DE1543639A1 - Process for the production of new substituted phenylacetic acids - Google Patents

Description

Poienfanwällo 2163 *

New complete registration documents P 15 > Y5 639-2

Process for the production of new substituted phenylacetic acids

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

Substituted phenylacetic acids of the general formula I,

(D

in which

R _{1 is} a lower alkyl or alkoxy radical, a halogen atom, up to atom number 35 or the trifluoromethyl group,

R ₂ and

Ro is hydrogen, a lower alkyl or alkoxy radical or a halogen atom up to atom number 35,

R4 is hydrogen, a lower alkyl or alkoxy radical Halogen atom up to atomic number 35 or the trifluoromethyl group,

R ₅ and 9 0 9 8 8 6/1686 bad original

Rg each hydrogen, a lower alkyl radical or a

Mean benzyl radical,

and their salts with inorganic and organic bases
not yet known. As has now been found, the compounds of general formula I and their salts have valuable pharmacological properties, in particular anti-inflammatory (anti-inflammatory), analgesic and antipyretic activity with a favorable therapeutic index. They can be used orally, rectally or, especially in the form of aqueous solutions of their salts, also parenterally, especially intramuscularly, for the treatment of rheumatic, arthritic and other inflammatory diseases. The anti-inflammatory effectiveness can be demonstrated in animal experiments, for example, on the UV egg erythema of guinea pigs
and detect it on the bolus alba edema of the rat.

In addition, these substances have the ability to absorb UV rays at 290-300 μm and are therefore used as UV absorbers for cosmetic purposes, for example in sun protection creams
suitable because they absorb the harmful, reddening rays, while they let through the desired tanning, over 315 πιμ.

In the compounds of general formula I and the corresponding starting materials mentioned below, R-. to R ^ independently of one another as lower alkyl radicals, for example methyl or ethyl radicals. Some of the symbols mentioned can
e.g. also n-PropyP, isopropyl, η-butyl, sec. Butyl, or
tert. Butyl radicals significantly lower alkoxy radicals or halogen atoms R, to R ^ are, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy radicals, or chlorine, fluorine or B τοπία atoms .

909888/1686

For the preparation of an acid of the general formula I and A compound of the general formula II is used for their salts with inorganic and organic bases

(II)

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

Water-containing lower alkanols, such as ethanol, methanol or n-butanol, are also particularly suitable as solvents ethylene glycol or dimethylformamide can also be used. The hydrolysis is carried out, for example, at or just below its boiling point by means of at least one equivalent of an alkali metal hydroxide or carbonate or alkaline earth metal hydroxide, in particular sodium or potassium hydroxide, completed.

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

C - COOR.

(III)

9098 86/1686

in which '

A is hydrogen or an acyl radical, in particular a lower alkanoyl radical, and R _{7 is} a lower alkyl or an aralkyl radical, in particular

means the benzyl while R, - Rg have the meaning indicated above, with an alkali metal hydroxide, carbonate or bicarbonate, an alkaline earth metal _hydroxide:: ~

or a basic ion exchanger in the heat, or if R _{7 is} the benzyl radical, this is split off by hydrogenolysis with catalytically activated hydrogen. Suitable solvents for the hydrolysis are particularly water-containing lower alkanols, such as methanol, ethanol, n-butanol, and also ethylene glycol or dimethylformamide. The hydrolysis is carried out, for example, at or slightly below its boiling point by means of at least one equivalent of base. The hydrogenolysis is advantageously carried out at normal pressure and room temperature to a moderately elevated temperature in the presence of Pd-carbon in alcohol.

According to a third process, compounds of the general formula I are obtained by adding a compound of the general formula Formula IV,

(IV)

wherein R ₁ - Rg and A have the meaning given above, with

σ> an alkali metal hydroxide in a water-based solvent in the heat. Particularly suitable solvents are water-containing lower alkanols, such as ethanol, methanol or

n-butanol, also ethylene glycol or dimethylformamide. the Hydrolysis takes place, for example, at or just below their boiling point by means of at least two equivalents of an alkali metal hydroxide, especially completed by sodium or potassium hydroxide.

The starting materials of the general formula II, which can be referred to as l-aryl-2-indolinones, 1-aryl-oxindoles or lactams of 2-arylaminophenylacetic acids, are in turn new compounds. For the introduction of the radicals R ₅ and Rg, such 1-aryl -2-indolinone in the presence of sodium hydride or sodium amide; ■ alkylated in dimethylformamide by means of an alkyl halide or treated with an aralkyl halide, preferably with benzyl chloride. ^; A benzyl radical can also be introduced by first reacting with benzaldehyde and then reducing the resulting ϊ l-aryl-3-benzal-2-indolinone, for example with activated hydrogen. ^: The compounds of general formula II are prepared, for example, analogously to that of the known l-phenyl-2-indolinone from the corresponding unsymmetrically substituted diphenylamines by chloroacetylation to give substituted 2-chloro-N-phenyI-acetanilides, and the latter is heated to temperatures with aluminum chloride by 160 ° or through. Heating with aluminum chloride in suitable solvents such as tetrachloroethane or nitrobenzene at 100-150 °. A number of according to the definition for R ₁ - R ^ substituted ^ th diphenylamines are known, and others are analogous to the! known to be produced, for example according to that of AW, Chapman, J. Ghem.Soc. ·

to 1929 _T 569-572 described method by heating ίϊ, Q-Dio

to aryl imino esters and hydrolysis of those formed by rearrangement 00

^ Ν, Ν-diarylamides, or according to that of R.B. Moffett et al, J, Am. Chem. _ * Soc. 82 ,, 1605 (1960) used method, starting from if necessary substituted o-chloro or o-bromobenzoic acids and sub-}

substituted arilines and decarboxylation of the resulting j

ο-anil inobenzo e acids. ·

A particularly favorable method for the preparation of diphenylamines substituted according to the definition of R-, - FL is the method of Goldberg, Ber .40 4 541 (1907), according to which an optionally substituted acetanilide is reacted with a bromobenzene substituted _{according to the definition of R 4.}

Compounds of the general formula II which have a lower alkyl group as Rr and _{hydrogen as R 6} can be obtained by reacting α-haloalkanoic acid halides with diphenylamines substituted according to the definitions from R 1 to R ^ and subsequent ring closure. Any isomer mixtures formed must be separated.

Another method for the preparation of compounds of the general formula II consists in the acidic saponification of compounds of the
Enough

The starting materials of the general formula III with a lower alkyl group as R ₇ and an acyl group as A can be obtained, for example, by converting the corresponding cyano compounds into imino ether hydrochlorides and decomposing the latter with water.

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

The lower alkyl and aralkyl esters of the general formula

^ mel III can also be carried out by other known esterification processes

^ can be obtained, e.g. after the Ν, Ν-dimethylformamide-dineopentyl- °> acetal method, by H. Büchi, K.Steen and A. Eschenmoser (Ang. 00

^m Chemie 73 (1963) 1176), or with thionyl chloride at -10 ° in

BAD ORIGINAt

absolute alkyl or aralkyl alcohol according to Brenner (HeIv. Chim Acta 34 (1953) 1114).

The starting materials of the general formula IV are obtained, for example, by reacting α-halogen-N-aryl-o-toluidines or -toluidides with sodium or potassium cyanide. Surprisingly, α-chloro-o-toluidines or oc-chloro-o-toluidides are formed in a one-step reaction from o-arylamino-benzyl alcohols, namely when the latter is boiled with acetyl chloride. Individual representatives of the o-arylaminobenzyl alcohols substituted according to the definition for R-, - R ₄ are known and others are known, for example, by reducing N-aryl anthranilic acid alkyl esters with lithium aluminum hydride in ether or tetrahydrofuran, sodium borohydride in methanol or sodium borohydride and lithium bromide in diethylene glycol dimethyl ether available. The N-Aiyl-anthranilic acids can be reduced, for example, with lithium aluminum hydride.

Lower alkyl groups R ^ and R ^ can also be obtained by alkylation the compounds unsubstituted in the α-position of the general Formulas III and IV are introduced.

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

Suitable salts for therapeutic use are those with pharmacologically harmless inorganic and organic bases, i.e. with bases in the dosages in question show no physiological intrinsic effect or a desired effect, e.g. in parenteral application forms in particular a local anesthetic effect. Suitable salts are e.g. sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts with ethylamine, triethylamine, ethanolamine,

Diethanolamine, diethylaminoethanol, ethylenediamine, benzene , procaine, pyrrolidine, piperidine, morpholine, 1-ethyl-piperidine or 2-piperidinoethanol.

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

Unit dosage forms for oral use contain as active ingredient preferably between 1 % and 90 % of an acid of the general formula I or a pharmacologically acceptable salt thereof. To produce them, the active ingredients are combined, for example, with solid, powdery carriers, such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols (Garbowaxen) of suitable molecular weights, to tablets or to Dragöe kernels. The latter is coated, for example, with concentrated sugar solutions, which may contain, for example, gum arabic, talc and / or titanium dioxide, or with a lacquer dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, for example to indicate different doses of active ingredient.

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

909886/1686

BATH ORIGINAL

a) 1000.0 g of active ingredient, e.g. [o- (2,6-dichloro-m-toluidino) phenyl] acetic acid or their calcium or lithium salt, are • mixed with 550.0 g of lactose and 292.0 g of potato starch, the Mixture moistened with an alcoholic solution of 8.0 g gelatin and granulated through a sieve. Mix after drying 60.0 g of potato starch, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are added and the mixture is pressed of 10,000 tablets, each weighing 200 mg and containing 100 mg of active ingredient, if desired with partial notches for a finer adjustment the dosage can be provided.

b) 200.0 g of active ingredient, e.g. [o- (2,6-dichloro-m-toluidino) phenyl] acetic acid, are mixed well with 16 g of corn starch and 6.0 g of colloidal silica. The mixture is made with a Solution of 2.0 g of stearic acid, 6.0 g of ethyl cellulose and 6.0 g of stearin in about 70 ml of isopropyl alcohol and moistened with a . Sieve III (Ph. HeIv. V) granulated. The granules will take about 14 hours dried and then beaten through sieve HI-IIIa. This is followed by 16.0 g of corn starch, 16.0 g of talc and 2.0 g of magnesium stearate mixed and pressed into 1000 dragee cores. Turn this over coated with a concentrated syrup of 2.000 g lacca, 7.500 g gum arabic, * 0.150 g color, 2.000 g highly dispersed silicon dioxide, 25.000 g talc and 53.350 g sugar and dried. The coated tablets each weigh 360 mg and each contain 200 mg of active ingredient.

Comes as unit dose forms for rectal use

<o e.g. suppositories, which consist of a combination of an acid of the ο

* ° general formula I or a suitable salt thereof made with a _m ^ eutralfettgundlage, or gelatin Rektalkap-

- * be, which is a combination of an active ingredient or a suitable

<° Neten salt of the same with polyethylene glycols (Carbowaxen) of suitable molecular weight, into consideration. _{r (} ., _rtl! M

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

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

[o- (2,6-dichloro-anilino) -phenyl] -acetic acid 1.0 g

Paraffin oil, thin 1.0 g

Polyoxyethylene sorbitan monostearate 2.0 g

Polyethylene sorbitol lanolin derivative 1.5 g

Sorbitol solution 70 pounds 3.0 g

Stearic acid 15.0 g

Preservative + perfume qs
Water ad 100.0 g

[o- (2,6-dichloro-anilino) -phenyl] -acetic acid 1.0 g

Propylene glycol 28.0 g

Glycerol monostearate 18.0 g

Rüyoxjöthylei sorbitan monolaurate 8,, 0 g

Thimerosal (solution 1: 1000) 1.0 g

Perfume q.s.

Water ad 100.0 g

The following examples explain the implementation the method according to the invention, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Celsius.

909886/1686

example 1

Γ ο- (2.6-dichloro-m-toluidlno) -phenyl1-acetic acid

A solution of 40 g of 1- (2,6-dichloro-m-tolyl) -2-indolinone in 280 ml 1-n. Sodium hydroxide solution and 420 ml of ethanol is 2 hours refluxed. The clear solution is cooled and the ethanol is distilled off at a bath temperature of 40 ° below 11 torr. The aqueous residue is extracted with 100 ml of ether, the ether is separated off and the aqueous solution is removed by adding ice (approx. 50 g) and external cooling cooled to 5 °. This is followed by 2-n with stirring. Hydrochloric acid until the pH of the solution is approx. 6. the The acid which has precipitated out is taken up in 400 ml of ether, the ethereal solution is separated off and the aqueous solution is again mixed with 200 ml of ether extracted. The ethereal solutions are washed with 50 ml of water. combined, dried over sodium sulfate and concentrated at 11 Torr, without heating. After the addition of petroleum ether, [o- (2,6-dichloro-m-toluidino) phenyl] acetic acid crystallizes from the concentrated ethereal solution the end. After recrystallization from ether-petroleum ether it melts at 146-149 °.

The following compounds were prepared in an analogous manner :

[2- (2 ^l , 6 ¹ -dichloroanilino) -5-chloro-phenyl] -acetic acid, m.p. 181-183 ° from methanol \

[2- (2 ', 6'-dichloro-anilino) -phenyl] -acetic acid m.p. 156-158 °; [2- (2 ', 6'-dichloro-m-toluidinoJ-S-chlorophenyl] acetic acid, m.p.

152-156 ° from ether-petroleum ether;

[2- (2 ', ⁶ ' -Dichloro-m-toluidino) -5-methoxyphenyl] acetic acid, m.p.

120-122 ° from ether-petroleum ether \

[2- (2 ', 6'-dichloro-anilinoJ-S-bromophenylj-acetic acid decomposes at 161 °, from ether / petroleum ether

BATH ORIGINAL 909886/1686

The raw materials required for this are obtained, for example, as follows:

a) 2,6-dichloro-N-phenyl-m-toluidine

7 g of N- (2,6-dichloro-m-tolyl) anthranilic acid are during Heated to 280 ° for 2 hours. The cooled melt is dissolved in 30 ml of benzene and the benzene solution with 5 ml of 2-n. sodium and extracted 5 ml of water. The solution is dried with sodium sulfate and evaporated. The residue is distilled, the 2,6-dichloro-N-phenyl-m-toluidine being obtained as a yellow oil is, bp 115-120 ° / 0.001 Torr.

The following are obtained analogously:

e bp 123-125 ° / 0.01 torr} ■, »es} bp 126-127YO ₁ OL torr \ N-Phenyl-2,3-xylidine, bp 100-102 ° / 0.005 torr \ 2.6 -Dichlorodiphenylamine, bp 109-111 ° / 0.003 Torr} -ee,. 6 · 2.6, &'- trichloro-diphenylarain, b.p. 123-125 ° / 0.001 torr; 2,6-dichloro-diDhenene laminate .

15 g of 2,6-dichloroacetanilide 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 refluxed for 4 days, the resulting water is separated off by means of a water separator. The mixture is then cooled and subjected to a Steam distillation. The residue is extracted with 200 ml of ether. The ether solution is filtered through Hyflo and concentrated Torr to dryness. The residue is then dissolved in 60 ml of the above

_o Ethanolic potassium hydroxide solution and heat the solution during

oo 3 hours at reflux. The solution is then reduced to below 11 Torr

«At 40 ° to dryness. The residue is mixed with 10 ml of water ^ water and extracted with 100 ml of ether. The ethereal solution is removed

> cn separates and extracted with 20 ml of water. Then you dry the essential one Solution with sodium sulfate and concentrate it below 11 torr

BAD ORJG »NAL

Dry up. The residue is distilled in a high vacuum. The 2,6-dichlorodiphenylamine boils at 115 ° / 0.0l Torr as a yellow oil. The yield is 43 % of theory.

Analog are produced s

2,6-dichloro-N-phenyl-m-toluidine, b.p. 117-120 ° / 0.001 Torr} N-phenyl-2,3-xylidine, b.p. 100-102 ° / 0.005 Torr \ N-phenyl-2, 6-xylidin, b.p. 125 ° / 0.01 torr; N- (4 ^I -chlorophenyl) -2,6-xylidine, b.p. 124 ° / 0.01 Torr ; 2,6-dichloro-4'-chloro-diphenylamine, b.p. 121 ° / 0.01 torr; 2,6-dichloro-Np-tolyl-m-toluidine, b.p. 131-135 ° / 0.005 torr, 2 _> 6.4'-trichloro-N-phenyl-m-toluidine, b.p. 135-145 ° / 0.005 Torr 5

ffteVVioxHpVimyl

2,6-dichloro-N ~ p- & ft4re4.-m-toluidine, b.p. 115-130 ° / 0.001 torr

The 2,6-dichloro-acetanilide was prepared as follows: 2,6-dichloro-acetanilide

40 ml of acetyl chloride are slowly added dropwise to a solution of 81 g of 2,6-dichloro-aniline in 30 ml of glacial acetic acid. The solution is then heated on a water bath until the evolution of hydrochloric acid has ceased. It is cooled to room temperature and the mixture is poured onto ice. The precipitated crystals are filtered off and recrystallized from glacial acetic acid. The 2,6-dichloroacetanilide melts at 18O-181 ⁰ . The yield is 70 % of theory.

The following was produced in the same way:

2,6-Bichloro- *. ^ E © 4j4.toluidid, m.p. 179-181 °, from glacial acetic acid water,

xylidid, m.p. 175-177 ° from glacial acetic acid-water ;

, Snip. 181 ° from glacial acetic acid-water j These compounds are known, b) N-Phenvl-2,2'.6'-trichloro-m-toluidide aceto-4 g of 2,6-dichloro-N-phenyl-m-toluidine with 40 ml of freshly distilled chloroacetyl chloride boiled under reflux for one hour. The dark solution is then under 11 torr and one

909886/1686

Evaporated bath temperature of 50 °. The residue is in 70 ml Dissolved ethyl acetate-ether 1: 1. This solution is mixed with 10 ml of 2-n. Extracted potassium bicarbonate solution and 10 ml of water, dried over sodium sulfate and evaporated under 11 torr. N-phenyl-2,2 ', 6'-trichloro-aceto-m-toluidide crystallized from cyclohexane, melting point 117-118 °.

The following are produced in the same way:

2,2 ', 6', 4 "-tetrachloroacetyl-diphenylamine, m.p. 130-131 ° from ethanol-water £ - CVW-N-Jp-« dorfVi «^ |) W - (2,6-oieWlorpht »VO

2-chloro-N-phenyl-aceto-2 ^I , 3'-xylidide, m.p. 124-126 ° from cyclohexane 2,2 ', δ'-trichloroacetyl-diphenylamine, m.p. 143-144 ° from methanol ι

«C« lo-V.6'-MaU0 <d
2-chlorine-. y, m.p. 94-96 °

Ethanol;

2,4 "-Dichlor-M-phenyl-aceto-2 ^I , 6'-xylidide, m.p. 104-106 ° from ethanolj Np-toluyl-2,2 ', 6 · -trichloro-aceto-m-toluidide, m.p. 67-69 ° from ether-petroleum ether;

N-phenyl-2,2 ¹ , 6 '^ "- tetrachloro-aceto-m-toluidide, m.p. 106-107 °

from ethyl acetate-petroleum ether;
HtVViOKM f> Vmu0-

N-p-6--2,2 ', 6' -trichloro-aceto-m-toluidide as a yellow oil.

c) 1- (2.6-dichloro-m-tolyl) -2-indolinone 4 g of N-phenyl-2,2 ', 6'-trichloro-aceto-m-toluidide and 4 g of aluminum chloride are mixed well and mixed for 2 hours to 160 ° heated. The melt is cooled and poured onto approx. 50 g of ice while it is still warm. The precipitated oil is dissolved in 50 ml of chloroform, and the chloroform solution is washed with 10 ml of water, over. Dried sodium sulfate and evaporated under 11 torr. The residue is distilled. The 1- (2,6-dichloro-yn-tolyl-2-indolinone boils at 128-130VO.001 Torr. The oil obtained, which crystallizes on standing, melts at 129-132 *.

The following are produced in the same way: - '

l- (2,6-dichlorophenyl) -5-chloro-2-indolinone, m.p. 130-131 ° from ethanol

909886/1686

BAD ORJGINAL

Water ;

1- (2,6-dichlorophenyl) -2-indolinone, melting point 126-127 ° from methanol; 1- (2,6-dichloro-m-tolyl) -5-chloro-2-indolinone, melting point 152-154 ° from ethyl acetate-petroleum ether.

1- (2.6-dichloro-m-tolvl) -S-hydroxv-Z-indolinone

10. g of Np - 2,2 ', 6'-trichloro-aceto-m-toluidide are mixed with 20 g of finely powdered aluminum chloride and heated to 280 ° for one hour while stirring in a nitrogen atmosphere. It is allowed to cool and a lot of ice and water are added to the solidified melt. A black precipitate is formed, which is filtered off and dried at 80 ° and 11 Torr. The 1- (2,6-dichloromolyl) -5-hydroxy-2-indolinone, purified by chromatography on neutral aluminum oxide, melts at 184-187 ° \ yield 60 % of theory.
1- (2 «6-dichloro-m-tolvl.) -5-methoxv-2-indolinone

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

1- (2v6-Dlchlorphenvl) -5-bromo-indolinone

^m A solution of 11.2 g of l- (2,6-dichlorophenyl) -2-indolinone ^ in 700 ml of ethanol becomes a solution of 8 g of potassium bromide

cn and 2.08 g of bromine in 160 ml of water. The mixture becomes vigorous shaken and then left to stand for 3 hours at 0 °. The alcohol is then evaporated and the insoluble precipitate of

BAD OHiGiH /

the remaining aqueous solution is filtered off. This is then taken up in methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated to dryness under 11 torr. The residue consists of a mixture which contains 60 % 1- (2,6-dichlorophenyl) -5-bromo-2-indolinone. This is purified by repeated chromatography on a silica gel column and melts after it has been crystallized several times from ether or ether-petroleum ether at 188-190 °.

Example 2

Γ ο- (a «a« α-Trlfluoro-m-toluldlno) -phenyl1-acetic acid

9.5 g of a-cyano-N-iajdja-trifluoro-m-tolylJ-aceto-o-toluidide are dissolved in 100 ml of ethanol and 90 ml of 1-n. Sodium hydroxide solution dissolved. The solution is refluxed overnight. It is cooled and concentrated under 11 torr at 40 ° to approx. 70 ml. The aqueous alkaline solution is extracted with 50 ml of ether, this ethereal solution is separated off and the aqueous phase with 2-n. Hydrochloric acid acidified, it is shaken with 50 ml of ether, wi süMBgy washes the ether extract with water, the ether solution is dried over sodium sulfate and concentrated below 11 torr without heating. The residue crystallizes from ether-petroleum ether. After recrystallization

from ether-petroleum ether the [o- (a, a, a-trifluoro-m-toluidino) -phenyl] -acetic acid melts at 112-114 °. The yield is -35 % of theory.
ο

However, this substance can also be produced in the following way

__ be asked :

^ A solution of 16.4 g of o- [N- (a, a, a-trifluoro-m-tolyl) - cn acetamido] phenylacetic acid ethyl ester in 225 ml of ethanol 95jCigem ^m and 67 ml of 2-n. Sodium hydroxide solution is refluxed for 16 hours.

Then the ethanol is distilled off under 11 Torr at 40 ° and

BAD ORIGWAt

extracted the remaining aqueous solution with 40 ml of ether. The ethereal phase is separated off, the aqueous phase is cooled to 0-5 ° by adding ice and is washed with 2-n. Hydrochloric acid acidified to pH 6. The precipitated oil is dissolved in 200 ml of ether, the ethereal solution is washed with 20 ml of water and dried over sodium sulfate. Then we concentrated under 11 Torr without heating. After the addition of petroleum ether, the [o- (a, a, a-trifluoro-m-toluidino) phenyl] acetic acid crystallizes out, m.p. 112-

The starting materials for this example can be produced as follows, for example:

a) o- (g «ag-Trlfluor-m-toluldino) -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 glyme. The mixture is stirred for 1/2 hour at room temperature. Then a solution of 14.8 g of N- (oc, a, a-trifluoro-m-tolyl) -anthranilic acid methyl ester in 40 ml of anhydrous diglyme is added dropwise. The mixture is then heated to 100 ° for 3 hours, cooled and poured onto a mixture of 300 g of ice and 30 ml of concentrated hydrochloric acid. After brief stirring, the oil which has separated out is extracted with 300 ml of ethyl acetate. The ethyl acetate solution is with 2-n. Washed potassium bicarbonate solution and water, dried over sodium sulfate and evaporated under 11 torr at 40 °. The residue is fractionally distilled using a short Vigreux column. The o- (a, a, a-trifluoro-m-toluidino) ~

Co benzyl alcohol boils at 127-129 ° / 0.001 Torr. The yield is ο

75 % of theory.

a ¹ ) 9.97 g of lithium aluminum hydride diluted in 100 ml of absolute

_ ^ Ether suspended and cooled to 5 ° with stirring. Under embroidery

When externally cooled with a bis bath, the substance becomes a solution of o> ·

36.8 g of N- (a, a, o-trifluoro-ni-tolyl) -anthranilic acid methyl ester in 140 ml of absolute ether were slowly added dropwise. Then will

• 'BAD Or'G ^ AL

- 16 -

the mixture was stirred for 18 hours at room temperature. The mixture, which has cooled to 0 °, is added dropwise with stirring Add 10 ml of water, 10 ml of 15 # strength sodium hydroxide solution and another 30 ml of water. The mixture is then stirred for one hour at room temperature and filtered away. The filtrate is evaporated under 11 torr at 40 °. Of the The residue is fractionated using a short Vigreux column. The o- (α, α, α-trifluoro-m-toluidino) -benzyl alcohol is used as yellow oil obtained, b.p. 130-131 ° / ö, 001 Torr. Analog is obtained :

o- (2,3 -Xylidino) -benzyl alcohol, bp 136-141 ° / O.0O5 Torr j o- (6-Methoxy-m-toluidino) benzyl alcohol, melting point 138-139 ° from methanol; o- (a, a, a-Trifluoro-6-chloro-m * toluidino) -benzyl alcohol, m.p. 100-101 ° from petroleum ether

4-chloro-2- (2 ', 6' = aiäöS ^ Öi5iaaÖ-benzyl alcohol, m.p. 141-142 ° ; 5-methoxy-2- (2 ^f , 6 ^l -dichloroanilino) benzyl alcohol, m.p. 112-113 ° from cyclohexane.

a) A solution of 7 g of N- (a, a, a-trifluoro-m-tolyl) -anthranilic acid methyl ester in 60 ml of methanol is added dropwise to 9 g of sodium borohydride. Then the suspension is 2 hours at room. stirred temperature and heated under reflux for 3 hours. It is cooled, diluted with 80 ml of water and extracted with 300 ml of ethyl acetate. The ethyl acetate solution is separated off, dried over sodium sulfate and evaporated under 11 torr. The residue is fractionally distilled. The o- (a, a, a-trifluoro-m-toluidino) -benzyl alcohol boils at 128-131 ° / 0.001 Torr. The yield is _o 55% of theory.

tO TTT

α> a) 4-chloro-2 ~ C2'.6'-dichloro-anillno) -benzyl alcohol

co.

^m To 8 g lithium aluminum hydride in 50 ml absolute tetra-

UJ * hydrofuran is a suspension of 50 g of 4-chloro-2-cn (2 ¹ , 6'-dichloroanilino) benzoic acid in 250 ml of absolute tetrahydro-

ORIGINAL BATHROOM.

furan dripped. The reaction mixture is 1/2 hour at 5 °, 1 Stirred for 1 hour at 25 ° and 3 hours at reflux and then at 0-5 ° with 30 ml 2-n. Sodium hydroxide solution is carefully added drop by drop. After adding 200 ml of tetrahydrofuran, the organic

Sucked off solution of the crystalline precipitate and this with Tetrahydrofuran washed well.

The combined solutions are evaporated, taken up in ethyl acetate and 2-n. Washed Sbda solution and saturated saline solution. Evaporation of the organic phase gives 44.4 g of a dark brown oil, which is distilled. 195-2QQ ° / 0.003 torr, m.p. 151-152 °. Yield 31.5 g (66 ° C) (ether-petroleum ether). b ^ a-Chlor-N-Ca.aa-trlfluor-m-tolyD-aceto-toluidid

A solution of 23 g of ο- (α, α, α-trifluoro-m-toluidine) benzyl alcohol in 70 ml of acetyl chloride is under nitrogen for one hour heated to boiling under reflux * The orange-colored solution 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 with 20 ml of 2-n. Potassium bicarbonate solution and 20 ml Washed with water, dried over sodium sulfate and under vacuum some 3t. What remains is a light oil made from ether-petroleum ether crystallized. The obtained a-chloro-N- (a, «, a-trifluoro-m-

Tolyl) -aceto-o-toluidide melts at 83-85 ° .. ΛηαΙβ * wwd erV »* tW * H A- CViWr-U- (♦ ¥)> *!« »c) aC

To a suspension of 2.2 g of sodium eyanide in 20 ml of dimethyl sulfoxide a solution of 11.6 g is obtained at 40 ° with stirring

a-chloro-N- (a, a, a-trifluoro-m-tolyl) -aceto-o-toluidide in 60 ml Ditto

^ methyl sulfoxide added within 10 minutes. The temperature must not exceed 40 °. Then the mixture is stirred for 3 hours at ^ 40 ° , cooled to 10 ° and diluted old 200 ml of water.

The solution is extracted four times with 150 ml of ethyl acetate, over ' ethyl acetate solutions are extracted with 200 ml of 6-n. Hydrochloric acid and then shaken with 30 ml of water, then dried with sodium sulfate and concentrated under 11 torr at 40 °. The a-cyano-N-CajO ^ a-trifluoro-m-tolylJ-aceto-otoluidide that remains as a yellow oil can be further processed directly. Analogous to vwö ^ * ^ * d) ο-ΓN- (a «aq-Trlfluoro-m-tolvl) -acetamidoI-phenylacetic acid ethyl ester

A solution of 50 g of a-cyano-N- (a, a, oc-trifluoro-m-tolyl) -aceto-o-toluidide in 550 ml of absolute ether and 375 ml of absolute ethanol, with stirring and with exclusion of moisture, to 0-5 ° cooled down. Dry hydrogen chloride is passed into the solution over a period of 4 hours, the temperature not exceeding 5 °. Hydrogen chloride is then passed in at room temperature for a further 5 hours. Then you leave the solution over tfach't stand at room temperature and evaporate them to dryness under 11 torr at a bath temperature of 40 °. The residue is dissolved in 140 ml Water, covered with 150 ml of ether and heated the whole thing for 2 hours under reflux on the steam bath. Then you cool down, separates the ether phase and extracts the aqueous solution again with 200 ml of ether. The combined ether solutions are dried over sodium sulfate and evaporated at 40 ° under a water jet vacuum. The residue is collected by means of a Vigreux colon.

vacuum fractionated. The o- [Ν- (α, α, α-trifluoro-m-tolyl) -acetamido] - phenylacetic acid ethyl ester boils at 110-115 ° / 0.001 torr.

| O, oo »

909886/1686 ^ßAD original

Example 3

[ο - (^ - trifluoromethyl-ö-chloro-anilino) -phenyl] -acetic acid

A solution of 18.4 g of a-cyano-N- (3-trifluoromethyl-6-chloro-phenyl) -o-toluidine in 120 ml 1-n. Sodium hydroxide solution and 120 ml of ethanol is refluxed for 10 hours. Then it will be the reaction solution at 40 ° under reduced pressure to volume concentrated from about 80 ml and the aqueous solution extracted with 100 ml of ether. The aqueous-alkaline phase is then at with 2-n. Hydrochloric acid acidified and the precipitated oil in ether recorded. The ethereal solution is separated off, washed with water, dried over sodium sulfate and without heating at reduced Pressure restricted. When adding petroleum ether, the [o - (^ - Trifluoromethyl-o-chloro-anilino) -phenyl] -acetic acid crystallizes out, M.p. 94-96 °, yield 55 # of theory.

The following are produced in the same way:

o- (2,6-xylidino) phenylacetic acid, m.p. 120-127 ° *. o- (2, j5-xylidino) ~ phenylacetic acid, m.p. 112-113 °. o- (2-Methyl-j5-chloro-anilino) -phenylacetic acid, m.p. 124-125 °.

The starting material, α-cyano-N- (3-trifluoromethyl-6-chlorophenyl) -o-toluidine were obtained as follows;

a) a-chloro-N- (3-trifluoromethyl-6-chlorophenyl) -o-toluidine A solution of 20 g of o- (3-trifluoromethyl-6-chloro-anilino) -benzyl alcohol in 70 ml of acetyl chloride is under a nitrogen atmosphere for 16 hours heated to reflux. Then the solution is evaporated at about 40 ° under reduced pressure. The residue is taken up in 40 ml of benzene and concentrated again. Then take up the residue with 200 ml of ether, and wash the ethereal solution

BAD OBIG »NAL 909886/1686

solution with 2-η. Sodium carbonate solution and water, dries over Sodium sulfate and evaporate the solvent under reduced pressure. The remaining oil is distilled in a high vacuum, bp. 120 ° / 0.001 torr. The α-chloro-N- (3-trifluoromethyl-6-chlorophenyl) -o-toluidine can be crystallized from petroleum ether. M.p. 50-51 ° The yield is J52 # of theory.

The following is obtained analogously:
4-chloro-2- (2 ^f , 6'-dichloroanilino) benzyl chloride

909886/1686

4-chloro-2- (2% 6'-dimethylanilino) benzyl chloride, m.p. 113-117 ° \ 5-methoxy-2- (2 ', 6 · -dlchloroanilino) benzyl chloride, m.p. 82-. 84 ° from petroleum ether.

b) g-Cyano-SO-trifluoromethvl-o-chlorophenvD-o-toluidln

A suspension of 6 g of sodium cyanide in 120 ml of dimethyl sulfoxide is heated to 40 ° * Then a solution of 33 g of a-chloro-SO-trifluoromethyl-e-chlorophenyD-o-toluidine in 150 ml of dimethyl sulfoxide is added with stirring, the temperature being 40 ° should not exceed. The mixture is stirred for 3 hours at 40 ° and then diluted with 600 ml of water. The solution is then extracted three times with 1000 ml of ethyl acetate each time. The combined MBS extracts are then washed with 100 ml of 6-n. Hydrochloric acid and 100 ml of water, dry them over sodium sulfate and distill off the solvent under reduced pressure. The residue is distilled in a high vacuum. The a-cyano-N- (3-trifluoromethyl-6-chlorophenyl) -o-toluidine boils at 122-126 ° / 0.01 Torr and can be crystallized from petroleum ether. After recrystallization, the srap lies. at 58-59 °. The yield is 74 % of theory.

The following is obtained analogously:

α-cyano-4-chloro-N- (2,6-dichlorophenyl) -o-toluidine, mp 113-115 °; α-cyano-4-chloro-M- (2,6-xylyl) -o-toluidine, m.p. 131-132 °; α-Cyano-S-methoxy-ii-Cije-dichlorophenyD-o-toluidine, m.p. 169-171 °.

The conversion to α-bromotoluidines was SHMi with hydrobromic acid executed:

c) 4-chloro-2- (2 '«6 * -dichloro-anilino) -benzyl bromide

In a solution of 3.3 g of 4-chloro-2- (2 ^l -6 '-dichloroanilino) - \ m 50 ftt /

Benzylalkoholk'wird introduced hydrogen bromide over 15 minutes, then stirred while blowing nitrogen through for 1/2 hour. The user solution is 2-n. Washed soda solution and evaporated.

^909886/1686 SADORIG.NAU

The resulting crystals are used without further purification. Yield 92 #.

The following were produced in the same way:

4-chloro-2- (2 · , ö'-dimethylanilinoJ-benzyl bromide m.p. 107-109 ° )

5-methoxy-2- (2, 6'-dichloroanilino) benzyl bromide, m.p. 102-104 °.

Example 4

o- (2.6-dichloro-m-toluldino) -hy.dratropasäuf e 2-Γ o- (216-dichloro-m-toluidlno) -phenylI-propionic acid

A solution of 3.1 g of l- (2,6-dichloro-m-tolyl) -3-methyl-2-indolium in 35 ml of ethanol and 20 ml of 1-n. Sodium hydroxide solution is refluxed for 1 hour. The solution is then concentrated under torr at 50 °, the residue is dissolved in 200 ml of water and the aqueous solution is extracted with 50 ml of ether. The aqueous solution is separated off and treated with 2-n. Hydrochloric acid acidified at 5 °. The precipitated oil is dissolved in 100 ml of ether, the ethereal solution is washed with a little water, dried over sodium sulphate and concentrated cold under torr. The residue is crystallized from ether-petroleum ether. The o- (2,6-dichloro-m-toluidino) hydrate joic acid melts after crystallization from ether-petroleum ether at 143 ° -14 °. The yield is 30 % of theory.

Q Analog is produced:

oo o- (2,6-dichloro-phe * v *) - hydratjopaic acid, Srap. 154-156 ° from Aetheroo
'&> Petroleum ether

^ 2- [o- (2, 6-dichloro-m-toluidino) -phfenyl] butyric acid \ S [o- (2 '6-Dlchlor ■ -anlllno') - phenyl ^ »- benzyl-eailgsäure, September 132-133 ° from Aether / Ρβtrollther j

The indolinones required for this were produced as follows:

as-

a) N-phenyl-2,2 ', 6'-trichloropropionic SS-m-toluldid

A solution of 5 g of 2,6-dichloro-N-p'henyl-m-toluidine (obtained according to Example 1a) in 20 ml of α-chloro-propionyl chloride is refluxed for one hour while passing in nitrogen. It is evaporated to dryness in vacuo at 40 ° and the residue is dissolved in ethyl acetate-chloroform 1: 1. The solution is with 2-n. Extracted potassium bicarbonate solution and water, dried over sodium sulfate and evaporated under 11 torr at 40 °. The residue is distilled in a bulb tube. The N-phenyl-2,2 ¹ , 6 ', - trichloropropionyl-mtoluidid boils at 155-160 ° / 0.001 torr. Crystallized from ether-petroleum ether, the compound melts at 105-107 °. The yield

It accounts for 59 % of the theory.

Analog is produced:
! ', ö'-Trlchlar-N-propionyl-diphenylamine, ^{m.p. 123-125 0} ^ from Metha- and

2-chloro-2 ', o'-cLLaethyl-N-propionyl-diphenylamine, m.p. 126-128 ° from Methanol.

b) 1- (2-6-dichloro-m-tolvl) -3-methyl-2-indolinone

A mixture of 31.2 g of N-phenyl-2.2 ^l , 6'-trichloro-propionyl-m-toluidide and 31.2 g of aluminum chloride is heated to 160 ° for 2 hours. The melt is cooled and poured onto 500 g of ice. The precipitated oil is dissolved in 100 ml of ether. The ether solution is with 50 ml of 2-n. Washed potassium bicarbonate solution and 100 ml of water, dried over sodium sulfate and concentrated in vacuo at 40 °. The residue is chromatographed on 500 g of neutral aluminum oxide.

Fractions 3-7, eluted with benzene, contain there · 1- (2,6 ~ Diehlor-m-tolyl) -3-methyl-2-indolinone. They are combined and crystallized from ether, m.p. 110-130 ·. The yield is 44 % of theory. 909I88 / H88

Analog is produced :

1- (2,6-dichlorophenyl) -3-methyl-2-indolinone, melting point 98-99 °, from ethyl acetate-petroleum ether. '>

c) 3-Ethyl-1- (2.6-dichloro-dhenyl) -2-indolinone To a suspension of 1 g of sodium hydride mineral oil suspension in 30 ml of absolute dimethylformamide, a solution of 5.6 g of l- (2 , 6-dichlorophenyl) -2-indolinone in 10 ml of absolute dimethylformamide was added dropwise. The mixture is then stirred at 10 ° for 40 minutes. 3.2 g of ethyl iodide are then added dropwise and the mixture is stirred for 15 hours at room temperature. It is poured onto ice and extracted with 200 ml of ether. The ether solution is separated off, washed with water, dried over sodium sulfate and evaporated to dryness under 11 torr. The residue is chromatographed on 200 g of neutral aluminum oxyä. Fractions 2 and 3, eluted with ether-petroleum ether III, contain pure 3-ethyl-1- (2,6-dichlorophenyl) -2-indolinone. After two crystallizations, the compound melts at 100-101 °. The yield is 15 % of theory. d) l- (2.6-dichlorophenyl) -3-benzal-2-indolinone 2.78 g of l- (2,6-dichlorophenyl) -2-indolinone were dissolved in 50 ml of absolute ethanol, then with 1.06 g of benzaldehyde and 2 drops of piperidine are added and the mixture is heated to 50 ° for 5 hours. The reaction mixture is then evaporated in vacuo and the residue is purified by chronographing on an aluminum oxide column . The 1- (2,6-dichlorophenyl) -3-ben * al-2-indolinone crystallizes from ether, resounds at 135-136 *. Yield 80 % theory of 4.

3 f of the 1- (2,6-dichloro-henyl) -3-b * nial-2-indolinone just obtained dissolved in 100 % of Diexan. Then 0.2 g of 5% platinum charcoal are added and the mixture is hydrogenated at aau temperature and pre-chamber pressure. Is formed l- (2, # - dichlorophenyl) -3 - "* nsyl-2-indolinone" (O Jl, yield.

909186/1111

ÖAD ORIGINAL Example 5

0- (2 «6-dichloro-m-toluidino) -a-methvl-hydratopic acid 2-fo- (2 «a-dichloro-m-toluidino) -phenyl! -2-methyl-propionic acid

A solution of 1.5 g of l- (2,6-dichloro-phenyl) -3,3-dimethyl-2-indolinone in 15 ml of ethanol and 10 ml of 2-n. Sodium hydroxide solution is refluxed for 48 hours. It is then cooled to room temperature and 50 ml of water are added. The precipitated crystals are filtered off. The filtrate is extracted with 30 ml of ether. The ether solution is separated off and the aqueous phase with 2-n. Acidified hydrochloric acid. The precipitated crystals are dissolved in chloroform / ether 1: 1, the organic phase is washed with water), dried over sodium sulfate and concentrated under 11 torr at 40 °. The residue crystallizes from ether. The o- (2,6-dichloro-m-toluidino) -a-methyl-hydratiopaic acid melts after recrystallization from ether at 187-192 °. The yield is 20 % of theory.

The starting materials are prepared as follows: a) 1- (2.6-dichlorophenyl) -3.3-dimethyl-2-indolinone To a suspension of 2.1 g of atrium hydride mineral oil (1: 1) in 30 ml of absolute dimethylformamide a solution of 5.6 g of 1- (2,6-dichlorophenyl) -2-indolinone (melting point 126-127 °) in 10 ml of absolute dimethylformamide is added dropwise under nitrogen at 0-5 °. The mixture is stirred for 40 minutes at 10 ° and then 7 g of methyl iodide are added dropwise. The mixture is then stirred for 15 hours at room temperature and poured onto crushed ice. It is extracted 5 times with 200 ml of ether. The ether extracts are combined and washed with 100 ml of water, dried over sodium sulfate and evaporated under 11 torr. The residue is crystallized from ether. The 1- (2,6 ~ dichlorophenyl) -3,3-dimethyl-2-indolinone melts at 128-130 °.

The yield is 67 % of theory.

9 0 9 8 8 6/1686 _BAD

example S *

Γ ο- (2.6-dichloro-anilino) -phenvli-acetic acid

A solution of 1 g of [o- (2,6-dichloro-anilino) -phenyl] -acetic acid methyl ester in 20 ml of methanol and 5 ml of 2-n. Potassium carbonate solution is refluxed for 15 hours. It is concentrated to dryness in vacuo, diluted with 70 ml of water and the aqueous solution is extracted with 20 ml of ether. The aqueous solution is with 2-n. Acidified hydrochloric acid, extracted the precipitated oil with ether and washed the ethereal solution with water, dried over sodium sulfate and concentrated cold under 11 torr. The [o- (2,6-dichloro-anilino) -phenyl] -acetic acid crystallizes from ether-petroleum ether, melting point 156-158 °. The yield is 75 % of theory.

In the same way, the [o- (2,6-dichloro-anilino) -phenyl] -acetic acid ethyl ester, Saponify melting point 50-52 °. The ester was obtained as follows:

a) Γ ο- (2.6-dichloro-anilino) -phenvl1-acetic acid methyl ester To a solution of 10 g [o- (2,6-dichloro-anilino) -phenylj-

acetic acid (m.p. 156-158 °) in 150 ml of absolute ether is slowly added dropwise 100 ml of 2% ethereal diazomethane solution. The solution is left to stand overnight at room temperature and then concentrated to dryness under 11 torr at 40 °. The residue is dissolved in 100 ml of ether. The ether solution is with 50 ml 1-n. Extracted potassium bicarbonate solution and water, dried over sodium sulfate and concentrated under 11 torr at 40 °. The residue crystallizes from ether-petroleum ether. The methyl [o- (2,6-dichloro-anilino) -phenyl] -acetate melts at 101-102 °. The yield is 72 % of theory. ·.

b) fP- (2,6-dichloro-anilino) -phenyl-acetic acid! thylester A solution of 16 g [o- (2,6-dichloro-anilino) -phenyl3-acetic acid in 1600 ml water and 40 ml 2- n. Sodium hydroxide solution is cooled to 5 °. 10 ml of diethyl sulfate are added with stirring,

909886/1686

BAD ORJGiNAL

the solution being cooled with an ice bath. The mixture is stirred for 2 hours at 5-10 ° and then another 20 ml of 2-n. Sodium hydroxide solution and 10 ml of diethyl sulfate. The reaction mixture is then stirred for 15 hours at room temperature. The precipitated crystals are filtered off, washed well with water and dissolved in 100 ml of ether. The ethereal solution is extracted with 30 ml of water, dried over sodium sulfate and concentrated under reduced pressure at 40 °. The ethyl [o- (2,6-dichloro-anilino) -phenyl] -acetic acid crystallizes from ether-petroleum ether, melting point 50-52 °. The yield is 15 % of theory.

example

Γ ο- (2 «6-dichloro-anilino) -phenyl! -Acetic acid

1> 2 g of benzyl [o- (2,6-dichloro-anilino) -phenyl] -acetate are dissolved in 50 ml of fine spirits and, after adding 0.2 g of Seiger Pd carbon, hydrogenated at low pressure and room temperature. The hydrogenation is complete after 1 1/4 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under 11 torr at room temperature. The residue will be off. Recrystallized ether-petroleum ether, m.p. 156-158 °. The yield is 67 % of theory.

The benzyl ester is obtained as follows: a) Γ ο- (2.6-dichloro-anilino) -phenyl-acetic acid benzyl ester A solution of 2.96 g [o- (2,6 ~ dichloro-m-äöSBfee * BBÖ-phenyl] -acetic acid, 1.2 g of absolute benzyl alcohol and 3 g of dimethylformamideineopentyl acetal in 40 ml of methylene chloride are stirred under nitrogen for 55 hours.

9 09886/1686 BADdFJQiNAt

Distilled off chloride. It is diluted with 50 ml of ethyl acetate, the solution is extracted with water and dried over sodium sulfate. The solution is concentrated to dryness under 11 torr at 40 °. The residue is chromatographed on 60 g of neutral aluminum oxide. Fractions 2 and 3, eluted with ether-petroleum ether 7: 3, contain the pure benzyl [o- (2,6-dichloro-anilino) -phenyl] -acetate. The yield is 30 % of theory.

But it can also be obtained in the following way: To 40 ml of absolute benzyl alcohol one leaves at -10 ° Thoroughly stirring and passing in nitrogen, 6 ml of thionyl chloride are added dropwise. After 5 minutes, a solution of 2.96 g is obtained at -10 °

aniline ο

[o- (2,6-dichloro-m-ääsd * feBSt) -phenyl] -acetic acid in 10 ml of absolute benzyl alcohol was added dropwise. The reaction mixture is then stirred for 15 hours at room temperature and poured onto ice. The precipitated oil is extracted with 100 ml of ether. The ether extract is washed with 10 ml 2-n. Potassium bicarbonate solution and water, dried over sodium sulfate and evaporated the ethereal solution under 11 Torr at 40 ° to dryness. The residue is chromatographed on 90 g of neutral aluminum oxide. Fractions 1 and 2, eluted with ether-petroleum ether 1: 1, contain the pure benzyl [o- (2,6-dichloroanilino) phenyl] acetic acid ester. The yield is 48 % of theory.

909 886 / $ 168

Example 8 ^Γ ο- (2.6-Ρ1οΗ1θΓ-βη111ηο) -ρ1ΐ6ηνΐ1 -acetic acid

A solution of 0.5 g of [o- (2,6- * dichloro-anilino) -phenyl] -acetic acid methyl ester (melting point 101-102 °) in 40 ml of 75% ethanol with 12 g of Dowex 1 ion exchanger ( OH form, 20-50 mesh) stirred for 15 hours at 50 °. Then it is filtered off. The residue is suspended in 20 ml of water and acidified at 5 ° with 1-n. Hydrochloric acid. 30 ml of ether are added, the mixture is shaken and the ethereal solution is separated off. The ether solution is washed with 10 ml of water, dried over sodium sulfate and concentrated to dryness under 11 torr. [O- (2,6-dichloro-anilino) -phenyl] -acetic acid crystallizes from ether-petroleum ether, melting point 156-158 °. The yield is 45 % of theory.

Γo- (2.6-chloro-anilino) -phenyl! -Acetic acid. Na-salt

A solution of 186 g of l- (2,6-dichlorophenyl) -2-indolinone in 660 ml of ethanol and 660 ml of 2-n. Sodium hydroxide solution is refluxed for 4 hours. The solution is then cooled and left to stand for 4 hours at 0-5 °. The precipitated crystals are filtered off and recrystallized from water ) -phenyl] -acetic acid sodium salt melts at 283-285 ° The yield is 97 % of theory.

ΐ
Analog is produced:

C 5-chloro-2- (2,6-dichloro-anilino) -phenyl] -acetic acid, sodium salt, M.p. 296 ° from water.

90ÜSI / 1686

3t

Example ld ro- (2.6-Dlchlor-anillno) -phenvl1-acetic acid-K-salt

To a solution of 8.9 g [o- (2,6-dichloro-anilino) -phenyl] acetic acid in 50 ml of ethanol is 20 ml of 8 $ ethanolic Potassium hydroxide solution added. The solution is boiled with activated charcoal for 10 minutes, filtered and concentrated under 11 torr. At the The addition of ether crystallizes the [o- (2,6-dichloro-anilino) -phenyl] -acetic acid-K-salt from melting point 300-330 ° decomposition.

0 9 8 8 6/1686

Claims (4)

Claims 1. Process for the preparation of new substituted phenylacetic acids of the general formula I, (D in which R, a lower alkyl or alkoxy radical, a halogen atom up to atomic number 35 or the trifluoromethyl group, Rp and
R ₃ each hydrogen, a lower alkyl or alkoxy radical, or a halogen atom up to atomic number 35, R 1 is hydrogen, a lower alkyl or alkoxy radical Halogen atom up to atomic number 35 or the trifluoromethyl group, R ₅ and * ■ '· Rg each is hydrogen, a lower alkyl radical or a benzyl radical mean, and their salts with inorganic and organic bases, thereby characterized in that one is a compound of the general formula 909886/1686 (Π) in which R ^ - Rg have the meaning given above, with a Alkali metal or alkaline earth metal hydroxide or an alkali metal carbonate converts in the heat and, if desired, releases the acid from the alkaline earth or alkali metal salt obtained. 2. Modification of the process according to claim 1 for the preparation of new substituted phenylacetic acids of the formula I, and their Salts, characterized in that a compound of the general formula III, C - COOR (III) in which R-, - Rg have the meaning given in the general formula I, and R _{7 is} a lower alkyl or aralkyl radical, in particular the benzyl radical and A is hydrogen or an acyl radical, in particular a lower alkanoyl radical, with an alkali metal hydroxide, carbonate or bicarbonate, an alkaline earth metal hydroxide, or converts a basic ion exchanger in the heat, or if R _{7 is} the benzyl radical, this splits off by hydrogenolysis with catalytically activated hydrogen, and if desired from the 909886/1886 ^mD original The alkaline earth or alkali metal salt obtained releases the acid. 3. Modification of the process according to claim 1 for the preparation of new substituted phenylacetic acids of the formula I,
and their salts, characterized in that a compound of the general formula IV ₉ C-CS (IV) wherein A and R, - R, those given in formulas I and III
Have meaning, reacts with an alkali metal hydroxide in a water-containing solvent in the heat and, if desired, liberates the acid from the alkali metal salt obtained. 4. Modification of the process according to claim 1 for the preparation of new phenylacetic acids and their salts, characterized in that a free acid thus obtained is converted into a salt with
an inorganic or organic base. $ Ss- ^. υ. l / l 909886/1686 Nu / yes / 22. 2.1966 "