IL31296A - The production of anilino-phenylacetic acids - Google Patents

Description

ThG p:ro&uction of anilinO-phenyl- acotic aol e C? 39452 and their salts with inorganic and organic bases. The substituted phenyl-acetic acids of the general Formula I and, their salts possess valuable pharmacological properties, in antipyretic activity with favorable therapeutic index. They can be administered orally, rectally or, especially in*' the form of aqueous solutions of their salts, also parenterally , in particular intramuscularly in the treatment of rheumatic, arthritic and other inflammatory diseases. Furthermore, these substances possess the ability to absorb ultra violet rays from 290-300 mu and are therefore suitable as UV-absorbers for cosmetic purposes, e.g. in protective sun creams, because they absorb the harmful, reddening rays, while allowing the desirable browning rays above 315 mn to pass through.

In the compounds of general Formula I and the corresponding starting materials, mentioned further below, R-^ to are independently of each other, for example, methyl or ethyl groups. Some of the symbols mentioned can, e.g., also denote n-propyl, isopropyl, n-butyl, sec. butyl or tert.butyl groups. As lower alkoxy groups or halogen atoms, to R^ are, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or ispbutoxy groups, or chlorine, fluorine or bromine atoms, respectively.

The phenyl-acetic acids of general Formula I and their salts are produced according to the invention in a technically advantageous manner from easily accesible starting materials by reacting a ring-substituted diphenylamine of the general Formula II R, wherein R^, R2 , and R^ have the meaning given under Formula I. with oxalyl chloride to give ring-substituted N-aryl-oxanilic acid chlorides of the general Formula III ! Cl wherein R^, ^ , R^ and R^ have the meaning given under Formula I, and converting the latter in the presence of Friedel-Crafts condensation agents, such as aluminium chloride, at room temperature, with ring-closure into the substituted indol-2 , 3 -diones (isatin) of the general Formula IV wherein ^ , R2 , R^ and R^ have the meaning given under Formula I, optionally recrystallising these compounds and producing the corresponding substituted phenylacetic acids of the general Formula I either direct/ by reaction with hydrazine or semicarbazides and alkaline splitting according to the method of Wolff-Ki shner , or firstly producing, by alkaline hydrolysis the substituted glyoxylic acids or their sodium salts of the general formula V wherein R ' represents hydrogen, a monovalent cation or the normal- equivalent of a polyvalent cation, and R, , R , R- and R, have the meaning given under Formula I and obtaining the substituted phenylacetic acids of the general Formula I by subsequent reaction with hydrazine or semicarbazides and also with an alkali hydroxide or alkali metal alcoholate according to the method of Wolff- ishner .

It is known that also substituted l-aryl-2-indolinones can be hydrolysed to give the corresponding substituted o- ani lino-phenylacetic acids. The substituted l-aryl-2- indolinones are produced, for example, analogously to the known l-phenyl-2-indolinone , from the substituted diphenyl- amines by chloracetylation to give substituted 2-chloro-N-■ phenyl-acetanilides and subsequent ring-closure reaction.

This can, however, only be obtained at relatively high temperatures in an aluminium chloride melt around 160°C, and only by heating for several hours.

Since under these reaction conditions, alkyl migrations can occur, additional processing problems arise. Another undesired secondary effect of these reaction conditions is the splitting of alkoxy groups. In contrast, it has now been found that by carrying out the process according to the invention, the substituted phenylacetic acids according to the general Formula I can be obtained in a technically simple manner, under favourable reaction conditions and with a high yield, avoiding at the same time undesirable secondary and subsequent reactions (e.g. subsequent alkylation of split alkoxy groups).

• A further advantage of the process is the extraordinarily smooth ring-closure reaction, occurring almost completely at room temperature (97% of the theoretical yield, see - - chlorides are converted into the correspondingly substituted indol-2 , 3 -diones (isatins) of the general Formula IV wherein , R2 , R^ and R have the meaning given under Formula I, the latter being then recrystallised and reacted with hydrazine or semicarbazide and with an alkali metal hydroxide or alkali metal alcoholate at a raised temperature according to the Wolff-Kishner reduction method, and optionally the resulting alkali metal salt of a substituted pheny1-acetic is acid of general Formula I/converted into the free acid or into another salt with an inorganic or organic base. The process according to the invention is carried out by either first converting the substituted indol-2 , 3-dione with hydrazine, which can also be used in the form of the hydrate, or with semicarbazide to the corresponding 3- (hydrazone) or 3- (semi-carbazone) , respectively, and decomposing this intermediate with an alkali metal hydroxide or alkali metal alcoholate, or by- contacting all three reaction components simultaneously.

The ' temperature for the main reaction, the action of the alkali metal hydroxide or alkali metal alcoholate, is in the range of 100-220° , preferably from 140-200°. The optionaly, previous lower temperatures, i.e. already at room temperature, or also at higher temperatures . Any water that may have been intror duced when the hydrazine hydrate is used or that has been set free by the reaction may be removed by distillation. A higher boiling organic solvent can be used, for example, as reaction medium. Examples of such solvents are ethylene glycol or mono-and thereof such as diethylene glycol, diethylene glycol monomethylether or triethylene glycol, also higher boiling alcohols such as benzyl alcohol, octyl alcohol or nitrilotriethanol , or. optionally also a lower alkanol when the reaction is carried out in a closed vessel. It is also possible, however, during the reaction to distill off the lower alkanol, e.g. ethanol or butanol, initially used as reaction medium together with excess hydrazine and water that is set free, until the reaction mixture which is gradually solidifying reaches a temperature between 150° and 200° . Examples of alkali metal hydroxides which can be used are in particular potassium or sodium hydroxide; while the alkali metal alcoholates which can be used, e.g. sodium alcoholates, are either derivatives of lower alkanols or of the higher boiling hydroxy compounds used as reaction media.

The alkali metal salts of substituted phenyl-acetic acids of general Formula I that are first obtained in the process according to the invention are optionally converted into the free acid in the usual manner using strong acids, e.g. hydrochloric acid. If desired, the acid obtained is converted into another salt, preferably a pharmaceutically acceptable one, withan sodium, potassium, lithium, magnesium, calcium and ammonium salts, furthermore salts with ethylamine, triethylamin , 2-amino ethanol, 2 , 2-iminodiethanol , 2-dimethylamino-ethanol , 2-diethyl-a'mino-ethanol , ethylenediamine , benzylamine, p-aminobenzoic acid 2-diethylamino-ethy 1 ester, pyrrolidine, piperidine, morpholine, no 1-ethy1-piperidirie or 2-piperidi^-ethanol . Salts which are considerably less soluble in a certain medium, e.g. water or aqueous lower alkanols , than the alkali metal salts can be produced by double conversion from the latter.

In converting the ring-substituted indol-2 ,3-diones (isatins) into the corresponding phenylacetic acids, the process can be carried out with an- additional intermediate . stage, namely the production of the ring-substituted (o-anilinophenyl) -glyoxylic acid: the ring-substituted isatin of the general Formula IV is initially only subjected to hydrolysis and the obtained ring-substituted (o-anilinophenyl) -glyoxylic acid or its salt of the general Formula V wherein R represents hydrogen, a monovalent cation or the normal. equivalent of a polyvalent cation, is reduced with hydrazine or semicarbazide and with an alkali metal hydroxide or alkali metal alcoholate at a raised temperature according to the Wolff-Kishner reduction method, and optionally the resulting alkali metal salt of a substituted pheny 1-acetic acid of general Formula I is converted into the free acid or into another salt with an inorganic or organic base .

The reduction is carried out by either first converting the substituted (o-anilinophenyl) -glyoxylic acid of general Formula V or a salt thereof with hydrazine, which can also be used in the form of the hydrate, or with semicarbazide to the corresponding hydrazone or semicarbazone , respectively, and decomposing this intermediate with an alkali metal hydroxide or alkali metal alcoholate, or by contacting all three reaction components simultaneously.

The following examples illustrate in more detail the process according to the invention as well as the production of intermediates which have not hitherto been known, without limiting in any way the scope of the invention. The temperatures are given in degrees Centigrade .

Example 1 dimethyl a) N-phenyl-2 ' , 6 ' -ay-ly-l-oxaniloyl chloride 162 ml of oxalyl chloride are slowly added dropwise at 5° to a solution of 101 g of N-pheny1-2 , 6-xylidine in 650 ml of anhydrous benzene. The suspension . is then stirred for 2 hour at room temperature and for 1/2 hour at 50°, whereby the suspension goes into solution. The reaction solution is cooled and evaporated to dryness under 11 Torr with a bath temperature of 40° .. The residue is dissolved in 400 ml of anhydrous benzene an the solution again evaporated to dryness under 11 Torr. The •residue is crystallized from benzene/petroleum ether. The N- dimethyl phenyl-2 ' , 6 ' -^-l-y-l--oxaniloyl chloride melts at 78-80°. The yield is 87% of the theoretical value.

The following are analogously produced: 110 g of N-ph.enyl-61 -chloro-3 ' -trifluoromethyl-oxaniloyl chloride (oil) are obtained starting from 81 g of N-phenyl-6-chloro- ,a,a-trifluoro-m-toluidine, B.P. 85-88°/0.001 Torr. 65 g of N-phenyl-6 ' -chloro-2 ' -methyl-oxaniloyl chloride (oil) are obtained starting from 57 g of N-phenyl-6-chloro-o-toluidine, B.P. 88°/0.05 Torr. 62 g of N-phenyl-2 ', 6 ' -dichloro-oxaniloyl chloride, M.P. 107-109° (from ether /petroleum ether) are obtained, starting from 50 g of 2 , 6-dichloro-diphenylamine , B.P. 111° /0.003 Torr . 42 g of N-phenyl-2 ', 61 -dichloro-3 ' -methy1-oxaniloyl-chloride, M.P. 102-103° (from ether/petroleum ether) are obtained from 34 g of N-phenyl-2 , 6-dichloro-m-toluidine , M.P. 76-79°. 82 g of N-phenyl- 61 -tnethoxy-31 --methyl-oxaniloyl-chloride (oil) are obtained, starting from 76 g of N-pheny 1- 6-methoxy-m-toluidine, B.P. 122 ° / 0. 001 Torr . 34 g of N- (p-tolyl) - 2 ' , 6 ' -dimethyl-oxaniloyl-chloride (oil) are obtained, starting from 22 g of N- (p-tolyl) -2 , 6-xylidine , B.P. 115 - 120° / 0 . 001 Torr.

The starting materials for Example la) are produced as follows : xylyi a^) N- (2 , 6-^-*1 y-t-) -anthranilic acid A mixture consisting of 525 g of o-chlorobenzoic acid and 195 g of 85%, potassium hydroxide in 1500 ml of n~pentanol is heated, while stirring, to 160°./. "Ga. 400 ml of n-pentanol are distilled off within 30 minutes. 1000 g of 2 , 6-xylidine and 12 . 5 g of copper powder are then added and the mixture is refluxed for 15 hours. The mixture is then cooled and poured into a solution of 180 g of sodium carbonate in 600 ml of water and the solution distilled with steam. After the excess 2 , 6-xylidine has been distilled off , the aqueous residue is filtered over Hyflo and the filtrate acidified with concentrated hydrochloric acid. The precipitated crystals are filtered off and re - crystallised from ethanol-water . 460 g of N- (2 , 6-xylyl) -anthranilic acid, M.P. 205 -208 ° are obtained. The yield is 577o .

The following are produced analogously : 180 g of N- (6-chloro- , , a-trifluoro-m-tolyl) -anthranilic acid, M.P. 183 - 185 ° (from ethanol) are produced, starting from 450 g of o-chlorobenzoic acid. 376 g of N- (6-chloro-o-tolyl) -anthranilic acid, M.P. 216 - ° 310 g of N- (2 , 6-dichloro-phenyl) -anthranilic acid, M.P. 212-213° (from ethanol) are obtained, starting from 960 g of o-chlorobenzoic acid. 93 g of N- (2 , 6-dichloro-m-tolyl) -anthranilic acid, M.P.1 247-249° (from ethanol) are obtained, starting from 168 g of o-chlorobenzoic acid. 140 g of N- (6-methoxy-m-tolyl) -anthranilic acid, M.P. 141-142° (from ether/petroleum ether) are obtained, starting from 168 g of o-chlorobenzoic acid. 65 g of N- (2 , 6-xylyl) -5-methyl-anthranilic acid, •M.P. 220-225° (from ethanol) are obtained, starting from 110 g of o-chlorobenzoic acid.

N-phenyl-2 , 6-xylidine 370 g of N- (2 , 6-xylyl) -anthranilic acid are heated for 2 1/2 hours to 280° . The cooled melt is dissolved in 1500 ml of ether. The ether solution is washed twice with 300 ml of 2N-sodium carbonate solution and 300 ml of water. The ether solution is separated, then dried over sodium sulphate and concentrated to dryness under 11 Torr at 40° . The residue is distilled, whereby the N-phenyl-2 , 6-xylidine is obtained as a yellow oil, B.P. 125°/0.01 Torr. The distillate is crystallised from petroleum ether. 230 g of N-phenyl-2 , 6-xylidine , M.P. 52-54° , are obtained.

The following are produced in an analogous manner: 57 g of 6-chloro-cc, a, a-trifluoro-N-pheny1-m-toluidine , B.P. 85-88°/0.001 Torr are obtained, starting from 100 g of N- (6-chloro-a,a, a-trifluoro-m-tolyl) -anthranilic acid , . . 1 -185°. 125 g of N-phenyl-6-chloro-o-toluidine, B.P. 88°/0.05 Torr are obtained, starting from 180 g of N- (6-chloro-o-tolyl) - anthranilic acid, M. P. 216-217° . 97 g of 2,6-dichloro-diphenylamine, B.P. lll°/0.003 Torr are obtained, starting from 141 g of N- (2 , 6-dichloro-phenyl) -anthranilic acid, M.P. 212-213°. 55 g of N-phenyl-2 , 6-dichloro-m-toluidine , M.P. 76-79° (from petroleum ether) are obtained, starting from 70 g of N- (2 , 6-dichloro-m-tolyl) -anthranilic acid, M.P. 247-249°. 120 g of N-phenyl-6-methoxy-m-toluid.ine, B.P. 122°/0.001 Torr, are obtained, starting from 145 g of N- (6-methoxy-m-tolyl) -anthranilic acid, M.P. 141-142°. 67 g of N-(p-tolyl)-2,6-xylidine, B.P. 115-120° /0.001 Torr are obtained, starting from 82 g of N- (2 , 6-xylyl) -5-methyl-anthranilic acid, M.P. 195-200°. b) l-(2, 6-xylyl) -indol-2 , 3-dione 58.6 g of pulverised aluminium chloride are added, in portions, to a solution of 124 g of N-phenyl-21 , 61 -dimethyl-oxaniloyl-chloride in 900 ml of tetrachlorethane. The mixture is stirred for 48 hours at room temperature. It is then poured on to a mixture of 1000 g of ice and 200 ml of 2N hydrochloric acid. 500 ml of chloroform are added and the mixture is well shaken. The tetrachloroethane/chloroform solution is separated, washed with 300 ml of 2N-sodium carbonate solution and subsequently with 300 ml of water. It is dried over sodium sulphate and concentrated to dryness under 0.1 Torr. The residue is crystallised from ether/petroleum ether. The l-(2,6- ° The following are produced in an analogous manner: 76.5 g of 1- (6-chloro-a, a -trifluoro-m- oly1) -indol-2 , 3-dione, M.P. 134-136° (from ether) are obtained, starting from 110.0 g of N-phenyl-61 -chloro-3 ' -trifluorometh 1-oxaniloyl chloride (oil) . 48.7 g of 1- (6-chloro-o-tolyl) -indol-2 , 3-dione , M.P. 163-165° (from ether) are obtained, starting from 65.0 g of N-phenyl-61 -chloro-2 ' -methyl-oxaniloyl chloride (oil). 42.3 g of 1- (2 , 6-dichlorophenyl) -indol-2 , 3-dione , M.P. 175-176° (from ethanol) are obtained, starting from '85.0 g of N-phenyl-2 ' , 6 ' -dichloro-oxaniloyl chloride, M.P. 107-109°. 38.8 g of 1- (2 , 6-dichloro-m-tolyl) -indol-2 , 3-dione , M.P. 162-165° (from ethanol) are obtained, starting from 57.0 g of N-phenyl-2 ', 6 ' -dichloro-3 ' -methyl-oxaniloyl chloride, M.P. 102-103°. 16.2 g of 1- (6-methoxy-m-tolyl) -indol-2 , 3-dione , M.P. 168-169° (from ethyl acetate) are obtained, starting from 31.0 g of N-phenyl-61 -methoxy-3 ' -methyl-oxaniloyl chloride (oil) 18.0 g of l-(2,6-xylyl)-5-methyl-indol-2, 3-dione, M.P. 158° (from ether) are obtained, starting from 34.0 g of N- (p-tolyl) -21 , 6 ' -dimethy1-oxaniloyl. chloride (oil), c) [o- (2 , 6-Xylidino) -phenyl ] -acetic acid 1.56 g of hydrazine hydrate are added to a solution of 3 g of 1- (2 , 6-xylyl) -indole-2 , 3-dione in 20 ml of diethylene glycol monomethyl ether. After 15 minutes, 1.34 g of pulverized potassium hydroxide are added. The solution is slowly heated ° continued for one hour. The solution is then cooled and poured onto ice. The resulting mixture is acidified with concentrated hydrochloric acid and extracted with ether. The ether solution is separated and extracted twice with 2 N sodium carbonate solution. The sodium carbonate solutions are combined and acidified with 2 N hydrochloric acid. The oil which ' precipitates is extracted with ether. The ether solution is washed with water, dried over sodium sulfate and concentrated at 40° under 11 Tor . The residue is crystallized twice from ether/petroleum ether. The [o- (2 , 6-xylidino) -phenyl ] -acetic acid melts at 120-127° with decomposition.

The following are produced in an analogous manner: 6.5 g of f6- (2 , 6-xylidino) -m-tolyl ] -acetic acid, M.P. 88-89° (from ethylacetate/petroleum ether) are obtained, starting from 9.2 g of 1- (2 , 6-xylyl) -5-methyl-indol-2 , 3 -dione , M.P. 158°. 12.0 g of [o- (2 , 6-dichloro-anilino) -phenyl ] -acetic acid, M.P. 156-158° (from ether /petroleum ether) are obtained, starting from 20.5 g of 1- (2 , 6-dichlorophenyl) -indol-2 , 3-dione, M.P. 175-176° . 2.5 g of [o- (6-methoxy-m-toluidino) -phenyl ] -acetic acid, M.P. 98-99° (from ether /petroleum ether) .are obtained, starting from 5.4 g of 1- (6-methoxy-m-tolyl) -indol-2 , 3 -dione , M.P. 168-169°.

Example 2 a) 1o- (2 , 6-xylidino) -phenyl ] -glyoxylic acid.

A solution consisting of 7.3 g of 1- (2 , 6-xylyl) -indole- ethanol is refluxed for 15 hours. The solution is then cooled and concentrated to dryness under 11 Torr at 40° . The residue is dissolved in 200 ml of water. The aqueous solution is extracted with ether, separated and acidified by adding 2 N hydrochloric acid. The yellow crystals which precipitate are dissolved in ether. The ether solution is separated, extracted with water, dried over sodium sulfate and concentrated under 11 Torr at 40° . The residue is crystallized from ether/ petroleum ether. The [o- (2 , 6-xylidino) -phenyl ] -glyoxylic acid melts at 135-137° . b) [ o- (2 , 6-Xylidino) -phenyl ] -acetic acid 2.25 g of hydrazine hydrate are added to a solution of 1.5 g of [o- (2 , 6-xylidino) -phenyl ] -glyoxylic acid in 10 ml of anhydrous ethanol. After the solution has cooled again to room temperature, a solution of 2.25 g of sodium in 55 ml of anhydrous .ethanol is added. The mixture is slowly heated to 200°, whereby ethanol, water and hydrazine evaporate, leaving a crystalline residue which is kept at 200° for 15 minutes longer, then cooled. The residue is dissolved in 20 ml of water; the solution is filtered through Hyflo and acidified with 2 N hydrochloric acid. The oil which precipitates is dissolved in ether. The ether solution is washed with 2 N potassium carbonate solution and water, the aqueous alkaline solution is separated and acidified with 2 N hydrochloric acid. The oil which precipitates is extracted with ether. The ether solution is washed with, water, dried over sodium sulfate and concentrated under 11 Torr at 40°. The residue is crystallized twice from ether/ 31296/2 melts at 120-127° with decomposition.

The following Is produced in an analogous manners 4.2 g of ^-(2,6-dlchloro-m-toluidino)-phenyj^7- a. Sodium aalt o o^(6-chlor^-aig.(i.-trlf,uorOH-i«p toluidino)-ph0ny7-glyoxylio acid solution of 32,5 g of l-(6-chloro-e#a,a-trifluoro- a-tolyl)-indole-2,5-dione in 100 ml of ethanol and 100 ml of 1 Kt sodium hydroxide solution is refluxed for one hour,, The solution is then cooled and concentrated to dryness unde 11 Torr at 50°» Anhydrous benzene is added twice to the residue, using 50 ml each time and concentrating the mixture each time to dryness under 11 Toxr at 40° to yield the pure sodium salt of ^-(6-cMoro a,a,«-tri^ acid. The sodium salt of ^-(6-chlpro-o-toluldino)-pheny7-glyoxylic acid is obtained analogously. h. o-(6-ohloro-c, t,a-trifluoro-m-toluidino)- phenyj -acetic acid To a solution of 36·6 § of sodium salt of the ^ -(6- chloro-a,a,a-trifluoro-m-toluidino)-phenyl7'*glyoxylic acid in 200 ml of absolute ethanol are added 37 β h hydrazine hydrate.

The solution;: Is heated for 15 minutes to 40° and a solution of 36.5 g of sodium in 1500 ml of absolute ethanol is then added. The solution is heated on boiling water bath and ca. 1000 ml of ethanol are thereby distilled off. The residue is then heated in a oil bath at a bath temperature of 170°, whereby the residual ethanol as well s water and hydrazine evaporate off. The orys^allised residue is dissolved in 2000 ml of water. The aqueous solution is extracted with ether, separated and is filtered through a layer of Hyflo. The aqueous solution is then acidified by addition of 2U hydrochloric acid. The precipitated oil is extracted with ether. The ether phase is washed with water, dried over sodium sulphate and concentrated b evaporation under 11 iorr at 40°. She residue is crystallised from ether/petroleum ether, fhe o«-(6-ohloro«- ,a,a-trifluoro-m-toluldino)-phenyj7-acetic acid melts at 94-96°· he following is obtained analogously: 8.5 g of ^(6~oliloro-o- olTddi o)*phonj^^cetie ; acid, M.P. 140*147° (from ether), starting with 14.2 g of ^-(6~chloro-o-toluidino>^^ sodium salt.

Starting from Ιθ.5 g of ^(0-(2,6-dichlorophenyl)-5«-ohloro-phenyl-glyo.yiio acid salt, U.0 g of β-(Ζ,6-dlchloro-phenyl)-5-ohloro-phenyl acetic acid, 181-183° (reorystallised from methanol) is obtained analogously.

Example 4 o-(2,6-xylidino).-m-toly37-acetio aoid-Na-salt 26.9 g Of o-(2,6-xyiidino)-m-toly37-acetio acid (see example 2) are dissolved in 100 ml of 1 H sodium hydroxide 1a solution. The solution is concentrated to dryness under 11 Torr with a bath temperature of 50° . The residue is mixed with 40 ml of absolute benzene, again concentrated to dryness and the residue crystallised from dioxane. The sodium salt of [o-(2,6- xylidino) -m-tolyl ] -acetic acid melts at 341-343°.

In an analogous manner, is obtained lo- (2 , 6-dichlorophenyl) 5-chloro-phenyl ] -acetic acid sodium salt, M.P. 295° (with decomposition) recrystallised from water.

Example 5 The 2 , 6-dichloro-4 ' -chloro-diphenyl amine, which is used as starting material for the [ o- (2 , 6-dichlorophenyl) -5-chloro-phenyl ] -acetic acid, analogously produced under example 3 is produced as follows : 2 , 6-dichloro-4 ' -chloro-diphenyl amine 220 g of 2 , 6-dichloro-acetanilide are dissolved in 1000 ml of 4-bromo-chlorobenzene . 100 g of anhydrous potassium carbonate and 10 g of copper powder are added. The mixture is then refluxed for 4 days, and the water which is formed is separated by means of a water separating apparatus . The mixture is then cooled and subjected to steam . distillation . The residue is extracted with 2500 ml of ether. The ether solution is filtered through Hyflo and concentrated to dryness under 11 Torr. The residue is then dissolved in 1400 ml of 10/Ό ethanolic potassium hydroxide solution and the solution is refluxed for 16 hour The solution is then concentrated to dryness under 11 Torr at 50° . The residue is mixed with 150 ml of water and extracted with 1500 ml of ethyl acetate. The ethyl acetate solution is separated, dried with sodium sulphate and . concentrated to dryness unde 11 T'orr . The residue is distilled under high vacuum The 2, 6-dichloro-4' -chloro-diphenyl amine boils at 121° /0.01 Torr . The yield is 45%, (relative to 2 , 6-dichloro-acetanilide) . The following is produced in an analogous manner: 13 g of N- (p-anisyl) -2 , 6-dichloro-p-anisidine , M.P. 127-129° (from ethanol) are obtained starting with 27 g of N-acetyl-2 , 6-dichloro-p-anisidine . 31296/2 '·.

Claims (2)

1. CLAIMS ΐί.· Process for the production of substituted anilino phenyl-acetic acids of the general ibrmula I - CO - OH wherei i . ' Ί - * ..,·» · Rl represents lower alkyl or alkoxy group, a halogen atom having an atomic number of at most 35, or the trifluoro- methyl group, R2 and ' R3 represent hydrogen, a lower alkyl group or a halogen atom having an atomic number of at most 35, whereby at least one position is taken by one of the substituents represented by R Rg or j arid does not therefore represent hydrogen,. ^ represents hydrogen,. a lower alkyl or alkoxy group, a halogen atom having an.Efcomic number of at most 35, and their salts with inorganic and organic bases, characterised' by reacting a ring-substituted diphenylamine' of the general formula. II ' 20 wherein R^, R2 , and have the meanings and position given under formula I, with oxalyl chloride in a .suitable solvent to give the ring-substituted N-aryl-oxanilic acid chlorides of the general formula III wherein R- , R2 , R^ and R^ have the meanings and position given under formula I, converting these in the presence of Friedel-Craf s condensation agents at room temperature with ring closure into the substituted indol-2 , 3 -diones of the general formula IV - 2.1 - wherein R-, , ^ a d have the meanings and position given under formula I, optionally recrystallising these compounds, reacting them with hydrazine or semicarbazide and with an alkali hydroxide or alkali metal alcoholate at increased temperature, under the conditions of reduction method of Wolff-Kishne , and, optionally, converting the initially obtained alkali, salt of a substituted phenyl acetic acid of the general formula I into the free acid or into another salt with an inorganic or organic base.
2. 2. Process according to claim 1, characterised by hydrolysing the indol-2 , 3-dione , obtained according to claim 1, into the corresponding (o-anilinophenyl) -glyoxylic acid or a salt thereof of the general formula V 9 wherein R represents hydrogen, a monovalent cation or the normal equivalent of a polyvalent cation, and , R2 , 3 and R^ have the meanings and position given under formula I, and reducing the compound of the formula V according to the method of Wolff-Kishner by reaction with hydrazine or semicarbazide and with an alkali hydroxide or alkali metal alcoholate at increased temperature, and, optionally, converting the initially obtained alkali salt of- a substituted phenyl acetic acid of the general formula I into the free acid or into another salt with an inorganic or organic base. 22.11.68 ES/ml Jp etc GB etc 23 for the Applicants KiNK¾L& CO^MD PARTNE S .