SU472499A3 - The method of obtaining - (aminophenyl) -aliphatic carboxylic acids or their derivatives or salts - Google Patents

Description

3-cyclohexenyl groups containing up to 4, preferably 1 or 2 lower alkyl, in particular methyl residues.

The cycloalkyl-lower alkyl or cycloalkenyl lower alkyl residue is one of the lower alkyl group, containing, and preferably up to 4 atoms and containing in any position, preferably at the extreme carbon atom, one of the above cycloalkyl or cycloalkenyl groups; such residues are, for example, cyclonepropylmethyl, 2-cycloylmethylethyl, or 3-cyclopentenylmethyl.

Phenylene residue Ph containing group

A k in position 2, preferably 3, and in

first of all in position 4, may in appropriate case contain in other positions of one or several substituents, preferably 1 or 2, identical or different. Such substituents are lower alkyl groups, free esterified esters of ethers or esters of aryl or mercano group, such as lower alkoxy, for example, methoxy, ethoxy, n-propyloxn, isopropyloxy, m-butyloxy or isobutyloxy, lower alkyl mercapto, for example, methyl m-butyloxy or isobutyloxy, lower alkyl mercapto, for example, methyl m-butyloxy or isobutyloxy, lower alkyl mercapto, for example, methyl butyloxy, isopropyl, m-butyloxy or isobutyloxy, lower alkyl mercapto, for example - or ethyl mercapto groups, or halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, trifluoromethyl groups, nitro groups, amino groups, preferably di-alkylamino, for example dimethylamino, N-ethyl-N-methlamine, diethylamine, di-to-propylamio, -, diisopropylamino, di-or nbutilamino- diisobutylamino, chizshy alkilenamino- alkenilenamino- or lower, e.g. pyrrolidino, piperidiI-IO-, pirrolino- or piperideinogrupny, monoaza-, monooksa- or monotialkilenamino- example piperazino, 4-nizschy alkilpiperazino- , morpholino, or thiomorpholino groups, or lower alkanoylamino, for example, acetylamino or pivaloylamino groups, then, in appropriate case, functionally modified carboxyl groups, such as carbonized alkoxy, for example, carbomethoxy or carbethoxy groups substituted, as appropriate, for example, lower alkyl residues, N-substituted carbamoyl groups, such as di-lower alkylcarbamoyl, for example dimethylcarbamoyl groups, or cyano groups, lower alkylsulfonyl, for example methylsulfonyl or ethylsulfonyl groups, or in the appropriate case, functionally modified sulfoglyl or ethylsulfonyl groups, or in the corresponding case, functionally modified sulfoglyl or ethylsulfonyl groups, or in the corresponding case, functionally modified sulfogram, or for example substituted sulfamoyl groups, for example, di-lower alkylsulfamoyl-, as dimethylsulfamoyl. The balance of Ph is, in particular 1,3- or 1,4phenylene-, (lower alkyl) -1,3- or -1,4-phenylene-, (lower alkoxy) -1,3- or -1,4-phenylene -, (mono- or dihalogen) -1,3- or -1,4-phenylene-, (trifluoromethyl) -1,3- or -1,4-phenylene-, (nitro) -1,3- or -1 , 4-feiilen-, (amino) -1,3- or -1,4-fennlen-, (di-alkylamino) -1.3 yl -1,4-phenylene-, or (lower alkylenamino) -1,3- or -1,4-phenylene group. The bicyclic alkenylamino group is preferably a suitably substituted residue, always containing 5-6 units in the ring and in the isocyclic part 1-3 double bonds. It is primarily a benzoalkenylene amine residue or the corresponding dihydronly tetrahydrobenzoalkenylene-amber residue, in which the alkenylene amine portion contains 5-6 units in the ring, and which can be

substituted in the appropriate case in the aromatic part, for example, the phenylene residue of Ph, in particular lower alkyl radicals, which are esterified into an ether or ester of hydroxy or mercaptogruips,

for example, lower alkoxy or lower alkanoyloxy groups, as well as halogen atoms, and which in the aliphatic part may also be substituted by oxo or tiono groups. Such groups are, for example,

1-IIDOLINYL-, 2-IZOINDOLINIL-, 1,2,3,4-tetrahydro-1-hiiolinyl- or 1,2,3,4-tetrahydro-2IZOH-CHINOLINIL-, as well as 4,5,6,7-tetrahydro- Ь INDOLINIL-, 4,5,6,7-tetrahydro-2-isoindolyNIL-, 4,7-dihydro-1-indolinyl-, 4,7-dihydro-2 isoindolinyl, 1,2,3,4,5,6 , 7,8-octahydro-1-hiiolINIL-, 1,2,3,4,4,6,7,8-octahydro-2-isoquinolinyl, 1,2,3,4,5,8-hexahydro-1 - quinolinyl or 1,2,3,4,5,8-hexahydro - 2-isochnolinyl groups, which may

be replaced.

The functional derivatives of the acid are preferably their esters, for example, lower alkyl or lower

alkenyl; cycloalkyl, cycloalkenyl, cycloalkyl lower alkyl or cycloalkenyl lower alkyl, where the cycloaliphatic residue contains 3-7 units in the ring; aryl or aryl lower alkyl, where the aromatic residue is a substituted phenyl group, as appropriate, for example, Ph residue; free or ether-esterified oxy-lower alkyl-, for example, lower alkoxy-lower

alkyl or cycloalkoxy-lower alkyl ethers, where cycloalkyl contains 3-7 units in the ring, or Greg-aminone-lower alkyl ether, where g / Z-amino group means, for example, di-lower alkylamino, for example dimethylamino or diethylamino, lower alkyleno-alkylamino, for example dimethylamino or diethylamino, lower alkyleno-alkylamino, for example dimethylamino or diethylamino, lower alkyleno-alkylamino; or monoaz-, monoox- or monothian-alkyleneamino-, for example piperazino-, 4-lower alkyliperazino-, for example 4-methylpiperaznno-nli 4-ethylpiperazino-, morpholino- or thiomorpholino. In the ester residues containing heteroatoms, the latter are separated from each other and from the oxygen of the carboxyl group of at least two

preferably 2-3, carbon atoms. Further functional derivatives of the acids of formula I are the appropriately substituted amides or thioamides, such as mono or di-lower alkylamides, arylamides or aryl-lowering alkylamides, where the aromatic residue is preferably substituted in the appropriate case, for example, as a Ph residue, phenylglucose, or monocyclic lower alkylene-, monoazylated alkylene-, mono-oxanized alkylene- or monothian-containing alkyleneamides, then the corresponding triamides, hydroxamic acids or nitriles. The functional amino amino derivatives are N-oxides or lower alkyl- or aryl-lower alkyl-quaternary ammonium salts, where aryl means preferably substituted, for example, as Ph, a phenyl group. Salts are ammonium or metal salts, as well as acid addition salts. The proposed method consists in that a compound of general formula II — Tv — ph — x, where X is a group of the formula —C (R) (R2) —Yi, where YI is a metal moiety, is reacted with a reactive, metal-free derivative coal nly formic acid. The metal moiety Y is, for example, an alkali metal atom, a lithium atom, or a substituted alkaline earth metal atom, zinc or cadmium, a halogen magnesium group, and a lower alkyl zinc or lower alkyl cadmium, for example, chlorine, bromine or iodo magnesium, and also methyl -, or ethylzinc-, then methyl- or ethylcadmiumgrupp. The metal compound NLI Grignard of formula II is reacted with a suitable free of metal produces carbonic or formic acid nredpochtitelno with carbon dioxide, or carbon disulfide, but also with sootvetstvuyunshm karboiatom NLI ester of haloformic acid such as diethyl carbonate or dietiltiokarbonatom, lower alkyl ester ortomuravnnoy acid as its ethyl or propyl ether, lower alkyl halide ester, its phenyl, or phenyl lower alkyl ester, where lower alkilfenil- fennlnizshy or alkyl groups may be substituted, if appropriate as ethyl chloroformate, its m / 9eg-butyl ether, allyl ether, 2-methoxyethyl. feiyl or benzyl esters, or a halogenated or carbamoyl halide, such as cyanamide or diethylcarbamoyl chloride. The resulting compounds can be converted into each other in a known manner. For example, the resulting free acids can be esterified into an ester using alcohols in the presence of esterification agents as strong acids, for example hydrochloric, sulfuric, benzenesulfonic or p-toluenesulfonic, and dicyclohexylcarbodiimide, diazo compounds, or convert them to acid halides. halogenation agents, thionyl halides, such as tnonnlhlind or phosphorus halides, or phosphorus oxyhalides, for example chloride, or phosphorus oxychlorides. The resulting esters can be grouped into free acids, for example, by treatment with suitable basic agents, such as aqueous hydroxides of I1, Christmas metals, or transesterified into other esters with the help of alcohols in the presence of acidic or alkaline substances, such as mineral acids or complex acids of heavy metals. as well as alkali carbonates or alcoholates. By treating with ammonia or the corresponding amines, the esters can be converted to amides. In esters, halides, anhydrides, amides, thioamides or nitro acids, a review of the choice of starting materials and the use of reagents, it is possible to not convert the obtained acid halides using alcohols, as well as ammonia or amines, and the resulting metal or ammonium salts using alcohols or the corresponding halides , for example, NLP bromide chlorides, or the corresponding chlorosulfites, thionyl halides, for example thionyl chloride, and phosphorus thioxide, phosphorus pentasulfide, phosphorus halides, for example phosphorus peitachloride, or oxyhalo phosphorus ide, for example phosphorus oxychloride, or other acyl halides, such as acyl chlorides. The resulting amides or thioamides can be hydrolyzed, alcoholized or not rectified under acidic or alkaline conditions, eg, by treatment with aqueous mineral and (or) carboxylic acids, or alkali metal hydroxides, then they can be desulfurized, eg, by treatment with mercury oxide (II) and lower alkyl halides, with the following hydrolysis. The nitriles obtained can be hydrolyzed or alcoholized using concentrated aqueous alkali acids or alkaline hydroxides of alkali metals, as well as alkaline hydrogen peroxide. Compound. containing oxo groups, it is possible to not convert to the corresponding tio compounds, for example, by treatment with pentasul gm of phosphorus. In the bicyclic residue without oxo groups, the latter can be introduced by pu

by oxidation, for example, by oxygen or other mild oxidizing agents, to the part containing the nitrogen atom as a member of the ring, in particular, to one or both of the cyclic nitrogen atom, the corresponding lactam or imide compounds are obtained from the amine.

The esters, salts or nitriles obtained in which at least one of the groups Ri and R2 means hydrogen can be metallized in the a-position into a functionally modified carboxyl group, for example, treatment with alkali metals or their derivatives - organic compounds of alkali metals, for example phenyl lithium or triphenylmethyl nitriles, or alkali metal alkoxides, such as hydrides, amides or sodium alkoxides, and then reacted with a reactive alcohol ester of the formula RI-OH and (or) R2- HE as the corresponding halide and thus introduce into the "-position" an organic group Ri or R2. The resulting compounds can be halogenated in the aromatic residue Ph, using, for example, halogen, preferably in the presence of Lewis acid-iron (III) halide, aluminum halide, antimony (III) or tin (IV), or halogenation of hydrochloric acid in the presence of hydrogen peroxide, or alkali metal chlorate, for example sodium chlorate, nitrosyl halide-nitrosyl chloride, or -bromide, halide-bromosuccinimide or bromophthalimide.

The nitro group can further be introduced into the aromatic residue by treating with nitric acid or nitrate salts under acidic conditions in the presence of sulfuric trifluoroacetic acid. In the nitro compound obtained, the nitro group can be reduced by treatment with catalytically activated hydrogen or chemical reducing agents (formed at the moment of hydrogen evolution) to give an amino group .

In these or other reduction operations, care must be taken to ensure that the unsaturated alkenylene amine residue is retained.

The resulting compounds containing the primary amino group can be reacted with reactive esters of alcohols or glycols, as well as reactive functional

derivatives, such as halides with acid chlorides or anhydrides, and thus converted into compounds containing secondary or tertiary amino groups or quaternary ammonium groups, as well as acylated amino groups. If the resulting compounds with a free amino group are treated with nitric acid, diazonium salts are obtained, which according to Zandmeier's reaction, for example, by hydrolysis at elevated temperature, by treatment with copper (II) halide or copper (P) cyanide, or with a lower alkanol or a lower alkylmer of itan, preferably with neutral or weakly acidic or alkaline conditions, can be converted to the corresponding hydroxy, halogen,

cyan, lower avTKOKCH- or lower alkyl mercapto compounds.

In the resulting products, phenolic hydroxy or merkaitol groups can be esterified into ether with the help of the corresponding metal-phenolic and thiophenol alkali metal phenols, by treatment with lower alkanols or cycloalkanols with reactive esters, such as lower alkyl or cycloalkyl halides,

sulphates or sulphonates, as well as diazo-compounds, as diazon-lowering alkanes. The resulting phenol ethers can be cleaved, for example, by treatment with strong acids or acid salts, such as hydrobromic and acetic acids, as well as pyridine hydrochloride. Aliphatic oxo compounds can be dehydrated using the method described above. The resulting unsaturated compounds can be saturated by treatment with catalytically activated hydrogen or chemical reductants (formed at the time of release with hydrogen), with the creation of double bonds, for example, in Ro-rpynne and / or group

ester.

In the resulting compounds with oxy groups which can be cleaved by hydroxy groups that are esterified into an ester in the residue A T, such groups can be removed together with hydrogen, i.e., by introducing a double bond,

for example, according to the above method.

The resulting free acid can be converted into a salt in a known manner, for example, by reacting with a stoichiometric amount of a suitable salt-forming agent ammonia, amine or carbonate hydroxide, or an alkali metal or alkaline earth metal bicarbonate.

The ammonium or metal salts thus obtained can be converted freely.

acid, adjusting them to the desired pH by treatment with acid-hydrochloric, sulfuric, or acetic acid.

The resulting basic compound can be converted to an acid addition salt by reacting with an inorganic or organic acid or anion exchange resin, followed by isolation of the salt formed. The resulting acid addition salt can be converted to the free compound by treating with a base, for example, an alkali metal hydroxide, ammonia or an oxy-ion exchanger. Pharmaceutically applicable, non-toxic acid addition salts are salts with inorganic hydrochloric acids,

hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, in particular organic carboxylic or sulfonic acids, such as formic, acetic, iropionic, succinic, glycolic, lactic, block, tartaric, citric, ascorbic, maleic, oximericineman, blocky, tartaric, citric, ascorbic, maleic, oximericinemericine, blockine, tartaric, citric, ascorbic, maleic, oximericinemericine, blocky, tartaric, citric, ascorbic, maleic, oximericine, block, tartaric, citric, lactic, blocky, tartaric, citric, ascorbic, maleic, oximericine, block, tartaric, citric, lactic, block, tartaric acid benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic or nicotine, and also methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethylene sulfonic, benzenesulf new, halogenbensenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid.

These and other salts, such as picrates, can also be used for purification, as can the definition of free compounds. Thus, the free compounds can be converted into their salts, separated from the crude mixture, and then the free compounds can be obtained from the isolated salts. In view of the close connections between new compounds in free form and in the form of their salts, free compounds or salts should be understood, depending on their meaning and purpose, corresponding salts or free compounds.

The resulting mixtures of isomers can be separated into individual isomers in a known manner, for example, by fractional distillation or crystallization and / or chromatography. Racemic products can be resolved onto optical anti-iodides by separating diastereoisomeric salts, such as fractionated crystallization of mixtures of diastereoisomeric salts, for example, d-or tartaric acid, or rf-a-phenylethylamine, (1-naphthyl) -ethylamine or / -cinquiidine and, if desired, isolation of free antipodes from salts.

The reactions are carried out in the presence or without diluents, preferably inert with respect to the participants of the reaction or dissolving the diluent, if necessary, in the presence of catalysts, con (with natural or neutralizing agents, in an inert atmosphere of nitrogen, with cooling or heating and / or with increased pressure.

Example 1. To a mixture of 0.25 g of magnesium, 10 ml of tetrahydrofuran and 1 drop of methyl iodide a solution of 3 g of (2-isoindolinyl) -phenyl ethyl bromide in 5 ml of tetrahydrofuran is added dropwise with stirring, the mixture is boiled under reflux. the reaction will not end. Then, carbon dioxide is passed under strong agitation for 50 minutes at 0 ° C, diluted with water, adjusted to pH 4 with hydrochloric acid, and extracted with diethyl ether. The organic extract is dried and mixed. The residue is recrystallized from ethyl acetate to give (4-isoindolinyl) -phenyl-propionic acid; m.p. 247-250 ° C .-

The source material can be obtained in the following way.

To a solution of 2.4 g of 4- (2-isoindolinyl) acetophenone in 30 ml of ethanol was added 0.75 g

sodium borohydride and refluxed for 2 hours, then diluted with water and concentrated under reduced pressure. The mixture is diluted with water and extracted with ethyl ether; organic

the extract is dried and evaporated under reduced pressure. Thus, (2-isoindolyiyl) -phenyl-ethanol is obtained.

A solution of 2.5 g (2-isoindolinyl) -phenyl ethanol in 20 ml of benzene is treated with 0.43 g

phosphorus pentachloride, the mixture is refluxed for 2 hours and cooled. It is washed with water, dried and diluted with a lower pressure. As a result of the operations performed,

(2 - isoindolinyl) -phenyl - ethyl bromide, which does not need to be purified for processing. In a similar way, one can obtain by choosing suitable starting materials and, if appropriate, after additional

The following are conversions:

(2-isoindolinyl) -phenyl acetic acid ethyl ester, mp. 118-120 ° C (after recrystallization from ether); a-3-chloro-4- (1,3-dioxo-2-isoindolinyl) -phenyl-propionic acid ethyl ester; m.p. 107-110 ° C (after recrystallization from ether;

(2-isoindolinyl) phenyl propionic acid ethyl ester; T. Il. 111-113 ° C

(after recrystallization from ethanol);

(1,3-dioxo-1,2,3,4-tetragndro-2-isohioolinyl) -phenyl-acetic acid ethyl ester; T. Il. 89-91 ° C (after recrystallization from ethanol);

a-3-chloro-4- (1-OXO-2-isoindolinyl) phenyl propionic acid ethyl ester; m.p. 111

o; - 3-chloro - 4 - (- oxo-2 - isoindolinyl) -phenyl-propionic acid; m.p. 178-180 ° C; (1-oxo - 2-pzoindolinyl) - phenyl-acetic acid, t. Pl. 206-208 ° C;

(1-oxo-2-isoindolinyl) phenyl acetic acid ethyl ester, m.p. 111 -

(1-oxo-2-isoindolinyl) phenyl propionic acid methyl ester; m.p. 129-132 ° C.

(1-oxo-2-isoindolinyl) phenyl propionic acid ethyl ester; so nl

104-Yub S;

  (1-Oxo-2-isoindolinyl) -phenyl-propionic acid p-propyl ester; m.p. 87-89 ° C;

(1-oxo-2-isoiidolinyl) -phenyl isopropyl ester; m.p. 118-121 ° C;

(1-oxo-2-isoindolinyl) -phenyl isobutyl ester; propioic acid; m.p. PO-113 C;

eleven

a-3-chloro-4- (2-isoindolinyl) -phenyl-propionic acid ethyl ester; m.p. 67-70 ° C and so on. Kip. 190–200 ° C (0.4 mmHg);

a-3-chloro-4- (1-oxo-2-isoindolinyl) -feiyl-butyl acid; m.p. 191-193 ° C;

cc-3-chloro-4- (1-oxo-2-isoindolyl) -phenyl-butyric acid ethyl ester; m.p. 230-240 ° C (0.35 mm Hg. Art.);

a-3-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-a-cycllopropyl acetic acid; m.p. 242-245 ° C;

cc-3-chloro-4- (1-OXO-2-isoindolinyl) -phenyl-a-cyclopropylacetic acid ethyl ester; t. cues. 225-235 ° C (0.33 mm Hg. Art.);

(1,3-dioxo-2,5,6,7-tetrachloro-2-isoindolinyl) phenyl acetic acid ethyl ester; m.p. 197-199 ° C;

a-cyclopropyl-a-4- (1 - oxo-2-isoindolinyl) -phenyl acetic acid; m.p. 186-88 ° C;

a-cyclopropyl-a-4- (1-oxo-2-isoindolinyl) -phenyl acetic acid methyl ester; m.p. 98-101 ° C; and

a-cyclopropyl-; a-4- (1-oxo2-isoindolinyl) phenyl acetic acid ethyl ester; m.p. 111 -113 ° C.

Example 2. A mixture of 1 g of a-3-chloro-4- (2-isoindolinyl) -phenyl-propionic acid ethyl ester, 50 ml of ethanol and 15 ml of 20% pure potassium carbonate is boiled for 1 hour under reflux and evaporated under reduced pressure. The residue was dissolved in water and the mixture was adjusted to 6 n. hydrochloric acid to pH 3 and extracted with ethyl acetate. The organic extract is dried, filtered and evaporated. The residue is recrystallized from ethyl acetate and a-3-chloro-4- (2-isoindolinyl) -phenyl-propionic acid is obtained; m.p. 148-150 ° C.

Example 3. A mixture of 4.5 g of ethyl (1-oxo-2-isoindolinyl) -phenyl-propionic acid ethyl ester and 1.6 g of potassium hydroxide in 2 ml of water and 250 ml of ethanol is refluxed under nitrogen atmosphere for 2 hours and evaporated under reduced pressure. The residue is dissolved in water, washed with chloroform, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic extract is dried and evaporated and the residue is recrystallized from ethyl acetate. Thus, (1-oxo-2-isoindolinyl) -phenyl propionic acid is obtained; m.p. 208-210 ° C.

Example 4. A mixture of 2.1 g of the acid chloride (1-OXO-2-isoindolinyl) -phenyl-propionic acid, 0.9 g of 4-chloroaniline and 1.5 g of triethylamine in 100 ml of benzene is boiled in B for 1 hour with reverse refrigerator, filtered and the filtrate is washed with water, dried and evaporated. The residue is recrystallized from acetonitrile and get N- (4-chlorophenyl) -amide (1-oxo-2-isoin12

Dolinyl-phenyl-propionic acid; m.p. 240-242 ° C.

The source material can be obtained as follows.

A mixture of 2.0 g of (1-oxo-2-isoindolinyl) phenylpropionic acid and 25 ml of thioiyl chloride is refluxed for half an hour under a nitrogen atmosphere and evaporated under reduced pressure. The residue is evaporated twice to dryness, added benzene; the anhydride (1-oxo-2-isoindolinyl) -phenyl-propionic acid thus obtained; m.p. 129-132 ° C.

Example 5. A mixture of 4.6 g of (2-isoindolinyl) phenyl acetic acid ethyl ester and 80 ml of a 25% aqueous solution of sodium hydroxide is boiled for 3 hours under reflux, then cooled and diluted with water. The mixture is acidified with hydrochloric acid, the precipitate is filtered and recrystallized from ethyl acid ester. It is obtained in this way (((2-isoipdolinyl) -phenyl-acetic acid; mp 237-239 ° C.

Example 6. To a solution of 0.5 g of a-4- (2-isoindolinyl) -phenyl-propionic acid ethyl ester in 50 ml of glacial acetic acid was added dropwise 6 ml of a saturated solution of chlorine in glacial acetic acid at stirring and the mixture is then evaporated under reduced pressure. The residue is dissolved in an aqueous solution of sodium bicarbonate and extracted with ether; the organic extract is dried, filtered and evaporated. The residue is chromatographed on silica gel (benzene-hexane 1: 1). As the main product, a-3-chloro-4- (2-isoipdolinyl) -phenyl-propionic acid ethyl ester is obtained, with a Rf value of 0.30 (starting material: Rf 0.26) and as a second product ethyl ether, 5-dichloro-4 (2-isoindolinyl) -phenyl-propionic acid with a Rf value of 0.395.

Example 7. If air is passed through for 2 hours with stirring through a concentrated solution of ethyl a-3-chloro-4- (2-isoindolinyl) -phenyl-propionic acid ester in dimethylformamide and the temperature is maintained at, then ethyl a-3 is obtained -chloro-4- (1-OXO-2-IZOindolinyl) -phenyl propionic acid, which is isolated by evaporation of the reaction mixture under reduced pressure, followed by distillation of the residue; the compound is obtained as Boiling at 200-210 ° C (0.4 mmHg) fraction.

According to the methods described above, you can also obtain получать-3-chloro-4- (5-chloro-1-oxo-2 isoindolinyl) -phenyl-propionic acid, its methyl and ethyl esters, or sodium or potassium salts, using suitable starting materials. 13 Subject of the invention. Method for the preparation of a- (aminophenyl) -aliphatic carboxylic acids of general formula I II.

where group means bicyclic

an alkenylene amino group with 1 to 3 double bonds and 5 to 6 links in each ring;

Ph is a substituted phenyl residue;

RI is hydrogen or a lower alkyl group; and

R2 is hydrogen, or lower alkyl-, lower alkenyl-, cycloalkyl-, cycloalkenyl-, cycloalkyl-lower alkyl- or cycloalkenyl-lower alkyl group,

or derivatives or salts thereof, characterized in that the compound of formula II

II

A N - Pn-Xi where X means a group of the formula Pa -C (R,) (R2) -Yi where YI means a metallic group of 35

Priority signs: 18.07.69:

a bicyclic alkenyleneaminoA group with 1–3 double bonds and 5–6 ring members in each ring, which can be substituted with lower alkyl, free or esterified into ether or ester, or mercapto groups or oxo groups, as appropriate;

12.09.69:

 is a bicyclic

30 RI and R2 are as defined above; interact with a reactive metal-free carbonic or formic acid derivative, such as carbon dioxide, carbon disulfide, followed by isolating the desired product in free form or converting it into derivatives or salts, or dividing the resulting mixture of isomers into individual isomers by known techniques. an alkenyleneamino group with 1 to 3 double bonds and 5 to 6 ring members in each ring, which may be substituted with a thiono group if appropriate.