IL27708A - Substituted o-anilino phenylacetic acid esters and their preparation - Google Patents

Description

27708/2 omsni mania Sew substituted o-anilino phenylacetic acid esters and their preparation . R. GEIGY AO :26256 J. R. GEIGY A.G. BASEL 21 4-2369* pnocBGo Fori MIE PRODUCTION OF NEW QUDDTITUTED PHENYLACETIC ACID BDTBiG The present invention concerns a process for the production of new substituted phenylacetic acid esters, these new compounds themselves and medicaments which contain them as well as the use thereof.

Substituted phenylacetic acid esters of the general formula I wherein R-, represents a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the trifluoro- methyl group, represents hydrogen or a substituent corresponding to the definition of R^, represents hydrogen, a low alkyl or alkoxy group or a halogen atom up to the atomic number 35, represents hydrogen, a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the tri- fluoromethyl group, and and RFI represent hydrogen, low alkyl groups or benzyl groups, and R^ represents a low alkyl or aralkyl group, in particular the benzyl group, have not been described hitherto.

It has now been found that these new esters have valu-able 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 or rectally for the treatment of rheumatic, arthritic and other inflammatory diseases. The anti-phlogistic action can be determined in pharmacological tests, for example on UV erythema in the guinea pig and on Bolus alba oedema in the rat. In addition, the esters of general formula I are suitable as UV absorbers for cosmetic purposes, e.g. as components of sunburn creams as they absorb the injurious, reddening rays of 290 - 300 mu but do not stop the desired, browning rays of over 315 mu.

In the esters of general formula I and the corresponding starting materials mentioned below, to R^, as low alkyl groups are, independently of each other, for example, methyl or ethyl groups. Some of these symbols can also be, e.g. n-propyl, isopropyl, n-butyl, sec. butyl or tert. butyl groups. Low alkoxy groups or halogen atoms R-^ to R^ are, e.g. methoxy, ethoxy, n-propoxy, n-butoxy or isobutoxy groups or chlorine, fluorine or bromine atoms. R^ and Rg, as low alkyl groups, are preferably the methyl or ethyl groups} but when Rg is a hydrogen atom, R^ can also be n-propyl, isopropyl, n-butyl, isobutyl, tert. utyl, n-pentyl or isopentyl groups. is, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, benzyl, phenethyl or 3-phenyl-propyl group.

To produce the esters of general formula I, acids of the general formula II wherein R- Rj, R3, R^, ^ and g have the meanings given in formula I, are converted by known methods, but avoiding elevated temperatures when the reaction medium is acid, into their low alkyl esters or aralkyl esters. The esterification is performed by reacting the carboxylic acids of the general formula II with, e.g. low molecular diazo-alkanes in inert organic sol-vents such as ether, or with acetals of Ν,Ν-dimethyl formamide having the low alkanols or aryl alkanols desired as ester components (with 1 , 1-dialkoxy-trimethylamines or 1 , 1-diaralkoxy-trimethylamines) in inert solvents such as methylene chloride or benzene (cf. H.Brechbiihler , H.Biichi, E.Hatz, J.Schreiber and A.Eschenmoser, Ang. Chemie 15, 296 [1963] and also H.Vor-briiggen, ibid. 296-297), or with benzyl alcohol or low alkanols in the presence of Ν,Ν-dimethyl formaldehyde dineopentyl acetal (1,1-dineopentyloxy-trimethylamine) . (cf. H.Biichi, K.Steen and A.Eschenmoser, Ang. Chemie Τ5_, 1176-1177 [1963 ]).

In addition, the acids of general formula II can also be converted into salts, e.g. alkali metal salts, and these can be reacted with reactive esters of low alkanols or aryl alkanols, e.g. with dimethyl sulphate, diethyl sulphate, methyl iodide, ethyl iodide, propyl bromide, butyl bromide, benzyl chloride, benzyl bromide or p-toluene sulphonic acid methyl ester, in a suitable reaction medium such as water or an inert organic solvent which, optionally, can be mixed with water, depending on the solubility of the reaction components.

An example of an esterification which can be performed under mild conditions in an acid reaction medium is the reaction of an acid of the general formula II with the reaction mixture composed of the low alkanol or arylalkanol desired as ester component and thionyl chloride. The maintenance of temperatures of, at most, -5°C is advantageous both for the production of the reaction mixture and for the reaction thereof with acids, (cf. M.Brenner and W.Ruber, Helv. Chim. Acta 36, 1109-1115 [1953]).

The acids required as starting materials of general formula II are, in their turn, new compounds. They are produced for example, by starting from diphenylamines substituted corres-ponding to the definition of R- Rg, R3 and R^, some of which are known and others of which can be produced analogously thereto. By reaction of these diphenylamines with 2-chloracetyl chloride, first correspondingly substituted 2-chloro-N-phenyl acetanilides are produced from which, on heating with aluminium chloride at temperatures of about 160°Cor, in the presence of suitable solvents such as tetrachloroethane or nitrobenzene, at temperatures of 100 - 150° C, substituted l-phenyl-2-indolinones are obtained. Depending on the type and position of the sub-stituent(s) in one or both phenyl radicals, mixtures of isomers are obtained, which mixtures have to be separated. The substituted l-phenyl-2-indolinones can be hydrolysed, e.g. by boiling with aqueous/alkanolic sodium hydroxide solution to form acids of general formula II, wherein R^ and Rg are hydrogen atoms. Acids of general formula II having a low alkyl group R^ and hydrogen as Rg are obtained, for example, if, in the above sequence of reactions another low alkanoyl chloride is used in- stead of chloracetyl chloride. One or two low alkyl groups or benzyl groups, which are then present as R^ or Rg in the acid of general formula II, can also be introduced into the 3-position of the l-phenyl-2-indolinones substituted corresponding to the definitions of R-^, £, Rg and R^by converting these 1-phenyl-2-indolinone compounds first into their mono- or di-sodium compounds by reacting their activated methylene group in 3-position, e.g. with sodium hydride or sodium amide in dimethyl formamide and then reacting these salts with the corres-ponding amount of a low alkyl halide or a benzyl halide. A benzyl radical can also be introduced into the 3-position of the substituted 1-phenyl-2-indolinones mentioned, by first condensing these compounds with benzaldehyde and hydrogenating the substituted l-phenyl-3-benzylidene-2-indolinones formed.

A second sequence of reactions for the production of the acids of general formula II starts from substituted N-phenyl anthranilic acids, some of which are known. Their low alkyl esters are reduced, for example, with lithium aluminium hydride in ether or tetrahydrofuran, or with sodium boro-hydride and lithium bromide in diethylene glycol dimethyl ether, to form substituted o-anilino-benzyl alcohols. It is surprising that by boiling these with acetyl chloride, substituted a-chloro-N-phenyl-o-toluidines or substituted a-chloro-N-phenyl-aceto-o-toluidides are formed, depending on the sub-stitution of the N-phenyl group. On reacting the a-chlorine compounds with sodium or potassium cyanide, substituted a-cy-ano-N-phenyl-o-toluidines or substituted a-cyano-N-phenyl-aceto-o-toluidides (substituted o-(N-phenyl-acetamido) -phenyl-acetonitriles) are obtained. These can be hydrolysed into acids of the general formula II by means of sodium or potassium toluidides can also first be converted into the corresponding imidoalkyl ester hydrochlorides by treatment with alkanolic hydrogen chloride solutions, which hydrochlorides can be decomposed with water to form the corresponding low alkyl esters, on hydrolysis of which the acids of the general formula II are obtained. One or two low alkyl groups or benzyl groups, which are then present in the acids of general formula II as radical R^ or radicals R^ and R^, can be introduced, if desired, into the a-position of the a-cyano compounds mentioned above, ana-logously to the introduction into the 3-position of the substituted l-phenyl-2-indolinones also mentioned above.

The substituted phenylacetic acid esters of the general formula I can be administered orally or rectally. They can also be used externally, as active components of ointments or sun-burn oils.

The daily dosages, to be taken internally, of esters of the general formula I, for the treatment of rheumatic, arthritic and other inflammatory diseases vary between 50 and 1500mg for adult patients. Suitable dosage units such as dragees, tablets or suppositories, preferably contain 25 - 300 mg of an ester of the general formula I.

Dosage units for oral administration preferably contain between 1% and 90% of an ester of general formula I as active substance. They are produced by combining the active substance with, e.g. solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights, T with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved 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 dragees: a) 1000.0 g of active substance, e.g. [o-( 2 , 6-dichloro-m-toluidino) -phenyl ]-acetic acid methyl ester, are mixed with 550.0 g of lactose and 292.0 g of potato starch. The mixture i moistened with an alcoholic solution of 8.0 g of gelatine and granulated through a sieve. After drying, 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed in, and the mixture is pressed into 10,000 tablets, each weighing 200 mg and containing 100 mg of active substance. If desired, the tab lets 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 methyl ester, 16 g of maize starch and 6.0 g of colloidal silicon dioxide are well mixed. 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. The granulate is dried for about 14 hours and then passed through another sieve. It is then mixed with 16.0 g of maize starch, 16.0 g of talcum and 2.0 g of magnesium stearate and pressed into 1000 dragee cores. These are coated with a concentrated syrup made from 2.000 g of shellac, 7.500 g of gum arabic, 0.150 g of dyestuff, 2.000 g of highly dispersed silicon dioxide, 25.000 g of talcum and 53.350 g of sugar and dried. The dragees obtained each weigh 360 mg and contain 200 mg of active substance .

Examples of dosage units for rectal administration are suppositories which consist of a combination of an ester of the general formula I with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of an active substance with polyethylene glycols of suitable molecular weight.

One of the following prescriptions can be used for the production of sunburn creams; [o-( 2, 6-dichloranilino) -phenyl ]- acetic acid methyl ester 1.0 g paraffin oil, (thin liquid) 1.0 g polyoxyethylene-sorbitan monostearate 2.0 g polyoxyethylene-sorbitol-lanolin derivative 1.5 g sorbitol solution 10% 3.0 g stearic acid 15.0 g preservative + perfume q.s. water ad 100.0 g [o-(2 , 6-dichloranilino) -phenyl ]- acetic acid ethyl ester 1.0 g propylene glycol 28.0 g glycerine monostearate 18.0 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 per-formance of the process according to the invention, but in no way limit the scope of the invention. The temperatures are given in degrees Centigrade.

Example 1 [o-(2,6-dichloro-m-toluidino) -phenyl ]-acetlc acid methyl ester 100 ml of 2% ethereal dlazomethane solution are slowly added dropwise to a solution of 10 g of [o-(2 , 6-dichloro-m-toluidino) -phenyl ]-acetic acid (M.P. 146-149°) in 150 ml of absolute ether. The solution is left to stand overnight at room temperature and then evaporated to dryness at 40° under 11 Torr. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 50 ml of IN potassium bicarbonate solution and with water, dried over sodium sulphate and concentrated at 40° under 11 Torr. The residue crystallises from ether/petroleum ether. The [o-(2 , -dichloro-m-toluidino) -phenyl ]-acetic acid methyl ester melts at 110 - 112°. The yield is 10% of the theoretical.

The acid necessary as starting material can be pro-duced, for example, in the manner described below: a) 2 , 6-Dichloro-N-phenyl-m-toluidine 7 g of N-(2, 6-dichloro-m-tolyl) -anthranilic acid are heated for 2 hours at 280°. The cooled melt is dissolved in 30 ml of benzene. The benzene solution is extracted with 5 ml of 2N sodium carbonate solution and 5 ml of water, then dried with sodium sulphate and concentrated. The residue is distilled under high vacuum whereupon 2 , 6-dichloro-N-phenyl-m-toluidine is obtained as a yellow oil, B.P. 115 - 120°/0.001 Torr. b) N-Phenyl-2r 2 ' .6 '-trich or-aceto-m-toluidide 4 g of 2, 6-dichloro-N-phenyl-m-toluidine 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 an ethyl acetate/ether 1:1 solution. This solution is extracted with 10ml of 2N potassium bicarbonate solution and 10 ml of water, dried over sodium sulphate and concentrated under 11 Torr. The N-phenyl-2, 2 ' , 6 '-trichlor -aceto-m-toluidide crystallises from cyclohexane, M.P. 117 - 118°. c) l-(216-dichloro-m-tolyl) -2-indolinone 4 g of N-phenyl-2, 2' , 6 '-trichlor-aceto-m-toluidide and 4 g of aluminium chloride are well mixed together and the mixture is heated for 2 hours at 160°. The melt is cooled and poured onto about 50 g of ice while 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 under high vacuum. The l-( 2 , 6-dichloro-m-tolyl) -2-indolinone boils at 128 - 130°/0.001 Torr. The oil obtained crys-tallises on standing. The crystals melt at 129 - 132°. d) [o-(2, 6-dichloro-m-toluidino) -phenyl ]-acetic acid A solution of 40 g of l-(2, 6-dichloro-m-tolyl) -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 40° under 11 Torr. The aqueous residue is extracted with 100 ml of ether, the ether is removed and the aqueous solution is cooled to 5° by 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 acid which precipitates is taken up in 400 ml of ether, the ether solution is removed and the aqueous solution is again extracted with 200 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. On adding petroleum ether to the concentrated ethereal solution, the [o-(2, 6-dichloro-m-toluidino) -phenyl ]-acetic acid crystallises. After recrystallisation from ether/ petroleum ether, it melts at 146 - 149°.

Example 2 [o-(2, 6-dichloranilino) -phenyl ]-acetic acid methyl ester, M.P. 101 - 102° (from ether/petroleum ether) [2-(2, 6-dichloranilino) -5-chlorophenyl ]-acetic acid methyl ester, M.P. 87 - 88° (from ether/petroleum ether); and [2-( 2 , 6-dichloro-m-toluidino) -5-chlorophenyl ]-acetic acid methyl ester, are obtained analogously to Example 1.

The acids used as starting materials are produced as follows: a) 216-dichlorodiphenylamine g of 2 ' , 6 ' -dichloracetanilide are dissolved in 150 ml of bromobenzene . 5.5 g of calcined potassium carbonate and 0.5 g of copper powder are added. The mixture is then re-fluxed for 4 days, water formed being removed in a water separator. It is then cooled and the reaction mixture is steam distilled. The residue is extracted with 200 ml of ether. The ether solution is filtered through Hyflo and evaporated to dryness under 11 Torr. The residue, crude N-(2, 6-dichlorophenyl) -N-phenyl-acetamide , is dissolved in 60 ml of 10% ethanolic potassium hydroxide solution and the solution is refluxed for 3 hours. The solution is then evaporated to dryness at 40° under 11 Torr. 10 ml of water are added to the residue which is then extracted with 100 ml of ether. The ether solution is washed with 20 ml of water. The ethereal solution is then dried with sodium sulphate and evaporated to dryness under 11 Torr. The residue is distilled under high vacuum. The 2,6-di- chlorodiphenylamine boils at 115°/0.01 Torr and is a yellow oil. 2,6, 4' -trichlorodiphenylamine, B.P. 121°/0.01 Torr, and N-(p-chlorophenyl) -2 , 6 -dichloronn-toluidine , B.P . 135 - 145°/ 0.005 Torr, are produced analogously. b) 2-chloro-N-(2, 6-dichlorophenvl) -N-nhenyl-acetamide, M.P. 143 - 144° (from methanol) 2 -chloro-N-(p-chlorophenyl) -N-(2 , 6 -dichlorophenyl) -acetamide, M.P. 130 - 131° (from ethanol/water) ; N-(p-chlorophenyl) -2,2' ,6 '-trichlor-aceto-m-toluidide , M.P. 106 - 107° (from ethyl acetate/petroleum ether) are produced analogously to Example 1 b) from the compounds according to 2 a) . c) l-( 2 , 6-dichlorophenyl) -2-indolinone, M.P, 126 - 127° (from methanol); 1- ( 2 , 6-dichlorophenyl) -5-chloro-2-indolinone , M.P. 130 - 131° (from ethanol/water) l-(2 , 6-dichloro-m-tolyl) - -chloro-2-indolinone , M.P. 152 - 154° (from ethyl acetate/petroleum ether) are obtained by cyclisation analogously to Example 1 c) . d) [o-(2.6-dichloranilino) -phenyl ]-acetic acid, M.P. 156 - 158°; [2-(2,6-dichloranilino) -5-chlorophenyl ]-acetic acid, M.P. 152 - 156° (from ether/petroleum ether); [2-( 2 , 6-dichloro-m-toluidino) -5-chlorophenyl ] -acetic acid, M.P. 152 - 156° (from ether/petroleum ether) are obtained by hydrolysis analogously to Example 1 d) .

Example 3 [2-(2, 6-dichloro-m-toluidino) -5-methoxyOhenyl J-acetic acid methyl es,ter is produced analogously to Example 1 and is purified by distil-lation under high vacuum as well as recrystallisation from The acid necessary as starting material is produced as follows: a) 2 , 6-dichloro-N-(p-methoxyphenyl) -m-toluidine , B.P, 115-130°/0.001 Torr, is produced analogously to Example 2a) starting from 2 ' , 6 '-dichlor- aceto-m-toluidide and 4-bromo-anisol. b) N-(p-metho yphenyl) -2.2' .6 '-trichlor-aceto-m-toluidide , (oily) is obtained by chloracetylation analogously to Example 1 b) . c) 1-C2 , 6-dichloro-m-tolyl) -5-hvdroxy-2-indolinone g of N-(p-ethoxyphenyl) -2,2* ,6 '-trichlor-aceto-m-toluidide and 20 g of finely pulverised aluminium chloride are mixed and the mixture is heated for 1 hour at 280° while stirring under an atmosphere of nitrogen. It is allowed to cool and a large amount of ice and water is added to the solidified melt. A black precipitate is formed, which is filtered off and dried at 80° under 11 Torr. The l-(2,6-dichloro-m-tolyl) -5-hydroxy-2 -indolinone, purified by chromatography on a neutral aluminium oxide column, melts at 184 - 187°. Yield: 60% of the theoretical. d) l-(2 , 6-dichloro-m-tolyl) -5-methoxy-2-indolinone 8.1 g of crude l-(2 , 6-dichloro-m-tolyl) -5-hydroxy-2-indolinone are dissolved in 26,3 ml of IN sodium hydroxide solution. 3.7 g of dimethyl sulphate are added to 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 sodium sulphate and concentrated to dryness under 11 Torr. The residue is purified on an aluminium oxide column and, after recrystallisation from ether/petroleum ether, melts at 135 -136°. e) [2-C 2 , 6-dichloro-m-toluidino) -5-methoxyOhenyl ]-a,cetic ¾cifl is obtained analogously to Example 1 d) by hydrolysis.

M.P. 120 - 122° (from ether/petroleum ether).

Example 4 or. [2- ( 2 , 6-dichl-^nilino) -5-bromophenyl ]-acetic acid methyl ester is produced analogously to Example 1 and is purified by recrystallisation from ether/petroleum ether.

The corresponding acid is obtained as follows: a) l-( 2 r 6-dichlorophenyl) -5-bromo-indolinone A solution of 11.2 g of l-( 2 , 6-dichlorophenyl) -2-indo-linone (cf. Example 2 a) - c)) in 700 ml of ethanol is added to a solution of 8 g of potassium bromide and 2.08 g of bromine in 160 ml of water. The mixture is vigorously shaken and then left to stand for 3 hours at 0°. The ethanol is evaporated and the insoluble precipitate is filtered off from the remaining aqueous solution. The precipitate is taken up in methylene chloride. The methylene chloride solution is dried over sodium sul-phate and evaporated to dryness under 11 Torr. The residue consists of a mixture which contains, to 60%, l-( 2 , 6-dichlorophenyl) -5-bromo-2-indolinone. This is purified by repeated chromatography on a silicagel column and, after being repeatedly recrystallised from ether or ether/petroleum ether, melts at 188 - 190°. b) [2-(2t6-dichloranilino) -5-bromophenyl ]-acetic acid is obtained analogously to Example 1 d) from the above indolinone by hydrolysis. It is purified by recrystalisa-tion from ether/petroleum ether. It decomposes at 161°.

Example 5 [o-(a,a,a-trifluoro-m-toluidino) -phenyl ]-acetic acid methyl ester is obtained analogously to Example 1 and is purified by distillation under high vacuum instead of recrystallisation. B.P. 1200/0.01 Torr. [o-(6-methoxy-m-toluidino) -phenyl ]-acetic acid methyl ester is also obtained analogously to Example 1.

The acids necessary as starting materials are produced, e.g. as follows: a) o-(at t -trifluoro-m-toluidino) -benzyl alcohol 8.7 g of lithium bromide are added to a solution of 3.8 g of sodium borohydride in 160 ml of anhydrous Diglyme (diethylene glycol dimethyl ether) . The mixture is stirred for half an hour at room temperature, then a solution of 14.8 g of N- ( , , a-tri-fluoro-m-tolyl) -anthranilic acid methyl ester in 40 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 hydrochloric acid. After stirring for a short time, the oil which separates is extracted with 300 ml of ethyl acetate. The ethyl acetate solution is washed with 2N Ootassium bicarbonate solution and with water, dried over sodium sulphate and concentrated at 40° under 11 Torr.

The residue is fractionally distilled over a short Vigreux column. The o-(a, a, a-trifluoro-m-toluidino) -benzyl alcohol boils at 127 - 129°/0.01 Torr. The yield is 75$ of the theoretical. o-(6-Methoxy-m-toluidino) -benzyl alcohol, M.P. 138 -139°, (from methanol) is obtained analogously. b) -chloro-N-C , , a-trifluoro-m-tolyl) -aceto-o-toluidide A solution of 23 g of o-(a,a,a-trifluoro-m-toluidino) -benzyl alcohol in 70 ml of acetyl chloride is refluxed for 1 hour under an atmosphere of nitrogen. The orange coloured solu-tion is then concentrated under 11 Torr and a bath temperature of 40°. The residue is dissolved in 150 ml of ethyl acetate/ ether 1:1. The organic phase is washed with 20 ml of 2N potassium bicarbonate solution and with 20 ml of water, dried over sodium sulphate and concentrated under vacuum. A pale oil re-mains which crystallises from ether/petroleum ether. The a-chloro-N-( , a, -trifluoro-m-tolyl) -aceto-o-toluidide obtained melts at 83 - 85°. a-Chloro-N-(6-methoxy-m-tolyl) -aceto-o-toluidide , M.P. 121 - 123° (from ether/petroleum ether) is obtained analogous-ly. c) a-Cvano-N-(a.a , a-trifluoro-m-tolyl) -aceto-o-toluidide A solution of 11.6 g of a-chloro-N-(a,a,a-trifluoro-m-tolyl) -aceto-o-toluidide in 60 ml of dimethyl sulphoxide is added within 10 minutes at 40° while stirring to a susoension of 2.2 g of sodium cyanide in 20 ml of dimethyl sulphoxide. 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 combined ethyl acetate solutions are then shaken with 200 ml of 6N hydrochloric acid and then with 30 ml of water, dried over sodium sulphate and concentrated under 11 Torr at 40°. The a-cyano-N-(a,a,a-tri-fluoro-m-tolyl) -aceto-o-toluidide which remains as a yellow oil can be used directly. a-Cyano-N-(6-methoxy-m-tolyl) -aceto-o-toluidide, which d) [o-( t . -trifluoro-m-toluidino) -phenyl ]-acetic acid 9.5 g of a-cyano-N-(a,a5a-trifluoro-m-tolyl) -aceto-o-toluidide are dissolved in 100 ml of ethanol and 90 ml of IN sodium hydroxide solution. The solution is refluxed for 14 hours. It is then cooled and concentrated to about 70 ml at 40° under 11 Torr. The aqueous, alkaline solution is extracted with 50 ml of ether, this ether solution is separated and the aqueous phase is acidified with 2N hydrochloric acid. The acid solution is extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated, without warming, under 11 Torr. The residue crystallises from ether/ petroleum ether. After recrystallisation from ether/petroleum ether, [o-( , , -trifluoro-m-toluidino) -Ohenyl ]-acetic acid melts at 112 - 114°. The yield is 35$ of the theoretical. [o-(6-Methoxy-m-toluidino) -phenyl ]-acetic acid, M.P. 105- 107° (from ether) is obtained in an analogous way.

Example 6 [o-( ,a, -trifluoro-6-chloro-m-toluidino) -nhenyl ]-acetic acid methyl ester is obtained analogously to Example 1 from the corresponding acid. The following sequence of reactions can serve for the production of the acid: a) o-(a,a,q-trifluoro-6-chloro-m-toluidino) -benzyl alcohol is produced analogously to Example 5 a) starting from Ν-( ,α, -trifluoro-6 -chloro-m-tolyl) -anthranilic acid methyl ester, M.P. 100 - 101° from petroleum ether. b) a-Chloro-N-( ,qf a-trifluoro-6 -chloro-m-tolyl) -o-toluidine A solution of 20 g of o-(a,a,a-trifluoro-6-chloro-m-toluidino) -benzyl alcohol in 70 ml of acetyl chloride is re-fluxed for 16 hours under an atmosphere of nitrogen. The solu- tion is then concentrated at about 40° under reduced pressure. The residue is taken up in 40 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 under reduced pressure. The oil which remains is distilled under high vacuum, B.P. 120°/0.00l Torr. The a-chloro-N-( , , -trifluoro-6-chloro-m-tolyl) -o-toluidine can be crystallised from petroleum ether, M.P. 50-51°. The yield is 32% of the theoretical. c) a-Cvano-N-(aT a, a-trifluoro-6 -chloro-m-tolyl) -o-toluidine A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulphoxide is heated to 40°. A solution of 33 g of a-chloro-N-( , , a-trifluoro-6 -chloro-m-tolyl) -o-toluidine in 150 ml of dimethyl sulphoxide is then added while stirring, during which addition the temperature should not rise above 40°. The mixture is stirred for 3 hours at 40° and is 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 6N hydrochloric acid and 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 a-cyano-N-(a,a,a-trifluoro-6-chloro-m-tolyl) -o-toluidine boils at 122 - 126°/0o01 Torr and can be crystal-lised from petroleum ether . After recrystallisation, it melts at 58 - 59°. The yield is 74 of the theoretical. d) [°~(αι T a-trifluoro -6 -chloro-m-tolyl) -phenyl ]-acetic acid A solution of 18.4 g of a-Cyano-N-(a,a,a-trifluoro-6-chloro-m-tolyl) -o-toluidine in 120 ml of IN sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours. The reaction solution is then concentrated to a volume of about 80 ml at 40° under reduced pressure 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 separated, washed with water, dried over sodium sulphate and concentrated without heating under reduced pressure. On adding petroleum ether, the [o-(a, ,a-trifluoro-6-chloro-m-toluidino) -phenyl ]-acetic acid crystallises out, M.P. 94 - 96°. Yield: 55% of the theoretical.

Example 7 o-(2t6-dichloranilino) -hvdratropic acid methyl e¾aer, M.P. 83-85° (from ether/petroleum ether) is obtained analogously to Example 1. ' ' o-(2,6-dichloro-m-toluidino) -hydratropic acid methyl ester; o-(2, 6-dichloranilino) -5-chlorohydratropic acid methyl ester, are also produced analogously.

The acids used as starting materials are obtained as follows: a) 2-Chloro-N-(2 ? 6-dichlorophenyl) -N-phenyl-proOionamide A solution of 5 g of 2 , 6-dichlorodiphenylamine (cf» Example 2 a)) in 20 ml of 2-chloropropionyl chloride is refluxed for 1 hour while introducing nitrogen. It is evaporated to dryness at 40° under 11 Torr and the residue is dissolved in ethyl acetate/chloroform 1:1. The solution is extracted with 2N potassium bicarbonate solution and water, dried over sodium sulphate and concentrated at 40° under 11 Torr. The residue is distilled in a bulb tube and the distillate is crystallised from methanol. The 2-chloro-N-(2,6-dichlorophenyl) -N-phenyl- N-(p-chloropheny-0-2 , 2 ' , 6 '-•trichloro-propiono-m-toluidide, Μ.Ρ. 105-107° (from ether-petroleum ether) 5 2-Chloro-n-(p-chlorophenyl) -N-( 2 , 6-dichlorophenyl) -proplonamlde , are produced analogously. b) l-(2.6-dichloroOhenyl) -3-methyl-2-lndollnone A mixture of 29.8 g of 2-chloro-N-(2, 6-dichlorophenyl) -N-phenyl-propionamide and 29.8 g of aluminium chloride is heated for 2 hours at 160°. The melt is cooled and poured onto 500 g of ice. The oil which separates is dissolved in 100 ml of ether. The ether solution is washed with 50 ml of 2N potassium bicarbonate solution and 100 ml of water, dried over sodium sulphate and concentrated at 40° under 11 Torr. The residue is chromatographed on 500 g of neutral aluminium oxide.

The fractions 3-7, eluted with benzene, contain the 1-(2, 6-dichlorophenyl) -3-methyl-2-indolinone. They are combined and crystallised from ethyl acetate/petroleum ether, M.P. 98 -99°. l-(2,6-dichloro-m-tolyl) -3-methyl-2-indolinone, M.P. 110 -112° (from ether) 5 1- (2, 6-dichlorophenyl) -3-methyl-5-chloro-2-indoline, are pro-duced analogously. c) o-C 2 , 6-dichloranilino) -hvdratropic acid A 'solution of 3.0 g of l-(2, 6-dichlorophenyl) -3-methyl- 2-indolinone in 35 ml of ethanol and 20 ml of IN sodium hydroxide solution is refluxed for 1 hour. The solution is then con-centrated at 50° under 11 Torr, the residue is dissolved in 200 ml of water and the aqueous solution is extracted with 50ml of ether. The aqueous solution is then acidified at 5° with 2N hydrochloric acid. The oil which separates is dissolved in 100 ml of ether, the ethereal solution is washed with a little water, dried qver sodium sulphate and concentrated cold under 11 Torr. The residue is crystallised from ether/petroleum ether. The o-(2, 6-dichloranilino) -hydratropic acid melts, after recrystallisation from ether/petroleum ether, at 154 - 156°; o-(2, 6-dichloro-m-toluidino) -hydratropic acid, M.P. 143 - 145° (from ether/petroleum ether) 2-(2, 6-dichloranilino) -5-cMkOro-hydratropic acid are produced analogously.

Example 8 2-[o-(2, 6-dichloranilino) -phenyl ]-butyric acid methyl ester is produced analogously to Example 1. The acid necessary is produced as follows: a) 3-ethyl-l-C 2 T 6-dichlorophenyl) -2-indolinone A solution of 5.6 g of l-(2,6-dichlorophenyl) -2-indolinone (cf. Example 2 a)) in 10 ml of absolute dimethyl formam-ide is added dropwise to a suspension of 1 g of sodium hydride/ mineral oil suspensionCl: 1) in 30 ml of absolute dimethyl form-amide, the addition being made at 0-5°. The mixture is then stirred for 40 minutes at 10°. 3.2 g of ethyl iodide are added dropwise and the mixture is stirred for 15 hours at room temperature. It is then poured onto ice and extracted with 200 ml of ether. The ether solution is washed with water, dried over sodium sulphate and concentrated to dryness under 11 Torr. The residue is chroma tographed on 200 g of neutral aluminium oxide. The fractions 2 and 3, eluted with ether/petroleum ether 1:1, contain the pure 3-ethyl-l-( 2 , 6-dichlorophenyl) -2-indoline . After recrystallising twice, the compound melts at 100-101°. The yield is 15% of the theoretical. b) 2-[o-(2 , -dichloranilino) -phenyl ]-butyric acid is obtained by hydrolysis of the above indolinone in a manner analogous to Example 7 c) .

Example 9 [o- (2 ,6-dichloranilino) -phenyl]-benzyl acetic acid methyl ester is produced analogously to Example 1. The starting material is obtained as follows: a ) 1- (2 , 6-dichlorophenyl ) -3-benzylidene-2-indolinone 2.78 g of l-(2 ,6-dichlorophenyl)-2-indolinone (cf. Example 2 a) - c)) are dissolved in 50 ml of abs. ethanol, then 1.06 g of benzyldehyde and 2 drops of piperidine are added and the whole is heated for 5 hours at 50°. The reaction mixture is then concentrated under vacuum and the residue is purified by chromatography on an aluminium oxide column- The l-(2,6-dichlorophenyl) -3-benzylidene-2-indoline crystallisises from ether. It melts at 135-136°. Yield 80% of the theoretical. b) 1- (2 ,6-dichlorophenyl)-3-benzyl»2-indolinone 3 g of the l-(2 ,6-dichlorophenyl)-3-benzylidene-2-indolinone obtained above are dissolved in 100 ml of dioxane. 0.2 g of 5% platinum charcoal are then added and hydrogenation is performed at room temperature « 1- (2 ,6-dichlorophenyl) -3-benzyl-2-indolinone is formed. Yield 60% of the theoretical. c ) ("o-(2 ,6-dichloranilino)-phenyl]-benzyl acetic acid M.P. 132-133° (from ether/petroleum ether) is obtained by hydrolysis of the above indolinone analogously to Example 7 c)» Example 10 o- (2 , 6-dichloranilino) -cc-methyl-hydratropic acid methyl ester (2- [o- (2 ,6-dichloranilino) -phenyl ]-2-methyl-propionic acid methyl ester) is produced analogously to Example 1.

The following sequence of reactions serves for the production, of the starting material: a) 1- (2 ,6-dichlorophenyl)-3 , 3-dimethyl-2-indolinone At 0-5°, a solution of 5.6 g of 1- (2 , 6-dichlorophenyl ) -2-indolinone (cf. Example 2 a) - c)) in 10 ml of abs. dimethyl formamide is added dropwise under an atmosphere of nitrogen to a suspension of 2.1 g of sodium hydride/mineral oil (1:1) in 30 ml of abs. dimethyl formamide. The whole is stirred for 40 minutes at 10° and then 7 g of methyl iodide are added dropwise. The mixture is stirred for 15 hours at room temperature and then poured onto crushed ice. It. is extracted five times with 200 ml of ether. The ether extracts are combined and washed with 100 ml of water, dried over sodium sulphate and concentrated under 11 Torr. The residue is crystallised from ether < The 1- (2 ,6-dichlorophenyl)-3, 3-dimethyl-2-indoline melts at 128-130°. The yield is 67 of the theoretical. b) o- (2 , 6-dichloranilino ) - -methyl-hydratropic acid (2- \ o- (2 ,6-dichloranilino)-phenyl]~2-methyl-propionic acid). Absolution of 1.5 g of l-(2,6-dichlorop enyl)-3,3-dimethyl-2-indolinone in 15 ml of ethanol and 10 ml of 2N sodium hydroxide solution is refluxed for 48 hours. It is then cooled to room temperature and 50 ml of water are added. The crystals which separate out are filtered off. The filtrate is extracted with 30 ml of ether. The ether solution is removed and the aqueous phase is acidified with 2N hydrochloric acid. The crystals which separate are dissolved in chloroform/ether 1:1, the organic phase is washed with water, dried over sodium sulphate and concentrated at 40° under 11 Torr.

The residue crystallises from ether. The o- (2 , 6-dichlor-anilino) - -methyl-hydratropic acid melts, after recrystalli sa-tion from ether, at 187-192°. The yield is 20% of the theoretical .

Example 11 [o- (2 , 6-dichloranilino) -phenyl ]-acetic acid ethyl ester A solution of 16 g of [o- (2 ,6-dichloranilino)-phenyl]-acetic acid (cf. example 2 d)) in 1600 ml of water and 40 ml of 2N sodium hydroxide solution is cooled to 5°. 10 ml of diethyl sulphate are added while stirring, the solution being cooled with an ice bath. Stirring is continued for 2 hours at 5-10° and then another 20 ml of 2N sodium hydroxide solution and 10 ml of diethyl sulphate are added. The reaction mixture is then stirred for 15 hours at room temperature. The precipitated crystals are filtered off, well washed with water and dissolved in 100 ml of ether. The ethereal solution is extracted with 30 ml of water, dried over sodium sulphate and concentrated at 40° under reduced pressure. The [o-(2,6-dichloranilino) -phenyl ]-acetic acid ethyl ester crystallises from ether/petroleum ether, M„P. 50-52°. The yield is 15% of the theoretical.

Starting from the acids used in examples 1 and 3-10 the following ethyl esters can be produced in an analogous way: [o- (2 , 6-dichloro-m-toluidino) -phenyl ]-acetic acid ethyl ester; [2-(2 ,6-dichloro-m-toluidino)-5-methoxyphenyl]-acetic acid ethyl ester; [2- (2 , 6-dichloranilino) -5-bromophenyl ]-acetic acid ethyl ester 5 [o- ( ,a ,a-trifluoro-m-toluidino) -phenyl ]-acetic acid ethyl ester ; [ό- ( ,α ,a-trifluoro-6-chloro-m-toluidino) -phenyl ]-acetic acid ethyl ester; o- (2 , 6-dichloro) -hydratropic acid ethyl ester; 2-|~o-(2 ,6-dichloranilino)-phenyl]-butyric acid ethyl ester; [o- (2 , 6-dichloranilino) -phenyl ]-benzyl acetic acid ethyl ester; o-(2 ,6-dichloranilino)- -methyl-hydratropic acid ethyl ester; [2- (2 , 6-dichloro-m-toluidino)-5-chlorophenyl ]-acetic acid ethyl ester ; [2- (2 , 6-dichloranilino) -5-chlorphenyl]-acetic acid ethyl ester; o-(2 , 6-dichloro-m-toluidino) -hydratropic acid ethyl ester; 2-(2 ,6-dichloranilino)-5-chlor-hydratropic acid ethyl ester.

Example 12 |"o- (2 ,6-dichloranilino)-phenyl ]-acetic acid benzyl ester A solution of 2.96 g of [o- (2 ,6-dichloranilino)-phenyl]-acetic acid (cf. example 2d)), 1.2 g of abs. benzyl alcohol and 3 g of dimethyl formamide dineopentyl acetal (1,1-dineopentyloxy-trimethylamino) in 40 ml of methylene chloride is stirred for 55 hours under an atmosphere of nitrogen. 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 sulphate. The solution is concentrated to dryness at 40° under 11 Torr. The residue is chromatographed on 60 g of neutral aluminium oxide. The fractions 2 and 3, eluted with ether/petroleum ether 7:3, contain the pure Γο- (2 , 6-dichloranilino) -phenyl ]-acetic acid benzyl ester. The yield is 30% of the theoretical. M.P. 132-133°.

Example 13 |"o-(2 ,6-dlchloranlllno)-phenyl]-acetic acid benzyl ester 6 ml of thionyl chloride are added dropwise to 40 ml of abs. benzyl alcohol, the addition being made at -10° while stirring well and indroducing nitrogen. After 5 minutes, at -10°, a solution of 2.96 g of [~o- (2 , 6-dichloranilino) -phenyl ]-acetic acid (cf. example 2d)) in 10 ml of abs. benzyl alcohol is added dropwise. The reaction mixture is then stirred for 15 hours at room temperature and poured onto ice. The oil which separates is extracted with 100 ml of ether. The ether extract is washed with 10 ml of 2N potassium bicarbonate solution and water, dried over sodium sulphate and the ether solution is concentrated to dryness at 40° under 11 Torr. The residue is' chromatographed in 90 g of neutral aluminium oxide. The fractions 1 and 2, eluted with ether/petroleum ether 1:1, contain the pure [o- (2 , 6-dichloranilino) -phenyl ]-acetic acid benzyl ester. The yield is 48% of the theoretical.

M.P. 132-133°.

Claims (11)

HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is! Patent Claims

1. Process for the production of new phenylacetic acid esters of the general formula I wherein R^ represents a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the trifluoro- methyl group, R2 represents hydrogen or a substituent corresponding to the definition of R- R3 represents hydrogen, a low alkyl or alkoxy group or a halogen atom up to the atomic number 35, R4 represents hydrogen, a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the tri- fluoromethyl group, and R5 and Rg represent hydrogen, low alkyl groups or benzyl groups , and R7 represents a low alkyl or aralkyl group, characterised by converting an acid of the general formula II - 27 - Jp etc. GB etc. wherein ¾ have the meanings given in formula I, into a low alkyl ester or aralkyl ester, but with avoidance of raised temperature when the reaction media are acid .

2. Process according to claim 1, characterized by esterifying an acid of the general formula II by means of a low molecular diazo-alkane in an inert organic solvent.

3. Process according to claim 1, characterized by esterifying an acid of the general formula II by means of a 1 ,1-dialkoxy-trimethylamine or a 1 ,1-diaralkoxytrimethylamine in an inert solvent .

4. Process according to claim 1, characterized by esterifying an acid of the general formula II by means of a low molecular alkanol or benzyl alcohol in the presence of 1 ,1-dineopentyloxy-trimethylamine .

5. Process according to claim 1, characterized by reacting a salt of an acid of the general formula II with a low alkyl or aralkyl halide, sulfate or sulfonate.

6. Process according to claim 1, characterized by esterifying an acid of the general formula II by reaction at a temperature of at most -5°C with a mixture comprising thionyl chloride and a low alkyl or aralkyl alcohol. - - * ·

7. New substituted phenylacetlc acid esters of the general formula I wherein R-^ represents a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the trifluoro- methyl group, R2 represents hydrogen or a substituent corresponding to the definition of R- R2 represents hydrogen, a low alkyl or alkoxy group or a halogen atom up to the atomic number 35, R4 represents hydrogen, a low alkyl or alkoxy group, a halogen atom up to the atomic number 35 or the tri- fluoromethyl group, and R5 and Rg represent hydrogen, low alkyl groups or benzyl groups, and R7 represents a low alkyl or aralkyl group.

8. [o- (2 ,6-Dichloro-m-toluidino)-phenyl]-acetic acid methyl ester] .

9. [o-(2 ,6™Dichloranilino)-phenyl]-acetic acid methyl ester.

10. [o-(2 ,6-Dichloranilino)-5~chlorcphenyl]-acetic acid methyl ester .

11. [o- ( , , -Trifluoro-m-toluidino)-phenyl]-acetic acid methyl ester. - 29 - GB etc 27708/2 ,ς. · · - 30 - 0 12, o-(2,6-Dic loranilino)-hydratropic acid methyl eater. 13· [o-(2,6~Dlchloraitilino)-pheiiyl3--^,cetic acid ethyl ester. 14* £o-C216-Dich ornnllino)~phenylj-acetic acid benzyl ester. 15· A process for the production of new substituted phenylacetic acid esters as claimed in Claims 1 to 6 substantially as described in any of the examples. 16· Sew substituted phenylacetic acid esters when produced by a process as claimed in any of Claims 1 to 6. X7. ew substituted phenylacetic acid eaters as claimed in any of the Claims 7 to 14. 18· Therapeutic re r io s for the treatment of rheumatic arthritic and other inflammatory diseasest characterised by content of a substituted phenylacetic acid ester of the general formula I defined in Claim 7 wherein IL^ R2» B^, H^, Hg and have the meanings there given, in combination with an inert carrier and, optionally, further additives. PC-BH