DK143104B - METHOD OF ANALOGUE FOR THE PREPARATION OF ANILINOPHENYLACETAMIDE DERIVATIVES OR SALTS THEREOF - Google Patents

Description

(S) \ r & / (11) PUBLICATION 143104 DENMARK im c,. * C o? c 83/10 (21) Application no. 4 ^ 1 7/71 (22) filed on 2 Sep. 1971 llSw / (24) Løbed8fl 2. S ep. 1971 (44) The application submitted and the petition published on JO. ΠΧ & Γ. 1 §8l

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority requested from 9 September. 1970, 13415/70, ch

July 10. 1971, 10580/71, CH

(71> _CIBA-GEIGY Ag, 4002 Basel, CH.

(72) Inventor: Alfred sallmann, Joachim's fields at 12, Bottmingen / BL, CH: Rudolf Pfister, 128 Neubadstrasse, Basel, CH.

(74) The clerk during the blessing

Dansk Patent Kontor ApS.

(54) Analogous process for the preparation of anilinophenylacetamide derivatives or salts thereof.

The present invention relates to an analogous process for the preparation of therapeutically effective novel novel anilinophenylacetamide derivatives of the formula CH2 - C2-2 / NH2 - OH (I) 4

RJ - J-R

\ 2

2 1431 OA

Wherein R, R and R are independently hydrogen, alkyl of 1 = 6 C atoms, preferably 1-3 C atoms, alkoxy of 1-6 C atoms, preferably 1 C atom, or halogen through atomic number 35 2 and R hydrogen, alkyl of 1-6 C atoms, preferably 1-3 C atoms, alkoxy of 1-6 C atoms, preferably 1 C atom, halogen through 12 3 atomic numbers 35 or trifluoromethyl, while R, R and R may not simultaneously mean hydrogen, or salts thereof.

In the following, the term "low" in the context of alkyl groups and groups derived from these groups is used to characterize such groups containing up to 6 and preferably 1-3 carbon atoms.

Alkyl groups having 1-6 C atoms are methyl, ethyl, propyl, isopropyl or straight or branched, butyl, pentyl or hexyl groups at any position.

Alkoxy groups having 1-6 C atoms are methoxy, ethoxy, propoxy, iso-propoxy, butoxy, pentyloxy and hexyloxy groups.

12 3 4

The substituents R, R, R and R are as alkyl preferably an alkyl group of 1-2 carbon atoms, i.e. a methyl or ethyl group.

As the alkoxy, a substituent is preferably a methoxy group.

12 3 4

Among halogen atoms as substituents R, R, R and R, especially fluorine and chlorine should be emphasized.

12 3

Said substituents R, R and R are preferably in the o and / or 4 m position. The substituent R preferably represents a chlorine atom and is preferably in the β-position of the anilino group.

In the process of the invention, the compounds of formula I are optionally obtained in the form of their salts. For the use of the compounds as drugs, such salts which are pharmaceutically acceptable are preferred. In particular, salts with such bases are to be understood if the anions at the dosages at issue show either no pharmacological effect or a desired pharmacological effect. Furthermore, it is an advantage when the salts to be used as active substances are well crystallizable and not or only slightly hygroscopic. For salt formation with compounds of formula I, e.g. inorganic bases such as e.g. aqueous or aqueous-alcoholic solutions of alkali or alkaline earth metal hydroxides.

The compounds prepared according to the process of the present invention have valuable pharmacological properties. Thus, they exhibit anti-inflammatory (anti-inflammatory), analgesic and antipyretic effects, as can be demonstrated in animal studies, e.g. by oral administration to mice at doses of ca. 3-50 mg / kg. Furthermore, the compounds are characterized by relatively low toxicity and good gastrointestinal tolerance, as can also be demonstrated in standard animal studies. For example, the analgesic effect of the subject compounds of formula I can be demonstrated by oral administration to mice following that of E.Siegmund, R. Cadmus and G.Lu, Proc. Soc. Exp.

Biol. With. 95, 729 (1957), disclose the amount of substance necessary to prevent the syndrome caused by intraperitoneal injection of 2-phenyl-1,4-benzoquinone.

The anti-inflammatory effect of the substituted o-anilino-phenylacetydroxamic acids of Formula I may be e.g. is detected by oral administration to guinea pigs in that of G.Willhelmi, Switzerland. With. Weekschrift 79, 577 (1949), described UV erythema tests as well as for rats in the Bolus alba edema test after G.Willhelmi, Jap. J. Pharmacol, July 5, 187 (1965).

According to Danish Patent Nos. 120,027 and 124,943, similar therapeutically effective compounds are known, namely anilinophenylacetic acid esters and acetamides, respectively. Surprisingly, it has been found that the anilinophenyl-acetamide derivatives prepared according to the invention have substantially better inflammation-inhibiting effect than the compounds known from these patents, as can be seen from the test results below.

The compounds investigated for anti-inflammatory effect are: 1. [o- (a, a, α-trifluoro-m-toluidino) -phenyl] -acetic acid methyl ester 2. [o- (2,3-xylidino) -phenyl] -acetic acid methyl ester 3. [o- (2,6-dichloro-anilino) -phenyl] -N, N-dimethylacetamide 4. [o- (2,6-dichloro-anilino) -phenyl] -acetamide 5. [o- (3-chloro-o -toluidino) -phenyl] -acetamide 6. [o- (2, β-dichloroanilino) -phenyl] -acetydroxamic acid 7. [o- (3-chloro-oluidino) -phenyl] -acethyroxamic acid 4 143104

Compounds 1-2 and 3-5 are known from Danish Patent Specifications Nos. 120,027 and 124,943, respectively, while Compounds 6-7 are two compounds prepared by the process of the invention.

As a test object, Bolus alba edema was used in rats and the experiment was performed after that of G ·. Wilhelmi in Jap. J. Pharmacol. 15 (1965), pages I87-I98, described method. In 6 white male rats, the mean swelling reduction obtained with the test substance was determined. The results are given in the table below.

Compound Dose p.o. Swelling change (mg / kg) in $> 1 400 - 45 2 200 - 39 3 400 - 41 4 400 - 31 5 100 - 35 6 10 - 31 7 10 - 41

It will be seen that the compounds 6 and 7, when administered orally to rats, are significantly more effective than the known compounds.

A further test of the anti-inflammatory effect and tolerance should be mentioned the cotton granuloma test. In this, two approx.

1 cm long cotton rolls subcutaneously under the dorsal skin of rats under ether anesthesia. Subsequently, the test substance is administered successively for 10 days in the same doses. On the 11th day the animals are killed; the resulting granulomas are peeled off and their wet and dry weight determined. By comparing the dry weight of rat granulomas given the test substance with control animal granulomas, the extent of the granuloma inhibition is calculated.

As a measure of tolerance, the weight gain of animals is measured during administration of the test substances.

The gastrointestinal tolerance is measured, for example, on the ulcerogenic effect on rats, the active substance being administered orally twice every 15 hours; the animals are killed 21 hours after the first administration and the digestive tracts are evaluated for ulceration and other changes in the mucosa.

5 143104

To determine the antipyretic effect, the compounds of formula I are orally administered at appropriate doses to groups of rats on which a suspension of 15% yeast with 1% tragacanth and 1% sodium chloride in distilled water was injected 16-8 hours before intramuscularly into a distilled water. amount of 1 ml per 100 g body weight. The fever temperatures induced by the yeast were rectally measured every half hour, one hour and a half before administration of the test substances and for the period from half an hour to 5 hours after administration of the test substances, and the maximum temperature reduction and the arithmetic mean lowering of the temperature during the 5 hours. after the administration of the test substances with the average of the two measurements before administration as a baseline was found.

The present substituted o-anilino-phenylacetydroxamic acids of formula I are suitable as active substances for orally, rectally, parenterally or percutaneously useful drugs for the relief and removal of pain and inflammation of various kinds, for example of post-traumatic and post-operative nature, and for oral, rectal , parenterally or percutaneously useful drugs for the treatment of rheumatic, arthritic and other inflammatory diseases.

Particularly noteworthy are compounds of the formula / * 2 -c (

J \ / XNH - OH

T (Ia)

kA

NH

3f A 1 '

Ir --- 1-R1 in r

wherein R is hydrogen, methyl or halogen through atomic number 2T

35, R hydrogen, methyl, halogen through atomic number 35 or tri-3f fluoromethyl and R 2 hydrogen, methyl or halogen up to atomic number II 2 '3 t 35, excluding the simultaneous definition of R, R and Il as hydrogen, and salts of such compounds.

Particularly preferred are compounds of formula 6 143104

ISLAND

ch2 - (X *

/ s / ΧϊΗ - OH

U,

NH

"V / · V \ 2.

ir τη 2n wherein R is methyl or chlorine, R is hydrogen, methyl or chlorine and R is hydrogen, methyl or chlorine, and salts thereof.

Due to their particularly favorable pharmacological properties, [o- (2,6-dichloroanilino) -phenyl] -acetydroxamic acid, [o- (2,6-dichloro-m-toluidino) -phenyl] -acetydroxamic acid, [o- (3-chloro-o-toluidino) -phenyl] -acetydroxamic acid, [o- (6-chloro-o-toluidino) -phenyl] -acetydroxamic acid and [o- (2,6-xylidino) -phenyl] -acetydroxamic acid.

The compounds of formula I and their salts are prepared in a manner known per se according to the process of the invention by reacting an amide or ester of an acid of the formula / ° ch 2 - c (·, / V «K - I (II) v

NH

3-F-V-R

X

V

Wherein R, R, R * 5 and R 2 - have the meaning given in formula I, with hydroxylamine or a salt thereof in basic medium and if desired transfer a obtained compound of formula I to a salt with an inorganic base.

As amides of an acid of formula II, compounds which are unsubstituted by the amide nitrogen are preferably used. Preferably, lower alkyl esters are used as esters of an acid of formula II. As activated esters, e.g. p-nitrobenzyl, ethoxycarbonylmethyl, methoxymethyl, p-nitro-thiophenyl esters and preferably cyanomethyl or p-nitrophenyl esters of acids of formula II are used.

The reaction is carried out in an organic solvent, preferably at a temperature between 20 and 100 ° C or at the boiling temperature of the solvent used, and at a reaction time between 20 minutes and 15 hours.

As suitable solvents, organic solvents which are inactive under the reaction conditions, such as lower alkanols, acetonitrile or chloroform, are used. In addition, acetone, diethyl ether, di-n-butyl ether, acetic acid ethyl ester, 1,2-dichloroethane, dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, methylene chloride, nitromethane, petroleum ether, tetrachlorethylene, carbon tetrachloride or trichloroethylene and benzene, nitrobenzene, or toluene.

The selection of the solvent advantageous in each case also depends on the nature of the starting materials used. Eg. For example, the reaction of a lower alkyl ester or an amide of an acid of formula II is carried out in a lower alkanol, preferably methanol. For example, in the reaction of an activated ester of formula II, acetonitrile, chloroform, dimethylformamide or acetic acid ethyl ester are used as the solvent.

Said amides and esters of acids of general formula II are reacted with hydroxylamine or a salt thereof in stoichiometric amounts or with an excess of hydroxylamine. In the reaction of the said acid derivatives with hydroxylamine hydrochloride, a base of excess which is stronger in comparison with the hydroxylamine must be added.

In the reaction of lower alkyl esters or amides with acids of formula II, an amount equivalent to the hydroxylamine hydrochloride is added, but preferably a quadruple excess of a base such as e.g. sodium alcoholate or alcoholic sodium hydroxide solution, for reaction.

When activated esters, such as, for example, the cyanomethyl ester or p-nitrophenyl ester of an acid of formula II, are added to an amount of a tertiary organic base at least twice the hydroxylamine hydrochloride, such as e.g. triethylamine or pyridine.

Some representatives of the lower alkyl esters and amides of an acid of formula II are known and others may be prepared analogously to the known ones. Lower alkyl esters are prepared, for example, by esterification of the corresponding acids of formula II or by alcoholysis of the corresponding nitriles. Of the lower alkyl esters obtained, after reaction with ammonia, the corresponding amides are known.

The substituted o-anilino-phenylacetic acid cyano methyl esters are prepared from the corresponding substituted o-anilino-phenylacetic acids of formula II by reaction with chloroacetonitrile in the presence of the equivalent amount of triethylamine or by reacting the Na salts of said acids with chloroacetonitrile such as dimethyl sulfoxide; analogously, the substituted o-anilino-phenyl-acetic acid p-nitrobenzyl esters, ethoxycarbonylmethyl esters and methoxymethyl esters are obtained. The substituted p-nitrophenyl esters of acids of formula II are obtained from the corresponding acids by reaction with trifluoroacetic acid p-nitrophenyl ester in the presence of pyridine; analogously, p-nitro-thiophenyl ester is also available.

If desired, the obtained novel phenylacetydroxamic acids of formula I are then transferred in the usual manner to salts thereof with inorganic bases.

For salt formation with compounds of formula I, alkali metal hydroxides, e.g. sodium or potassium hydroxide, or alkaline earth metal hydroxides, e.g. calcium hydroxide.

The substituted phenylacetydroxamic acids of formula I may be administered orally, rectally or parenterally. They can also be used externally, for example, incorporated in ointment.

Drugs for the aforementioned indications contain as active substances at least one compound of formula I in combination with an inert carrier and, if desired, other additives. The drugs preferably consist of dosage unit forms suitable for oral, rectal or parenteral administration of daily doses between 3 and 50 mg / kg of the active substance to warm blooded animals. Suitable dose 9 unit dosage forms for the oral, rectal or parenteral application, such as dragees, tablets, capsules, suppositories or ampoules, preferably contain 25-500 mg of a compound of the general formula I.

The following examples further illustrate the process of the invention.

Example 1.

[O ~ (2,6-dichloroanilino) phenyl] -acethydroxamsyre

For a solution of 1S, 7 g of sodium in 400 ml of abs. methanol a solution of 17.5 g of hydroxylamine hydrochloride in 260 ml of abs is added at room temperature. methanol. To the suspension is added 77.6 g of [o- (2,6-dichloroanilino) -phenyl] -acetic acid methyl ester (mp 101-102 ° C) and then refluxed for 30 minutes. The mixture is cooled and evaporated to dryness under 11 mm Hg pressure at 40 ° C. To the residue, add 4000 ml of water and 500 ml of ether, stir 20 minutes, separate the aqueous solution and make it acidic with 6 N hydrochloric acid. The suspension is extracted with 2000 ml of ether; The ether solution is washed with 200 ml of water and 200 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 40 ° C. The residue is twice crystallized from ethyl acetate-petroleum ether. [o- (2,6-Dichloroanilino) -phenyl] -acetydroxamic acid melts at 164-165 ° C.

Analogously, [o- (2,6-dichloro-m-toluidino) -phenyl] -acet hydroxamic acid is obtained, m.p. 140-145 ° C (of ether-petroleum ether), starting from 16.2 g of [o- (2,6-dichloro-m-toluidino) -phenyl] -acetic acid methyl ester, m.p. 110-112 ° C; [o- (6-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 159-162 ° C (ethyl acetate-petroleum ether), starting from 29.1 g of [o- (6-chloro-o-toluidino) phenyl] -acetic acid methyl ester, m.p. 99-100 ° C (of cyclohexane); [o- (2,6-xylidino) -phenyl] -acetydroxamic acid, m.p. 134-136 ° C (ethyl acetate-petroleum ether) yielding 4.9 g of [o- (2,6-xylidino) phenyl] -acetic acid methyl ester, m.p. 79-SO ° C (of ether-petroleum ether); [o- (3-chloro-o-toluidino) -phenyl] -acet-hydroxamic acid, m.p. 135-136 ° C (of ether-petroleum ether), starting from 7.2 g of [o- (3-chloro-o-toluidino) -phenyl] -acetic acid methyl ester, m.p. 47-4 ° C (of ether-petroleum ether).

For example, [o- (3-Chloro-o-toluidino) -phenyl] -acetic acid methyl ester is obtained as follows: a) N- (3-Chloro-o-tolyl) -anthranilic acid

One. mixture of 665 g of o-bromobenzoic acid and 220 g of $ 5% fs potassium hydroxide in 1000 ml of n-pentanol is heated with stirring to 160 ° C. Within 30 minutes, approx. 400 ml of n-pentanol. 940 g of 3-chloro-o-touludin and 12.5 g of copper powder are then added and the mixture is refluxed for 15 hours. The mixture is then cooled, the mixture is poured into a solution of 1β0 g of sodium carbonate in 600 ml of water and the solution is distilled with water vapor. After the excess 3-chloro-o-toluidine is distilled off, the aqueous residue is filtered and the filtrate acidified with concentrated hydrochloric acid. The separated crystals are filtered off and crystallized by ethanol-water. N- (3-chloro-tolyl) -anthranilic acid is obtained, m.p. 212-215 ° C.

b) N-Phenyl-3-chloro-o-toluidine 150 g of N- (3-Chloro-o-tolyl) -anthranilic acid are heated 2/2 hours to 2S0 ° C. The cooled melt is dissolved in 700 ml of ether. The ether solution is washed twice with 150 ml of 2 N sodium carbonate solution and 150 ml of water. The ether solution is then separated, dried over sodium sulfate and evaporated to dryness under 11 mm Hg pressure at 40 ° C. The residue is distilled to give N-phenyl-3-chloro-o-toluidine as a yellow oil, b.p. 117 ° G / 0.01 mm Hg pressure.

c) N-Phenyl-3T-chloro-2T-methyl-oxaniloyl chloride

To a solution of 94} 5 g of N-phenyl-3-chloro-o-toluidine in 560 ml of anhydrous benzene, 137 ml of oxalyl chloride are slowly dropped at 5 ° C. Then the suspension is stirred for 2 hours at room temperature and 1 / Z hour at 50 ° C, whereby the suspension dissolves. The reaction solution is cooled and evaporated to dryness under 11 mm Hg pressure at a bath temperature of 40 ° C. The residue is dissolved in 400 ml of anhydrous benzene and the solution is again evaporated to dryness under 11 mm Hg pressure. residue; W-phenyl-3T-chloro-2'-methyl-oxaniloyl chloride is present as an oil.

d) 1- (3-Chloro-o-tolyl) -indole-2,3-dione

To a solution of 134 g of N-phenyl-3'-chloro-2T-methyl-oxaniloyl chloride in 900 ml of tetrachloroethane is added portionwise $ 5, 6 g of powdered aluminum chloride. The mixture is stirred for 20 hours at room temperature. It is then poured into a mixture of 2000 g of ice and 200 ml of 2N hydrochloric acid.

11 143104

Add 500 ml of chloroform and shake well. The tetrachloroethane chloroform solution is separated, washed with 300 ml of 2 N sodium carbonate solution and then with 300 ml of water, dried over sodium sulfate and evaporated to dryness under 0.1 mm Hg pressure. The residue is crystallized by ethyl acetate. 1- (3-Chloro-o-tolyl) -indole-2,3-dione melts at 173-174 ° C.

e) The sodium salt of -O- (3-chloro-o-toluidino) -phenyl-glyoxylic acid

A solution of 57 g of 1- (3-chloro-o-tolyl) -indole-2,3-dione in 800 ml of ethanol and 210 ml of 1 N sodium hydroxide solution is evaporated to dryness under 11 mm Hg pressure at 40 ° C. For the residue, add abs. benzene twice, each time 100 ml, and each time evaporating the mixture to dryness under 11 mm Hg pressure at 40 ° C to give pure sodium salt of [o- (3-chloro-o-toluidino) -phenyl] -glyoxylic acid .

f) -o- (3-Chloro-o-toluidino) -phenylT-acetic acid

To a solution of 35.5 g of sodium salt of [o- (3-chloro-o-toluidino) phenyl] glyoxylic acid in 455 ml of abs. ethanol is added at 50 ° C 28.5 g of hydrazine hydrate and 5 minutes then 66.2 g of sodium methylate. The solution is then heated in an oil bath at a bath temperature of 150 ° C, whereupon the ethanol is slowly distilled off. At the same time, 455 ml of ethylene glycol monoethyl ether are added dropwise. The internal temperature thereby rises to 130 ° C. After the drop is completed, the solution is stirred for another hour at 150 ° C, cooled and diluted with 3000 ml of water. The solution is extracted twice, each time with 300 ml of ether, and then acidified with concentrated hydrochloric acid. The separated yellow oil is extracted with 200 ml of ethyl acetate. The ethyl acetate solution is washed with 200 ml of water, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 30 ° C, whereby [o- (3-chloro-o-toluidino) -phenyl] -acetic acid crystallizes, m.p. 124 "125 ° C.

g) Ro- (3-Chloro-o-toluidinol-phenyl-acetic acid methyl ester

To a solution of 10 g of [o- (3-chloro-o-toluidino) -phenyl] -acetic acid (mp 124-125 ° G) in 100 ml of ether is slowly allowed to drop 100 ml of 2 $ f of ethereal diazomethane solution. The solution is allowed to stand for 2 hours at room temperature and then evaporated to dryness under 11 mm Hg pressure at 40 ° C. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ral 2 N sodium bicarbonate solution and water, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 40 ° C.

The residue of gasoline is crystallized. [o- (3-Chloro-o-toluidino) - phenyl] -acetic acid methyl ester melts at 47-4 ° C.

Example 2.

Γ ο - (2,6-Dichloro-anilino) -phenyl] -acethydroxamic acid

To a mixture of 6.7 g of [o- (2,6-dichloro-anilino) -phenyl] -acetic acid cyanomethyl ester (mp 100-104 ° C) and 0.7 g of hydroxylamine hydrochloride in 27 ml of acetonitrile are added. drops of glacial acetic acid and 1.01 g of triethylamine. The mixture is stirred for 30 minutes at room temperature, again 0.35 g of hydroxylamine hydrochloride and 0.5 g of triethylamine are added and stirred for an additional 15 hours at room temperature. Then the mixture is evaporated under 11 mm Hg pressure at 50 ° C. To the residue is added 30 ml of water and 100 ml of ethyl acetate. The ethyl acetate solution is separated and evaporated under 11 mm Hg pressure. The residue is dissolved in 100 ml of ether and the ether solution is extracted with 10 ml of 1 N sodium hydroxide solution, whereby [o- (2,6-dichloro-anilino) -phenyl] -acethydroxamic acid-Na salt is crystallized. The crystals are filtered off, suspended in 50 ml of ether and the suspension is shaken with 20 ml of 6 N hydrochloric acid. The clear ether phase is separated, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 40 ° C. The residue of ether is crystallized. [α- (2,6-Dichloro-anilino) -phenyl] -acetydroxamic acid melts at 164-165 °.

Analogously: [o- (2,6-dichloro-m-toluidino) -phenyl] -acetydroxamic acid, m.p. 140-145 ° C (of ether-petroleum ether) starting from [o- (2,6-dichloro-m-toluidino) -phenyl] -acetic acid cyano methyl ester; [o- (6-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 159-162 ° C (of ethyl acetate-petroleum ether) starting from [o- (6-chloro-o-toluidino) -phenyl] -acetic acid cyano methyl ester; [o- (2,6-xylidino) -phenyl] -acetydroxamic acid, m.p. 134-136 ° G (of ethyl acetate-petroleum ether) starting from [o- (2,6-xylidino) -phenyl] -acetic acid cyano methyl ester; [α- (3-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 135 ° -136 ° C (of ether-petroleum ether) starting from [o- (3-chloro-o-toluidino) -phenyl] -acetic acid cyano methyl ester.

The starting materials are obtained as follows: a) [(2,6-Pichloroanilino) -phenyl] -acetic acid-cyanomethyl ester A mixture of 2.96 g of [o- (2,6-dichloroanilino) -phenyl] -acetic acid (m.p.

13 143106 156-158 ° C of ether-petroleum ether), 1.13 g of chloroacetonitrile and 1.51 g of triethylamine in 30 ml of ethyl acetate are stirred for 15 hours at 60 ° G, cooled and separated from the separated triethylamine hydrochloride. The filtrate is washed with 5 ml of 1N hydrochloric acid and three times each with 5 ml of 1N sodium hydrogen carbonate solution and 5 ml of water, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 50 ° C. The residue of methanol is crystallized. [o- (2,6-Dichloroanilino) -phenyl] -acetic acid cyano methyl ester melts at 100-104 ° C.

Analogously, [o- (2,6-dichloro-m-toluidino) -phenyl] -acetic acid cyano-methyl ester is obtained, starting from [o- (2,6-dichloro-m-toluidino) -phenyl] -acetic acid , m.p. 146-149 ° C (of ether-petroleum ether); [o- (6-chloro-o-toluidino) -phenyl] -acetic acid cyano-methyl ester, starting from [o- (6-chloro-o-toluidino) -phenyl] -acetic acid, m.p. 140-147 ° C (of ether-petroleum ether); [o- (2,6-xylidino) -phenyl] -acetic acid cyano-methyl ester, starting from [o- (2,6-xylidino) -phenyl] -acetic acid, m.p. 112-113 ° C (of ether-petroleum ether); [o- (3-chloro-2-methyl) -phenyl] -acetic acid cyano-methyl ester, starting from [o- (3-chloro-o-toluidino) -phenyl] -acetic acid, m.p. 124-125 ° C (of ether-petroleum ether).

b) [(2,6-Dichloroanilino) -phenyl] -acetic acid cyano methyl ester

To a solution of 5.0 g of [[2,6-dichloroanilino) -phenyl] -acetic acid Na salt (mp 283-285 ° C of water) in 30 ml of dimethyl sulfoxide is added 30 ml of chloroacetonitrile at room temperature. The mixture is stirred for 20 minutes at room temperature, poured into 100 g of ice and extracted with 200 ml of ether. The ether solution is washed with 30 ml of 2 N potassium hydrogen carbonate solution and three times each with 30 ml of water, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 40 ° C. The residue of methanol is crystallized. [o- (2,6-Dichloroaninilo) -phenyl] -acetic acid cyano methyl ester melts at 100-104 ° C.

Analogously, [o- (2,6-dichloro-m-toluidino) -phenyl] -acetic acid cyano-methyl ester is obtained, starting from [o- (2,6-Dichloro-m-toluidino) -phenyl] -acetic acid -Na-salt, m.p. 287-289 ° C (water); [O- (6-chloro-o-toluidino) -phenyl] -acetic acid cyano methyl ester, starting from [o- (6-chloro-o-toluidino) -phenyl] -acetic acid K-salt, m.p. . 2S5-300 ° C (decomposition, of methanol); [o- (2,6-xylidino) -phenyl] -acetic acid cyano-methyl ester, starting from [o- (2,6-xylidino) -phenyl] -acetic acid Na salt, m.p. 29S-305 ° C (of water).

Example 3

[2- (2,6-Dichloroanilino) -phenyl] -acethydroxamic acid

To a suspension of 4.17 g of [o- (2,6-dichloroanilino) phenyl] -acetic acid p-nitrophenyl ester (mp 105-106 ° C) and 0.69 g of hydroxylamine hydrochloride in 50 ml abs. chloroform is added at room temperature 2.76 g of triethylamine. The clear solution is stirred for 30 minutes at room temperature and evaporated to dryness under 11 mm Hg pressure. To the residue are added 100 ml of ether and 5 ml of 2N hydrochloric acid. The ether solution is separated, washed twice, each time with 40 ml of water, dried over sodium sulfate and evaporated under 11 mm Hg pressure at 40 ° G. The residue of ether is crystallized. [O- (2,6-dichloroanilino) phenyl] -acethydroxam acid. melting at l64-l65 ° G.

Analogously, mon: [o- (3-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 135 ** 136 ° G (of ether-petroleum ether) starting from [o- (3-chloro-o-toluidino) -phenyl] -acetic acid p-nitrophenyl ester.

The starting material is obtained as follows: [2- (2,6-Dichloroanilino) -phenyl] -acetic acid p-nitrophenyl ester

To a solution of 6.0 g of [o- (2,6-dichloroanilino) -phenyl] -acetic acid in 20 ml of pyridine is added portionwise with stirring 6.0 g of trifluoroacetic acid p-nitropheyl ester (prepared as prescribed by S. Sakakibara and N. Inukai, Bull.Chem.Soc.Jap., 19¾ [1965]) · The mixture is stirred for one hour at room temperature and evaporated under 11 mm Hg pressure at 30-40 ° C. To the residue was added 20 ml of water and extracted with 50 ml of chloroform. The aqueous phase is separated and extracted again with 30 ml of chloroform. The combined chloroform solutions are extracted with 20 ml of 1N hydrochloric acid, 20 ml of 1N potassium hydrogen carbonate solution and twice each 20 ml of water, separated, dried over sodium sulfate and evaporated under 11 mm Hg pressure. The residue of methanol is crystallized. [O- (2,6-dichloroanilino) -phenyl] -acetic acid p-nitrophenyl ester

15 1431 OA

melting at 105-106 ° C.

Analogously, [o- (3-chloro-o-toluidino) -phenyl] -acetic acid-p-nitrophenyl ester is obtained, starting from [o- (3-chloro-o-toluidino) -phenyl] -acetic acid , m.p. 124-125 ° C (of ether-petroleum ether).

Example 4

Γ o- (2,6-Dichloroanilino) -phenyl-1-acetic hydroxamic acid

To a solution of 1.84 g of sodium in 80 ml of methanol is added at 50 ° C a solution of 1.82 g of hydroxylamine hydrochloride in 30 ml of methanol. To the suspension is added, with stirring, a solution of 5.8 g of [o- (2,6-dichloroanilino) -phenyl] -acetamide (mp 188-89 ° C) in 80 ml of methanol and then refluxed for 18 hours. The red suspension is cooled and evaporated to dryness under 11 mm Hg pressure at 40 ° C. The residue is shaken with 600 ml of water and 100 ml of ether. The aqueous phase is separated and acidified with 2N hydrochloric acid. The suspension is extracted with 200 ml of ether; the ether solution is separated, washed with water, dried over magnesium sulfate and evaporated under 11 mm Hg pressure at 40 ° G. The residue of ether is crystallized to give [o- (2,6-dichloroanilino) -phenyl] -acetydroxamic acid, m.p. L64-L65 ° C.

Analogously obtained: [o- (3-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 135-136 ° C (of ether-petroleum ether), starting from 4.2 g of [o- (3-chloro-o-toluidino) -phenyl] -acetamide, m.p. 139-141 ° C (of ether-petroleum ether); [o- (2,6-dichloro-m-toluidino) -phenyl] -acetydroxamic acid, m.p. 140-145 ° C, starting from [o- (2,6-dichloro-m-tcluidino) -phenyl] -acetamide; [o- (6-chloro-o-toluidino) -phenyl] -acetydroxamic acid, m.p. 159-162 ° C, starting from [o- (6-chloro-o-toluidino) -phenyl] -acetamide, m.p. 166-l68 ° C; [o- (2,6-xylidino) -phenyl] -acetydroxamic acid, m.p. 134-136 ° C, starting from [o- (2,6-xylidino) -phenyl] -acetamide.

The starting material is obtained as follows: Γo- (3-Chloro-o-toinoidino) -phenyl] -acetamide

A mixture of 7.8 g of [o- (3-chloro-o-toluidino) -phenyl] -acetic acid methyl ester (mp 47-48 ° C) and 100 ml of liquid ammonia is stirred for 4 days.

Claims (1)

16 143104 at room temperature in autoclave. The ammonia is then evaporated and the residue is chromatographed on 240 g of neutral alumina. Fractions 1-15, eluted with ether-chloroform 1: 1, contain N- (3-chloro-o-tolyl) -indolinone, fraction 16-22, eluted with chloroform-methanol 99: 1, contains [o - (3-chloro-o-toluidino) -phenyl] -acetamide, m.p. 139-141 ° C (of ether-petroleum ether). PATEIIKEAV. Analogous Process for Preparation of Anilinophenyl Acetamide Derivatives of the Formula / CH2 "C r ^ Y NiH - OH ΪΓ - IV \ (i) m R3-H (-H1 X2 wherein r \ R ^ and R ^ independently represent hydrogen, alkyl with 1-6 C atoms, preferably 1-3 C atoms, alkoxy with 1-6 C atoms, preferably 2 C atoms, or halogen through atomic number 35 and R hydrogen, alkyl of 1-6 C atoms, preferably 1-3 C atoms, alkoxy of 1-6 C atoms, preferably 1 C atom, halogen through atomic numbers 35 or 12 3 trifluoromethyl, however, R, R and R cannot simultaneously represent hydrogen or salts thereof, characterized by reacting an amide or ester of an acid of the formula