IL25545A - Substituted phenylacetic acids,their preparation and use - Google Patents

Description

PATENTS AND DESIGNS ORDINANCE SPECIFICATION New substituted phenylacetie acids, preparation and use j naan , mv*rti m*sama n *e*R »3a xnsain 1 (we) J.R. GEIGY S.A,, a Swiss Company, of Baale, Switzerland do hereby declare the nature of this invention and in what manner the same is to he performed, to he particularly described and ascertained in and by the following statement : - The present invention concerns new substituted phenylacetic acids and their salts, a process for the production thereof and medicaments containing them.

Substituted phenylacetic acids of the general formula; wherein represents a lower alkyl or lower alkoxy group, a halogen atom up to the atomic number 35 or a trifluoro-methyl group j It, and fi^ represent, independently of each other, a hydrogen atom, a lower alkyl or lower alkoxy group or a halogen atom up to the atomic number 35; and represents a hydrogen atom, a lower alkyl or lower alkoxy group, a halogen atom up to the atomic number 35 or a ifluoromethyl group, aad their salts with inorganic and organic bases, have not been known hitherto. It has now been found that the compounds of ; general formula I and their salts have valuable pharmacological properties, in particular antiphlogistic (anti-inflammatory), analgetic and antipyretic activity with, at the same time, a favourable therapeutic index. They can be administered orally, rectally or, particularly in the form of aqueous solutions of their salts, also parenterally , in particular intramuscularly, for the treatment of rheumatic, arthritic and other inflammatory-diseases. The antiphlogistic action can be proved in pharmacological trials, for example on the UV erythema in the guinea pig and bolus alba oedema in the rat.

In addition, these substances are capable of absorbing UV rays at 290 - 300 m . , which are responsible for sun burn, and they are therefore suitable as UV absorbers for cosmetic purposes , e.g. in sun tan lotions, because they allow the desired tanning · rays over 315 niju to come through.

In the compounds of general formula I and i the corresponding starting materials mentioned below, to R^ independently of each other represent, as low alkyl radicals, e.g.' methyl or ethyl radicals. Some of the symbols mentioned can also represent, e . . n-propyl , isopropyl, n-butyl, sec butyl or tert. butyl radicals. Low alkoxy radicals or halogen atoms R-^ to R^ are, e.g. msthoxy, ethoxy, n-propoxy, isopropoxy, n» butoxy or isobutoxy radicals or chlorine, fluorine or bromine atoms. 25545/2 To produce an acid of the general formula I and its salts with inorganic or organic bases, a compound of the general formula II wherein R-^ - ^ have the meanings given above, is reacted with an alkali, metal, hydroxide , alkali metal..carbonate or alkaline earth'ffietal hydroxide while heatin and, if desired, the acid is liberated from the alkali or alkaline earth salt obtained*-This- can be converted into another salt wit .an organic or inorganic base if desired.

Suitable solvents are, in particular, aqueous low alkanols such, as ethanol, methanol or n-butanol; ethylene glycol or dimethyl formamide can also be used. The hydrolysis is performed, e.g. at or at a little under the boiling tempera ture of the solvent; at least one equivalent of an alkali metal hydroxide or carbonate or alkaline earth metal hydroxide particularly sodium or potassium hydroxide, is used therefor.

The compounds of general formula I are produced by a second process by reacting, while heating, a compound of the general formula III ■ ■ 25545/2 wherein A represents hydrogen or an acyl radical, particularly a lo '.alkanoyl radical, and ■..Rcj represents a low alkyl or... an aralkyl radical, particu- larly the benzyl radical, and' R^ - R^ have the meanings given above, with an alkali metal hydroxide, carbonate or bicarbonate, an alkaline earth metal hydroxide or a basic ion exchanger, or if is. the. enzyl radical, splitting this off by hydrogenoly-sis v/ith catalytically activated hydrogen. Suitable solvents for the hydrolysis are, in particular, aqueous low alkanols such as methanol, ethanol, n-butanol, and also ethylene glycol or dimethyl formamide. The hydrolysis is performed, e.g. at or at ust' below the boiling point of the solvent using at least one equivalent of the base. More advantageously, the hydrogenolysis is performed under normal pressure and at- room temperature to moderately raised temperature in the presence of palladium charcoal in alcohol.

Compounds of the general formula I are obtained by a third process by reacting, "while heating, a compound of general ; formula IV 25545/2 wherein - and A have the meanings given above, with an alkali metal hydroxide in an aqueous solvent. Suitable solvents are, in particular, aqueous lo : alkanols such as ethanol, methanol or n-butanol, and also ethylene -glycol or dimethyl -forma ide . The hydrolysis is . erformed , e.g. at or at a little under the boiling temperature of the solvent using at least two equivalents of an alkali metal hydroxide, in particular sodium or potassium hydroxide. ■ The starting materials of general formula II, which can be termed l-aryl-2- indolinones , 1-aryl-oxindoles or lactams of 2-arylamino-phenylacetic acids, are, in their turn, new compounds. The compounds of general formula II are produced, e.j?:. analogously to the known l-phenyl-2-indolinone from' corres onding, unsymmetrically substituted diphenylamines by · N-phenyl-chloracetylating them to form substituted ^--chloro-S1—p&eGjpi--acetanilides and heating the latter with aluminium · chloride at temperatures about l6c C or by heating them with aluminium chloride in suitable solvents such as tetrachloro-etnane or nitrobenzene at IOC - 1?0ϋ0. · Some diphenylamines substituted corresponding to the definition ot" - are known, and others can be produced analogously, e.g. according to A. W. Chapman, J. Chem. 3oc. 1929, 569-572, by heating ,0-diaryl-iminoesters and hydrolysing the ,N-diarylamides formed by rearrangement, or according to the method used by R.B.

Moft'ett et al, J. Am. Chem. Soc. o2, lo05 (I960), starting from optionally substituted o-chloro- or o-bromo- benzoic acids and substituted anilines and decar boxylating the o-anilino-benzoic acids formed. ' .

A particularly suitable method for the production of diphenylamines substituted corresponding to the definition of RX - RL, is- that of Goldberg, Ber. O, V H1 (1907) by which an optionally substituted acetanilide is reacted with a bromo- · benzene substituted corresponding to the definition of R^.

Another method for the production of compounds: of general formula II consists in acid saponification of compounds of general formulae III and IV whereby ring closure .occurs, The starting materials of general formula III having a low alkyl group as R^ and an acyl group as A can be obtained, e.g. by converting the corresponding cyatio compounds in imino-ether hydrochlorides and decomposing the latter with water. - o - . 25545/2 t • These starting materials can also be obtained, however, starting t'.rom the acids of general formula I by treating the latter in the known way with alkylating agents such as diazo alkanes or diaikyl sulphates.

The low alkyl and aralkyl esters of general formula III can also be obtained by other known esterification processes, e.g. by the , N-dimeth l formamide-dineopentyl acetal process of H. Biichi, . Steen- and Ά. Eschenmoser (Ang. Chemie 75. (1963) II76) or with thionyl chloride at -10°C in abs. alkyl -or aralkyl alcohol according to Brenner (Helv. Chim. Acta _3j±5 ' (1953) lllW) .

The starting materials of general formula IV are obtained, for example, by reacting a-halogen-N-aryl-o-toluidines or -toluidides with sodium or potassium cyanide. Surprisingly, (x-chloro-o-toluidines or oc-chloro-o-toluidides are formed in a one- step reaction from o-arylamino-ben¾yl alcohols, i.e. on boiling the latter with acetyl chloride. Some of the o-aryl- arnlno-benzyl alcohols substituted corresponding to the definition of - are known and others can be obtained, e. . by reduction of N-aryl-anthranilic acid alkyl esters with .lithium aluminium hydride in ether or tetrahydrofuran, sodium borohydride in methanol, or sodium borohydride and lithium bromide in diglyme (diethylene glycol dimethyl ether). The N-aryl-anthranilic acids can be reduced, e.g. with lithium aluminium hydride.

The substituted phenylacetic acids of general formula I and their salts with inorganic and organic bases can be ■/. administered orally, rectally or parenterally, in particular intramuscularly. They can also be applied externally in 1 foundations for sun-tan oils and ointments.

Salts suitable for therapeutic administration are those with pharmacologically acceptable inorganic and organic bases, i.e. with bases which themselves do not have a physiological action in the usual dosages or w ich have a desired action, e.g. in forms for parenteral administration, those which have, in particular, a local anaesthetic action. Suitable salts are, e.g. sodium, potassium, lithium, magnesium, calcium and ammonium salts as well as salts with ethylamine , triethylamine , ethanolamine , diethanolamine , diethylami noetha-nul, etiiylenediamlne , bensylamine , procaia, pyrrolidine, piperi dine, morpholine, 1-ethyl piperidine or 2-piperidino etnanol.

The daily dosages to be taken internally of free acids of general formula I or of pharmacologically acceptable salts thereof for the treatment of rheumatic, arthritic and other inflammatory diseases vary between 100 and 1500 rng for adult patients. Suitable dosage units such as dragees (sugar coated tablets), tablets, suppositories or ampoules, preferably contain 25 - 300 mg of a free acid or a pharmacologically acceptable salt thereof.

Dosage units for oral administration preferably contain between 1% and 90% of an acid of general formula I or of a pharmacologically acceptable salt thereof as active substance They are produced by combining the active substances, e0g„ with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, mai¾e starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition 7 « ethylene glycols (Carbowaxes) of suitable molecular weights, to^ form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dis-solved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

The following prescriptions further illustrate the production of tablets and elragees: a) 100.0 g of active substance, e.g. [o-(2,6-dichloro-m-toluidino^-phenylj-acetic acid or its calcium or lithium salt are mixed with 550.0 g of lactose and 292.0 g of potato starch, the mixture is moistened with an alcoholic solution of 8.-.0 g of gelatine and granulated through a sieve. After drying, 60.0 g of potato starch, όθ.Ο g of talcum, 10.0 g of magnesium stear-, ate and 20.0 g of colloidal silicium dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing 200 mg and containing 100 mg of active substance. The tablets can be grooved for better adaptation of the dosage. b) 200.0 g of active substance, e„g. [o-(2,6-dichloro-m-toluidino) -phenyl]-acetic acid are well mixed with 16 g of maize starch and 6.0 g of colloidal silicium dioxide. The mixture is moistened 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 granulated through a sieve III (Ph. Helv. V). The granulate is dried for about l hours and then passed through sieve III - Ilia, It is then mixed with l6.0 g of maize starch, l6.0 g of talcum and 2.0 g of magnesium stear-ate and pressed into 1000 dragee cores. These are coated with arable, 0.150 g of dyes tuff, 2.000 g of highly dispersed " silicium dioxide, 25.000 g of talcum and 3.3 0 g of sugar and dried. The dragees obtained each weigh 360 mg and contain 200 mg of active substance.

Dosage units for rectal administration are, for example, suppositories which consist of a combination of an acid of general formula I or a suitable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules contain a combination of an active substance or a suitable salt thereof with polyethylene glycols (Garbowaxes) of suitable molecular weight.

Ampoules for parenteral, particularly intramuscular, administration preferably contain a water soluble salt, e.g. the sodium salt, of a substituted phenylacetic acid of general formula I, in a concentration of, preferably, 0.5 ~ 5%? i aqueous solution, optionally together with suitable stabilising agents and buffer substances.

One of the following prescriptions can be used for the production of sun-tan creams: [o-(2,6-dichloyQanllino)-phenyl]-acetic acid 1.0 g paraffin oil, thinly liquid 1.0 g polyoxyethylene sorbitan monostearate " 2.0 g polyoxyethylene sorbiol lanoline derivative 1„ 5 g sorbitol solution 70% 3.0 g stearic acid 15.0 g preservative + perfume q„s. water ad 100.0 g _ / [o-(2,6-dichlor-^anili o)-phenylJ-acetic acid 1.0 g propylene glycol 2δ„0 g glycerine monostearate l8.0 g polyoxyethylene-sorbitan monolaurate 8.0 g, thimerosal (solution 1:1000) 1.0 g perfume q.s. water ad 100.0 g The following examples further illustrate the performance of the processes according to the invention but they in no way limit the scope of the invention. -The temperatures are given in degrees Centigrade and percentages are "by weight unless expressly stated otherwise.

Example 1 2- (2 , 6-DICHLORO- 3-METHYLA ILINO) -PHENYL ACETIC ACID A . N-phenyl-2 , 6-dichloro-- 3-methylaniline . 7 g of 2-(2,6-dichloro-3-methylanilino)-benzoic acid ar heated for 2 hours at 280°. The cooled melt is dissolved in 30 ml of benzene and the benzene solution is extracted with 5 ml of 2N sodium carbonate and 5 ml of water. The solution is dried with sodium sulphate and concentrated. The residue is distilled whereupon N-phenyl-2 , 6-dichloro-3-methylaniline is obtained as a yellow oil, B.P. ' 115- 120°/0.001 Tor'.

The following are obtained analogously: a) N-phenyl-2, 6-dichloroaniline, B.P. 109-111° /0.001 Torr; b) N-phenyl-2-chloro-6-methylaniline, B.P. 88°/0.005 Torr.

N-phenyl-2. ,6- dichloro- 3-methylaniline can also be produced as follows : A' i ) N-acety1-2 , 6-dichloroaniline .

HO ml of acetyl chloride are slowly added dropwise to a solution of 81 g of 2,6-dlcalora iline in 50 ml of glacial acetic acid. he solution is then heated in a water bach until the development of hydrogen chloride has been couple ed. I is then cooled to room temperature and t e -aixfcure is poured onto ice. Tne crystals which separate are filtered off and recrys- N-acetyl-2,6-dichloro-3-methylaniline, M.P. 179-181° from acetic acid/water is obtained analogously: ii) N-phenyl-2 , 6-dichloro-3-methylaniline . g of N-acetyl-2, 6-dichloroaniline are dissolved in 150 ml of bromobensene . 5.5g of calcinated potassium carbonate and 0.5 g of copper puwder are added. The mixture is then ret'luxed for days the water formed being removed by a water separator. The mixture is then cooled and subjected to steam dis illation. The residue is extracted with 200 ml of ether. The ether solutio is filtered through hyflo and the residue is concentrated to dryness under 11 Torr. The residue is dissolved in 6o ml of lO/o ethanolic potassium hydroxide solution and the solution is refluxed for 3 hours. The solution is then concentrated bo dryness at cu under 11 Torr. 10 ml of water are added the residue which is then extracted with 100 ml of ether. The etuer solution is removed and extracted with 20 mi of water. The ether solution is then dried with sodium sulphate and concentrated to dryness under 11 Torr. T:.e residue is distilled under high vacuum. The N-phenyl-2 , 6-dichloroaniline boils as a yellow oil, a 115°/0.01 Torr. The yield is kjfi of tiie theore ical.

The following are obtained analogously: c) N- (4-chlorophenyl) -2 , 6-dichloroaniline , B.P. 121°/0.01 Torr; d) N- (4-chlorophenyl) -2 , 6-dichloro-3-methylaniline , B .P . 135-145°/0.005 Torr; ' e) N- (4-methoxyphenyl) -2, 6-dichloro- 3-methylaniline, B.P. 115-130° /0.001 Torr; f) N- (4-methoxyphenyl) -2 , 6-dichloroaniline , M.P. 75-77° from chloroform.

B N- chloroacetyl-N-phenyl-2 , 6-dichloro- 3-methylaniline . 4 g of N-phenyl-2.6-dichloro-3-methylanil.ine and 40 ml of freshly distilled chloracetyl chloride are refluxed for 1 hour., The dark solution is then concentrated at a bath temperature of 50° under 11 Torr. The residue is dissolved in 70 ml of ethyl acetate/ether 1:1. This solution is extracted with 10 ml of 2N potassium bicarbonate solution and 10 ml of water, dried over sodium sulphate and concentrated under 11 Torr. The "N-chloroacetyJ.-N-phenyl-2,6-dichloro-3-methylaniline crystallises from' cyclohevgne, M.P. 117-118°.

The following are obtained analogously: a) N-chloroacetyl-N-phenyl-2, 6-dichloroaniline , M.P. 143-144° from ethanol; •b) N-chloroacetyl-N-phenyl-2-chloro-6-methylaniline , M.P. 110-112° from ether; c) N-chloroacetyl-N- (4-chlorophenyl) -2 , 6-dichloroaniline , M.P. 130-131° from ethanol/vater ; d) N-chloroacetyl-N- (4-chlorophenyl) -2 , 6-dichloro-3- methylaniline , M.P. 106-107° from ethe /petroleum ether; e) N-chloroacetyl-N- (4-methoxyphenyl) -2 , 6-dichloro- 3- methylaniline as a yellow oil and f) N-chloroacetyl-N- (4-methoxyphenyl) -2 , 6-dichloroaniline , M.P. 127-128° from methanol .

C. 1- (2 ,6-Dichloro-3-methylphenyl)-2-indolinone . 4 g of N-chloroacetyl-N-ohenyl-2 , 6-dichloro~3-methylaniline k g of aluminium chloride are well mixed together and heated for 2 hours at l60°. The melt Is cooled and poured onto about 50 g of ice whilst it is still warm. The oil which separates is dissolved in 50 ml of chloroform, the chloroform solution is washed with 10 ml of water, dried over sodium sulphate and concentrated under 11 Torr. The residue is distilled. The 1~(2,6-dichloro-3-methylphenyl)-2-indolinone boils at 12*-13O°/0.001 Torr The oil obtained which crystallises on standing, melts at 129- 132°. 25545/2 The following are obtained analogously: a) 1- (2,6-Dichlorophenyl)-2-indolinone, M.P. 126-127° from methanol; b) 1- (2-Chloro-6-methylphenyl)-2~indolinone, M.P. 96-98° from e her ; c) 1- (2 , 6-Dichlorophenyl)-5-chloro-2-indolinone , M.P. 130- 131° from ethanol /water and d) 1- (2 , 6-Dichloro- 3-methylphenyl) -5-chloro-2- indolinone , M.P. 152-154° from acetic acid/petroleum ether.

By using the methoxy substituted compounds from parts 3(e) and (f) of this example, hydroxy substituted products obtained may subsequently be alkylated. e) g of N-chloroacetyl-N- (4-methoxyphenyl) -2 , 6-dichloro- 3-methyl aniline and 20 g of finely pulverised aluminium chloride are mixe and the mixture is heated for 1 hour at 280° under an atmosphere of nitrogen. It is cooled aad a large quantity of ice and water are added to the melt which has solidified. A black precipitate Is formed which is filtered off and dried at 8o° under 11 Torr. The l-(2,6-diciiloro-m-tolyl)-5-hydroxy-2-iadulinone, when purified by chromatography on a neutral aluminium oxide column, melts at l84-l&7°; yield' 60,2 of the theoretical. 25545 2 8.1 g of crude 1- (2,6-dichloro-3~methylphenyl)-5-hydroxy-2-indolinone are dissolved in 26.3 ml cf IN sodium hydroxide solution. 3.7 g of dimethyl sulphate are then added tu the solution and the whole is refluxed for half an hour. After cooling, the reaction solution is extracted with 400 ml of ethyl acetate. The organic phase is filtered, the filtrate is washed once with water and once with saturated sodium chloride solution, dried over sudium sulphate and concentrated, under li Torr, to dryness. -The residue, 1- (2 ,6-dichlor¾-- 3-Tse tiyL-phenyl) -5-rneihoxy-2- indolinone , is purified by chromatography on an aluminium oxide column and, after recrystallisation from ether /petroleum ether, it melts at 135-136°; yield 20% of the theoretical . f) 1- (2 ,6-dichlorophenyl)-5-methoxy-2-indolinone , M.P. 144-145° from ether/petroleum ether, is obtained analogously via 1- (2,6-dichlorophenyl)-5-hydroxy-2-indolinone, M.P. 204-205° from methanol /benzene .

Bromo- substituted compounds may be obtained e.g. as follow a/ A solution of 11.2 g of 1- (2, 6-dichlorophenyl) -2-indo- linone in 700 ml of ethanol is added to a solution of 8 g of potassium bromide and 2.08 g of bromine in loO ml of water. Ti mixture is vigorously shaken and then left to stand for > hours at 0°. The alcohol is then evaporated off and the insoluble precipitate is filtered off from the remaining aqueous solution The latter is then taken up in methylene chloride. The Methylene chloride solution is dried over sodium sulphate and" coocen r trated to dryness under 11 Torr. The residue consists of a mixture, 6c$ of which is 1- (2, 6-dichlorophenyl)-5-bromo~2---indoliaune. This is purified by repeatedly chromatographing a silica gel column and, after having been crystallised sev times from ether or ethe /petroleum ether, it melts at 1-3S-1 D . 2- ( 2 , 6-Dichloro- 3-TTiethyl anil ino) -phenylacetic ac 1d .

A solution of HO g of 1- ( 2 , 6-d ichloro- 3-methylanilino) - 2-indolinone in 280 ml of IN- 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 0° under 11 Torr. The aqueous residue is extracted with 100 ml of ether and cooled to 5° fry the addition of ice (about 50 g) and external cooling. 2N hydrochloric acid is then added while stirring until the pH of the solution is about 6. The precipitated acid is taken up in HOO ml of ether, the ether solution is separated and the aqueous solution is again extracted with 20C ml of ether. The ether solutions are washed with 50 ml of water, combined, dried over sodium sulphate and concentrated under 11 Torr without heating. ' After adding petroleum ether to the concentrated ethereal solution, [o- ( 2 , 6-dichloro- -methvlanilino) -phenyl acetic acid crystallises out. After re-crystallisation from ether/petroleum ether, it melts at l 6 - 1 9°. - " 25545 2 The following are obtained analogously : a) 2- (2 , 6-Dichloroanilino) -phenylacetic acid, M.P. 156-158° b) 2- (2-Chloro-6-methylanilino) -phenylacetic acid, M.P. 140-147° from ether; c) 2- (2 , 6-Dichloroanilino) -5-chloro-phenylacetic acid, M.P. 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-methoxy-phenylacetic acid, M.P. 120-122° from ether/petroleum ether; f) 2- (2 , 6-Dichloroanilino) -5-methoxy-phenyiacetic acid, M.P. 134-136° from ethe /petroleum ether and g) 2- (2 , 6-Dichloroanilino) -5-bromo-phenylacetic acid, re-crystallised from ether/petroleum ether, decomposes at 161°.

- - EXAMPLE 2 2- (3-TRIFLUOROMETHYLANILINO) -PHENYL ACETIC ACID.

A . 2- (3-Trifluoromethylanilino) -benzyl alcohol . i) 8.7 g of lithium bromide are added to a solution of 5.8 g of sodium borohydride in loO ml of anhydrous diglyme .

The mixture is stirred for half an hour at room tem perature. A solution of l .8 g of 2- (3- trifluoromethylanilino) benzoic acid methyl ester in O ml of anhydrous diglyme is added dropwise. The whole is then heated for '3 hours at 100°, cooled and poured onto a mixture of 300 g of ice and 30 ml of concentrated hydrociiloric acid. After stirring for a short time, the oil which separates is extracted with 300 ml of ethyl acetate. The ethyl acetate - solut ion is washed with 2N potassium bicarbonate solution and water, dried over sodium sulphate and concentrated at ½0υ under 11 Torr. The residue is distilled on a short Vigreux column. The 2- (3- rifluoromethylanilino) -benzyl alcohol boils at 127-129°/0.001 Torr. The yield is 5 of s e theoretical. ii) According to a second, alternative method 9.97 g of lithium aluminium hydride are suspended i 100 ml of abs . ether and the suspension is cooled to 5° while stirring. A solution of 6,8 g of 2- (3- trifluoromethylanilino) - benzoic acid methyl ester in ikO ml of abs. ether is added slowly drop ise, the addition being made under an atmosphere of nitrogen with external cooling. The mixture is then stirred for l8 hours at room temperature. 10 ml of water, 10 ml of 1?% sodium hydroxide solution and another 30 ml of water are added dropwise to the stirred mixture which has been cooled to 0°.

The whole is stirred for 1 hour at room temperature and then filtered. The filtrate is concentrated at ^0 under 11 I'orr, The residue is fractionated by means of a short Vigreux column.

In this way 2- (3- trifluoromethylanilino) -benzyl alcohol is obtained as a yellow oil, B.P. 130-131° /0.001 Tor .

The following are obtained analogously: a) 2- (2-Methoxy-5-methylanilino) -benzyl alcohol, M.P. 138-139° from methanol; b) 2- (2, 3-Dimethylanilino) -benzyl alcohol, B.P. 136-141°/0.005 Torr ; c) 2- (2-Chloro-5- rifluoromethylanilino) -benzyl alcohol, M.P. 100-101° from petroleum ether and d). 2- (2 , 6-Dichloroanilino)-5-methoxy-benzyl alcohol, M.P. 112-113° from cyclohexane.

In the above reduction processes sodium borohydride may be employed in place of the lithium aluminium hydride as reducing agent .

According to a third alternative method for producing starting materials as described above, a free benzoic acid derivative is reduced directly with lithium aluminium hydride e.g. as follows : e) A suspension of 65 g of 2- (2 , 6-dichloroanilino) -benzoic acid in 500 ml of abs . tetrahydrofuran is added drcpwi.se to 30 g of lithium- aluminium-hydride in 50 ml of absolute tetrahydrofuran. The reaction mixture is stirred for half an hour at 5°, for 1 hour at 25° and for 3 hours under reflux whereupon, at 0-5°, 30 ml of 15% sodium hydroxide solution and 90 ml water are carefully added dropwise . After adding 200 ml of tetrahydrofuran, the organic solution is removed from the crystalline precipitate by filtration under suction and the latter is well washed with tetrahydrofuran.

The combined solutions are concentrated, taken up in ethyl acetate and washed with 2N sodxum carbonate solution and saturated sodium chloride solution. Concentration of the organic phase yields 44.4 g of 2- (2 , 6-dichloroanilino) -benzyl-alcohol as a dark brown oil, M.P. (recrystallised from ether/ petroleum ether) 110-112°.

Analogously is obtained: f) 2- (2-Methyl-3-chloroanilino)-benzylalcohol , M.P. 51-52° B ' N- acetyl- 2- (3- trifluoromethylanilino) - benzylchloride .

A solution of 23 g of 2- (3- trifluoromethylanilino) -benzyl alcohol in 70 ml of acetyl chloride is refluxed for 1 hour under art atmosphere of nitrogen. The orange coloured solution is then concentrated at a bath temperature of 0° under 11 Torr. The residue is dissolved in 150 ral of ethyl acetate ether 1:1. The organic phass is washed with 2 ml of 2N potassium bicarbonate solution and 20 ml of water, dried over sodium sulphate and concentrated in vacuo. ■ A pale oil remains which crystallises from ether /petroleum ether. The N-acetyl-2- (3-trifluoromethylanilino -benzyl chloride obtained melts at 83-85° a) N-acetyl-2- (2-methoxy-5-methylanilino) -benzylchloride . M.P. 121-123° from petroleum ether, is obtained analogously.

C · N-acetyl-2- (3-trifluorometh l nilino) -phenylaceto nltril ■ A solution of 11,6 g of N-acetyl-2- (3- trifluoromethyl- anilino) -benzyl chloride in 60 ml of dimethyl sulphoxide is added within 10 minutes to a suspension of 2.2 g of sodium cyanide in 20 ml of dimethyl sulphoxide, the addition being made at 40° while stirring. The temperature should not exceed 40° during the addition. 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 then shaken r water, dried over sodium sulphate and concentrated at 40° under 11 Torr. The N- acetyl- 2- (3-trifluoromethylanilino) - phenyl acetonitrile which remains as a yellow oil can be used directly for the next step. a) N-Acetyl- 2- (2-methoxy- 5-methylanilino) -phenylacetonitrila , M.P. 108-109° from cyclohexane, is obtained analogously.

D 2 (3-Trifluoromethylanilino) -phenylacetic acid . i . 9.5 g of N-acetyl-2- O- trifluoromethylanilino) -phenyl-acetonitrile are dissolved in 100 ml of etiiaaul and 90 ml of IN sodium hydroxide solution. The solution is refluxed overnight. It is cooled and concentrated to about 70 ml at Lv0° under 11 ■· Torr. The aqueous alkaline solution is extracted with 0 ml of ether, this ether solution is separated and the aqueous phase is acidified with 2N hydrochloric acid. The acid solution is extracted with 50 ml of ether, the ether extract is washed with water, the ether solution is dried over sodium sulphate and concentrated under 11 Torr without heating. The residue crystallises from ether/petroleum ether. After recrystal lisa ion from ether /petroleum ether, 2- (3-trifluoromethyl anlllho - ohenylacetic acid melts- at 112-114°. The yield is / of the theoretical .

The following provides an alternative synthesis: A solution of 50 g of .N-acetyl-2- (3- trifluoromethyl- anilinoVphenylacetonitrile in 550 ml of abs. ether and 75 ml of abs. ethanol is cooled to 0-5° while stirring and excluding moisture. Jry hydrogen chloride is introduced into the solution for W hours, during which the temperature should not exceed 5°. Hydrogen chloride is then introduced for another 5 hours at room temperature. The solution is then left to stand overnight at room temperature after v/hich it is evaporated to dryness at a bath temperature of o° under 11 Turr. The residue is dissolved in lAo ml of water, the solution is covered with 1 0 ml of ether and the whole is refluxed for 2 hours on a steam bath. It is then cooled, the ether phase is removed and the aqueous -solution is again extracted with 200 ml of ether. The combined ether solutions are dried over sodium sulphate and evaporated at G° under water .-jet vacuum. The residue is fractionated by means of a Vigreux column under -anilinq high vacuum. The N-acetyl-2- (3- trifluoromethyl) -pneny^acetic acid ethyl ester boils at 110 -115°/0.00l orr .

A solution of 16.4 g of the s^ rl ethyl ester in 225 ml 95% etiianol and 6'7 ml of 2N sodium hydroxide solution is refluxed for l6 hours. The ethanol is then distilled off at o° under 11 Torr and the aqueous solution wnich remains is extracted with Wo ml of ether. The ethereal phase is separated, the aqueous phase Is cooled to 0-5 by the addition of ice and acidified tu pH 6 with 2N hydrochloric acid. The oil which separates out is dissolved ia 200 ml of ether, the ethereal solution is washed with 20 ml υΐ' water and dried over sodium sulphate. It is then concentrated under 11 Torr without warii-ing. On adding petroleum ethe , 2- (3- trifluoromethy{^phenyl)- acetic acid crystallises out, M.P. 112-114°. a) 2- (2-Methoxy-5-methylanilino) -phenylacetic acid, M.P. 105-107° from ether, is obtained analogously via -acetyl- 2- (2-methoxy-5-methylanilino) -phenylacetic acid ethyl ester, B.P. 130-135°/0.001 Torr.

Example 3 2- (2-CHLORO-5-TRIFLUOROMETHYLANILINO) -PHENYL ACETIC ACID A. 2- (2-Chloro-5- rifluoromethylanilino) -benzyl chloride .

A solution of 20 g of 1- (2-chloro-5- rifluoromethyl-anilino)-benzyl alcohol prepared according to the process of Example 2A (c)] in 70 ml of acetyl chloride is refluxed for l6 hours under an atmosphere of nitrogen. The solution is then concentrated at about Uo° under reduced pressure. The residue is taken up in ml of benzene and again concentrated. The residue is then taken up in 200 ml of ether, the ethereal solution is washed with 2N sodium carbonate solution and water, dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The oil which remains is distilled under high vacuum, B.P. 120°/C.001 lurr. The 2- (2-chloro- 5- tri- fluoromethylanilino) -benzyl chloride can be crystallised from petroleum ether, M.P. 50-51°. The yield is 32^ of the theoretical . analogous a) According to an aLfceEnative procedure 150 ml 5N etherial hydrochloric acid is added dropwise, with stirring, to a solution of 5 g of 2- (2 , 3-dimethylanilino) -benzyl alcohol [obtained according to the process of Example 2A(b) ] in 150 ml absolute ether. Crystals precipitate which redissolve on the addition of a further 400 ml of abs . ether The solution is stirred for 30 minutes at room temperature nd concentrated at 40°C and 11 Tor . The remainder cr s- ; are filtered and taken up in a mixture of 20 ml water and 100 ml ether. The ether solution is separated, extracted with water, and dried over sodium sulphate at 11 Torr . The 2- (2 , 3-dimethylanilino)-benzyljchloride remains as an oil and may be used directly for further reaction.

The following are obtained analogously: b) 2- (2-Methyl-3-chloroanilino) -benzyl chloride as a yellow oil [from the corresponding benzyl alcohol q.v.

Example 2A(£) ] . c) 2- (2 ,6-Dichloroanilino) -benzyl chloride as a yellow oil [from the corresponding benzyl alcohol q.v. Example 2(e)]. d) 2- (2 , 6-Dimethylanilino) -benzyl chloride. e) 2- (2 ,6-Dichloroanilino) -5-methoxy-benzyl chloride, M.P. 82-84° from petroleum ether [from the corresponding benzyl alcohol q.v. Example 2A(d)].

B 2- (2-Chloro- 5- trifluoromethyl nil ino) -phenylace onitrile A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulphuxide is heated to k0° . Then a solution of 33 g of 2- (2-chloro-5-trifluoromethylanilino)-benzyl chloride in 150 ml of dimethyl sulphoxide is added while stirring, during which addition the temperature should not rise above Uo°. The mixture is stirred for 3 hours at o° and then diluted with 600 ml of water. The solution is then extracted tnree times with 10C0 ml of ethyl acetate each time. The combined extracts are washed with 100 ml of oN hydrochloric acid and with 100 ml of water, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is distilled under high vacuum. The 2- (2-chloro-5- trifluoromethyl-anilino) -plieriylacetonitr Lie boils at 122-126° /0.01 Torr and can be crystallised from petroleum ether. After recrystall isation it melts at 58-59°. The yield is ^% of the theoretical.

The following are obtained analogously: a) ■ 2- (2, 3-Dimethylanilino) -phenylacetonitrile, M.P. 95-96°; b) 2- (2-Methyl-3-chloroanilino) -phenylacetonitrile , M.P. 86-88°; c) 2- (2 , 6-Dichloroanilino) -phenylacetonitrile , M.P. 71-72° from ethylether /petroleum ether. d) 2- (2 , 6-Dimethylanilino) -phenylacetonitrile ; , e) 2- (2 , 6-Dichloroanilino) -5-me hoxy-phenylacetonitrile , M.P. 169-171°.

C . 2- (2-Chloro- 5- trifluoromethylaniliio) -phenylacetic acid .

A solution of 18 g of 2- (2-chloro-5- rifluoromethylanilino) -phenylacetonitrile la 120 ml of IN sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours. The volume of the reaction solution is then reduced at 0° under reduced pressure to about 8o ml and the aqueous solution is extracted with 100 ml of ether. The aqueous-alkaline phase is then acidified at 5° with 2N hydrochloric acid and the oil which separates is taken up in ether. The ether solution is removed, washed with water, dried over sodium sulphate and, without heating, is concentrated under reduced pressure. On addling petroleum ether, the 2- (2-chloro-5- trifluoromethylanilino)-phenylacetic acid crystallises out, M.P. ^-96°; yield 55 of the theoretical.

The following alternative method of effecting hydrolysis is also available: a) 2 g of 2- (2 , 3-dimethylanilino)-phenylacet.onitrile is hydroxide refluxed with 3 g of potassium/in 60 ml n-butanol for 2 hours The solution is concentrated at 0.1 Torr and at 60°. The remainder is then dissolved in water. The aqueous solution is extracted with ether, separated and acidified with 2N acetic acid. The resulting oil is extracted with ether.

The ether solution is washed with water, dried over magnesium sulfate and finally concentrated to dryness at 11 Torr. The residue is crystallised from ether /petroleum ether. The ob- τ ) tained 2- (2 , 3-dimethylanilino) -phenyl-acetic acid melts at 112-113°.

The following are obtained analogously: b) 2- (2-Methyl-3-chloroanilino) -phenylacetic acid, M.P. 124 125° from ethe /petroleum ether; c) 2- (2 , 6-Dichloroanilino) -phenylacetic acid, M.P. 156-158° from ether/petroleum ether; d) 2- (2 , 6-Dimethylanilino) -phenylacetic acid, M.P. 120-127 c e) 2- (2 , 6-Dichloroanilino) -5-methoxy-phenylacetic acid, M.P 134-136°. y EXAMPLE 4 2- (2 , 6-DICMLOROA ILINO) -PHENYLACETIC ACID A solution of 1 g of - 2 - (2 , 6-dichloranilino) -phenyl - acetic acid methyl ester in 20 ml of methanol and 5 nil ° 2N potassium bicarbunate 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 2 hydrochloric acid, the oil which separates is extracted with ether and the ether solution is washed with water, dried over sodium sulphate and concentrated, without heating, under 11.Torr. The 2-(2,6- dichloraailino) -phenyl acetic acid crystallises from ether/ petroleum etner, K.P. 156-158°. The yield is 75% of the theoretical.

The following alternative procedure may also be employed: A solution of 0.5 g o 2- (2, 6-dichloranilinc)-phenyl -· acetic acid methyl ester (K.P. 101-102°) in Uo ml of 75f» ethaaol and 12 g of Jowex 1 ion exchanger (OH ~ form, 20-50 mesh) are stirred for 15 hours in a round flask at 5 ° and then filtered. The residue is suspended in 20 ml of water and the suspension is acidified at 5° with 1I hydrochloric acid. ml of ether are added, the whole is shaken and the ether solution is separated. The ether solution is washed with 10 ml of water, dried over sodium sulphate and, when- cold, is concentrated to dryness under 11 Torr. The 2-(2,0-dic lorar.ilino)-pheaylacetic acid crystallises t'rora ether/petroleum ether, if.?. 155-153°. The yield is of the theoretical.

. EXAMPLE 5 2- (2 , 6-DICHLOROA ILI O) -PHENYLACETIC ACID . 1.2 g of 2- (2,6-dichloranilino)-phenyl acetic acid ben¾yl ester are dissolved ia 50 ml of ethaaol and, after the addition of 0.2 g of palladium charcoal, the solution is hydrogenated at room temperature and low pressure. The hydro™ genation is complete after 1 hours. The catalyist is filtered off and the filtrate is conceircrated to dryness at room temperature under 11 Torr. The residue is recrys tallised from ether/petroleum ether, M.P. 15 -158°. The yield is 6 o o the theore ical.

- - EXAMPLE 6 2- (2, 6-DICHLOROANILINO) -PHENYLACETIC ACID SODIUM SALT.

A solution of l8S g of 1- (2, 6-di.c loro.;henyl)-2-indo- linone in 660 ml of ethanol and 66o ml of 2N sodium hydroxide solution is refluxed for hours. The solution is then cooled and left to stand for k hours at 0 - 5°. The crystals which form are filtered off and recrystalllsed from water. The sodium salt of [o-(2,6-dichloranilino)-phe:.yl]-acetic acid melts at 283-265°. The yield is 97 of the theoretical.

The sodium salt of [ 5-chloro-2-(2,6-dichloranilino)- phenylj-acetic acid is produced analogously. It melts at 29 ° on recrystallisa ion from water.

The following are obtained analogously: a) 2- (2 ,6-Dichloroanilino)-5-chlorophenylacetic acid sodium salt, M.P. 296° from water; b) 2- (2 , 6-Dichloro-3-methylanilino)-phenylacetic acid sodium salt, M.P . 287-289° from water; c) 2- (2-Chloro-5- rifluoromethylanilino) -phenylacetic acid sodium salt, M.P. 225-230° from water.

EXAMPLE 7 2- (2 :6-DICHL0R0ANILIN0)-PH£NYLACETIC ACID POTASSIUM S ml of 8% ethanolic potassium hydroxide solution a added to a solution of 8.9 g of 2- ( 2 , 6-dichloranilino ) --phenyl acetic acid in 50 ml of ethanol. The solution is boiled for 10 minutes with active charcoal, filtered and concentrated under 11 Torr. On adding ether, the potassium salt of 2- (2,6 dichloranilino ) -phenyl acetic . acid crystallises out, M.P. 300 - 330° with decomposition.

Claims (9)

1. 25545/2 What we claim is : 1. Substituted phenylacetic acids having the formula I wherein R^ represents a lower alkyl or lower alkoxy group, a • halogen atom up to the atomic number 35 or a trifluoro- I methyl grou , R.2 and represent, independently of each other., a hydrogen atom, a lower alkyl or lower alkoxy group, or a halogen atom up to the atomic number 35 , and represents a hydrogen atom, a lower alkyl or lower alkoxy group , a halogen atom up to the atomic number 35 or a trifluoromethyl group, and their pharmaceutically acceptable salts with bases.

2. Substituted phenyl acetic acids having the formula I as illustrated in claim 1 wherein , R2 and R^ have the meanings given in claim 1 and R^ represents a hydrOgen atom, and their pharmaceutically acceptable salts with bases. 25545/2

3. 2- (2 , 6-Dichloro- 3-rnethylanilino) -phenylacetic acid.

4. 2- (3-Trifluoromethylanilino) -phenylacetic acid.

5. 2- (2-Chloro-5- trifluoromethylanilino) -phenylacetic acid

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

7. 2- (2 , 6-Di.methylanilino) -phenylacetic acid.

8. 2- (2-Methyl-3-chloroanilino) -phenylacetic acid. 9.. 2- (2-Chloro-6-methylanilino) -phenylacetic acid. 10. 2- (2 , 3-Dimethylanilino) -phenylacetic acid. 11. Pharmaceutically acceptable salts of a compound as claimed in any one of claims 3 to 10 with bases . 12. The sodium salt of a compound as claimed in any one of claims 3,5 and 6. 13. The potassium salt of the compound claimed in claim 6. 14. Process for the production of substituted phenylacetic acids having the formula I as defined in claim 1, and their pharmaceutically acceptable salts with bases, which comprises reacting, while heating, the corresponding compound having the formula II 25545/2 in which ϊ^, R^, R^ and have the same meaning as in Claim 1 with an alkali metal or alkaline earth metal hydroxide or with and an alkali metal carbonate ,/when required, converting the alkaline earth metal or alkali metal salt of a substituted phenylSCGt 1C clCid thus obtained into the free acid or into another , pharmaceutically acceptable salt .thereof with a base. 15. Process as claimed in claim 14 wherein the reaction is effected using an alkali metal or alkaline earth metal carbonate and wherein represents, specifically, a hydrogen atom, whereby a substituted phenyl acetic acid as claimed in claim 2 or a pharmaceutically acceptable salt thereof with a base is obtained. 16. Process for the production of substituted phenyl acetic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with bases, which comprises reacting, while heating, the corresponding compound having the formula III 25545/2 wherein R^, R2, R3 and R4 have the same meaning as in Claim 1, R,. represents a low alkyl or aralkyl radical and A represents a hydrogen atom or an acyl radical, with an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate or bicarbonate, or with an ion-exchange resin, or, when R^ represents an aralkyl radical, subjecting said compound to hydrogenolysis with catalytically activated hydrogen and, when required, converting the alkaline earth metal or alkali metal salt of a substituted phenyl acetic acid thus obtained into the free acid or into another pharmaceutically acceptable salt thereof with a base, or converting a substituted phenyl acetic acid thus obtained into a pharmaceutically acceptable salt thereof with a base. r 17. Process as claimed in claim 16 wherein R^ represents a benzyl radical . 18. Process as claimed in claim 16 or 17 wherein A represents an alkanoyl radical having at most 4 carbon atoms. 25545/2 1

9. Process as defined in claim 16 wherein a compound having the formula III wherein represents, specifically, a low alkyl group and A, specifically an acyl radical, is reacted with an alkali metal hydroxide or an alkaline earth metal hydroxide, whereby a substituted phenyl acetic acid as claimed in claim 2 or a pharmaceutic lly acceptable salt thereof with a base is obtained. 20. Process for the production of substituted phenyl acetic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with base which comprises reacting, while heating, the corresponding compound having the formula IV in which R^, 2, R^ and have the same meaning as in Claim 1 and A represents a hydrogen atom or an acyl radical, with an alkali metal hydroxide in an aqueous solvent and, when required^ converting an alkali metal salt of a substituted phenyl acetic acid thus obtained into the free acid or into another pharmaceutically acceptable salt thereof with a base. 21. Process as defined in claim 20 wherein R, represents. specifically, a hydrogen atom and A, specifically, an acyl radical whereby a substituted phenyl acetic acid as claimed in claim 2 or a pharmaceutically acceptable salt thereof with a base is obtained. 22. Process for the production of substituted phenyl acetic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with bases, substantially as hereinbefore described with reference to any one of the foregoing Examples . 23. Substituted phenyl acetic acids and their pharmaceutically acceptable salts with bases whenever prepared by a process as claimed in any one of claims 14, 16 to 18 and 20. 24. Substituted phenyl acetic acids and their pharmaceutically acceptable salts with bases whenever prepared by a process as claimed in any one of claims 15, 19 and 21. acetic acids and their pharmaceutically acceptable salts with bases whenever prepared by a process as claimed in claim 22. 26. Pharmaceutical compositions comprising a substituted 0 phenyl acetic acid as claimed in claim 1 or a pharmaceutically acceptable salt thereof with a base, together with a pharmaceutically acceptable diluent or carrier therefor. 27. Pharmaceutical compositions comprising a substituted phenyl acetic acid as claimed in claim 2 or a pharmaceutically acceptable salt thereof with a base, together with a pharmaceutically acceptable diluent or carrier therefor. For the Applicants DR. REINHOLD COHN AND PARTNERS .1.70/GSG/jh/ Isr