of the reaction product thus obtained by gas = liquid chromatography shows that 85.3% of the 3,4-dichloroaniline has been converted to the desired ethyl oc- (3,4-dichloroanilino) propionate. with a selectivity of 94.4 mole percent. The yield is therefore 80.3%, calculated on the aniline.

Example 8.

Preparation of ethyl cc- (3,4-dichloroanilino) propionate (using triallylamine).

Analogous to that described in Example 1, a mixture of 54.6 g (0.4 mole) of ethyl o-chloropropionate, 32.4 g (0.2 mole) of 3,4-di = chloroaniline and 25.4 g ( 0.185 moles of triallylamine at 145 ° C for 12 hours under a nitrogen atmosphere. In working up, 150 ml of toluene is used.

According to gas-liquid chromatography, 68.9 mole percent of the 3,4-dichloroaniline has been converted with a selectivity of 94.2%, corresponding to a yield of the desired ethyl-α- (3,4-dichloroanilino) <= propionate of 93.2% (calculated on the aniline). The preparation of the N-benzoyl derivative is carried out in a separate experiment where 39.3 g (0.28 mol) of benzoyl chloride is added to the solution of the crude reaction product - after removal of the resulting triallylamine hydrochloride and 100 ml of toluene - over 20 minutes at a temperature of 120 ° C and the mixture is then kept for 4 hours at 120 ° C. Bone excess amount of benzoyl chloride, ethyl 2-chloropropionate and N-toluene is removed by distillation under reduced pressure, the N-Benzoyl derivative thus obtained having a selectivity of 95.3 mol% at a conversion of 96.0 mol%.

Claims (3)

A process for the preparation of α-anilinocarboxylic acids and / or derivatives thereof of the general formula I X-N-CH-Y I R 2 R 4 R 3 12 3 wherein each of the symbols R, R and R represents a hydrogen or halogen atom or an alkyl, haloalkyl or alkoxy group, R4 represents a hydrogen atom or an alkyl group, Y represents a carboxyl group or a corresponding salt or ester group or a corresponding carboxamide group which may be substituted on the nitrogen atom by one or two hydrocarbon groups or if the nitrogen atom is part of a cyclic system and X represents a hydrogen atom or an acyl group, in which process a compound of the general formula II, wherein R, R and R have the above meanings, is reacted with a compound of the general formula III Hal-CH-Y III R1 wherein Hal represents a halogen atom and R1 and Y have the meanings set forth above, characterized in that the reaction type components having the general Formulas II and III, respectively, are heated in the presence of a tertiary amine to form a compound of formula I wherein X represents a hydrogen atom, wherein the crude product of general formula I obtained is optionally subjected to an acylation reaction after removal of the hydrohalide of the tertiary amine. forming a spring compound of formula I wherein X represents an acyl group. Process according to claim 1, characterized in that as an tertiary amine an aliphatic amine is used, wherein each of the substituents on the nitrogen atom contains a maximum of 6 carbon atoms. Process according to claim 2, characterized in that tri-n-butylamine is used as tertiary amine. Process according to any one of claims 1 to 3 characterized in that the tertiary amine or at least a part thereof is added gradually to the reaction mixture during the reaction.