DE1793592A1 - Process for the production of new substituted phenylacetic acids - Google Patents

Description

J.R. Geigy A.G., CH-4000 Basel 21

Dr. F. Zumsteln sen. - Dr. E. Assmann Dr. R. Koenigsborgor - Dipl. Phys. R. Holzbauer

Dr. F. Zumstoin jun.

Patent attorneys

8 Munich 2, Bräuhausstraße 4 / ill

2163 * A

Process for the preparation of new substituted phenyl

acetic acids

[Removal from patent ....... (Pat.Anm, P 15 43 639.2-42)}

The present invention relates to a process for the preparation of new substituted phenylacetic acids and their salts, these new compounds themselves and medicaments containing them, and their use.

Substituted phenylacetic acids of the general Formula I,

- CH ₉ - COOH

(D

in which

R, a lower alkyl or alkoxy radical, a halogen atom up to atom number 35 or the trifluoro methyl group,

R ₀ and R ~ are each hydrogen, a lower alkyl or alkoxy radical or a halogen atom up to atom number 35 and

BAD ORfQINAL

209817/1585

R, hydrogen, a lower alkyl or alkoxy radical, a halogen atom up to z; ir atom number 35 or the trifluorotethyl group means,

and their salts with inorganic and organic bases are hitherto not known. As has now been found, the compounds of general formula I and their salts are valuable pharmacological properties, in particular anti-inflammatory (anti-inflammatory), analgesic and antipyretic activity with a favorable therapeutic index. You can use oral, rectal,

^ or, especially in the form of aqueous solutions of their salts, can also be used parenterally, especially intramuscularly, for the treatment of rheumatic, arthritic and other inflammatory diseases. The anti-inflammatory effectiveness can be demonstrated in animal experiments, for example, on 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 used as UV absorbers for cosmetic purposes, e.g. in sun protection creams, suitable because they absorb the harmful, reddening rays, while they let through the desired tanning rays, over 315 mp.

In the compounds of general formula I and the corresponding, Starting materials mentioned below are R- to R, independently of one another as lower alkyl radicals, for example Methyl or ethyl radicals. Some of the symbols mentioned can e.g. also n-propyl, isopropyl, η-butyl, sec. Butyl, or tert. Mean butyl residues. Lower alkoxy radicals than R, to R, are e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or

209817/1585 ""

BATH

Isobutoxy radicals; the substituents R-. to R, as halogen atoms mean chlorine, fluorine or bromine atoms.

To prepare an acid of the general formula I and its salts with inorganic and organic bases, one uses a Compound of general formula II,

(II)

in which R, to R, have the meaning given above with a Alkali metal hydroxide, alkali metal carbonate or alkaline earth metal hydroxide in the heat and, if desired, releases the acid from the alkali metal or alkaline earth metal salt obtained. This can If desired in another salt with an organic or inorganic base can be converted.

Water-containing lower alkanols, such as ethanol, methanol or n-3utanol, are also particularly suitable as solvents ethylene glycol or dimethylformamide can also be used. The hydrolysis takes place, for example, at or just below the boiling point of the reaction mixture by means of at least one equivalent of an alkali metal hydroxide or carbonate or alkaline earth metal hydroxide, especially sodium or potassium hydroxide.

According to a second "method, the compounds of the general formula I by producing a compound of the general formula III,

209817/158 5

CH ₉ - COOR ₁

(III)

in which

A is hydrogen or an acyl radical, especially one

lower alkanoyl radical and
R ₁ - a lower alkyl or an aralkyl radical, in particular

denotes the benzyl radical, and ■

R to R have the meaning given above, with an alkali metal hydroxide. carbonate or bicarbonate, an alkaline earth metal hydroxide or a basic ion exchanger converts in the heat, or if A is hydrogen and R, -der Benzyl radical, the benzyl radical by hydrogenolysis with catalytic split off activated hydrogen. Lower water-containing solvents are particularly suitable for the hydrolysis Alkenols, such as methanol, ethanol, n-butanol, and also ethylene glycol or dimethylformamide. The hydrolysis is carried out e.g. at or slightly below the boiling point of the reaction mixture by means of

one
at least one equivalent / base completed. The hydrogenolysis is advantageously carried out at normal pressure and room temperature to moderately elevated temperature in the presence of Pd-carbon in alcohol.

A third method leads to connections of the general formula I by adding a compound of the general Formula IV, '

209817/1585

(IV)

wherein R to Rv and A have the meaning given above, with an alkali metal hydroxide in a water-containing 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 z.3. at or a little below the boiling point of the reaction mixture by means of at least two equivalents of an alkali metal hydroxide, in particular of sodium or potassium hydroxide.

The starting materials of the general formula II, which are l-aryl-2-indolinones, 1-aryl-oxindoles or lactams of 2-arylaminophenylacetic acids are themselves new connections. The preparation of the connections of the general For example, formula II is analogous to that of the known 1-phenyl-2-indolinone from the corresponding unsymmetrically substituted Diphenylamineη by chloroacetylation to 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 corresponding to the Definition for R, to R, substituted diphenylamines is known and others can be produced analogously to the known ones, e.g.

209817/1585

according to the method described by AW Chapman, J. Chem. Soc. 1929 , 569-572 described method by heating Ν, Ο-diaryl-iminoesters and hydrolysis of the Ν, Ν-diarylamides formed by rearrangement, or according to that of RB Moffet et al, J. Am. Chem. Soc. 82_, 1605 (1960) used method, starting from optionally substituted ο-chloro- or o-bromobenzoic acids and substituted anilines and decarboxylation of the resulting o-anilino-benzoic acids.

A particularly cheap method of making accordingly the definition of R, to R, substituted diphenylamines is the method of Goldberg, Ber. 40_, 4541 (1907), according to which an optionally substituted acetanilide is reacted with a bromobenzene substituted according to the definition of R 1.

The starting materials of the general formula III with a lower alkyl group as R ₅ and an acyl group as A can be obtained, for example, by converting the corresponding cyano compounds into imino ether hydrochlorides and decomposing the latter with water.

However, they can also be obtained starting from the acids of the general formula I by converting them into the known Way with alkylating agents such as diazoalkanes or dialkyl sulfates treated.

The lower alkyl and aralkyl esters of the general Formula III can also be obtained by other known esterification processes

209817/1585

obtained, e.g. by the Ν, Ν-dimethylformamide-dineopentylaceta, l method, by H. Büchi, K. Steen and A. Eschenmoser in

Ang. Chemie 75. (1963), 1176, or with thionyl chloride at -10 ° in absolute alkyl or aralkyl alcohol according to Brenner (HeIv. Chim. Acta 34: 1114 (1953)).

The starting materials of the general formula IV are e.g. by reacting a-halogen-N-aryl-o-toluidines or -toluidides obtained with sodium or potassium cyanide, α-chloro-o-toluidine or a-chloro-o-toluidides surprisingly arise in a one-step reaction from o-arylamino-benzyl alcohols, namely when boiling the latter with acetyl chloride. Of the o-arylaminobenzyl alcohols substituted according to the definition for R 1 to R 1 individual representatives are known and others e.g. 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 e.g. be reduced with lithium aluminum hydride.

The substituted phenylacetic acids of the general Formula I and its salts with inorganic and organic bases can be administered orally, rectally or parenterally, especially intramuscularly. They can also be used externally, in ointments or Sun oil bases incorporated, are used.

Suitable salts for therapeutic use are those with pharmacologically acceptable inorganic and organic salts Bases, i.e. with bases which, in the dosages in question, show no physiological intrinsic effect or a desired one Effect, e.g. with parenteral application forms in particular

209817/1585

a local anesthetic effect. Suitable salts are e.g. 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 ones Salts of the same for the treatment of rheumatic, arthritic, and other inflammatory diseases are in motion 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 a pharmacologically acceptable salt thereof.

Unit dosage forms for oral use preferably contain between 1% and 90% of an acid as the active ingredient general formula I or a pharmacologically acceptable salt thereof. The active ingredients are combined to produce them e.g. 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 (carbowaxene) of suitable molecular weights, for tablets or for coated tablets. Latter For example, if you coat with concentrated sugar solutions, which e.g. still arabic gum, talc and / or titanium dioxide

2 09817/1585

may contain, or with one in volatile organic Solvent or solvent mixtures dissolved paint. Dyes can be added to these coatings, "e.g. for identification different doses of active ingredients.

The following regulations are intended to facilitate the manufacture of Explain tablets and dragees in more detail:

a) 1000.0 g of active ingredient, for example 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 of 8 , 0 g of gelatin moistened and granulated through a sieve. After drying, 60.0 g of potato starch, 60.0 g talc, 10.0 g of magnesium stearate and 20.0 g of colloidal Siliciumdiöxyd to mixing and the mixture is compressed to 10 ¹ OOO form tablets each weighing 200 mg and 100 mg of active ingredient that If desired, they can be provided with partial notches for more precise adjustment of the dosage.

b) 200.0 g of active ingredient, e.g. 2- (2,6-dichloroanilino) ~ Phenylacetic acid are made with 16 g of corn starch and 6.0 g of colloidal Silicon dioxide mixed well. The mixture is made 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 and moistened with a Sieve III (Ph. HeIv. V) granulated. The granulate is approx. 14 Dried for hours and then beaten through sieve III-purple. On that it is made with 16.0 g corn starch, 16.0 g talc and 2.0 g magnesium stearate mixed and pressed into 1000 dragee cores. These

■ ■ ■ "■ *

are made with a concentrated syrup of 2,000 g Lacca, 7,500 g gum arabic, 0.150 g dye, 2.000 g highly dispersed

209817/1585

Silica, 25,000 g talc and 53,350 g sugar coated and dried. The coated tablets each weigh 360 mg and contain 200 mg of active ingredient each.

Comes as unit dose forms for rectal use z, B. Suppositories which are made from a combination of an acid of the general formula I or a suitable salt thereof with consist of a neutral fat base, or gelatin rectal capsules, which is a combination of an active ingredient or a suitable salt thereof with polyethylene glycols (Carbowaxeri) of suitable molecular weight.

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

One of the following recipes can be used for the production of sun protection creams:

2- (2,6-dichloroanilino) phenylacetic acid 1.0 g

Paraffin oil, thin 1.0 g

Polyoxyethylene sorbitan monostearate 2.0 g

Polyoxyethylene sorbitol lanolin derivative 1.5 g

Sorbitol solution 70% 3.0 g

Stearic acid 15.0 g

Preservative + perfume qs water ad 100.0 g

209817/1585

■: .-. ■: y - Il -

2- (2, δ-dichloroanilino) phenylacetic acid propylene glycol Glycerine monostearate polyoxyethylene sorbitan monolaurate Thitnerosal (solution 1: 1000) perfume

water

The following examples explain the implementation of the method according to the invention in more detail, but are intended to illustrate the scope Do not limit the invention in any way. The temperatures are given in Celsiusgraderi.

1793592 G 1.0 G 28.0. G 18.0 G 8.0 G 1.0 q. s. ad 100.0

209817/1585

example 1

2- (2, o-DICHLORO-B-METHYLANILTNQ) -PHENYLACIC ACID

A. N-phenyl ^ .o-dichloro-S-methylaniline

7 g of 2- (2,6-dichloro-3-methylanilino) benzoic acid

[alternatively referred to as N- (2,6-dichloro-m ~ tolyl) -anthranilic acid] are heated to 280 ° for 2 hours. The cooled melt is dissolved in 30 ml of benzene and the benzolisehe solution with 5 ml of 2-n. Sodium carbonate and 5 ml of water extracted. The solution is dried with sodium sulfate and evaporated. The residue is distilled W , the N-phenyl-2,6-dichloro-3- <nethylanilit]

(alternatively referred to as 2,6 ~ dichloro-N-phenyl- * n ~ toluidine) is obtained as a yellow oil, boiling point 115-120 ° / 0.001 Torr. The following are obtained analogously:. ■

a) N-phenyl-2,6-dichloroaniline, boiling point 109-111 ° / Ό, 003 Torr;

b) N-phenyl ^ -chloro-o-methylaniline, b.p. 88 ° / Ο, ΌΟ5 Torr.

Alternatively, these substituted N-phenylanilines can also be produced analogously to the following process:

To a solution of 81 g of 2,6-dichloro-aniline in 30 ml

»Glacial acetic acid is slowly added dropwise to 40 ml of acetyl chloride. The solution is then heated on a water bath until the evolution of hydrochloric acid has ceased. 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 180-181 °. The yield is 70 % of theory.

Analogously one obtains:
N-acetyl-2,6-dichloro-3-methylaniline, melting point 179-181 ° from glacial acetic acid and water.

209817/1585

15 g of N-acetyl-2,6-dichloroaniline are dissolved in 150 ml of bromobenzene. 5.5 g of calcined potassium carbonate and 0.5 g are used Copper powder too. The mixture is then refluxed for 4 days, the water formed by means of a Water separator is separated. Then you cool off and undergo the mixture of a steam distillation. The residue is extracted with 200 ml of ether. The ethereal solution is filtered by Hyflo and concentrated to dryness below 11 torr. The residue is then dissolved in 60 ml of 10% strength ethanolic potassium hydroxide solution and reflux the solution 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 ether solution is separated and with 20 ml Water extracted. The ethereal solution is then dried with sodium sulfate and concentrated to dryness under 11 torr. The The residue is distilled in a high vacuum. The N-phenyl-2,6-dichloroaniline boils at 115 ° / 0.01 torr as a yellow oil. The yield is 43% of theory. £ Analogously one obtains:

c) N- (4-chlorophenyl) -2,6-dichloroaniline, boiling point 121VO ₁ Ol Torr;

d) N- (4-chlorophenyl) -2,6-dichloro-3-methylaniline, bp 135-145 ° / 0.005 torr;

e) N- (4-methoxyphenyl) -2,6-dichloro-3-methylaniline, bp 115-130 ° / 0.001 torr;

f) N- (4-Methoxypheny1) -2,6-dichloroaniline, m.p. 75-77 ° from Chloroform.

209817/1585 <

B. N-chloroacetyl-N-phenyl ^ .o-dichloro-S-methylaniline

4 g of N-phenyl ^ .o-dichloro-S-methylaniline are mixed with 40 ml freshly distilled chloroacetyl chloride refluxed for one hour. The dark solution is then below 11 torr and a bath temperature of 50 ° evaporated. The residue is dissolved in 70 ml of ethyl acetate-ether 1: 1. This solution comes with 10 ml 2-n. Extracted potassium bicarbonate solution and 10 ml of water, dried over sodium sulfate and evaporated under 11 torr. That Product also called N-phenyl-2,2 ', 6'-trichloro-aceto-m-toluidide can be designated, crystallized from cyclohexane, m.p. 117-118 °.

Analogously one obtains:

a) N-chloroacetyl-N-phenyl-2,6-dichloroaniline, melting point 143-144 ° from Ethanol;

b) N-chloroacetyl-N-phenyl-1-chloro-o-methylaniline, m.p. 110-112 ° from ether;

c) N-chloroacetyl-N- (4-chlorophenyl) -2,6-dichloroaniline, m.p. 130-131 ° from ethanol / water;

d) N-chloroacetyl-N- (4-chlorophenyl) -2,6-dichloro-3-methylaniline, M.p. 106-107 ° from ether / petroleum ether;

e) N-chloroacetyl-N- (4-methoxyphenyl) -2,6-dichloro-3-methylaniline as yellow OeI and

f) N-chloroacetyl-N- (4-methoxyphenyl) -2,6-dichloroaniline, M.p. 127-128 ° from methanol.

209817/1585

C. 1- (2,6-dichloro-3-methy! Phenyl) -2-indolinone

4 g of N-chloroacetyl-N-phenyl-2,6-dichloro-3-methylaniline and 4 g of aluminum chloride are mixed thoroughly and heated to 160 ° for 2 hours. The melt is cooled and reduced to approx. 50 g Poured ice while it is still warm. The precipitated oil is dissolved in 50 ml of chloroform, the chloroform solution with 10 ml Washed water, dried over sodium sulfate and evaporated under 11 torr. The residue is distilled. 1- (2,6-dichloro-3-methylphenyl) -2-indolinone boils at 128-130 ° / 0.001 torr. The oil obtained, which crystallizes on standing, melts at 129-132 °.

Analogously one obtains:

a) 1- (2,6-dichlorophenyl) -2-indolinone, melting point 126-127 ° from methanol;

b) 1- (2-chloro-6-methylphenyl) -2-indolinone, m.p. 96-98 ° from Ether;

c) 1- (2,6-dichlorophenyl) -5-chloro-2-indolinone, m.p. 130-131 ° from ethanol / water;

d) 1- (2,6-dichloro-3-methylphenyl) -5-chloro-2-indolinone, m.p. 152-154 ° from ethyl acetate / petroleum ether.

When implementing the methoxy-substituted compounds In this example, the corresponding free hydroxyl group can be formed, which is then again alkylated in the following manner can:

e) 10 g of N-chloroacetyl-N- (4-methoxyphenyl) -2,6-dichloro-3-methy1-aniline are mixed with 20 g of finely powdered aluminum chloride and stirred for one hour in a nitrogen atmosphere 280 ° heated. Allow to cool and add the solidified

209817/1585

Melt with plenty of ice and water. A black precipitate is formed, which is filtered off and dried at 80 ° and 11 Torr will. 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.

1- (2,6-dichlorophenyl) -5-hydroxy-2-indolinone is obtained analogously, M.p. 204-205 ° from methanol / benzene.

8.1 g of crude l- (2,6-dichloro-3-methylphenyl) -5-hydroxy-2-indolinone are in 26.3 ml of 1-n. Sodium hydroxide solution dissolved. 3.7 g of dimethyl sulfate are then added to the solution and the mixture is refluxed for 1/2 hour. After cooling, the reaction solution is extracted with 400 ml of ethyl acetate. The organic phase is filtered, washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under 11 torr. For purification, the residue is chromatographed over an aluminum oxide column. The 1- (2,6-dichloro-3-methylphenyl) -S-methoxy - ^ - indolinone melts after recrystallization from ether-petroleum ether at 135-136 °; Yield 20 % of theory.

Analogously one obtains:

f) 1- (2,6-dichlorophenyl) -5-methoxy-2-indolinoni m.p. 144-145 ° from ether / petroleum ether.

The! - (substituted phenyl) -2-indolinones can like be brominated as follows:

g) A solution of 11.2 g of l- (2,6-dichlorophenyl) -2-indolinone 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. The mixture becomes vigorous

209817/1585

shaken and then left to stand for 3 hours at 0 °. The alcohol is then evaporated and the insoluble precipitate is filtered off from the remaining aqueous solution. This is then taken up in methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated to dryness under 11 torr. The residue consists of a mixture which contains 60 % 1- (2,6-dichlorophenyl) -S-bromo ^ -indolinone. This is purified by repeated chromatography on a silica gel column and melts after it has been crystallized several times from ether or ether-petroleum ether at 188-190 °.

D. 2- (2,6-dichloro-3-methylanilino) phenylacetic acid A solution of 40 g of l- (2,6-dichloro-3-methylanilino) -2-

indolinone in 280 ml 1-n. Sodium hydroxide solution and 420 ml of ethanol Boiled under reflux for 2 hours. The clear solution is cooled and the ethanol at a bath temperature of 40 ° below 11 torr distilled off. The aqueous residue is extracted with 100 ml of ether, the ether is separated off and the aqueous solution cooled to 5 ° by adding ice (approx. 50 g) and external cooling. This is followed by 2-n with stirring. Hydrochloric acid to until the pH of the solution is approx. 6. The precipitated acid is taken up in 400 ml of ether, the ether- solution separated and the aqueous solution extracted again with 200 ml of ether. The ethereal solutions are mixed with 50 ml of water washed, combined, dried over sodium sulfate and concentrated at 11 torr without heating. From the concentrated essential After the addition of petroleum ether, the 2- (2,6-dichloro-3-methylanilino) phenylacetic acid crystallizes out. After

209817/1585

crystallization from ether-petroleum ether melts at 146-149 ° Analogously one obtains:

a) 2- (2,6-dichloroanilino) phenylacetic acid, melting point 156-158 °;

b) 2- (2-chloro-6-methylanilino) phenylacetic acid, m.p. 140-147 ° from ether;

c) 2- (2,6-dichloroanilino) -5-chlorophenylacetic acid, melting point 181-183 ° from methanol;

d) 2- (2,6-dichloro-3-methylanilino) -5-chloro-phenylacetic acid, M.p. 152-156 ° from ether-petroleum ether;

e) 2- (2,6-dichloro-3-methylanilino) -5-methoxyphenylacetic acid, M.p. 120-122 ° from ether / petroleum ether;

f) 2- (2,6-dichloroanilino) -5-mechoxyphenylacetic acid, melting point 134-136 ° from ether / petroleum ether;

g) 2- (2,6-dichloroanilino) -5-bromophenylacetic acid, recrystallized from ether / petroleum ether, decomposes at 161 °.

209817/1585

Example 2

2- (3-TRIFLUORHETHYLANILiNO) -PHENYL ACIDIC ACID

A. 2- (3-Trifluoromethylanilino) benzyl alcohol

To a solution of 3.8 g of sodium borohydride in 160 ml 8.7 g of lithium bromide are added to anhydrous diglyme. The mixture is stirred for 1/2 hour at room temperature. Then one will Solution of 14.8 g of methyl 2- (3-trifluoromethylanilino) benzoate [alternatively referred to as N- (a, a, a-trifluoro-m-tolyl) anthranilic acid methyl ester] in 4C ml of anhydrous diglyme added dropwise. The mixture is then heated for 3 hours 100 °, cools and poured onto a mixture of 300 g of ice and 30 ml of concentrated hydrochloric acid. Extracted after brief stirring the precipitated oil with 300 ml of ethyl acetate. The ethyl acetate solution becomes with 2-n. Washed potassium bicarbonate solution and water, dried over sodium sulfate and under 11 torr at Evaporated 40 °. The residue is removed with a short Vigreux column fractionally distilled. The 2- (3-trifluoromethylanilino) benzyl alcohol [alternatively referred to as o- (a, oc, a-trifluoro-mtoluidino) -benzyl alcohol] boils at 127-129 ° / 0.001 torr. The yield is 75% of theory.

According to an alternative, second method, 9.97 g of lithium aluminum hydride are suspended in 100 ml of absolute ether and cooled ^{to 5 ° C. with stirring.} A solution of 36.8 g of methyl 2- (3-trifluoromethylanilino) benzoate in 140 ml of absolute ether is slowly added dropwise under nitrogen with external cooling with an ice bath. The mixture is then stirred at room temperature for 18 hours. To the cooled to 0 °

209817/1585

Mixture is added dropwise 10 ml of water, 10 ml 15% sodium hydroxide solution and another 30 ml of water. Then one touches one hour at room temperature and filtered off. The filtrate is evaporated under 11 torr at 40 °. The residue will fractionated by means of a short Vigreux column. The 2- (3-trifluoromethylanilino) benzyl alcohol is obtained as a yellow oil, Bp 130-131 ° / 0.001 torr.

Analogously one obtains:

a) 2- (2-Methoxy-5-methylanilino) -benzyl alcohol, m.p. 138-139 ° from methanol;

b) 2- (2,3-dimethylanilino) benzyl alcohol, bp. 136-141 ° / 0.005 torr;

c) 2- (2-chloro-5-trifluoromethylanilino) benzyl alcohol, m.p. 100-101 ° from petroleum ether;

d) 2- (2,6-dichloroanilino) -5-methoxy-benzyl alcohol, m.p. 112-113 ° from cyclohexane.

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:

e) To 30 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran, a suspension of 65 g of 2- (2,6-dichloroanilino) benzoic acid in 500 ml of absolute tetrahydrofuran is added dropwise at 5-15 °. 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 separated from the crystalline precipitate

209817/1585

. sucked off and this * washed well with tetrahydrofuran.

The combined solutions are evaporated, taken up in ethyl acetate and with. 2-n. Sodal solution and saturated saline solution washed. Evaporation of the organic phase gives 44.4 g of a dark brown oil, which is made from ethyl ether / petroleum ether crystallized. The 2- (2,6-dichloroanilino) benzyl alcohol melts at 110-112 °.

Analogously one obtains:

f) 2- (2-methyl-3-chloroanilino) benzyl alcohol, m.p. 51-52 ° from Ethyl ether / petroleum ether.

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 refluxed under nitrogen for one hour. The orange-colored solution is then concentrated to below 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 with 20 ml of 2-n. Washed potassium bicarbonate solution and 20 ml of water, dried over sodium sulfate and concentrated in vacuo. What remains is a light oil that crystallizes from ether-petroleum ether. The product obtained [alternatively named as α-chlorine -N- (a, a, a-trifluoro-m-tolyl) -aceto-o-toluidide] melts at 83-85 °.

Analogously one obtains:

a) N-acetyl-2- (2-methoxy-5-methylanilino) -benzyl chloride, melting point 121-123 ° from petroleum ether.

209817/1585

C. N-acetyl (1) -Q-trifluoromethylanilino) phenylacetonitrile

To a suspension of 2.2 g of sodium cyanide in 20 ml of dimethyl sulfoxide, a solution of 11.6 g of N-acetyl-2- (3-trifluoromethylanilino) benzyl chloride in 60 ml of dimethyl sulfoxide is added at 40 ° with stirring. The temperature must not exceed 40 °. The mixture is then stirred for 3 hours at 40 °, cooled to 10 ° and diluted with 200 ml of water. The solution is extracted four times with 150 ml of ethyl acetate. The ethyl acetate solutions are mixed with 200 ml of 6-n. Hydrochloric acid and then shaken with 30 ml of water, then concentrated ^ö dried with sodium sulfate and under 11 Torr at 40th The product remaining as a yellow oil [alternatively named as a-cyano-N- (a, a, a-trifluoro-m-tolyl) -aceto-o-toluidide] can be further processed directly.

Analogously one obtains:

a) N-acetyl-2- (2-methoxy-5-methylanilino) -phenylacetonitrile, M.p. 108-109 ° from cyclohexane.

D. 2- (3-Trifluoromethylanilino) phenylacetic acid

9.5 g of N-acetyl-2- (3-trifluoromethylanilino) phenylacetonitrile are in 100 ml of ethanol and 90 ml of 1-n. Sodium hydroxide solution dissolved. The solution is refluxed overnight. One cools from and concentrated under 11 Torr at 40 ° to approx. 70 ml. The aqueous alkaline solution is extracted with 50 ml of ether, this ethereal solution is separated off and the aqueous phase with 2-n. Acidified hydrochloric acid. It is shaken with 50 ml of ether and the ether extract is washed with water, the ethereal solution is dried over sodium sulfate and concentrated below 11 torr without heating. The residue crystallized from ether-petroleum ether. After recrystallization from

209817/1585

Ether-petroleum ether melts 2- (3-trifluoromethylanilino) phenylacetic acid [alternatively named as ο- (α, α, α-trifluoro-mtoluidino) -phenylacetic acid] at 112-114 °. The yield is 35% of theory.

But this substance can also be used in the following ways

getting produced:

A solution of 50 g of N-acetyl-2- (3-trifluonnethylanilino) -

phenylacetonitrile in 550 ml of absolute ether and 375 ml of absolute ethanol is brought to 0-5 ° with stirring and with exclusion of moisture cooled down. Dry hydrogen chloride is added to the solution for 4 hours initiated, whereby the temperature should not exceed 5 °. This is followed by a further 5 hours at room temperature Introduced hydrogen chloride. The solution is then left to stand at room temperature overnight and evaporated under 11 torr at 40 ° bath temperature to dryness. The residue is dissolved in 140 ml of water, covered with 150 ml of ether and heated Whole 2 hours under reflux on the steam bath. It is then cooled, the ether phase is separated off and extracted aqueous solution again with 200 ml of ether. The combined ethereal solutions are dried over sodium sulfate and under Evaporated water jet vacuum at 40 °. The residue is fractionated using a Vigreux column in a high vacuum. Ethyl N-acetyl-2- (3-trifluoromethyl) phenylacetate boils at 110-115 ° / 0.001 torr.

Analogously one obtains:

a) N-acetyl-2- (2-methoxy-5-methylanilino) -phenyl acetic acid ethyl ester, 180-185 ° / 0.001 Torr.

209817/1585

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. Sodium hydroxide solution is refluxed for 16 hours. The ethanol is then distilled off under 11 torr at 40 ° and the remaining aqueous solution is extracted with 40 ml of ether. The ethereal phase is separated off, the aqueous phase is cooled to 0-5 ° by adding ice and is washed with 2-n. Hydrochloric acid to pH 6 acidified. The precipitated oil is dissolved in 200 ml of ether, the essential solution washed with 20 ml of water and over sodium sulfate dried. It is then concentrated below 11 Torr without heating. After the addition of petroleum ether, the crystallized 2- (3-Trifluoromethylanilino) phenylacetic acid from, m.p. 112-114 °.

Analogously one obtains:

a) 2- (2-Methoxy-5-methylanilino) phenylacetic acid, m.p. 105-107 ° from ether.

209817/1585

Example 3

2- (2-CHLORO-S-TRIFLUOROMETHYLA NTLIN O ) -PHENTL ACID ACID

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, c)] in 70 ml of acetyl chloride is refluxed for 16 hours under a nitrogen atmosphere. Then the solution is evaporated at about 40 ° under reduced pressure. The residue is taken up in 40 ml of benzene and concentrated again. The residue is then taken up with 200 ml of ether and the ethereal solution is washed 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 120 ° / 0.001 Torr. The 2- (2-chloro-5-trifluoromethylanilino) benzyl chloride can be crystallized from petroleum ether, melting point 50 ° -51 °. The yield is 32 % of theory.

a) Alternatively, a solution of 5 g of 2- (2,3-dimethylanilino) benzyl alcohol [prepared according to Example 2 A. b)] in 150 ml of abs. Ether dropwise with stirring 150 ml 5-n. Section. ethereal hydrochloric acid (produced by introducing hydrochloric acid gas into absolute ether). Crystals separate out, which after the addition of a further 400 ml of abs. Aether go back into solution. The solution is stirred for 30 minutes at room temperature and evaporated under 11 torr at 40 °. The residue crystallizes after a little ether has been added. The crystals are filtered off and a mixture of 20 ml of water and 100 ml of ether is added. The ether solution is separated off, extracted with water, over

209817/1585

Sodium sulfate dried and dried to dryness under 11 torr steams. The 2- (2,3-dimethylanilino) benzyl chloride remains as an oil and will be implemented immediately. Analogously one obtains:

b) 2- (2-methyl-3-chloroanilino) benzyl chloride as a yellow oil, starting from the corresponding benzyl alcohol [prepared according to Example 2 A. f)];

c) 2- (2,6-dichloroanilino) benzyl chloride as a yellow oil from the corresponding benzyl alcohol [prepared according to Example 2 A.e)];

w d) 2- (2,6-dimethylanilino) benzyl chloride, prepared from the corresponding benzyl alcohol;

e) 2- (2,6-dichloroanilino) -5-methoxy-benzyl chloride, m.p. 82-84 ° from petroleum ether, starting from the corresponding benzyl alcohol [prepared according to Example 2 A. d)].

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

A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulfoxide is heated to 40 °. A solution of 33 g of 2- (2-chloro-5-trifluoromethylanilino) benzyl chloride in 150 ml of dimethyl sulfoxide is then added with stirring, the temperature not exceeding 40 °. The mixture is stirred for 3 hours and then diluted with 600 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 6-n. Hydrochloric acid and 100 ml of water, dry them over sodium sulfate and distill off the solvent under reduced pressure. The residue is distilled in a high vacuum. The 2- (2-chloro-5-trifluoromethylanilino) -phenyl-. acetonitrile boils at 122-126 ° / 0.01 Torr and can be obtained from petroleum ether

209817/1585 ^

be crystallized. After recrystallization, the m.p. is included 58-59 °. The yield is 74% of theory. Analogously one obtains:

a) 2- (2,3-dimethylanilino) phenylacetonitrile, melting point 95 ° -96 °;

b) 2- (2-methyl-3-chloroanilino) phenylacetonitrile, m.p. 86-88 °;

c) 2- (2,6-dichloroanilino) phenylacetonitrile, m.p. 71-72 ° from Ethyl ether / petroleum ether;

d) 2- (2,6-dimethylanilino) phenylacetonitrile from the corresponding Benzyl chloride;

e) 2- (2,6-dichloroanilino) -5-methoxyphenylacetonitrile, melting point 169-171 °.

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

A solution of 18.4 g of 2- (2-chloro-5-trifluoromethylanilino) -phenylacetonitrile in 120 ml of 1-n. Sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours. The reaction solution is then concentrated at 40 ° under reduced pressure to a volume of about 80 ml and the aqueous solution is extracted with 100 ml of ether. The aqueous-alkaline phase is then at 5 ° with 2-n. Hydrochloric acid acidified and the precipitated oil taken up in ether. The ether solution is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure without heating. When petroleum ether is added, the 2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid crystallizes out, melting point 94 ° -96 °, yield 55 % of theory. The saponification can also be carried out using the following alternative methods:

209817/1585

a) 2 g of 2- (2,3-Dimethylanili.no) -phenylacetonitrile are mixed with 3 g Potassium hydroxide in 60 ml of n-butanol boiled under reflux for 2 hours. Then the solution is concentrated under 0.1 torr at 60 °. The residue is dissolved in water. The aqueous solution is with Aether extracted, separated and with 2-n. Acidified hydrochloric acid. The precipitated oil is extracted with ether. You wash them Ether solution with water, dry it over magnesium sulfate and constricts them to dryness below 11 torr. The residue is crystallized from ether-petroleum ether. 2- (2,3-Dimethylanilino) phenylacetic acid melts at 112-113 °. Analogously one obtains:

b) 2- (2-Methyl-3-chloroanilino) -phenylacetic acid, Srap. 124-125 ° from ether / petroleum ether;

c) 2- (2,6-dichloroanilino) phenylacetic acid, m.p. 156-158 ° from Ethyl ether / petroleum ether;

d) 2- (2,6-dimethylanilino) phenylacetic acid, melting point 120-127 °;

e) 2- (2,6-dichloroanilino) -5-methoxyphenylacetic acid, M.p. 134-136 °.

209817/1585

Example 4

2- (2, G-DICHLORANILINO) -PHENYL ACID ACID

A. 2- (2, e-Dichloranil i no) -phenylacetic acid methyl ester

To a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid (Srap. 156-158 °) in 150 ml of absolute ether is slowly added dropwise 100 ml of 2 70% ethereal diazomethane solution. The solution is left to stand overnight at room temperature and then concentrated to dryness under 11 torr at 40 °. The residue is dissolved in 100 ml of ether. The ether solution is with 50 ml 1-n. Extracted potassium bicarbonate solution and water, dried over sodium sulfate and concentrated under 11 torr at 40 °. The residue crystallizes from ether-petroleum ether. The methyl 2- (2,6-dichloroanilino) phenylacetate melts at 101-102 °. The yield is 72 % of theory.

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

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

A solution of 1 g of 2- (2,6-dichloroanilino) phenylacetic acid methyl ester in 20 ml of methanol and 5 ml of 2-η. 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 with 2-n. Acidified hydrochloric acid, extracted the precipitated oil with ether and washed the ethereal solution with water, dried over sodium sulfate and concentrated cold under 11 torr. The 2- (2,6-dichloroanilino) phenylacetic acid crystallizes out

Ether-petroleum ether, m.p. 156-158 °. The yield is 75%

209817/1585

the theory.

In the same way, you can use the 2- (2,6-dichloroanilino) phenylacetic acid ethyl ester, Saponify melting point 50-52 °.

. Alternatively, you can proceed as follows:
A solution of 0.5 g of 2- (2,6-dichloroanilino) phenylacetic acid methyl ester in 40 ml of 75% ethanol with 12 g of Dowex! Ion exchanger (OH form, 20-50 mesh) 15 is placed in a round bottom flask
Stirred at 50 ° for hours. Then it is filtered off. The residue
it is suspended in 20 ml of water and acidified at 5 ° with 1-n. Hydrochloric acid. 30 ml of ether are added, the mixture is shaken and the ethereal solution is separated off. The ether solution is washed with 10 ml of water, dried over sodium sulfate and concentrated to a cold temperature of less than 11 torr
Dry up. The 2- (2,6-dichloroanilino) phenylacetic acid crystallizes from ether-petroleum ether, melting point 156-158 °. The yield
is 45% of theory.

209817/1585

Example 5

2 - (2,6-DICHLORANILINO) -PHENYL ACID ACID

A. 2- (2,6-Dichloroanilino) phenylacetic acid benzyl ester

A solution of 2.96 g of 2- (2,6-dichloroanilino) phenylacetic acid, 1.2 g of absolute benzyl alcohol and 3 g of dimethylformamide dineopentyl acetal in 40 ml of methylene chloride is stirred under nitrogen for 55 hours. The methylene chloride is then distilled off under 12 torr. It is diluted with 50 ml of ethyl acetate, the solution is extracted with water and dried over sodium sulfate. The solution is concentrated to dryness under 11 torr at 40 °. The residue is chromatographed on 60 g of neutral aluminum oxide. Fractions 2 and 3, eluted with 7: 3 ether-petroleum ether, contain the pure benzyl 2- (2,6-dichloroanilino) phenylacetate. The yield is 30 % of theory.

The above ester can also be obtained as follows: To 40 ml of absolute benzyl alcohol is allowed to at -10 ° with good stirring and introduction of nitrogen to-6 ml of thionyl chloride '; added m.. After 5 minutes, a solution of 2.96 g of 2- (2,6-dichloroanilino) phenylacetic acid in 10 ml of absolute benzyl alcohol is added dropwise at -10 °. The reaction mixture is then stirred 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 10ml 2-n. Potassium bicarbonate solution and water are dried over sodium sulphate and the ethereal solution is evaporated to dryness under 11 torr at 40 °. The residue is chromatographed on 90 g of neutral aluminum oxide. The factions

209817/1585

1 and 2, eluted with ether-petroleum ether 1: 1, contain the pure 2- (2,6-dichloroanilino) phenylacetic acid benzyl ester. The yield is 48 % of theory.

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

1.2 g of 2- (2,6-dichloroanilino) phenylacetic acid ^ benzyl ester are dissolved in 50 ml of fine spirits and after adding 0.2 g 5% "Pd-charcoal hydrogenated at low pressure and room temperature. After The hydrogenation is complete for 1 1/4 hours. The catalyst is filtered off and the filtrate under 11 torr at room temperature Evaporated to dryness. The residue is recrystallized from ether-petroleum ether, the 2- (2,6-dichloroanilino) phenylacetic acid obtained melts at 156-158 °. The yield is 67% of theory. -

209817 / 1S85

Example 6

2 ~ (2,6-DICHLORANILINo) -FHENYL ACID, NATRIDE SALT

A solution of 186 g of 1- (2,6-dichlorophenyl) -2-indolinone in 660 ml of ethanol and 660 ml of 2-n. Sodium hydroxide solution is refluxed for 4 hours. The solution is then 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 at 283-285 °. The yield is 97 % of theory. ' Analogously one obtains:

a) The sodium salt of 2- (2,6-dichloroanilino) ~ 5-chlorophenylacetic acid » M.p. 296 ° from water;

b) The sodium salt of 2- (2,6-dichloro-3-methylanilino) phenylacetic acid, M.p. 287-289 ° from water;

c) The sodium salt of 2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid, M.p. 225-230 ° from water.

209817/1585

Example 7

2 - (2,6-DICHLORANILINO) -PHENYL ACIDIC ACID, POTASSIUM SALT

To a solution of 8.9 g of 2- (2,6-dichloroanilino) phenylacetic acid 20 ml of 8% ethanolic potassium hydroxide solution are added to 50 ml of ethanol. The solution is made with activated charcoal

Boiled for 10 minutes, filtered and concentrated below 11 torr. When % ether is added, the potassium salt of 2- (2,6-. ^ "

Dichloroanilino) phenylacetic acid from, m.p. 300-330 ° below ™ decomposition.

ORIGINAL INSPECTED 209817/1585

Claims (14)

Claims /1.j Compounds of the general formula I ₄ in which R, a lower alkyl or alkoxy radical, a halogen atom up to atomic number 35 or the trifluoromethyl group, R _? Hydrogen, a lower alkyl or alkoxy radical, or a halogen atom up to atomic number 35, R is hydrogen, a lower alkyl or alkoxy radical or a halogen atom up to atomic number 35 and R, hydrogen, a lower alkyl or alkoxy radical A halogen atom up to atomic number 35 or the trifluoromethyl group,
and their salts with inorganic and organic bases. 2. 2- (2,6-dichloro-3-methylanilino) phenylacetic acid and their salts with pharmaceutically acceptable inorganic or organic bases. 3. Sodium salt of 2- (2,6-dichloro-3-methylanilino) phenylacetic acid. " 4. 2- (3-Trifluoromethylanilinc) -phenylacetic acid and its salts with pharmaceutically acceptable inorganic or organic bases ...- .. * 209817/1585 .t r- 5. 2- (2-chloro-5-trifluoromethylanilino) phenylacetic acid and their salts with pharmaceutically acceptable inorganic or organic bases. 6. Sodium salt of 2- (2-chloro-5-trifluoromethylanilino) '- phenylacetic acid. '· 7. 2- (2,6-dichloroanilino) phenylacetic acid and its salts with pharmaceutically acceptable inorganic or organic bases. 8. Sodium salt of 2- (2,6-dichloroanilino) phenylacetic acid. 9. Kaliumsalζ of 2- (2,6-dichloroanilino) phenylacetic acid. , 10. 2- (2,6-Dimethylanilino) phenylacetic acid and its salts ■ with pharmaceutically acceptable inorganic or organic bases, 11. 2- (2-Methyl-3-chloroanilino) phenylacetic acid and its Salts with pharmaceutically acceptable inorganic or organic bases. . · ·· · 12. 2- (2-Chloro-6-methylanilino) phenylacetic acid and its Salts with pharmaceutically acceptable inorganic or organic bases. ^ 13. 2- (2,3-Dimethylanilino) phenylacetic acid and its Salts with pharmaceutically acceptable inorganic or organic Bases. 14. Use of the compounds of the formula I or their Salts with organic or inorganic bases as an active ingredient in 15 · Pharmaceutical compositions, characterized by a content of compounds of the formula I or their salts organic or inorganic bases as active ingredients. 209817/158 5 BATH