DE1793592C3 - Substituted phenylacetic acids and their salts and pharmaceutical compositions containing these compounds - Google Patents

Description

I +

in which

Ri is a lower alkyl or lower alkoxy radical, a halogen atom up to atom number 35 or the trifluoromethyl group,

R »hydrogen, a lower alkyl or lower Alkoxy radical or a halogen atom up to atom number 35,

R ι hydrogen, a lower alkyl or lower Alkoxy radical or a halogen atom up to atom number 35 and

R _{4 is} hydrogen, a lower alkyl or lower alkoxy radical, a halogen atom up to atomic number 35 or the trifluoromethyl group,

and their salts with pharmaceutically or cosmetically usable inorganic and organic bases.

2.2- (2,6-dichloroanilino) pheny / acetic acid.

3. Sodium salt of 2- (2, b-dichloroanilino) phenylacetic acid.

4.2- (2,6-dimethylanilino) phenylacetic acid c.

5.2- (2-methyl-3-chloroanilino) phenylacetic acid.

6. Pharmaceutical compositions, characterized by a content of compounds of the Formula I or their salts with pharmaceutically acceptable organic or inorganic Bases as an active ingredient.

The present invention relates to substituted phenylacetic acids, their salts and these compounds containing pharmaceutical compositions according to the preceding claims.

The compounds mentioned above have not yet become known. As has now been established, own the compounds of general formula I and their salts with pharmaceutically or cosmetically usable inorganic or organic bases have valuable pharmacological properties, especially anti-inflammatory properties (anti-inflammatory), analgesic and antipyretic effectiveness with favorable therapeutic Index. They can be administered orally, rectally or, especially in the form of aqueous solutions of their salts, also parenterally, especially intramuscularly for the treatment of rheumatic, arthritic and other inflammatory diseases Diseases are used. The anti-inflammatory effectiveness can be found in animal experiments, for example on Detect UV erythema in guinea pigs and, on bolus alba, edema in rats.

In addition, these substances have the ability to absorb UV rays at 290-300 mu and are therefore as a UV absorber for cosmetic purposes, e.g. B. in sun protection creams, because they protect the harmful, absorb reddening rays, while they let through the desired tanning, over 315 ιτιμ.

In the compounds of general formula I and the corresponding starting materials mentioned below, Ri to Ri are independently of one another as lower alkyl radicals, for example methyl or ethyl radicals. Some of the symbols mentioned can e.g. B. also n-propyl, isopropyl, η-butyl, sec. Mean butyl or tert-butyl radicals. Lower alkoxy radicals than Ri to R <are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy radicals; the substituents R ₁ to R ₄ as halogen atoms mean chlorine, fluorine or bromine atoms.

For the preparation of an acid of the general formula 1 and its salts with pharmaceutical or cosmetic usable inorganic or organic bases are used a compound of the general formula II

R,

(II)

R,

in which Ri to R _{4 have} the meaning given above

.10 have, with an alkali metal hydroxide, alkali metal carbonate or alkaline earth metal hydroxide in the heat and, if desired, sets from the obtained Alkali or alkaline earth salt releases the acid. If desired, this can be converted into a different salt with a organic or inorganic rabbit.

Water-containing solvents are particularly suitable as solvents lower alkanols, such as ethanol, methanol or n-butanol, and also ethylene glycol or Dimethylformamide can be used. The hydrolysis is carried out e.g. B. at or just below the boiling point of the reaction mixture using at least one equivalent of an alkali metal hydroxide or carbonate or alkaline earth metal hydroxide, especially sodium or potassium hydroxide, completed.

According to a second process, the compound of the general formula I can be prepared by that one is a compound of the general formula

CU, -COOR ₅

(HI)

in which

A is hydrogen or an acyl radical, in particular

re a lower alkanoyl radical and

R ', a lower alkyl or an aralkyl radical,

in particular denotes the benzyl radical, and

Ri to R4 have the meaning given above,

with an alkali metal hydroxide, carbonate or bicar

bonat, an alkaline earth metal hydroxide or a basic ion exchanger in the heat, or if A is hydrogen and R _{5 is} the benzyl radical, the benzyl radical is split off by hydrogenolysis with catalytically activated hydrogen. Suitable solvents 5 for the hydrolysis are particularly water-containing lower alkanols, such as methanol, ethanol, n-butanol, and also ethylene glycol or dimethylformamide. The hydrolysis is carried out e.g. B. completed at or a little below the boiling point of the reaction mixture by means of ininde- ι ο least one equivalent of a base. The hydrogenolysis is advantageously carried out at normal pressure and room temperature to moderately elevated temperature in the presence of Pd-carbon in alcohol. ι s

A third process leads to compounds of the general formula I ₁ by adding a compound of the general formula IV,

R ₄

CH, - CN

N Λ

(IV)

i-4

Ri

R,

wherein Ri to R4 and A have the meaning given above have reacted with an alkali metal hydroxide in a water-based solvent in the heat. Particularly suitable solvents are water-containing lower alkanols, such as ethanol, methanol or n-butanol, and also ethylene glycol or dimethylformamide. the Hydrolysis is carried out e.g. B. at or a little below the boiling point of the reaction mixture by means of at least two equivalents of an alkali metal hydroxide, especially of sodium or potassium hydroxide.

The starting materials of the general formula II, which are used as l-aryl-2-indolinones, 1-aryl-oxindoles or lactams der 2-Arylaminophenylacetic acids are in turn new compounds. the The compounds of general formula II are prepared, for. B. analogously to that of the known 1-phenyl-2-indolinone from the corresponding unsymmetrically substituted diphenylamines by chloroacetylation substituted 2-chloro-N-phenyl-acetanilides and heating the latter with aluminum chloride to temperatures around 160 ° or by heating with aluminum chloride in suitable solvents such as tetrachloroethane or nitrobenzene at 100-150 °. A number of substituted according to the definition for Ri to R4 Diphenylamines are known and others can be prepared analogously to the known ones, e.g. B. after that of A. W. Chapman, J. Chem. Soc. 1929, 569-572, method described by heating N, O-diaryl-iminoesters and hydrolysis of the Ν, Ν-diarylamides formed by rearrangement, or according to that of R. B. M ο f f e ι et al., J. Am. Chem. Soc. 82, 1605 (1960) used Method based on optionally substituted o-chloro or o-bromobenzoic acids and substituted ones Anilines and decarboxylation of the resulting o-anilino-benzoic acids.

A particularly favorable method for the production of according to the definition from Ri to Ra

40

55

60 substituted diphenylamines is the method of G ο ld be rg, Ber. 40, 4541 (1907), according to which one optionally substituted acetanilide with a substituted according to the definition of R4 Reacts bromobenzene.

The starting materials of the general formula Hl with a lower alkyl group than R-, and an acyl group as A can e.g. B. by converting the corresponding cyano compounds into imino ether hydrochloridc and decomposing the latter with water.

But they can also be obtained starting from the acids of the general formula I by these treated in the known manner with alkylating agents such as diazoalkanes or dialkyl sulfates.

The lower alkyl and aralkyl esters of the general formula III can also be known by other means Esterification processes can be obtained, e.g. B. after the Ν, Ν-dimethylformamide-dineopentyl-acetal method, by H. Büchi, K. Steen and A. Eschen moser in Ang. Chemie 75 (1963), 1176, or with thionyl chloride - 10 ° in absolute alkyl or aralkyl alcohol according to Brenner (HeIv. Chim. Acta 34 [1953J 1114).

The starting materials of the general formula IV are z. B. by reacting «-halogen-N-arylo-toluidinen or -toluididen with sodium or Obtain potassium cyanide. «-Chlor-o-toluidine or A-chloro-o-toluidides surprisingly arise in a one-step reaction from o-arylamino-benzyl alcohols, namely when the latter is cooked with Acetyl chloride. Of the o-arylamino-benzyl alcohols substituted according to the definition for R 1 to R 4 individual representatives are known and other z. B. by reducing N-aryl-anthranilic acid-alkyl esters with Lithium aluminum hydride in ether or tetrahydrofuran, sodium borohydride in methanol or sodium borohydride and lithium bromide in diethylene glycol dimethyl ether available. The N-aryl-anthranilic acids can z. B. be reduced with lithium aluminum hydride.

The substituted phenylacetic acids of the general Formula I and its salts with pharmaceutically or cosmetically usable inorganic or organic bases can be used orally, rectally or parenterally, especially intramuscularly. They can also be used externally, incorporated into ointments or sun oil bases.

Suitable salts for therapeutic use are those with bases which are included in those in question Dosages show no physiological intrinsic effect or have a desired effect, e.g. B. in parenteral forms of administration, in particular a local anesthetic effect. Suitable salts are e.g. B. Sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts with ethylamine, triethylamine, ethanolamine, diethanolamine, diethylaminoethanol, ethylenediamine, benzylamine, procaine, pyrrolidine, Piperidine, morpholine, 1-ethyl-piperidine or 2-piperidinoethanol.

The daily internal doses of free acids of the general formula I or of pharmacologically acceptable salts thereof for the treatment of rheumatic, arthritic and other inflammatory diseases range between 50 and 1500 mg for adult patients. Suitable unit dosage forms, such as dragees, tablets, suppositories or ampoules, preferably contain 25-300 mg of a free acid or one pharmacologically acceptable salt thereof.

Unit forms for peroralc use contain as active ingredient preferably between 1% and 90% of an acid of the general formula I or one pharmacologically acceptable salt thereof. To produce them, the active ingredients are combined, for. B. with solid, powdery carriers such as lactose, Sucrose, sorbitol mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or Gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols with suitable molecular weights Tablets or tablet cores. The latter is coated with concentrated sugar solutions, for example, which z. B. can contain gum arabic, talc and / or titanium dioxide, or with an in highly volatile organic solvents or solvent mixtures dissolved paint. Dyes can be added to these coatings, e.g. B. to Identification of different doses of active ingredient.

Ais unit dose forms for rectal use come e.g. B. suppositories, which consists of a combination of an acid of the general formula I or one suitable salt of the same with a neutral fat base, or gelatin rectal capsules, which is a combination of an active ingredient or a suitable salt thereof with polyethylene glycols of suitable molecular weight.

Ampoules for parenteral, especially intramuscular administration preferably contain a water-soluble salt, e.g. B. the sodium salt, a substituted phenylacetic acid of the general formula I, in one Concentration of preferably 0.5-5%, optionally together with suitable stabilizing agents and buffer substances in aqueous solution.

The progress in application technology that can be achieved with the compounds according to the invention is evident from the can be seen in the following pharmacological test results.

The tested compounds are numbered, with the number, the chemical constitution and the corresponding example can be seen from the following table 1.

Table 1

\ O \ - CH ₂ -COOX

NH

No. Ri 3-CH, H Ra X IWi-
spicl 5 2-CI 4-CHj ₁ O 6-CI H H 16 6th 2-CI 3-CH, H H H IX 7th 2-CH, 3-Cl H H H 13th χ 2-CH, H 6-CH, H H 5 9 2-CH, 6-C ₂ H ₅ H H H 6th IO 2-C ₂ H ₅ H 6-Cl H H 19th 11th 2-CI H N / A 20th

Jr. R, R ₂ R., R ₄ X at
game I. 2-CI 3-CH, 6-CI H N / A 20th 2 2-CI H 6-Cl H H 4th 3 2-CI H 6-CH, H H 14th 4th ? -CI H 6-CI Cl N / A 20th

12 Comparative substance N- (2,3-dimethylanilino) anthranilic acid, described in DT-AS 1186073

The above compounds were tested for their anti-inflammatory and antinociceptive activity using the following experimental set-ups:

Anti-inflammatory activity (kaolin paw edema, rat)

Method: HeIv. Physiol. Acta 25, pp. 156-159, 1967

Local, inflammatory edema is triggered by subplantar injection of 0.05 ml of a 25% kaolin suspension, the intensity of which occurs after 4 hours is determined volumetrically. The test substances are administered orally 60 minutes before the kaolin injection administered. By graphical interpolation according to Miller and Tainter, that dose becomes one Test substance determined which compared to a untreated control collective the paw swelling reduced by 50%. The test substances are administered in 3 different doses. The investigation a test substance is carried out on at least 15 animals.

Antinociceptive activity (phenyl-p-benzoquinone writhing test mouse)

Method:

Proc. Soc. Exp. Biol. NY.95, pp. 729-731, 1957

Through i. p. Injection of 0.2 ml of a 0.025% strength Phenyl-p-benzoquinone solution is an antinocicepti-

ve reaction (writhing movements) triggered The number of writhing movements is triggered during 10 Minutes counted after the irritant was injected. The test substances are orally 60 minutes before Irritant applied. Through graphic interpolation

according to Miller and Tainter that dose of a test substance is determined which in comparison to a In the untreated control group, the number of writhing movements was reduced by 50%. The test substances are administered in 3 different doses Examination of a test substance is carried out on at least 15 animals.

The test results are shown in Table 2 below.

Table 2

No. (Table I) kaolin paste,

of the tested rat

Compound Dliw mg / kg p. ii.

2
3
4th
5
6th
7th
8th
9
10
II

24.0
1.3
8.0

18.0
4.0

26.0

24.0
5.5
7.0

38.0
1.2

63.0

Phenyl-p-ßen / udiinone. Writhing Tcsi. mouse
DI: «) mg / kg po

40.0
24.0
46.0
60.0
30.0
GO.O
50.0
20.0
42.0
46.0
4.3

100.0

Result

The 11 compounds according to the invention are significantly more effective than the known one in both tests Compound No. 12. Compounds No. 2,3,5,8,9 and 11 are particularly effective.

The following examples explain the preparation of the compounds according to the invention as well as pharmaceutical compositions thereof. The temperatures are given in degrees Celsius.

example 1
2- (2,6-dichloro-3-methylanilino) phenylacetic acid

A. N-Phenyl-2,6-dichloro-3-methylaniline

7 g of 2- (2,6-dichloro-3-methy! Anilino) benzoic acid [alternatively referred to as N- (2,6-dichloro-m-toly!) - anthranilic acid] are heated to 280 ° for 2 hours. The cooled melt is dissolved in 30 ml of benzene and the benzene solution extracted with 5 ml of 2N sodium carbonate and 5 ml of water. The solution is with Dried sodium sulfate and evaporated. The residue is distilled, the N-Phenyi-I.ö-dichior-S-methylaniline (alternatively referred to as 2,6-dichloro-N-phenyl-m-tcluidine) obtained as a yellow oil, b.p. 115-120 ° / 0.001 Torr.

Alternatively, the foregoing N-phenylaniline can also be analogous to the procedure indicated in Example 4.3 A from N-acetyl-2,6-dichloro-3-methylaniltn (mp. 1 ⁷ 9-181 ° from glacial acetic acid and water) are prepared.

B. N-chloroacetyl-N-phenyI-2,6-dichloro

3-methylaniline

4 g of N-phenyl-2,6-dichloro-3-methylaniline are mixed with 40 ml of freshly distilled chloroacetyl chloride during refluxed for an hour. The dark solution is then below 11 torr and a bath temperature evaporated from 50 ° The residue is dissolved in 70 ml of ethyl acetate-ether 1: 1. This solution is with 10 ml of 2N potassium bicarbonate solution and 10 ml of water extracted, dried over sodium sulfate and under 11 Evaporated torr The product, also called N-Phenyl-2 ^ ', 6'-trichIor-aceto-m-toluidid can be designated, crystallized from cyclohexane, m.p. 117-118 °.

C. 1- (2,6-Dichloro-3-methylphenyl) -2-indolinone

4 g. N-chloroacetyl-N-phenyl ^ e-dichior-S-methylaniline and 4 g of aluminum chloride are mixed thoroughly and heated to 160 ° for 2 hours. The melt will

cooled and poured onto approx. 50 g of ice while it is still warm. The precipitated oil is dissolved in 50 ml of chloroform dissolved, the chloroform solution with 10 m! Water washed, dried over sodium sulfate and evaporated under 11 torr. The residue is distilled. The 1- (2,6-dichloro-3-methylphenyl) -2-indolinone boils at 128-130 '/ 0.001 torr. The oil obtained, which at Standing crystallizes, melts at 129-132 °.

D. 2- (2.6-Dichloro-3-methylanilino) phenylacetic acid

A solution of 40 g of 1 - (2,6-dichloro-3-methylanilino) -2-indolinone in 280 ml of 1 η sodium hydroxide solution and 420 ml of ethanol is refluxed for 2 hours. the clear solution is cooled and the ethanol is distilled off at a bath temperature of 40 ° below II Torr. the Aqueous residue is extracted with 100 ml of ether, the ether is separated off and the aqueous solution is passed through Addition of ice (approx. 50 g) and external cooling, cooled to 5 °. 2N hydrochloric acid is then added with stirring until the pH of the solution is around 6. The precipitated acid is taken up in 400 ml of ether, the ether solution is separated off and the aqueous solution is extracted again with 200 ml of ether. The ether solutions are washed with 50 ml of water, combined, dried over sodium sulfate and at 11 torr concentrated without heating. From the concentrated ethereal solution crystallizes after the addition of Petroleum ether, 2- (2,6-dichloro-3-methylanuino) phenylacetic acid out. After recrystallization from ether-petroleum ether, it melts at 146-149 °.

Example 2

2- (3-trifluoromethylanilino) phenylacetic acid
Example 2.1.

Hydrolysis of nitrile
A.2- (3-Trifluoromethylanilino) benzyl alcohol

To a solution of 3.8 g of sodium borohydride in 160 ml of anhydrous diethylene glycol dimethyl ether 8.7 g of lithium bromide are added. The mixture is stirred for 1/2 hour at room temperature. Then it will be a solution of 14.8 g of methyl 2- (3-trifluoromethylanilino) benzoate [alternatively referred to as N- (aA, «- trifluoro-m-tolyl) -anthranilic acid methyl ester] in 40 ml of anhydrous diethylene glycol dimethyl ether added dropwise. Then 3 Hours to 100 °, cools and poured onto a mixture of 300 g of ice and 30 ml of concentrated hydrochloric acid. To brief stirring, the separated oil is extracted with 300 ml of ethyl acetate. The ethyl acetate solution is with Washed 2 N potassium bicarbonate solution and water, dried over sodium sulfate and under 11 Torr at 40 ° evaporated The residue is fractionally distilled with a short Vigreux column 2- (3-trifluoromethylanilino) benzyl alcohol [alternatively referred to as o - {«AA-trifluoro-rn-toluidino) -benzyl alcohol!] boils at 127-129 ° / 0.001 Torr. The yield is 75% the theory.

According to an alternative, second method, 937 g of lithium aluminum hydride in 100 ml of absolute Ether suspended and cooled to 5 ° with stirring. Under nitrogen, with external cooling with a Ice bath a solution of 36.8 g of methyl 2- (3-trifluoromethylanilino) benzoate in 140 ml absolute

Ether slowly added dropwise. The mixture is then kept at room temperature for 18 hours touched. To the mixture, which has cooled to 0 ", is added while stirring dropwise 10 ml of water, 10 ml of 15% Sodium hydroxide solution and another 30 ml of water. The mixture is then stirred for one hour at room temperature and filtered off. The filtrate is evaporated under 11 torr at 40 ". The The residue is fractionated using a short Vigreux column. The 2- (3-trifluoromethylanilino) -benzyl alcohol Obtained as a yellow oil, b.p. 130-131 "/ 0.001 torr.

Sodium borohydride can also be used for the above reduction.

In a third, alternative process, the free benzoic acid is reduced with lithium aluminum hydride (see example 4.4 A).

B. N-Acetyl-2- (3-trifluoromethylanilino) -

benzyl chloride

A solution of 23 g of 2- (3-trifluoromethylanilino) benzyl alcohol in 70 ml of acetyl chloride is under Nitrogen heated to boiling under reflux for one hour, the orange-colored solution is then under 11 Torr and a bath temperature of 40 °. The residue is dissolved in 150 ml of ethyl acetate-ether 1: 1. The organic phase is mixed with 20 ml of 2N potassium bicarbonate solution and 20 ml of water, dried over sodium sulfate and concentrated in vacuo. What remains is a light-colored oil made from ether-petroleum ether crystallized. The product obtained [alternatively named as ac-chloro-N - ^. Ä.a-trifluoro-m-tolylJ-aceto-o-toluidide] melts at 83-85 °.

C. N-Acetyl-2- (3-trifluoromethylanilino) -

phenylacetonitrile

A suspension of 2.2 g of sodium cyanide in 20 ml of dimethyl sulfoxide is added at 40 ° with stirring Solution of 11.6 g of N-acetyl-2- (3-trifluoromethylanilino) benzyl chloride in 60 ml of dimethyl sulfoxide added within 10 minutes. The temperature may be 40 ° not exceed. Then the mixture is stirred for 3 hours at 40 °, cooled to 10 ° and with 200 ml Water diluted. The solution is extracted four times with 150 ml of ethyl acetate. The ethyl acetate solutions are shaken with 200 ml of 6 η hydrochloric acid and then with 30 ml of water, then dried with sodium sulfate and concentrated below 11 torr at 40 °. That as yellow oil Remaining product [alternatively named as <x-Cyano-N- (a, a, «- trifluoro-m-tolyl) -aceto-o-toluidide] can be further processed directly.

D. 2- (3-Trifluoromethylanilino) phenylacetic acid

9.5 g of N-acetyl-2- (3-trifluonnethylanilino) phenylacetonitrile are dissolved in 100 ml of ethanol and 90 ml of 1 η sodium hydroxide solution. The solution is overnight Heated to reflux. It is cooled and concentrated below 11 torr at 40 ° to approx. 70 ml. The aqueous alkaline solution is extracted with 50 ml of ether, this ethereal solution becomes separated and the aqueous phase acidified with 2N hydrochloric acid. Shake with 50 ml of ether, wash the Ether extract with water, the ether solution dries over Sodium sulfate and concentrated below 11 torr without heating one. The residue crystallizes from ether-petroleum ether. After recrystallization from ether-Peiroläther melts 2- (3-trifluoromethylanilino) phenylacetic acid [alternatively named as o- (iXA, «- trifluoro-m-toluidino) phenylacetic acid] bci 112-114 ". The yield is 35% the theory.

Example 2.2
Hydrolysis of the ethyl ester

A solution of 50 g of N-acetyl-2- (3-trifluoromelhyl-S anilino) phenylacetonitrile in 550 ml of absolute ether and 375 ml of absolute ethanol is stirred and Exclusion of moisture is cooled to 0-5 ". Dry hydrogen chloride is added to the solution over a period of 4 hours initiated, the temperature not exceeding 5 °

ίο should. Then for a further 5 hours at Room temperature hydrogen chloride introduced. The solution is then left at room temperature overnight stand and steam them under 11 Torr at 40 ° Bath temperature to dryness. The residue is dissolved in 140 ml of water, covered with a layer of 150 ml of ether and reflux for 2 hours on the steam bath. Then one cools down, separates the Ether phase and extracted the aqueous solution again with 200 ml of ether. The combined ethereal solutions are dried over sodium sulfate and evaporated at 40 ° under a water jet vacuum. The residue is fractionated by means of a Vigreux column in a high vacuum. Ethyl N-acetyl-2- (3-trifluoromethyl) phenylacetate boils at 110-115 ° / 0.001 Torr.

A solution of 16.4 g of N-acetyl-2- (3-trifluoromethylanilino) phenylacetic acid ethyl ester in 225 ml of 95% ethanol and 67 ml of 2 n soda lye each becomes 16 Boiled under reflux for hours. Then you distill

,? o the ethanol under 11 Torr at 40 ° and extracted the remaining aqueous solution with 40 ml of ether. The ethereal phase is separated off, the aqueous phase cooled to 0-5 ° by adding ice and acidified to pH 6 with 2η hydrochloric acid. The eliminated

is oil is dissolved in 200 ml of ether, the essential solution washed with 20 ml of water and dried over sodium sulfate. It is then narrowed down to below 11 Torr without to warm up. After adding petroleum ether, the 2- (3-trifluoromethylanilino) phenylacetic acid crystallizes out, 112-114 °.

Example 3

2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid

^4S A. 2- (2-chloro-5-trifluoromethylanilino) -

benzyl chloride

A solution of 20 g of 2- (2-chloro-5-trifluoromethylanilino) benzyl alcohol (prepared as in Example 2 A.) in 70 ml of acetyl chloride is 16 under a nitrogen atmosphere Heated to reflux for hours. Then the solution is evaporated at about 40 ° under reduced pressure. the The residue is taken up in 40 ml of benzene and concentrated again. Then you take the residue

with 200 ml of ether and wash the ethereal solution with 2N sodium carbonate solution and water, dry over sodium sulfate and evaporate the solvent under reduced pressure. The remaining oil is distilled in a high vacuum, boiling point 12OVO ₁ OOl Torr. The

i> o 2- (2-chloro-5-trifluoromethylanilino) benzyl chloride leaves crystallize from petroleum ether, m.p. 50-51 ". The yield is 32% of theory.

B. 2- (2-chloro-5-trifluoromethylanilino) - _(IS phenylacetonitrile

A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulfoxide is heated to 40 ". Then a solution of M g of 2- (2-chloro-5-iriflii-

ormethylanilino) benzyl chloride in 150 ml of dimethyl sulfoxide is added, the temperature not exceeding 40 ". The mixture is stirred for 3 hours at 40" and then diluted with 100 ml of water. The solution is then extracted three times with 1000 ml of ethyl acetate each time. The combined extracts are then washed with 100 ml of 6η hydrochloric acid and 100 ml of water, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is distilled in a high vacuum. The 2- (2-chloro-5-trifluoromethylanilino) phenylacetonitrile boils at 122-126'VO ₁ oil Torr and can be crystallized from petroleum ether. After recrystallization the snip is at 58-59 ° ^C. The yield is 74% of theory.

C. 2- (2-Chior-5-trifluoromethylaniiino) phenylacetic acid

A solution of 18.4 g of 2- (2-chloro-5-trifluoromethyI-anilino) -phenylacetonitrile in 120 ml of 1N sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours heated. Then the reaction solution is at 40 ° under reduced pressure to a volume of about 80 ml concentrated and the aqueous solution extracted with 100 ml of ether. The aqueous alkaline phase is then at Acidified 5 ° with 2η hydrochloric acid and the precipitated oil was taken up in ether. The ether solution is separated, washed with water, dried over sodium sulfate and without heating at reduced Pressure restricted. When petroleum ether is added, the 2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid crystallizes off, m.p. 94-96 °; Yield 55% of theory.

The saponification can also be carried out with potassium hydroxide in n-butanol.

Example 4
2- (2,6-dichloroanilino) phenylacetic acid

Example 4.1
Hydrolysis of the lower alkyl esters

A.2- (2,6-Dichloroanilino) -phenyl-acetic acid methyl ester

To a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid (M.p. 156-158 °) in 150 ml of absolute ether is slowly allowed to 100 ml of 2% ethereal Add dropwise diazomethane solution. The solution is left to stand at room temperature overnight and then concentrated below 11 torr at 40 ° to dryness. The residue dissolve in 100 ml of ether. The ether solution is extracted with 50 ml of 1N potassium bicarbonate solution and water, dried over sodium sulfate and concentrated under 11 torr at 40 °. The residue crystallizes out Ether-petroleum ether. The 2- (2,6-dichloroanilino) phenylacetic acid methyl ester melts at 101 - 102 °.

Similarly, 2- (2,6-dichloroanilino) phenylacetic acid ethyl ester is obtained, 50-52 °.

B.2- (2,6-dichloroanilino) phenylacetic acid c

A solution of 1 g of methyl 2- (2,6-DichIoraniIino) phenylacetate in 20 ml of methanol and 5 ml of 2N potassium bicarbonate solution is refluxed for 15 hours. It is concentrated to dryness in vacuo, diluted with 70 ml of water and the aqueous solution is extracted with 20 ml of ether. The aqueous solution is acidified with 2N hydrochloric acid, the precipitated oil is extracted with ether and the ether solution is washed with water, dried over sodium sulfate and concentrated cold under 11 torr. The 2- (2,6-dichloro-anilino) -phcnylcssigsäurc crystallized from ether-petroleum ether, mp. 15b-1 ¹ JS ".

s The 2- (2, b-dichloroanilino) phenyl acetic acid ethyl ester can be saponified in the same way.
Alternatively, you can proceed as follows:
A solution of 0.5 g of 2 (2,6-DichloraniIino) -phenylacetic acid methyl ester in

id 40 ml of 75% ethanol with 12 g of a fine-grained strongly basic anion exchanger (styrene-divinylbenzene copolymer) in the OH form stirred for 15 hours at 50 °. Then it is filtered off. The residue is suspended in 20 ml of water and acidified at 5 "

is 1 n-hydrochloric acid. Add 30 ml of ether, shake and separates the ethereal solution. The ether solution is washed with 10 ml of water, dried over sodium sulfate and concentrated under 11 torr cold to dryness. From ether-petroleum ether crystallizes the 2- (2,6-dichloroanilino) -phenyles-

2 <> acetic acid, m.p. 156-158 °. The yield is 45% the theory.

Example 4.2
2s Reductive cleavage of the henzyl ester

A. 2- (2,6-dichloroanilino) phenylacetic acid

benzyl ester

A solution of 2.96 g of 2- (2,6-dichloroanilino) -phe-

\ o nylessigsäurc, 1.2 g of absolute benzyl alcohol and ig dimethylformamide dineopentyl acetal in 40 ml of methylene chloride is stirred under nitrogen for 55 hours. Then the methylene chloride is distilled off under 12 torr. Dilute with 50 ml

is ethyl acetate, the solution extracted with water and dry over sodium sulfate. The solution is concentrated to dryness under 11 torr at 40 °. The residue Chromatographs are carried out on 60 g of neutral aluminum oxide. Fractions 2 and 3, eluted with diethyl ether / Petroleum ether 7: 3, contain the pure 2- (2,6-dichloroanine! Ino) -p / ienylacetic acid benzy! Ester. The yield is 30% of theory.

The above ester can also be obtained as follows:

To 40 ml of absolute benzyl alcohol is added at - 10 " b ml of thionyl chloride are added dropwise with thorough stirring and introduction of nitrogen. After 5 minutes, the -10 ° a solution of 2.96 g of 2 (2,6-dichloroanilinoj-phenylacetic acid in 10 ml of absolute ben-

SU zyl alcohol was added dropwise. Then stir it Reaction mixture for 15 hours at room temperature and poured onto ice. The precipitated oil is extracted with 100 ml of ether. The ether extract is washed with 10 ml of 2N potassium bicarbonate solution and water and dried over

S5 sodium sulfate and evaporate the ethereal solution under 11 Torr at 40 ° to dryness. The residue is chromatographed on 90 g of neutral aluminum oxide. Fractions 1 and 2, eluted with ether / petroleum ether 1: I, contain the pure 2- (2,6-dichloroanilino) -

(10 phenylacetic acid benzyl ester .. The yield is 48% of theory.

B. 2- (2,6-dichloroanilino) phenylacetic acid

1.2 g 2- (2,6-DichloraniIino) -phenyIessigsäurc-ben / .yl-

* 'S esters are dissolved in 50 ml of fine spirit and added afterwards hydrogenated by 0.2 g of 5% Pd-carbon at low pressure and room temperature. After ΡΛ hours it is Hydrogenation ended. The catalyst is reduced

and the filtrate under 11 torr at room temperature Evaporated to dryness. The residue is recrystallized from ether-Pctroläther, the resulting 2- (2,6-dichloroanilino) phenylacetic acid melts at 156-158 '. The yield is 67% of theory.

Example 4.3
(Procedure analogous to example 1)

A. N-Phenyl-2,6-dichloroaniline

7 g of 2- (2,6-dichloroanilino) -benzoic acid [alternatively called N- (2,6-dichlorophenyl) -anthranilic acid] heated to 280 ° for 2 hours. The cooled melt is dissolved in 30 ml of benzene and the benzene solution extracted with 5 ml of 2N sodium carbonate and 5 ml of water. The solution is made with sodium sulfate dried and evaporated. The residue is distilled, whereby the N-phenyl-2,6-dichloroaniline (alternatively referred to as 2,6-dichloro-N-phenylaniline) as yellow oil is obtained, b.p. 109-11 Γ / 0.003 torr. Alternatively, N-phenyl-2,6-dichloroaniline can also be obtained using the following procedure:

To a solution of 81 g of 2,6-dichloro-aniline in 30 ml Glacial acetic acid is slowly added dropwise 40 ml of acetyl chloride. Then the solution is heated on a water bath, until the evolution of hydrochloric acid has ended. It is cooled to room temperature and the mixture is poured onto ice. The precipitated crystals are filtered off and recrystallized from glacial acetic acid. The N-acetyl-2,6-dichloroaniline melts at 180-18Γ. The yield is 70% of theory.

15 g of N-acetyl-2,6-dichloroanine are dissolved in 150 ml of bromobenzene. 5.5 g of calcined potassium carbonate are used and 0.5 g of copper powder. The mixture is then refluxed for 4 days, the resulting water is separated by means of a water separator. Then you cool off and undergo that Mixture of a steam distillation. The residue is extracted with 200 ml of ether. One filters the Ether solution through a filter aid based on diatomaceous earth and concentrated to dryness below 11 Torr. Then the residue is dissolved in 60 ml of 10% ethanolic potassium hydroxide solution and heated Solution under reflux for 3 hours. The solution is then concentrated to dryness under 11 Torr at 40 °. The residue is mixed with 10 ml of water and extracted with 100 ml of ether. The ethereal solution becomes separated and extracted with 20 ml of water. Then the essential solution is dried with sodium sulfate and concentrate them to dryness below 11 torr. The residue is distilled in a high vacuum. The N-phenyl-2,6-dichloroaniline boils at 115 ° / 0.01 torr as yellow oil. The yield is 43% of theory.

B-N-chloroacetyl-N-phenyl-io-dichloroaniline

4 g of N-phenyl- ^ e-dichloroaniline are fresh with 40 ml distilled chloroacetyl chloride refluxed for one hour. The dark solution then becomes evaporated in vacuo at a bath temperature of 50 ° The residue is dissolved in 70 ml of ethyl acetate / ether Dissolve 1: 1 This solution is mixed with 10 ml of 2N potassium bicarbonate solution and extracted 10 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue is crude N-chloroacetyl-N-phenyl-2,6-dichloroaniline, which after crystallization from ethanol melts at 143-144 °.

C. 1- (2,6-dichlorophenyl) -2-indolinone

4 g of N-chloroacetyl-N-phenyl-2,6-dichloroaniline and 4 g of aluminum chloride are mixed well and 2 Heated to 160 "for s hours. The melt is cooled and poured onto approx. 50 g of ice while it is still warm. The precipitated oil is dissolved in 50 ml of chloroform, the chloroform solution washed with 10 ml of water, over Dried sodium sulfate and evaporated in vacuo. ίο The residue is distilled. The 1- (2,6-dichlorophynyl) -2-indolinone boils at 124-126 ° / 0.001 Torr. Ks crystallizes on standing, melts at 126-127 ° and is crystallizable from methanol.

D. 2- (2,6-Dichloroanilino) phenylacetic acid

A solution of 38.3 g of 1- (2,6-dichloroanilino) -2-indolinone in 280 ml of 1 η sodium hydroxide solution and 470 ml of ethanol is refluxed for 2 hours. The clear one Solution is cooled and the ethanol at a

; o bath temperature of 40 ° distilled off in vacuo. the Aqueous residue is extracted with 100 ml of ether, the ether is separated off and the aqueous solution is passed through Addition of ice (approx. 50 g) and external cooling, cooled to 5 °. 2N hydrochloric acid is then added with stirring until the pH of the solution is around 6. The precipitated acid is taken up in 400 ml of ether, the ether solution is separated off and the aqueous solution is extracted again with 200 ml of ether. The ether solutions are washed with 50 ml of water, combined, dried over sodium sulfate and concentrated in vacuo, without heating. From the concentrated ethereal solution crystallizes after the addition of Petroleum ether removes 2- (2,6-dichloroanilino) phenylacetic acid. After recrystallization from ether / petroleum ether it melts at 156-158 °.

Example 4.4
(Procedure analogous to example 3)

A. 2- (2,6-Dichloroanilino) benzyl alcohol

2- (2,6-dichloroanilino) benzyl alcohol can be prepared analogously to Example 2.1.A or alternatively according to the following process:
A suspension of 65 g of 2- (2,6-dichloroanilino) benzoic acid in 500 ml of absolute tetrahydrofuran is added dropwise at 5-15 ° to 30 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. The reaction mixture is stirred for 1/2 hour at 5 °, 1 hour at 25 ° and 3 hours under reflux and then carefully added dropwise at 0-5 ° with 30 ml of 15% sodium hydroxide solution and 90 ml of water. After adding 200 ml of tetrahydrofuran, the organic solution is filtered off with suction from the crystalline precipitate and this is washed well with tetrahydrofuran.

The combined solutions are evaporated, taken up in ethyl acetate and treated with 2N soda solution and saturated saline solution. Evaporation of the organic phase gives 44.4 g of a dark brown Oil that crystallizes from ethyl ether / petroleum ether. the

fio 2- (2,6-dichloroanilino) benzyl alcohol melts at 110-112 °.

B.2- (2,6-dichloroanilino) phenylacetic acid

2- (2,6-dichloroanilino) benzylchloride is obtained analogously to Example 3 (yellow oil) and from it the 2- (2,6-dichloroanilino) -phenylacetonitrile (Melting point 71-72 °; recrystallized from diethyl ether / petroleum ether), which is hydrolytically into 2- (2,6-dichloroanilinoVrjhenvlessiffic acid.

M.p. 156-158 ° (from diethyl ether-petroleum ether) converted will.

Example 5

2- (2-methyl-3-chloroanilino) phenylacetic acid
A.2- (2-Methyi-3-chloroanilino) benzyl chloride

A suspension is made to 30 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran at 5-15 ° from bl g of 2- (2-methyl-3-chloroanilino) benzoic acid in 500 ml of absolute tetrahydrofuran added dropwise to the reaction mixture is stirred for 2 hours at 5 °, 1 hour at 25 ° and 3 hours under reflux and then at 0-5 ° with 30 ml of 15% sodium hydroxide solution and 90 ml Water is carefully added dropwise. After adding 200 ml of tetrahydrofuran, the organic The crystalline precipitate is filtered off with suction and this is washed well with tetrahydrofuran.

The combined solutions are evaporated, taken up in ethyl acetate and treated with 2N soda solution and saturated saline solution. Evaporation of the organic phase gives a dark brown oil, which from Diethyl ether / petroleum ether crystallized. The 2- (2-methyl-3-chloroanilino) -benzyl alcohol melts at 51-52 °.

6.0 g of it are abs in 50 ml. Dissolved ether and mixed with 100 ml of 5 η-ethereal hydrogen chloride. The mixture is shaken for 5 minutes, the crystals which have separated out go into solution. To an addition of another 200 ml of abs. The solution is shaken for 15 minutes and concentrated in ether Vacuum at 40 °. A little ether / petroleum ether (1: 1) is added to the residue Crystals are filtered off and treated with 30 ml of water and 200 ml of ether. The mixture is shaken and the ether solution separated, washed with 30 ml water, dried over sodium sulfate and under 11 Torr constricted. The 2- (2-methyl-3-chloroanilino) benzyl chloride that remains is processed further directly

B. 2- {2-methyl-3-chloroanilino) phenylacetonitrile

35

40

A suspension of 6 g of sodium cyanide in 120 ml Dimethyl sulfoxide is heated to 40 °. Then a solution of 31 g of 2- (2-methyl-3-chloroanilinoj-benzyl chloride in 150 ml of dimethyl sulfoxide added, the temperature not exceeding 40 ° target. The mixture is stirred for 3 hours at 40 ° and then diluted with 600 ml of water. The solution will be then extracted three times with 1000 ml of ethyl acetate each time. The combined extracts are then washed with 100 ml 6 η-hydrochloric acid and 100 ml of water, dry them over sodium sulfate and distill the solvent under reduced pressure. The 2- (2-methyl-3-ch! Oranilino) -phenylacetonitrile that remains can be crystallized from ether-petroleum ether and melts at 86-88 °.

C.2- (2-methyl-3-chlorocnilino) phenylacetic acid

A solution of 18 g of 2- (2-methyl-3-chloroanilino) phenylacetonitrile in 120 ml of 1 η sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours The reaction solution is then concentrated to a volume of approx. 80 ml at 40 ° under reduced pressure and the aqueous solution is extracted with 100 ml of ether. The aqueous-alkaline phase is then mixed with at 5 ° 2 η-hydrochloric acid acidified and the precipitated oil taken up in ether. The ethereal solution is separated.

washed with water, dried over sodium sulfate and concentrated under reduced pressure without heating. Crystallized when petroleum ether was added 2- (2-methyl-3-chloroanilino) phenylacetic acid from, m.p. 124-125 °.

Example 6

2- (2,6-DimethylaniIino) phenylacetic acid
A. 2- (2,6-Dimethylanilino) -benzylchloride

It is added to a solution of 5 g of 2- (2,6-dimethylanilino) benzyl alcohol in 150 ml abs. Ether dropwise with stirring 150 ml of 5 η abs. essential hydrochloric acid (produced by introducing hydrogen chloride gas into absolute ether). Crystals separate out, which after Addition of another 300 ml of abs. Ether go back into solution. The solution is 30 minutes at room temperature stirred and evaporated in vacuo at 40 °. The residue crystallizes after adding a little ether added. The crystals are filtered off and washed with a mixture of 20 ml of water and 100 ml of ether offset. The ether solution is separated off, extracted with water, dried over sodium sulfate and im Evaporated to dryness in vacuo. 2- (2,6-Dimethylanilinoj-benzyl chloride remains behind as oil and is further converted directly.

B.2- (2,6-dimethylanilino) phenylacetonitrile

A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulfoxide is heated to 40 ° a solution of 26 g of 2- {2,6-dimethylaniIino) benzyl chloride with stirring added in 150 ml of dimethyl sulfoxide, the temperature should not exceed 40 °. Man the mixture is stirred for 3 hours at 40 ° and then diluted with 600 ml of water. The solution will be then extracted three times with 1000 ml of ethyl acetate each time. The combined extracts are then washed with 100 ml 6 η-hydrochloric acid and 100 ml of water, dry them over sodium sulfate and distill the solvent under reduced pressure. The residue is crude 2- (2,6-dimethylanilino) phenylacetonitrile, which after Crystallize from ether / petroleum ether at 92-95 ° melts.

C.2- (2,6-Dimethylanilino) phenylacetic acid

2 g of 2- (2,6-dimethylaniIino) phenylacetonitrile are mixed with 8 g of potassium hydroxide in 100 ml of n-butanol for 18 hours boiled under reflux. The solution is then concentrated in vacuo at 60 °. The residue is dissolved in Water. The aqueous solution is extracted with ether, separated off and acidified with 2η hydrochloric acid. The The separated oil is extracted with ether. The ethereal solution is washed with water and extracted with 0.5 N sodium hydrogen carbonate solution, from which on acidification with hydrochloric acid to pH 5-6 the 2- (2,6-dimethylanilino) phenylacetic acid precipitates. It can be recrystallized from ether / petroleum ether and melts at 120-127 ° with decomposition.

Example 7
2- (2,6-dichloroanilino) -5-chlorophenylacetic acid

Analogously to Example 1, starting from N- (4-chlorophenyl) -2,6-dichloroaniline (boiling point 121 ° / 0.01 Torr)

via N-chloroacetyl-N-J4-chlorophenyI) -2,6-dichloroaniline (M.p. 130-131 °, from ethanol-water) and 1- (2,6-dichlorophenyl) -5-chloro-2-indolinone (M.p. 130-131 °, from ethanol-water) 2- (2,6-dichloroanilino) -5-chlorophenylacetic acid of m.p. 181-183 "(from methanol).

Example 10 Example 8

2- (2,6-dichloro-3-methylaiiilino) -5-chlorophenylacetic acid

Analogously to Example 1, starting from N - ^ - chlorophenyO- ^ e-dichloro-S-methylaniline (bp.

135-145 ° / 0.005 Torr), via N-chloroacetyl-N- (4-chlorophenyl) -2,6-dichloro-3-methylaniline (M.p. 106-107 ° from diethyl ether / petroleum ether) and 1- (2,6-dichloro-3-methylphenyl) -5-chloro-2-indolinone (M.p. 152-154 ° from ethyl acetate / petroleum ether) 2- (2,6-dichloro-3-methylanilino) -5-chlorophenylacetic acid of m.p. 152-156 ° (from diethyl ether / petroleum ether).

Example 9

2- (2,6-dichloro-3-methylanilino) -5-methoxyphenylacetic acid

Analogously to Example 1, starting from N- (4-methoxyphenyl) -2,6-dichloro-3-methylaniline (bp. 115-130 ° / 0.001 Torr), via N-chloroacetyl-N- (4-methoxyphenyl) -2,6-dichloro-3-methylaniline (yellow oil) and 1- (2,6-dichloro-3-methylphenyl) -5-methoxy-2-indolinone (Mp. 135-136 °; from diethyl ether / petroleum ether) 2- (2,6-dichloro-3-methylanilino) -5-methoxyphenylacetic acid of melting point 120-122 ° (from diethyl ether / petroleum ether).

When implementing the methoxy-substituted compounds of this example, the corresponding free Hydroxy group is formed, which can be realkylated again.

10 g of N-chloroacetyl-N - ^ - methoxyphenyl ^ .e-dichloro-3-methylaniline are mixed with 20 g of finely powdered aluminum chloride and stirred in a nitrogen atmosphere heated to 280 ° for one hour. It is allowed to cool and the solidified melt is added lots of ice and water. A black precipitate is formed, which is filtered off and stored at 80 ° and 11 Torr is dried. The 1- (2,6-dichloro-3-methylphenyl) -5-hydroxy-2-indolinone purified by chromatography on neutral aluminum oxide melts at 184-187 °; Yield 60% of theory.

8.1 g of crude 1- (2,6-dichloro-3-methylphenyl) -5-hydroxy-2-indolinone are dissolved in 26.3 ml of 1N sodium hydroxide solution. The solution is then made with 3.7 g of dimethyl sulfate added and refluxed for hour. After cooling, the reaction solution is extracted with 400 ml of ethyl acetate. The organic one is filtered Phase, washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporates to dryness below 11 torr. The residue is purified over an aluminum oxide column chromatographed. 1- (2,6-dichloro-3-methylphenyl) -5-methoxy-2-indoinone after recrystallization from ether-petroleum ether, it melts at 135-136 "; Yield 20% of theory.

The compound can be further processed into the end product as above; M.p. 120-122 °.

2- (2,6-dichloroanilino) -5-methoxyphenylacetic acid

Example 10.1.

(Procedure analogous to example 1)

Analogously to Example 1, starting from N- (4-methoxyphenyl) -2,6-dichloroaniline (melting point 75-77 °; from chloroform) via N-chloroacetyl-N- (4-methoxyphenyl) -2,6-dichloroaniline (melting point 127 ° -128 °; from methanol) and 1- (2,6-dichlorophenyl) -5-methoxy-2-indolinone (m.p. 144-145 °; from diethyl ether / petroleum ether) the 2- (2,6-dichloroanilino) -5-methoxyphenylacetic acid with a melting point of 134-136 ° (from diethyl ether / petroleum ether).

Since in the implementation of the methoxy-substituted compounds of this example, the corresponding free Hydroxy group can be formed, any l- (2,6-dichlorophenyl) -5-hydroxy-2-indolinone that has formed is transferred (M.p. 204-205 °; from methanol / benzene) analogously to Example 9 into the methoxy compound.

Example 10.2.
(Procedure analogous to example 3)

Starting from 2- (2,6-dichloroanilino) -5-methoxybenzyl alcohol (melting point 112-113 °; from cyclohexane) one over 2- (2,6-dichloroanilino) -5-methoxybenzylchloride (melting point 82-84 °; from petroleum ether) and 2- (2,6-dichloroanilino) -5-methoxyphenyl-acetonitrile (M.p. 169-171 °) 2- (2,6-dich! Oranilino) -5-methoxyphenyiacetic acid from m.p. 134-136 °.

Example U
2- (2,6-dichloroanilino) -5-bromophenylacetic acid

A solution of 11.2 g of 1- (2,6-dichlorophenyl) -2-indolinone (Example 4.3 C) in 700 ml of ethanol is added to a solution of 8 g of potassium bromide and 2.08 g of bromine in 160 ml of water are given. The mixture is shaken vigorously and then left to stand at 0 ° for 3 hours. The alcohol is then evaporated and the insoluble precipitate from the remaining aqueous solution filtered off. This is then taken up in methylene chloride. You dry them Methylene chloride solution over sodium sulfate and concentrated to dryness under 11 torr. The residue is there from a mixture containing 60% l- (2,6-dichlorophenyl) -5-bromo-2-indolinone contains. This is purified by repeated chromatography on a silica gel column and melts after repeated recrystallization from diethyl ether or diethyl ether / petroleum ether 188-190 °.

The 1- (2,6-dichlorophenyl) -5-bromo-2-indolinone obtained is analogous to Example 1 converted into the 2- (2,6-dichloroanilino) -5-bromo-phenylacetic acid, which, after recrystallization from diethyl ether / petroleum ether, decomposes at 16Γ.

Example 12
2- (2-methoxy-5-methylanilino) phenylacetic acid

Analogous to Example 2.1.A, starting from 2- (2-methoxy-5-methylanilino) -benzyl alcohol of m.p. 138-139 ° (from methanol) via N-acetyl-2- (2-methoxy-5-methylanilino) -benzyl chloride from m.p. '21 - 123 ° <«; (from petroleum ether) and N-acetyl-2- (2-methoxy-5-methylanilino) -phenylacetonitrile with a melting point of 108-109 ° (from cyclohexane) 2- (2-methoxy-5-methyl-nilino) -phenylacetic acid of m.p. 105-107 ° (from diethyl ether)

receive.

Alternatively, this compound can also be prepared analogously to Example 22 by hydrolysis of the N-acetyl-2- (2-methoxy-5-methylanüiino) -phenylacetic acid ethyl ester (bp. 180-185 * 70.001 Torr).

Example 13 2- (23-Dimethylanilino) phenyl acetic acid

A. 2- (2,3-Dimethylanirino) benzyl chloride.

To a solution of 5 g of 2- (23-dimethylanilino) benzyl alcohol (prepared analogously to Example 2.1.A; bp. 136-141 * 70.005 Torr) in 150 ml abs. Ether is used 150 ml of 5 η-absolute ethereal hydrochloric acid (prepared by introducing hydrochloric acid gas into absolute diethyl ether) dropwise with stirring. It divorced Crystals form, which go back into solution after adding another 400 ml of absolute DiethyJüther.

The solution is stirred for 30 minutes at room temperature and evaporated under 11 torr at 40 °. the The residue crystallizes after a little ether has been added. The crystals are filtered off and mixed with a mixture of 20 ml of water and 100 ml of ether is added. The ether solution is separated off with water extracted, dried over sodium sulfate and under 11 Torr evaporated to dryness. The 2- (2,3-dimethylanilino) benzyl chloride remains as an oil and becomes direct implemented further

B.2- (23-dimethylanilino) phenylacetonitrile

The compound is obtained from the above benzyl chloride analogously to Example 3B; M.p. 95-96 °.

G2- (2 _r } -Dimethylanilino) -phenylacetic acid

2 g of 2- (2,3-dimethylanilino) phenylacetonitrile become refluxed with 3 g of potassium hydroxide in 60 ml of n-butanol for 2 hours. Then the solution is below 0.1 Torr concentrated at 60 °. The residue is dissolved in water. The aqueous solution is extracted with ether, separated off and acidified with 2η hydrochloric acid. The separated oil is extracted with ether. Man Wash the ethereal solution with water, dry it over magnesium sulphate and concentrate it to dryness below 11 torr one. The residue is crystallized from ether / petroleum ether. 2- (23-Dimethylanilino) phenylacetic acid melts at 112-113 °.

Example 14 2- (2-chloro-6-methylanilino) phenylacetic acid

Analogously to Example 1, N-phenyl-2-chloro-6-methylaniline (b.p. 88 ° / 0.005 Torr) is converted into N-chloroacetyl-N-phenyl-2-chloro-6-methylaniline with a melting point of 110-112 ° (from Diethyl ether) and l- (2-chloro-6-methylphenyl) -2-indolinone of m.p. 96-98 ° (from diethyl ether) 2- (2-chloro-6-methylanilino) phenylacetic acid of m.p. 140-147 ° (from diethyl ether) obtained.

Example 15

2- (2-Chloroanilino) phenylacetic acid is obtained analogously to Example t, without the corresponding Intermediate connections are characterized in more detail; Mp. 116-117 ° (from diethyl ether / petroleum ether).

Example Ib

2- (2-Chloro-3-methylanilino) -phenylacetic acid is prepared analogously to Example 1 without isolating the intermediates obtained; m.p. 129-132 ° (from diethyl ether).

Example 17

2- (2,4-dichloroanilino) phenylacetic acid is analogous Example 1 obtained without isolation of the intermediates; M.p. 154-158 ° (from diethyl ether).

Example 18

2- (2,6-dichloro-4-methoxyanilino) phenylacetic acid c is obtained analogously to Example 1 without isolating the intermediates: mp. 160-165 ° (from diethyl ether).

Example 19

2- (2,6-Diethylanilino) -phenyl acetic acid is analogous Example 3 obtained without isolation of the intermediates; M.p. 88-90 "(from diethyl ether / pelro ether).

Example 20

2- (2,6-dichloroanilino) -phynylacetic acid, Sodium salt

A solution of 186 g of l- (2,6-dichloropheny [) - 2-indolinone, the preparation of which is described in Example 4.3.C, dissolved in 660 ml of ethanol and 660 ml of 2N sodium hydroxide solution, the mixture is refluxed for 4 hours. Then the Solution cooled and left to stand for 4 hours at 0-5 °. The precipitated crystals are filtered off and recrystallized from water. The sodium salt of 2- (2,6-dichloroanilino) phenylacetic acid melts 283-285 °.

.10 Analogously one obtains:

a) The sodium salt of 2- (2,6-dichloroanilino) -5-chlorophenylacetic acid, melting point 296 ° (from water);

b) The sodium salt of 2- (2,6-dichloro-3-methylanilinoj-pheny! acetic acid, m.p. 287-289 ° (from water

vs ser);

c) The sodium salt of 2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid, melting point 225-230 ° (from Water).

Example 21

2- (2,6-dichloroanilino) phenylacetic acid, Potassium salt

20 ml of 8% strength are added to a solution of 8.9 g of 2- (2,6-dichloroanilino) -phe-4.S nylacetic acid in 50 ml of ethanol Ethanolic potassium hydroxide solution added. The solution is boiled with activated charcoal for 10 minutes, filtered and concentrated below 11 torr. When ether is added, the potassium salt of 2- (2,6-dichloroanilino) phenylacetic acid crystallizes out, melting point 300-330 ° below Decomposition.

Example 22 ^ Preparation of Pharmaceutical Compositions

The following regulations are intended to explain the manufacture of tablets and coated tablets in more detail:

A. 1000.0 g of active ingredient, e.g. B. 2- (2,6-dichloroanilino) phenylacetic acid or its sodium or potassium salt, are mixed with 550.0 g of lactose and 292.0 g of potato starch, the mixture with an alcoholic solution moistened by 8.0 g of gelatin and granulated through a sieve. After drying, 60.0 g are mixed Potato starch, 60.0 g talc, 10.0 g magnesium stearate

fts and 20.0 g of colloidal silicon dioxide and presses the Mixture of 10,000 tablets each weighing 200 mg and containing 100 mg of active ingredient, if desired with Partial notches for finer adjustment of the dosage

can be provided.

B. 200.0g active ingredient, e.g. 2 (2,6 dichloroanilino) phenylacetic acid are mixed well with 16 g of corn starch and 6.0 g of colloidal silicon dioxide. The mixture is with a solution of 2.0 g of stearic acid, 6.0 g of ethyl cellulose and 6.0 g of stearin in about 70 ml of isopropyl alcohol moistened and granulated through a sieve with a mesh size of 1.5 mm. The granulate is about 14 hours dried and then passed through a sieve the mesh size

1.2-1.5 mm beaten. Then it becomes 16.0 g Corn starch, 16.0 g talc and 2.0 g magnesium stearate mixed and pressed to 1000 dragee cores. These are served with a concentrated syrup of 2,000 g Shellac, 7.500 g gum arabic, 0.150 g dye, 2,000 g of highly dispersed silicon dioxide. 25,000 g talc and 53,350 g sugar coated and dried Dragees obtained each weigh 360 mg and each contain 200 mg of active ingredient.

Claims (1)

Patent claims: 1. Substituted phenylacetic acids of the general formula I. COOH (I) NH