DE2046992A1 - Isoindolinophenyl-alkanoic acid esters and salts - - antiphlogistic, antipyretic and analgesic agents - Google Patents

Abstract

3-Substd. 4-isoindolinophenyl-acetic, -propionic and -butyric acids of formula: (where Z is free or esterified H, Mr or Et and R11 is H, Me, F, Cl or Br) are antiphlogistic, antipyretic, analgesic agents also exhibiting bacteriostatic, bactericidal, antiprotozal, diuretic, antiglycaemic, choleretic, anticholesterolaemic activities and protection against irradiation, and are prepd. e.g. by oxidn. of the cpds. in which Z is CHO or CH2OH in presence of metal catalysts.

Description

Isoindoline derivatives The invention relates to compounds of the general formula I. where Z is a free or esterified carboxyl group, R1 is H, CH3 or C2H5 and R2 is H, CH3, F, C1 or Br, and their physiologically acceptable salts.

It has been found that compounds of the formula I and their physiological harmless salts with good tolerance an excellent anti-inflammatory Have an effect that has a good analgesic and antipyretic effect is accompanied. Furthermore, bacteriostatic, bactericidal, antiprotozoal, diuretic, Blood-sugar-lowering, choleretic, cholesterol-lowering and radiation protection effects on.

The compounds of the formula I and their physiologically harmless ones Salts can therefore be used as pharmaceuticals and also as intermediates for manufacture other medicines are used.

The invention relates to compounds of the formula I in which R1, R2 and Z have the meanings given above, as well as their physiologically harmless ones Salts.

The invention also relates to the compounds of the following preferred formulas Ia to Ih which correspond to formula I and in which they do not radicals designated in more detail have the meaning given for formula I, but in which: Ia Z denotes a free or esterified carboxyl group with a total of 1-15 carbon atoms; Ib Z COOA1, A1 H or one optionally containing 1-2 C-C multiple bonds and / or by A2 one or more interrupted and / or branched alkyl, cycloalkyl, Cycloalkyl-alkyl, aryl or aralkyl groups each with up to 12 carbon atoms and A2 o, S, NH, N-alkyl with 1 - 6 carbon atoms optionally substituted by OH, N-aryl with 6-10 carbon atoms or N-aralkyl with 7-10 carbon atoms; Ic Z COOA3 and A3 H, alkyl with 1-6, dialkylaminoalkyl, pyrrolidinoalkyl, piperidinoalkyl or Morpholinoalkyl each having up to 10 carbon atoms; Id Z COOA4 and A4 is H or alkyl having 1 to 4 carbon atoms; Ie Z is COOH; If R1 is CH3; Ig R2 is CH3, Cl or Br; Ih Z COOA4, R1 CH3, R2 Cl and A4 H or alkyl with 1 - 4 carbon atoms.

The invention also relates to a process for the preparation of isoindoline derivatives of the formula I and their physiologically acceptable salts, characterized in that a compound of the formula II in which L is CHO or CH2OH and R1 and R2 have the meaning given above, treated with oxidizing agents, or that a compound of the formula III in which M1 is an equivalent of one Metal atoms or Mg-Hal and Hal are Cl, Br or I and R1 and R2 are as defined above, are reacted with e02, or a compound of the formula IV in which R1, R2 and Z have the meaning given above, treated with decarboxylating agents, or a compound of the formula V in which R3 denotes H, alkyl with up to 4 carbon atoms or phenyl and R1, R2 and Z have the meanings given above, treated with a strong base, or a compound of the formula VI in which Y is Hal, NH2, an optionally reactive esterified or etherified hydroxy group, and R1, R2 and Z have the meaning given above, treated with cyclizing agents, or in a compound of the formula VII in which R1 and Z have the meaning given above, the amino group is exchanged for the radical R2 after diazotization, or a compound of the formula VIII with a compound of the formula IX R¹ - X² IX wherein one of the radicals X1 or x2 is an equivalent of a metal atom, MgHal, CdR4 or ZnR4, the other is Hal and R4 CH3 or O2H5 and R1, R2 and Z have the meaning given above, or that one in a compound of formula X wherein Q denotes an optionally functionally modified COOH group and R1 and R2 have the meaning given above, the radical Q is converted into the radical Z by treatment with solvolyzing, thermolysing or ester-forming agents, or another compound corresponding to formula I, in which however, one or more reducible and / or hydrogen-replaceable groups and / or CC multiple bonds and / or a C = N double bond are also located, treated with reducing agents and / or converted a compound of the formula I into its racemates and / or optical antipodes cleaves and / or converts a compound of the formula I into its physiologically acceptable salts by treatment with an acid or base and / or a compound of the formula I by treatment with a base or

Sets acidity from its salts in praity.

In the above formulas, Z preferably denotes a free, but also an esterified COOH group, in which the alcohol part preferably has 1-14 carbon atoms Has. If it is assumed that the free carboxylic acids of the formula I (Z = COOH) the are actually physiologically active compounds and that the corresponding Esters are saponified under physiological conditions to give the free carboxylic acids the nature of the ester group is not critical as long as it is physiological is harmless. Of course, however, it is possible through a suitable selection the ester group to achieve additional physiological effects, e.g. B.

Depot effects through the use of long-chain or difficult to saponify Alcohol residues; Improvements in solubility through the incorporation of pn] arer groups (O atoms, N atoms); additional pharmacological effects through esterification of the acids I (Z = COOH) with OH bonds that show their own pharmacological effects (e.g. (E.g. pyridoxine, corticoid active 21-hydroxysteroids, etc.).

In particular, Z denotes COOA¹, COOA³ or COOA4.

The remainder A1, which, according to its definition, is also represented by OH, SK or NH2 can be substituted one or more times, preferably means: hydrogen; Alkyl, z. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl; Alkenyl, e.g. B. vinyl, allyl, orotyl; Alkynyl, z. B. propargyl; Hydroxyalkyl, e.g. Bo 2-hydroxyethyl, 2-hydroxypropyl, -3-hydroxypropyl; Alkoxyalkyl, e.g. B. 2-methoxyethyl, 2-ethoxyethyl, 3-oxa-5-hydroxypentyl,) -oxa-5-methoxy-pentyl, 3-oxa-5-butoxy-pentyl, 3,6-Dioxa-8-hydroxy-octyl, 3,6-Dioxa-8-methoxyl-octyl, 3,6-Dioxa-8-ethoxy-octyl, 3-oxa-5-ethoxypentyl; Aminoalkyl, e.g. Bo 2-aminoethyl, 3-atinopropyl; Dialkylaminoalkyl, z. Bo 2-dinjethylaminoethyl, 2-diethylaminoethyl, 2-di-n-propylaminoethyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 2-methyl-3-diethylaminopropyl; 4-dimethylaminobutyl, 4-diethylaminobutyl; Cycloalkyl, e.g. B.

Cyclopentyl, cyclohexyl; Cycloalkyl-alkyl, e.g. B. 2-cyclohexylethyl, 3-cyclohexylpropyl; Aza-cycloalkyl, e.g. B.

N-methylpiperidyl- (4); Aza-cycloalkyl-alkyl and related radicals, z. B. (N-methylpiperidyl-3) -methyl, 2- (N-methylpiperidyl-2) -ethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 2-homopiperidinoethyl, 2-morpholinoethyl, 2-thionorpholinoethyl, 2- (N-methylpiperazino) ethyl, 2- (N-ethylpiperazino) ethyl, 2- (N-phenylpiperazino) ethyl, 2- (N-2-Hydroxyäthylpiperazino) -äthyl, 2- (N-Methylhomopiperazino) -äthyl, 2-Pyrrolidinopropyl, 3-pyrrolidinopropyl, 2-piperidinopropyl, 3-piperidinopropyl, 2- (N-methylpiperazino) propyl, 2- (N-methylpiperazino) propyl, 3- (N-ethylpiperazino) propyl, 3- (N-phenylpiperazino) propyl, 2-morpholino-propyl, 3-morpholino-propyl, 3-thiomorpholino-propyl, 2-methyl-3-pyrrolidinopropyl, 2-methyl-3-piperidino-propyl, 2-methyl-3-morpholinopropyl; Mercaptoalkyl, e.g. Bo 2-mercaptoethyl; Alkyl mercaptoalkyl, e.g. B. 2-methylmercaptoethyl, 2-ethylmercaptoethyl, 3-methyl mercaptopropyl, 3-ethyl mercaptopropyl; Aryl, e.g. B.

Phenyl, o-tolyl, m-tolyl, p-tolyl, p-ethylphenyl, 1-naphthyl, 2-naphthyl; Aralkyl, e.g. B. benzyl, p-methylbenzyl, 1-phenylethyl, 2-phenylethyl.

M1 preferably represents MgCl, MgBr, MgI or Li, and also represents an equivalent of Zn or Cd. Y is preferably Cl or Br; but it can also z. B. NH2, OH, J, alkylsulfonyloxy with in particular 1 - 6 carbon atoms (æ. Bo methanesulfonyloxy), Arylsulfonyloxy with in particular 6-10 carbon atoms (e.g.

Benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy), Acyloxy with in particular 1 - 7 carbon atoms (e.g.

Acetoxy, benzoyloxy) or an etherified OH group with in particular 1 - 7 carbon atoms (e.g. methoxy, benzyloxy) mean 0 The aldehydes or alcohols of the Formula II (obtainable e.g. by implementing the formula XII below corresponding compounds, in which, however, instead of Z, there is a CH 2 O H or CHO group, with o-xylylene dibromide) can lead to the carboxylic acids of the formula I (Z = COOH) as in described in the literature are oxidized, in particular with air or oxygen, preferably with the addition of catalysts such as flax, Co, Fe, Ag, V205; with Ag20, preferred together with CuO; with H 2 O 2, preferably in the presence of alkalis; with organic Peracids such as peracetic acid, perbenzoic acid or perphthalic acid; with KIulnO4 in acidic, neutral or alkaline medium, optionally with the addition of MgSO4; with chromic acid or OrO3, preferably in glacial acetic acid, optionally with the addition of Benzene or sulfuric acid; with nitrous acid, preferably with 2 - 68 iger nitric acid, optionally under pressure (up to 100 at); with nitrogen oxides; or with melted NaOH and / or KOH and 02 in the melt; or with hypohalites. With these oxidations one works preferably in inert solvents, such as water, acetic acid, dioxane, Benzene, acetone, tetrahydrofuran, dimethylformamide, ethanol, methanol, or in mixtures this solvent at temperatures between -30 ° and 3000, expediently at room temperature.

Organometallic compounds of the formula III (in which M1 preferably Li or MgHal means) are obtainable by metalation of appropriately substituted Benzyl halides, especially with .4lkali or alkaline earth metals, preferably with Lithium or magnesium, or with cadmium or zinc dialkyl compounds. These deliver with solid or gaseous CO 2 according to known methods described in the literature the carboxylic acids of the formula I (Z = COOH). The metallization, for example the Grignardation, takes place in solvents such as ether, tetrahydrofuran, dioxane or mixtures thereof with aromatic hydrocarbons such as benzene at temperatures between preferably -100 and the boiling point of the solvents used. Preference is given to betting a large overload of a mixture of magnesium shavings and magnesium powder and already conducts a powerful stream of carbon dioxide during the Grignarding the reaction mixture to an organometallic synthesis of the Grignard compounds formed to push back with not yet converted halide.

Compounds of the formula IV, preparable, for. B by thermal decomposition of appropriately substituted aryloxaloacetic acid dialkyl esters (according to IV, but -CR1 (COO-alkyl) -CO-COO-alkyl instead of -CR1Z-COOH) and subsequent partial or complete alkaline saponification can, as described in the literature, for example by dry heating or by heating in solvents such as water, ethanol, Dioxane or xylene, at temperatures between 50 and 2500 to the compounds of Formula I can be decarboxylated. It is expedient to heat until the evolution of carbon dioxide has ended Isoindoline derivatives of the formula I are also by acid cleavage of 3-keto acid derivatives of the formula V obtainable by methods described in the literature. Ketoester of the formula V (Z = esterified COOH group) can e.g. B. be produced by condensation of lower fatty acid or benzoic acid esters with nitriles according to the formula I (ON instead of Z), converting them into salts (e.g.

Hydrochloride) of imido ethers according to the formula I (C = NH (O-alkyl) instead of Z) and partial hydrolysis. The acid cleavage of V takes place by treatment with a strong base such as NaOH, KOll or Ca (OH) 2 in solvents such as water, methanol, ethanol, ether, tetrahydrofuran, dioxane, benzene or mixtures thereof at temperatures between -10 and 2000. Nill man the free carboxylic acids I (Z = C00H) are obtained, it is preferably boiled for a few hours in an aqueous or aqueous-alcoholic solution. Compounds of the formula VI can be cyclized to compounds of the formula I by known methods, e.g. B. by heating in the presence or absence of a solvent, optionally in the presence of an acidic or basic catalyst. Compounds of formula VI are available e.g. Bo by reacting a compound of the formula XI wherein Y has the meaning given above, but the two groups Y can be identical or different and together can also mean 0 or NH, with a compound of the formula XII in which X1, R2 and Z have the meaning given above.

Compounds of the formula XI are those with the same groups Y preferred e.g. B. o-xylylene chloride, o-xylylene bromide, also o-xylylene iodide, phthalyl alcohol (o-hydroxymethylbenzyl alcohol) and its reactive esters, e.g. BO its bismethanesulfonate or bis-p-toluenesulfonate, o-xylylenediamine, phthalan (isocumaran) or isoindoline, But those with different groups Y are also used to produce the compounds VI suitable, zO Be o-chloromethyl-benzyl alcohol, o-bromomethyl-benzyl alcohol, o-methoxymethyl-benzyl bromide, o-chloromethyl benzyl bromide.

For the cyclization of VI are suitable solvents such. B. water, lower aliphatic alcohols (such as methanol, ethanol, isopropanol, n-butanol), glycols (such as ethylene glycol), ether (such as diethyl or diisopropyl ether, tetrahydrofuran, Dioxane), aliphatic (such as petroleum ether, hexane) or aromatic (such as benzene, toluene, Xylene) hydrocarbons, halogenated hydrocarbons (such as chloroform, chlorobenzene), Nitriles (such as acetonitrile), amides (such as dimethylformamide, dimethylacetamide), sulfoxides (such as dimethyl sulfoxide) or mixtures of these solvents. One cyclizes in the Usually at temperatures between 0 and 3000, preferably between room and boiling temperature the solvent used, which can be obtained by applying pressure (up to 200 at) if desired can increase. The selection of the catalyst depends on the type of catalyst to be split off Connection HY.

For Y = Hal, basic catalysts are preferred, e.g.

inorganic (alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates such as NaOH, KO, LiOH, Ba (OH) 2, Ca (OH) 2, Na2CO3, K2CO3, Li2CO3, NaOCH3, KOCH3, NaOC2H5, KOC2H5, K-tert. - Butlate) or organic (e.g. tertiary bases such as triethylamine, pyridine, picolines, quinoline). For Y = OH, alkoxy, acyloxy, alkyl or Arylsulfonyloxy, recommend against it acidic catalysts z. B. inorganic Acids (such as sulfuric acid, polyphosphoric acid, hydrobromic acid, hydrochloric acid) and / or organic acids (such as formic, acetic, propionic or p-toluenesulfonic acid), which, in excess, can also serve as solvents at the same time; usually stronger conditions are required for the cyclization of these substances. links VI (Y = NH2) split off ammonia when heated (e.g. melting), with the desired Isoindolines are formed.

A preferred procedure is to use the compounds of the formula VI not to isolate, but to produce them in statu nascendi with or without solvents (e.g. from XI and XII) and to cyclize directly to give compounds of the formula I.

The use of a catalyst, e.g. B. a base such as NaOH, KOH, Sodium or potassium carbonate is possible, but not absolutely necessary; it it is also possible to use an excess of the amino compound XII instead of the base use.

The reaction of o-xylylene bromide with XII is particularly advantageous in a boiling alcohol in the presence of K2C03, with compounds as intermediates VI (Y = Br) arise, which are cyclized in situ. Under these The reaction is complete after about 1 to 12 hours.

In diazonium compounds of the formula VII, the diazonium grouping exchanged for fluorine, chlorine or bromine according to methods described in the literature will. The compounds of the formula VII can be obtained as described in the literature Methods by diazotizing corresponding amino compounds (formula I, NH2 instead R2), e.g. B. in hydrochloric acid or hydrobromic acid aqueous solutions by addition the calculated amount of an inorganic nitrite, preferably NaN02 or KN02 at temperatures between -20 ° and +50, or in inert organic solvents, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether by adding an organic nitrite such as n-butyl nitrite, n-amyl nitrite or isoamyl nitrite at temperatures between -20 ° and +50.

To introduce a fluorine atom, diazotization is carried out, for example, in anhydrous Hydrofluoric acid and then heated, or the diazonium salts with HBF4 are added the sparingly soluble di azonium tetrafluoroborates, which are insulated and thermally can be decomposed to the isoindolines I (R2 = F).

The diazonium group is preferred to chlorine in aqueous solution exchanged in the presence of Cu2Cl2 according to the Sandmeyer method. The exchange against bromine, for example, in aqueous solution in the presence of Cu2Br2 Sandmeyer or by reaction with bromine in the diazonium perbromide and the following Cooking in solvents, such as water or lower alcohols. But it is also possible to convert the diazonium bromide with HgBr2 into the diazonium mercury bromide to convert and thermally decompose them to the desired bromine compounds, You can also use an organometallic compound for the synthesis of compounds of the formula I Compound of the formula VIII (X1 = equivalent of a metal atom or organometallic Remainder, preferably Na or Li), which can be obtained by direct metalation (for example with butyllithium, phenyllithium, sodium hydride, sodium amide or metallic sodium or magnesium) of the corresponding hydrogen or halogen compounds (VIII, H or Hal in place of ton X1) is obtained with an alkyl halide of the formula IX in inert React solvents such as benzene, xylene, dioxane or tetrahydrofuran. Preferred if a Priedel-Crafts catalyst, such as All3, FeCl, is added to the reaction mixture ZnC12, too.

On the other hand, a halogen compound of the formula VIII (X1 = Hal) with a metal compound of the formula IX (X2 = equivalent of a metal atom or organometallic radical), in particular with an alkali metal derivative such as lithium or Sodium methyl or ethyl, or with a Grignard compound such as methyl or ethyl magnesium iodide, alkylate under analogous conditions.

Compounds of the formula I are furthermore by solvolysis, thermolysis, Esterification or transesterification of compounds of the formula X available. In these Q denotes in particular one of the following radicals (in which R5 and R6 are each alkyl with 1 to 4 0 atoms, preferably 0113 or C2H5, and these Leftovers identical or different and together also tetruamethylene or pentamethylene, if appropriate interrupted by O, can be): COOH; CHal3; COF; COHal; COOR5; C (OR5) 3 ; COOAcyl; CN; COHN2; CONHR5; CORR5R6; CONHOH; C (OH) = NOH; CONHNH2; CO3; C (OR5) = NH; C (NH2) = NH2; C (NHNH2) = NH; CSOH; COSH; CSOR5; COSR5; CSNHW2; CSNNR5 or CSNR5R6.

Puncture derivatives (of the formula X) of compounds of the formula I. can according to methods described in the literature to the compounds of the formula I solvolyzed or thermolyzed, in particular hydrolyzed. A hydrolysis can in acidic or optionally alkaline medium at temperatures between -20 ° and 3000, preferably at the boiling point of the selected solvent, be performed. Suitable acidic catalysts are, for example, salt, sulfur, Phosphoric or hydrobromic acid; it is expedient to use the basic catalysts Sodium, potassium or calcium hydroxide, sodium or rali carbonate. As a solution medium one preferably chooses wet; lower alcohols such as methanol, ethanol; ether such as tetrahydrofuran, dioxane; Amides such as dimethylformulide; Nitriles such as acetonitrile; Sulfones such as tetramethylene sulfone; or mixtures thereof, especially those containing water Mixtures. But you can use the acid derivatives z. B. also in ether or benzene Addition of strong bases such as potassium carbonate or without solvents by fusing with alkalis such as KOH and / or NaOH or alkaline earths to form carboxylic acids of the formula I (Z = COOH) saponify.

A preferred embodiment of the invention is the saponification of Thioamides (X, Q = CSNR5R6), e.g. B. the corresponding thiomorpholiide, -piperidide, -pyrrlidide, -dimethylamides or -diethylamides. Such thionmides are produced by reaction appropriately substituted acetophenones with Schansfel and the amine in question available. Also the amides (K, Q = CONH2), obtainable by reaction of the acetophenones with ammonium polysulphide according to Willgerodt's methols known from literature, can be used as a starting material. The thioamides or amides are hydrolyzed prevented by heating with aqueous hydrochloric acid. The thioamides or amides need not necessarily to be grounded in isolation; you can also use the reaction mixture, in which they are formed, directly subject to hydrolysis.

By dry heating of, in particular, tertiary alkyl esters of Formula X (Q = COO-tert. Alkyl) at temperatures between 50 and 350 ° is obtained Acids of the formula I (Z = COOH) Thermolysis can also be carried out in inert solvents, such as Banzol, water, dimethylformamide, ethylene glycol, glycerine, dimethyl sulfoxide, Cyclohexanot, preferably with the addition of catalytic amounts of acids, such as p-toluenesulfonic acid, carry out.

Another preferred embodiment of the invention is hydrolysis of nitriles Cx, Q = ON), which are acidic (e.g. with acetic acid / hol) or alkaline (e.g. with KOH in cyclohexanol) medium.

Esters of the formula I (Z = esterified carboxyl group) can according to in methods described in the literature. So you can, for example an acid of formula I. (Z = COOfE) with the alcohol in question in the presence of an inorganic or organic acid such as HCl. HBr, HJ, H2SO4, H3PO4, trifluoroacetic acid, benzenesulfonic acid or p-toluenesulfonic acid, or one acidic ion exchanger, optionally in the presence of an inert solvent «Never z. B. benzene, toluene or xylene, at temperatures between 0 ° and preferably Convert boiling temperature. The alcohol is preferably used in excess. Preferred Alcohols are those of the formulas A¹OH, A³OH and A4OH (where A¹, A³ and A4 are the above have given meanings, but not mean H). one can continue to do so in the present water-binding agents work, e.g. B. of anhydrous heavy metal sulfates (such as CuSO4, Fe2 (SO4), NiSO4, CoSO4, ZnSO4) or from molecular sieves. Lian kaiin also remove the water of reaction azeotropically, advantageously hydrocarbons (e.g..

Benzene or toluene) or chlorinated hydrocarbons (e.g. E.

Chloroform or 1,2-dichloroethane) added. Under mild conditions the esterification proceeds when the water of reaction is preferably chemically added binds equimolar amounts of carbodiimides (e.g. N, N-dicyclohexylcarbodiimide), using inert solvents such as ether, dioxane, benzene or 1,2-dimethoxyethane used and bases such as pyridine can be added, the methyl ester (or atnyl or Benzyl esters) can also be obtained by reacting the free acids according to the literature described methods with diazomethane (or diazoethane or phenyldiazomethane) in an inert solvent such as ether, benzene or methanol. You can esters of the formula 1 (Z = esterified COOH group) also by addition of the Carboxylic acids (I, Z = COOH) to olefins (e.g. isobutylene, cyclohexene) or to acetylenes obtain.

This addition succeeds as described in the literature Metliodes preferably in the presence of catalysts (e.g. 13.

ZnCl2, BF3, H2SOR, aryl sulfonic acids, pyrophosphoric acid, boric acid, Oxalic acid) at temperatures between 0 and 2000, pressures between 1 and 500 at and in inert solvents such as ether, tetrahydrofuran, dioxane1 benzene, toluene or Xylene.

Esters of the formula I (Z = esterified COOH group) can also be prepared by reacting metal salts of the formula X (Q = COOM¹), preferably the alkali metal, Lead or silver salts, alkyl halides corresponding to the alcohol in question, z. 3. those of the formula R5Hal, optionally in an inert solvent, e.g. 3. Ether, benzene or petroleum ether, or with alkyl chlorosulfites, e.g. B. such the Formula R5OSOCl and thermolysis of the adducts obtained.

You can also use the acid halides, anhydrides or nitriles of the formula X * by reaction with an alcohol, e.g. B. an alcohol of the formula R501l, optionally in the presence of an acidic catalyst or a base such as NaOH, KOH, Na2CO3, K2O05 or pyridine, according to the methods described in the literature, in esters of the formula I (Z = esterified GOOlI) convert. An excess is preferably used of the alcohol in question and works at temperatures between 0 ° and boiling point.

Finally, you can use esters of the formula I (Z = esterified COOli group) by transesterification of other esters of the formula X (Q = COOR7; R7 = any organic Remainder) with an excess of the alcohol in question or by reacting the carboxylic acids I (Z = COOH) with any other esters of the alcohol in question, which are preferably in excess * (Q = COHal, COOAcyl or CN) be set, produce. The esterification methods described in the literature are used, especially in the presence of basic or acidic catalysts, e.g. B.

Sodium ethylate or sulfuric acid, and at temperatures between 0 ° and preferably boiling temperature.

Of interest among the esters of the formula I (Z = esterified COOII) those that are easily cleaved under physiological conditions. Genanllt be the vinyl, the tert -butyl, the tetrahydro-2-furyl and the tetrallydro-2-pyranyl esters, the z. B. by reacting the free carboxylic acids with acetylene, isobutylene, 2,3-dihydrofuran and 2,3-dihydropyran, especially with the addition of catalysts such as ZnCl2, BF3, H2SO4, arylsulfonic acids, pyrophosphoric acid, boric acid or oxalic acid at 0 - 120 ° in inert solvents such as ether, tetrahydrofuran, dioxane, benzene or xylene 0 maui esters of the formula I (Z = esterified COOH) can also be obtained, by using compounds of the formula X, wherein Q is a thioester, imino ether, oximino ether, Means hydrazone ether, thioamide, amidine, amidoxime or amidhydrazone grouping, with dilute aqueous bases or acids, e.g. 30 ammonia, Na0H, KOH, Na2O03, K2C03, HCl, H2S04, with the addition of the alcohol in question and the elimination of sulphurous water substance, ammonia, amines, hydrazine derivatives or hydroxylamine solvolyzed.

While z. B. most imino ether hydrochloride in watery solution instantly decompose into the esters and ammonium chlorides at room temperature the solvolysis of other derivatives, e.g. B. some amidoximes or thioamides, at temperatures up to 1000.

It is also possible to obtain a compound of the formula I by starting from a Gorproduk-t with the same basic structure, but that in addition or instead of hydrogen atoms, one or more reducible imd / or through Groups that can be replaced by hydrogen and / or g C-C double bonds and / or a C = N double bond contains, and this treated with hydrogen donating agents. With hydrogen In particular, Hal, OH, oxygen in a carbonyl group and benzyl can be replaced in an ester group and diazonium groups. Reducible is z. B. the N-oxide group.

Basically come to the reduction, depending on the starting material one chooses all the usual methods described in the literature in Prage.

Catalytic hydrogenations and / or Ilydrogenolysen are used as catalysts for example noble metal, nickel and cobalt catalysts are suitable. The precious metal catalysts can be on carriers (e.g. 3. palladium on carbon, calcium carbonate or strontium carbonate), as oxide catalysts (e.g.

Platinum oxide) or as finely divided metal catalysts. Nickel and cobalt catalysts are expediently used as Raney metals, nickel also on kieselguhr or pumice stone as supports. The hydrogenation can be carried out at room temperature and normal pressure or else at elevated temperature and / or elevated pressure. It is preferable to work at pressures between 1 and 100 at and at temperatures between -80 ° and 2000, especially between room temperature and +1000. The reaction is expediently carried out in the presence of a solvent such as water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dioxane, acetic acid or tetrahydrofuran; you can also use mixtures of this solution with one another. The hydrogenation of multiple bonds and the hydrogenolysis of benzyl groups is preferably carried out at normal pressure in such a way that the hydrogenation is terminated after the calculated amount of hydrogen has been taken up. You can basically work in an acidic, neutral or basic range. For compounds that contain a C = N double bond, especially the 1H-isoindolium salts XIII (obtainable by condensation of XII with o-halomethylbenzaldehydes), a reduction in a neutral or basic medium is preferred.

A special case is the reductive alkylation of XII with phthaldialdehyde, which also leads to the isoindolines I.

Either one first converts to the Schiff base and then hydrogenates with simultaneous cyclization, or the condensation is carried out under hydrogenation conditions through, which leads directly to the isoindolines I.

Implementation is also generally applicable as a reduction method with nascent hydrogen. This can be done, for example, by treating Metals with acids or Create bases. So you can z. B. a Mixture of zinc with acid or alkali, of iron with hydrochloric acid or acetic acid or use of tin with hydrochloric acid. The use of sodium is also suitable or another alkali metal in a lower alcohol such as ethanol, isopropanol or butanol.

You can also use an aluminum-nickel alloy in alkaline water Use the solution, if necessary with the addition of ethanol. Also sodium or aluminum amalgam in aqueous-alcoholic or aqueous solution are to generate the nascent Suitable for hydrogen. The implementation can also be carried out in a heterogeneous phase , an aqueous phase and a benzene or toluene phase being expediently used. The reaction temperatures used are between room temperature and the boiling point the solvent used.

Complex metal hydrides, such as lithium aluminum hydride, or sodium borohydride, e.g. B. in the presence of aluminum chloride or lithium bromide, come into use. The reaction conditions must be chosen so that the Group Z remains intact. It is expedient to work in the presence of an inert solvent, e. B. ether, tetrahydrofuran, ethylene glycol dimethyl ether. The implementation will be beneficial brought to completion by boiling the reaction mixture. The decomposition of the educated IxFetallkomplexe can in the usual way, e.g. B. with an aqueous ammonium chloride solution, take place.

Further suitable reducing agents are, for example, sodium dithionite in alkaline or ammoniacal Läsau iron (II) hydroxide; Tin (II) chloride ; Hydrogen sulfide hydrogen sulfides, sulfides and polysulfides; Hydriodic acid or sodium sulfite.

It is also possible to use a carbonyl group according to the literature known methods of Olemmensen or Wolff-Kishner to reduce CH2 groups.

It is also possible to use Hal atoms, in particular aromatic-bonded ones Hal atoms, to be replaced by hydrogen by adding] -I: 0 the corresponding Hal compounds in the associated OrrbL metal, z. B. Grignard, converts compounds and these hydrolyzed with water or dilute acids.

A compound of the formula I can with an acid in the associated Acid addition salts are transferred. Such acids are used for this reaction in Prage, which supply physiologically harmless salts. So organic are suitable and inorganic acids, such as. B. aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic or sulfonic acids, such as AmeisensK re, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, Succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, Amino carboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, Citric acid, gluconic acid, acorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, Ethane disulphonic acid, ß-hydroxyethanesulphonic acid, p-toluenesulphonic acid, naphthalene mono- and disulfonic acids, sulfuric acid, Nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, or phosphoric acids such as orthophosphoric acid.

On the other hand, the compounds of the formula I (Z = COOli) can through Reaction with a base in one of its physiologically harmless metal or Amnonium salts become overfilled.

In particular, the sodium, potassium, magnesium, calcium and ammonium salts into consideration, also substituted ammonium salts, such as. B. the Dimethyl and diethylammonium, monoethanol, diethanol and triethanolammonium, Cyclohexylammonium, dicyclohexylammonium and dibenzylethylenediammonium salts.

Conversely, compounds of the formula I can be prepared from their acid addition salts by treatment with strong bases, such as sodium or potassium hydroxide, sodium or Potassium carbonate, or from its metal and ammonium salts by treatment with acids, especially mineral acids such as hydrochloric or sulfuric acid, can be put in price.

If the compounds of the formula I contain a center of asymmetry, they are usually in racemic form.

If they have two centers of asymmetry, then they fall during the synthesis generally as mixtures of two racemates, from which one is known per se Way the individual racemates, for example by repeated recrystallization from suitable solvents, isolate and obtain in pure form.

The racemates can by a variety of known methods, such as are given in the literature, can be separated into their optical antipodes. So One can use some racemic mixtures as hEtektika instead of in the form of mixed crystals precipitate and separate in this way, in which case also a selective precipitation can be possible. However, the chemical separation method is preferred. Thereafter are made from the racemic mixture by reaction with an optically active auxiliary Diastereomers formed. So you can optionally with an optically active base the carboxyl group or an optically active acid with the amino group of a compound of formula I implement. For example, one can use diastereomeric salts of the compounds of the formula I (Z = COOH) with optically active amines, such as quinine, cinchonidine, brucine, Cinchonine, hydroxyhydrin amine, morphine, 7-phenylethylamine, 1-naphthylethylamine, Phenyloxynaphthylmethylamine, quinidine, strychnine, basic amino acids such as lysine, Arginine, amino acid esters, or with optically active acids, ie (+) - and (-) - tartaric acid, Dibenzoyl - (+) - and <-) - tartaric acid, diacetyl - (+) - and - (-) - tartaric acid, camphoric acid, ß-camphorsulfonic acid, (+) - and (-) - mandelic acid, (+) - and (-) - malic acid, (+) - and (-) - 2-Phenylbutyric acid, (+) - and (-) - dinitrodiphenic acid or (+) - and (-) - lactic acid form. Ester diastereomers can be produced in a similarly quiet manner by esterifying Compounds of the formula I (Z = COOH) with optically active alcohols, such as borneol, Prepare menthol, octanol-2. The difference in the solubility of the resulting diastereomeric salts or

Ester allows the selective crystallization of the one form and the Regeneration of the respective optically active compounds from the mixture.

The racemates or mixtures of racemates can also be done with the aid of chromatographic I; methods are separated. You can optically active support materials, such as. B. Tartaric acid, starch, cane sugar, cellulose or acetylated cellulose and optically inactive and / or optically active mobile phase for separation into the pure enantiomers use or an optically inactive carrier material, such as. B. silica gel or alumina in combination with an optically active solvent. The optical antipodes can also separated biochemically using selective enzymatic reactions will. So k v one the racemic acids of the formula I (Z = COOH) an asymmetric Exposing oxidase or optionally decarboxylase by oxidation or decarboxylation one form destroys while the other form remains unchanged. It is also possible the use of a hydrolase on a functional acid derivative of the racemic Mixture for preferentially forming an optically active form. So you can ester or Expose amides of acids of formula I (Z = C00H) to the action of a hydrolase, which selectively saponifies one enantiomer and leaves the other unchanged.

Furthermore, it is of course possible to use optically active compounds to obtain the methods described by using starting materials that are already optically active.

The compounds of the formula I and / or, if appropriate, their physiological Safe salts can be mixed with solid, liquid and / or semi-liquid Pharmaceutical carriers used as pharmaceuticals in human or veterinary medicine will. Such organic or inorganic substances are used as carrier substances in question, which are suitable for parenteral, enteral or topical application and the do not react with the new compounds as for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, Lactose, starch, magnesium stearate, talc, petrolatum, cholesterol. For parenteral Applications are especially solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. Suitable for enteral application tablets, coated tablets, canola, syrups, juices or suppositories, for the topical Use ointments, creams or powders. The specified preparations can optionally be sterilized or auxiliary materials such as lubricants, preservatives, stabilizers or wetting agents, emulsifiers, salts to influence the osmotic pressure, Contain buffer substances, parbohydrates, flavorings and / or aromas.

The substances are preferably used in dosages between 1 and 500 mg administered per dosage unit.

Above and below, the temperatures are given in degrees Celsius. “Customary work-up” means: the reaction mixture is optionally prepared by adding hydrochloric acid or sodium hydroxide solution to the specified pH value, extracted with ether, ethyl acetate or chloroform, dry over sodium sulfate, filtered, the solvent is distilled off and the residue crystallizes from the specified Solvent. D09l = dimethylformamide.

Example 1 a) 14.4 g of 2- (3-chloro-4-isoindolino-phenyl) -propanal IT. 58 °; produced by acid-catalyzed rearrangement of 2- (3-chloro-4-isoindolino-phenyl) -propane-1 , 2-diol are stirred into a solution of 25 g of silver nitrate in 200 ml of water and added 140 ml of ethanol. 360 ml of 0.5 are added dropwise with stirring over a period of 2 hours N NaOH added, stirred for 6 hours at room temperature under nitrogen, filtered off, the filtrate works as usual (pH 5) and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, P. 1480.

Analogously, 3-methyl-4-isoindolino-phenylacetaldehyde is obtained from 4-isoindolino-phenylacetaldehyde 3-fluoro-4-isoindolino-phenylacetaldehyde 3-chloro-4-isoindolino-phenylacetaldehyde 3-Bromo-4-isoindolino-phenylacetaldehyde 2- (4-isoindolino-phenyl) -propanal 2- (3-methyl-4-isoindolino-phenyl) -propanal 2- (3-fluoro-4-isoindolino-phenyl) -propanal 2- (3-Bromo-4-isoindolino-phenyl) -propana 2- (4-isoindolino-phenyl) -butanal 2- (3-methyl-4-isoindolino-phenyl) -butanal 2- (3-fluoro-4-isoindolino-phenyl) -butanal 2- (3-chloro-4-isoindolino-phenyl) -butanal 2- (3-bromo-4-isoindolino-phenyl) -butanal by oxidation with Ag20: 4-isoindolino-phenylacetic acid, 3-methyl-4-isoindolino-phenylacetic acid 3-fluoro-4-isoindolino-phenylacetic acid 3-chloro-4-idoindolino-phenylacetic acid, P. 175 - 177 ° 3-bromo-4-isoindolino-phenylacetic acid, P. 156 - 155 ° 2- (4-isoindolino-phenyl) -propionic acid, P. 2470 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid, F. 119 1210 2- (3-Fluoro-4-isoindolino-phenyl) -propionic 1 ure, F. 175 1770 2- (3-Bromo-4-isoindolinophenyl) propionic acid, F. 148 1490 2- (4-Isoindolinophenyl) butyric acid 2- (3-methyl-4-isoindolino-phenyl) -butyric acid 2- (3-fluoro-4-isoindolino-phenyl) -butyric acid, F. 158-15 2- (3-chloro-4-isoindolino-phenyl) -butyric acid 2- (3-bromo-4-isoindolino-phenyl) butyric acid b) To 3 g of 2- (3-chloro-4-isoindolino-phenyl) propionic acid dissolved in 20 ml of methanol, as much etherisc is added while stirring.

Diazomethane solution was added dropwise until no more nitrogen evolution is to be observed. After 20 minutes you steam an egg: works like Usually on and receives 2- (3-Clilor-4-isoindolino-phenyl) -propionic acid methyl ester, Bp 172 - 1800 / 0.01 mm.

Analogously, 4-isoindolino-phenyls are obtained from the abovementioned acids with diazomethane methyl acetate 3-methyl-4-isoindolino-phenylacetic acid methyl ester 3-fluoro-4-isoindolino-phenylacetic acid methyl ester 3-Chloro-4-isoindolino-phenylacetic acid methyl ester) -Bromo-4-isoindolino-phenylacetic acid methyl ester 2- (4-Isoindolino-phenyl) -propionic acid methyl ester 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid methyl ester 2- (3-fluoro-4-isoindolino-phenyl) -propionic acid methyl ester 2- (3-Bromo-4-isoindolinophenyl) propionic acid methyl ester, 2- (4-Isoindolinophenyl) butyric acid methyl ester 2- (3-Methyl-4-isoindolino-phenyl) -butyric acid-methyl ester 2- (3-Fluoro-4-isoindolino-phenyl) -butyric acid-methyl ester 2- (3-Chloro-4-isoindolino-phenyl) -butyric acid methyl ester 2- (3-Bromo-4-isoindolino-phenyl) -butyric acid methyl ester.

The corresponding ones are obtained analogously with diazoethane or phenyldiazomethane ethyl or benzyl ester, e.g. B.

Benzyl 2- (3-chloro-4-isoindolino-phenyl) propionate.

c) 15.1 g of 2- (3-chloro-4-isoindolino-phenyl) propionic acid are in Let 250 ml of ethanolic hydrochloric acid stand for 15 hours at room temperature. the The reaction solution is evaporated, the residue is dissolved in water and as usual worked up (pH 5). Ethyl 2- (3-chloro-4-isoindolino-phenyl) propionate is obtained, mp 70 - 720, bp 190-2000 / 0.01 mm.

Analogously, one obtains from the corresponding acids with ethanolic Hydrochloric acid, ethyl 4-isoindolino-phenylacetate, 3-methyl-4-isoindolino-phenylacetic acid, ethyl ester 3-fluoro-4-isoindolino-phenylacetic acid ethyl ester 3-chloro-4-isoindolino-phenylacetic acid ethyl ester, Bp. 1880 / 0.01 mm 3-Bromo-4-isoindolino-phenylacetic acid-ethyl ester, mp 85 ° 0 2- (4-isoindolino-phenyl) -propionic acid-ethyl ester, P. 105 ° 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid ethyl ester, bp 172-1740 / 0.01 mm 2- (3-Pluoro-4-isoindolino-phenyl) -propionic acid ethyl ester, P. 60 - 620, bp. 183-191 ° / 0.01 mm Ethyl 2- (3-bromo-4-isoindolino-phenyl) propionate, b.p. 198-2050 / 0.01 mm Ethyl 2- (4-isoindolino-phenyl) -butyric acid, ethyl 2- (3-methyl-4-isoindolino-phenyl) -butyric acid 2- (3-Fluoro-4-isoindolino-phenyl) -butyric acid ethyol ester, bp 190-1950 / 0.05 mm Ethyl 2- (3-chloro-4-isoindolino-phenyl) -butyric acid, boiling point 205-2080 / 0.02 mm 2- (3-Bromo-4-i soindolino-phenyl) -butyric acid ethyl ester and by reaction with HOl in methanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, n-hexanol, n-heptanol, n-octanol, 2-ethyl-hexanol, n-nonanol or n-decanol the corresponding methyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl and n-decyl esters, e.g. B.

2- (3-Chloro-4-isoindolino-phenyl) -propionic acid - methyl ester, b.p. 172 - 1800 / 0.01 mm -n-propylester, b.p. 200-2050 / 0.05 mm -isopropylester -n-butylester -isobutyl ester -sec.-butyl ester -tert-butyl ester -n-pentyl ester -isopentyl ester -n-hexyl ester -n-heptyl ester -n-octyl ester - (2-ethyl-hexyl ester) -n-nonyl ester -n decyl ester.

Example 2 a) 1 g of 2- (3-chloro-4-isoindolino-phenyl) -propapanal becomes cooled to 0-4 ° in a mixture of 20 ml of acetic acid and 20 ml of benzene and with stirring within 10 minutes with a solution of 0.25 g of CrO3 in 1 ml of water and 20 ml of acetic acid are added. After standing for one hour at room temperature 10 ml of methanol are added, then it is diluted with water. One extracts with ether, shakes the Ether phase with 4% NaOH, the alkaline works Extracts as usual to (pH 5.2 - 5.4) and contains 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, 148 ° F.

b) 6 g of 2- (3-chloro-4-isoindolino-phenyl) propionic acid and 1 g of ethanol are dissolved in 80 ml of absolute tetrahydrofuran and treated with 4.2 g of dicyclohexylcarbodiimide offset. The mixture is left to stand at room temperature for 24 hours, and the precipitated product is filtered off Dicyclohexylurea from, evaporates and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid ethyl ester, F. 70-720.

c) 7 g of 2- (3-chloro-4-isoindolino-phenyl) propionic acid and 4 g of 2-diethylamino-ethyl chloride hydrochloride are in a solution prepared from 1.07 g of Na and 70 ml of isopropanol for 8 hours cooked. It is evaporated, worked as usual to (pH 9) and obtained 2- (3-chloro-4-isoindolino-phenyl) -propionic acid (2-diethylamino-ethyl ester), Kp. 225 - 2300 / 0.05 mm.

You can also use the sodium salt of the acid with an equimolar amount of 2-diethylaminoethyl chloride realize.

Analogously with 2-dimethylaminoethyl chloride, 2-pyrrolidinoethyl chloride, 2-piperidinoethyl chloride, 2-morpholinoethyl chloride, 3-dimethylaminopropyl chloride, 3-diethylaminopropyl chloride, 3-pyrrolidinopropyl chloride, 3-piperidinopropyl chloride or 3-morpholinopropyl chloride 2- (3-chloro-4-isoindolino-phenyl) -propionic acid - 2-dimethylamino-ethyl ester -2-pyrrolidino-ethyl ester -2-piperidino-ethyl ester -2vmorpholino-ethyl ester -5-dimethylamino-propyl ester -3-diethylamino-propyl ester -5-pyrrolidino-propyl ester -3-piperidino-propyl ester -3-morpholino-propyl ester and with the others mentioned above Acids of the formula I (Z = COOH) the corresponding esters.

Example 3 6.8 g of 2- (3-chloro-4-isoindolino-phenyl) -1-propanol [available by reacting 2- (3-chloro-4-aminophenyl) -1-propanol with o-xylylenedibromijd dissolved in 40 ml of 10% H2504.

Add 2.5 g of Na2Cr207 2H20, stir for two hours at 60 °, cool from, works up as usual and obtained after chromatographic purification on silica gel 2- (3-Chloro-4-isoindolino-phenyl) -propionic acid, mp 148 °.

2- (4-Isoindolino-phenyl) -ethanol gives 2- (3-methyl-4-isoindolino-phenyl) -ethanol in a similar manner 2- (3-Fluoro-4-isoindolino-phenyl) -ethanol 2- (3-chloro-4-isoindolino-phenyl) -ethanol 2- (3-Bromo-4-isoindolino-phenyl) -ethanol 2- (4-isoindolino-phenyl) -1-propanol 2- (3-methyl-4-isoindolino-phenyl) -1-propanol 2- (3-fluoro-4-isoindolino-phenyl) -1-propanol 2- (3-bromo-4-isoindolino-phenyl) -1-propanol 2- (4-isoindolino-phenyl) -1-butanol 2- (3-methyl-4-isoindolino-phenyl) -1-butanol 2- (3-Fluoro-4-isoindolino-phenyl) -1-butanol 2- (3-chloro-4-isoindolino-phenyl) -1-butanol 2- (3-Bromo-4-isoindolino-phenyl) -1-butanol by oxidation of the corresponding carboxylic acids.

Example 4 6.5 g of 2- (3-fluoro-4-isoindolino-phenyl) -1-propanol become cooled to 5 ° in a mixture of 50 ml of acetic acid and 40 ml of benzene with stirring. A solution of 1.6 g of CrO) in 20 ml of acetic acid is added dropwise over the course of 20 minutes and add 2 ml of water, leave to stand for 1 hour at room temperature, add 10 ml of methanol to, works as usual on (pH 5) and receives 2- (3-fluoro-4-isoindolino-phenyl) -propionic acid, F. 175-177 ° Example 5 In a solution of 1- (3-methyl-4-isoindolino-phenyl) -ethyllithium (obtainable by adding 30 ml of a 20% solution of n-butyllithium in Hexane to a solution of 23.7 g of 1- (3-methyl-4-isoindolino-phenyl) ethyl bromide in 220 ml of absolute ether at -60 ° and stirring for half an hour at -60 °) is at -20 ° a dry C02 stream initiated. After 2 hours you pour into water and work as usual to (pH 5) and receives 2- (3-methyl-4-isoindolino-phenyl) -propionic acid, 119 - 121 °.

Example 6 a) A solution of crude 2-methyl-2- (3-chloro-4-isoindolinophenyl) malonic acid Obtainable by alkylating 2- (3 "chloro-4-isoindolino-phenyl) malonic acid diethyl ester with OH3J in the presence of NaH in DD? and saponification of 18.5 g of the 2-methyl-2- (3-chloro-4-isoindolinophenyl) malonic acid diethyl ester obtained with ethanolic KOH under N2] in 200 ml of acetic acid and 200 ml of 15 pointer HCl cooked under N2 until the end of CO2 evolution.

After cooling and the usual work-up (pH 5), 2- (3-chloro-4-isoindolino-phenyl) propionic acid is obtained, Pe 148 °.

Analogously, 2- (4-isoindolino-phenyl) -malonic acid is obtained by decarboxylation 2- (3-methyl-4-isoindolino-phenyl) -malonic acid 2- (3-fluoro-4-isoindolino-phenyl) -malonic acid 2- (3-Chloro-4-isoindolino-phenyl) -malonic acid 2- (3-Bromo-4-isoindolino-phenyl) -malonic acid 2-methyl-2- (4-isoindolino-phenyl) -malonic acid, 2-methyl-2- (5-methyl-4-isoindolino-phenyl) -malonic acid 2-methyl-2- (3-fluoro-4-isoindolino-phenyl) -malonic acid, 2-methyl-2- (3-bromo-4-isoindolino-phenyl) -malonic acid 2-Ethyl-2- (4-isoindolino-phenyl) -malonic acid 2-Ethyl-2- (3-methyl-4-isoindolino-phenyl) -malonic acid 2-ethyl-2- (5-fluoro-4-isoindolino-phenyl) -malonic acid 2-ethyl-2- (3-chloro-4-isoindolino-phenyl) -malonic acid 2-ethyl-2- (5-bromo-4-isoindolino-phenyl) -malonic acid the corresponding 2- (4-isoindolino-phenyl) -acetic-, propionic and butyric acids.

b) 7.5 g of 2- (3-chloro-4-isoindolino-phenyl) propionic acid and 15 g of vinyl acetate are shaken with 0.15 g of mercury acetate for 40 minutes. Then you heat to the Boil, add 1 drop of H2504, boil for 3 hours, add 200 mg sodium acetate, evaporates and works up as usual. 2- (3-chloro-4-isoindolino-phenyl) -propionic acid vinyl ester is obtained, Kp. 203 - 2050 / 0.05 mm.

c) To a solution of 7.5 g of 2- (3- (§hlor-4-isoindolinophenyl) propionic acid 1.5 g of NaH are added in 120 ml of absolute tetrahydrofuran. The mixture is stirred for 30 minutes at 250, cools, at 5 a solution of 3.6 g of allyl bromide in 25 ml of absolute Add tetrahydrofuran and stir again for 24 hours at 250. After evaporation and Customary work-up gives 2- (3-chloro-4-isoindolino-phenyl) propionic acid allyl ester, Bp 204-2090 / 0.01 mm.

Example 7 19.5 g of 2-methyl-2- (3-chloro-4-isoindolino-phenyl) -malonic acid monoethyl ester (obtainable by partial saponification of the diethyl ester with 1 mol of KOH in ethanol and acidification) slow down to 100 at 18 Torr until the end of CO 2 evolution - 1300 heated. Ethyl 2- (3-chloro-4-isoindolinophenyl) propionate is obtained, P. 70-720.

Example 8 17.5 g of 2-methyl-2- (3-methyl-4-isoindolino-phenyl) -butan-3-one acid ethyl ester (obtainable by carboxylation of 3-methyl-4-isoindolino-phenyl-acetone and subsequent Methylation) are stirred with 250 ml of 50% but KOH for 45 minutes at 900 under N2. It is cooled, water and HCl are added up to pH 10, washed with ether, works as Usually at (pH 5) and contains 2- (3-methyl-4-isoindolino-phenyl) -propionic acid, F. 119-121 ° is obtained analogously from 2- (4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2- (3-Methyl-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2- (3-Fluoro-4-isoindolino-phenyl) -butan-3-one-acid-ethyl Ester 2- (3-chloro-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2- (3-bromo-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2-Methy4 (4-i soindolino-phenyl) -butan-3-one-acid ethyl ster 2-Methy3i (3-methyl-4-isoindolino-phenyl) -butane-3- ethyl ester 2-methyl (3-fluoro-4-isoindoli.no-phenyl) butan-3-one ethyl ester 2-methyl-²- (3-chloro-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2-methy (3-bromo-4-isoindolino-phenyl) -butane-3-one-acid ethyl ester 2-Äthy4-isoindolino-phenyl) -butane-3-one-acid ethyl ester 2-Ethyl-² / - (3-methyl-4-isoindolino-phenyl) -butan-3-one acid ethyl ester 2-Ethy (3-fluoro-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2-EthylA (3-chloro-4-isoindolino-phenyl) -butan-3-one-acid ethyl ester 2-Ethyl-² / - (3-bromo-4-isoindolinophenyl) -butane-3-one-acid ethyl ester or the corresponding methyl esters from the corresponding methyl esters by acid cleavage 4-isoindolino-phenyl-acetic, propionic and butyric acids.

Example 9 a) 4 g of 2- (3-chloro-4-aminophenyl) propionic acid (y. 114 ~ 1150; obtainable from 2- (3-chloro-4-aminophenyl) propionitrile by saponifying with 25% HCl), 5.5 g of o-xylylene dibromide and 5.5 g of powdered K2CO3 are boiled in 40 ml of absolute ethanol for 6 hours. The reaction mixture is then in 2- (3-chloro-4- (o-bromomethyl-benzylamino) -phenyl] -propionic acid in the form of their Potassium salt is formed intermediate, cooled, filtered and evaporated.

2- (3-chloro-4-isoindolino-phenyl) -propionic acid is obtained, mp 1480 (Ethyl acetate).

Analogously, 3-methyl-4-aminophenylacetic acid is obtained from 4-aminophenylacetic acid 3-fluoro-4-aminophenylacetic acid 3-chloro-4-aminophenylacetic acid 3-bromo-4-aminophenylacetic acid g acid 2- (4-aminophenyl) propionic acid 2- (3-methyl-4-aminophenyl) propionic acid 2- (3-fluoro-4-minophenyl) propionic acid 2- (3-Bromo-4-aminophenyl) -propionic acid 2- (4-aminophenyl) -butyric acid 2- (3-methyl-4 -aminophenyl) -butyric acid 2- (3-fluoro-4-aminophenyl) -butyric acid 2- (3-chloro-4-aminophenyl) -butyric acid 2- (3 -Bromo-4-aminophenyl) butyric acid or from the corresponding esters of the above 4-aminophenyl acetic, propionic or butyric acids, especially the methyl, ethyl and n-propyl esters, e.g. B.

Methyl 2- (3-chloro-4-aminophenyl) propionate, ethyl 2- (3-chloro-4-aminophenyl) propionate 2- (3-Chloro-4-aminophenyl) propionic acid n-propyl ester 2- (3-Chloro-4-aminophenyl) propionic acid n-butyl ester Isobutyl 2- (3-chloro-4-aminophenyl) propionate, n-pentyl 2- (3-chloro-4-aminophenyl) propionate by reaction with o-xylylene dibromide or o-xylylene dichloride the corresponding Isoindoline derivatives.

b) 3.02 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid are in Dissolve 50 ml of ethanol and add the calculated amount of ethanolic NaOH. After the addition of 50 ml of diethyl ether and piltration, the sodium salt is obtained 2- (3-chloro-4-isoindolino-phenyl) propionic acid.

c) 3.02 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid are in Dissolve 50 ml of ethanol and add the calculated amount of ethanolic HOl Addition of 50 ml of diet ether and filtration gives the hydrochloride of 2- (3-chloro-4-isoindolino-phenyl) propionic acid.

Analogously, from the corresponding 4-isoindolinophenyl acetic acid, propionic or butyric acids by reaction with alkali metal or alkaline earth metal hydroxides respectively.

Amines or the corresponding salts with acids.

d) 1 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid methyl ester heated to 500 in 10 ml of 15% hydrochloric acid for 90 minutes. You cool off, work like Usually at (pH 5) and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, m.p. 1480.

The other esters falling under the formula I can be prepared analogously saponify to the corresponding acids, e) 1 g of ethyl 2- (3-chloro-4-isoindolino-phenyl) propionate is boiled with 1 g of KOH in 10 g of ethanol for 4 hours.

You work as usual on (pH 5) and get 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, F. 1480 The other esters falling under the formula I can be converted into the saponify free acids.

Example 10 13 g of 2- (3-methyl-4-o-hydroxymethylbenzylaminophenyl) propionic acid (obtainable by reacting 2- (3-methyl-4-alllinophenyl) propionic acid with 2-bromomethyl dibenzyl ether and subsequent hydrogenolytic ether cleavage) are at 800 in 150 g of polyphosphoric acid entered, heated to 1100 and held at 1100 for 10 minutes. One cools down, gives the reaction mixture in ice water and works up as usual. After chromatography on silica gel you get 2- (3-methyl-4-isoindolino-phenyl) -propionic acid, mp 119 - 121 °.

Analogously, from 4-o-Hydroxymethylbenzylaminophenylacetic acid is obtained 3-methyl-4-o-hydroxymethylbenzylaminophenylacetic acid 3-fluoro-4-o-hydroxymethylbenzylaminophenylacetic acid 3-chloro-4-o-hydroxymethylbenzylaminophenylacetic acid 3-bromo-4-o-hydroxymethylbenzylaminophenylacetic acid 2- (4-o-Hydroxymethylbenzylaminophenyl) propionic acid 2- (3-fluoro-4-o-hydroxymethylbenzylaminophenyl) propionic acid 2- (3-chloro-4-o-hydroxymethylbenzylaminophenyl) propionic acid * (pH 5) 2- (3-Bromo-4-o-hydroxymethylbenzylaminophenyl) propionic acid 2- (4-o-Hydroxymethylbenzylaminophenyl) butyric acid 2- (3-methyl-4-o-hydroxymethylbenzylaminophenyl) butyric acid 2- (3-Fluoro-4-o-hydroxymethylbenzylaminophenyl) -butyric acid 2- (3-chloro-4-o-hydroxymethylbenzylaminophenyl ) -butyric acid 2- (3-bromo-4-o-hydroxymethylbenzylamino-phenyl) -but; tertiary acid with Polyphosphoric acid the corresponding isoindoline derivatives.

Example 11 11.3 g of 2- (3-bromo-4-o-methoxymethylbenzylaminophenyl) propionic acid (obtainable by condensation of ethyl 2- (3-bromo-4-aminophenyl) propionate with o-methoxymethylbenzaldehyde, hydrogenation of the C = N bond and alkaline saponification) are boiled in 50 ml 65 pointer HBr and 20 ml acetic acid for 2 hours. One cools off, mixed with ice water, works up to (pH 5) as usual and receives 2- (3-bromo-4-isoindolino-phenyl) -propionic acid, 148-149 ° F.

Analogously, 4-o-methoxymethylbenzylaminophenylacetic acid is obtained 3-methyl-4-o-methoxymethylbenzylaminophenylacetic acid 3-fluoro-4-o-methoxymethylbenzylaminophenylacetic acid 3-chloro-4-o-methoxymethylbenzylamino-phenylacetic acid 3-bromo-4-o-methoxymethylbenzylamino-phenylacetic acid 2- (4-o-methoxymethylbenzylaminophenyl) propionic acid 2- (3-methyl-4-o-methoxymethylbenzylaminophenyl) propionic acid 2- (3-Fluoro-4-o-methoxymethylbenzylaminophenyl) propic acid 2- (3-chloro-4-o-methoxymethylbenzylaminophenyl) propic acid 2- (4-o-Methoxymethylbenzylaminophenyl) butyric acid 2- (3-methyl-4-o-methoxymethylbenzylaminophenyl) butter acid 2- (3-fluoro-4-o-methoxymethylbenzylamino-phenyl) -butter acid 2- (3-chloro-4-o-methoxymethylbenzylamino-phenyl) -butter acid 2- (3-bromo-4-o-methoxymethylbenzylamino-phenyl) -butters with HBr / acetic acid the corresponding isoindoline derivatives.

Example 12 19.5 g of 2- (3-methyl-4-o-aminomethylbenzylamino-phenyl) -pro @ acid dihydrochloride (obtainable by reacting 2-bromomethylbenzonitrile with 2- (3-methyl-4-aminophenyl) propion.

ethyl ester, saponification and catalytic hydrogenation of the nitrile group) are rubbed with about 100 g of sand and heated until they melt. After completion the NH3 cleavage is run cold, aqueous sodium hydroxide solution is added, and you work wic usual to (pH 5) and contains 2- (3-methyl-4-isoindolino-p @ en.

propionic acid, mp 119-121 °.

The dihydrochlorides of 4- (o-aminomethylbenzylamino) phenylacetic acid are obtained analogously 3-methyl-4- (o-aminomethyl-benzylamino) -phenylacetic acid 3-fluoro-4- (o-aminomethyl-benzylamino) -phenylacetic acid 3-chloro-4- (o-aminomethyl-benzylamino) -phenylacetic acid 3-Bromo-4- (o-aminomethyl-benzylamino) -phenylacetic acid 2- (4-o-aminomethylbenzylamino-phenyl) -propionic acid 2- (3-Fluoro-4-o-aminomethylbenzylamino-phenyl) -propionic acid 2- (3-chloro-4-o-aminomethylbenzylamino-phenyl) -propionic acid 2- (3-Bron-4-o-aminomethylbenzylaminophenyl) propionic acid 2- (4-o-aminomethylbenzylaminophenyl) butyric acid 2- (3-Methyl-4-o-aminomethylbenzylaminophenyl) -butyric acid 2- (5-fluoro-4-o-aminome ethylbenzylaminophenyl) butyric acid 2- (3-chloro-4-o-aminomethylbenzylaminophenyl) butyric acid 2- (5-bromo-4-o-aminomethylbenzylaminophenyl) butyric acid by thermal cyclization the corresponding isoindoline derivatives.

Example 13 A solution of 3.5 g of NaNO2 in 10 ml of water is added dropwise at 0 ° to a solution of 14.1 g of 2- (3-amino-4-isoindolino-phenyl) propionic acid in 125 ml of 15% hydrochloric acid. Then 12 ml of a 40% HBF4 solution added dropwise. It is buffered to pH 5-6 and the precipitated diazonium tetrafluoroborate is filtered off with suction off, wash it with water, dry it and add it in portions to 100 ml of boiling water Xylene. After the end of the decomposition, evaporate and work up as usual (Addition of coal, pH 5) and, after chromatographic cleaning on silica gel, receives 2- (3-fluoro-4-isoindolino-phenyl) -propionic acid, 175-177 ° F.

Analogously, from 3-amino-4-isoindolino-phenylacetic acid or

2- (3-Amino-4-isoindolino-phenyl) -butyric acid respectively. from the corresponding esters by diazotization and reaction with HBF4 the corresponding 3-Pluor connections.

Example 14 22 g of 2- (3-amino-4-isoindolino-phenyl) -propionic acid (available from 2- (4-chloro-3-nitrophenyl) propionic acid by reacting with isoindoline and then Hydrogenation in the presence of palladium carbon) are concentrated in 150 ml of water and 50 ml Dissolved HCl, mixed with 5.3 g NaNO2 in 12 ml water at 0 - 5 °, to a hot one Cu2Cl2 solution (obtained by reducing 16 g CuSO4 with S02 in 100 ml water in the presence of 20 g of NaCl) slowly added dropwise, a further 30 minutes at 90-95 ° heated, cooled, saturated with H2S and filtered. The filtrate is as usual (pH 5 - 5.5) worked up. 2- (3-chloro-4-isoindolino-phenyl) -propionic acid is obtained, 148 ° F.

Analogously, from 3-amino-4-isoindolino-phenylacetic acid or

2- (3-Amino-4-isoindolino-phenyl) -butyric acid or from the corresponding Esters (especially the methyl, ethyl or n-propyl esters), such as. B.

2- (3-Amino-4-isoindolino-phenyl) -propionic acid methyl ester 2- (5-Amino-4-isoindolino-phenyl) -propionic acid ethyl ester 2- (3-Amino-4-isoindolino-phenyl) -propionic acid n-propyl ester by diazotization and reacting with Cu2C12 the corresponding 3-chloro compounds.

Example 15 14.1 g of 2- (3-amino-4-isoindolino-phenyl) -propionic acid (available by reacting 2- (3-nitro-4-bromophenyl) propionic acid with isoindoline and then catalytic hydrogenation) are dissolved in 30 ml of water and 6 ml of concentrated H2504, at 0 - 50 with a solution of 3.5 g NaN02 in 10 ml water added dropwise, to a boiling solution of 3.3 g CuSO4 5i120, 7.7 g NaBr and 1 g copper powder (previously boiled for 4 hours and then mixed with -0.13 g Na2SO3-) added dropwise, 30 minutes heated to 950, cooled, saturated with H2S, filtered and the filtrate as usual worked up (pll 5). 2- (3-Bromo-4-isoindolino-phenyl) -propionic acid is obtained, P. 148 - t490.

Analog receives; from 3-amino-4-isoindolino-phenylacetic acid or

2- (3-Amino-4-isoindolino-phenyl) -butyric acid or from the corresponding Esters by diazotizing and reacting with haBr in the presence of copper sulfate die corresponding 3-bromine compounds.

Example 16 15.8 g of ethyl 3-chloro-4-isoindolino-phenylacetic acid are dissolved in 100 ml of DMF and after adding 3 g of NaH for 3 hours at 300 under N2 stirred. The Na derivative of the ester is formed in the process. 8 g of methyl iodide are added dropwise added, stirred for 24 hours at 30 °, worked up as usual and obtained ethyl 2- (3-chloro-4-isoindolino-phenyl) propionate, F. 70-720.

Analogously, from the esters, in particular the lower alkyl esters, of 4-isoindolino, 3-methyl-4-isoindol 1-no, 3-fluorine-4-isoindolino, 3-chloro-4-isoindolino or 7-nrom-4-isoindolino-phenylacetic acid via their Na derivatives by reaction with methyl iodide (or ethyl bromide or ethyl iodide) the corresponding 2- (4-isoindolino-phenyl) propionic acid esters (or butyric acid ester).

Example 17 To a solution of 19.5 g of ethyl X-bromo-3-chloro-4-isoindolinophenylacetate $ obtainable by bromination of 3 - (: chloro-4-isoindolino-pheIlylacigsäure-ethylsier) 25 ml of an ethereal 2M are added dropwise to 150 ml of absolute tetrahydrofuran at -20 ° Solution of CJ {5-Li, works up as usual and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid ethyl ester, F. 70-720.

An ethyl ester of α-bromo-4-isoindolino-phenylacetic acid is obtained analogously α-Bromo-3-methyl-4-isoindolino-phenylacetic acid ethyl ester α-Bromo-3-fluoro-4-isoindolino-phenylacetic acid ethyl ester α3-Dibromo-4-isoindolino-phenylacetic acid ethyl ester or from the corresponding Methyl or propyl esters by reaction with CH3Li (or C2H5Li) the corresponding 2- (4-Isoindolino-phenyl) -propionic acid ester (or -butyric acid ester).

Example 18 14 g of 2- (3-chloro-4-isoindolino-phenyl) -propionitrile (can be prepared from 2- (3-chloro-4-aminophenyl) propionitrile and o-xylylene bromide ) are boiled in 200 ml of ethanol and 20 ml of water with 20 g of KOII 40 btuiiden, the The solvent is distilled off and the residue is worked up as usual (pH 5). Man receives 2- (3-chloro-4-isoindolino-phenyl) propionic acid, mp 148 °.

Alkaline hydrolysis of 4-isoindolino-phenylacetonitrile is obtained analogously 3-methyl-4-isoindolino-phenylacetonitrile 3-fluoro-4-isoindolino-phenylacetonitrile 3-chloro-4-isoindolino-phenylacetonitrile 3-bromo-4-isoindolino-phenylacetonitrile 2- (4-isoindolino-phenyl) -propionitrile 2- (3-methyl-4-isoindolino-phenyl) -propionitrile 2- (3-fluoro-4-isoindolino-phenyl) -propionitrile 2- (3-Bromo-4-isoindolino-phenyl) -propionitrile 2- (4-isoindolino-phenyl) -butyronitrile 2- (3-methyl-4-isoindolino-phenyl) -butyonitrile 2- (3-fluoro-4-isoindolino-phenyl) -butyronitrile 2- (3-chloro-4-isoindolino-phenyl) -butyronitrile 2- (3-bromo-4-isoindolino-phenyl) -butyronitrile the corresponding carboxylic acids.

Example 19 14 g of 2- (3-chloro-4-isoindolino-phenyl) -propionitrile become with 60 ml of acetic acid and 60 ml of concentrated hydrochloric acid for 2 hours under nitrogen cooked. It is evaporated, dissolved in dilute NaOH, washed with ethyl acetate, worked as usual to (pH 5) and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, 148 ° F.

Those mentioned in Example 14 are obtained analogously by acid hydrolysis Nitriles the corresponding carboxylic acids.

Example 20 3 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid amide (obtainable by partial hydrolysis of the nitrile) and 5 g of KOH are in 100 ml Ethanol boiled under nitrogen for 3 hours.

It is evaporated, works as usual to (pH 5) and receives 2- (3-chloro-4-isoindolino-phenyl) -propionic acid, 148 ° F.

Alkaline hydrolysis of 4-isoindolino-phenylacetamide is obtained analogously 3-methyl-4-isoindolino-phenylacetamide 3-fluoro-4-isoindolino-phenylacetamide 3-chloro-4-isoindolino-phenylacetamide 3-Bromo-4-isoindolino-phenylacetamide 2- (4-isoindolino-phenyl) -propionic acid amide 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid amide 2- (3-fluoro-4-isoindolino-phenyl) -propionic acid amide 2- (3-Chloro-4-isoindolino-phenyl) -propionic acid amide 2- (3-Bromo-4-isoindolino-phenyl) -propionic acid amide 2- (4-Isoindolino-phenyl) -butyric acid amide 2- (3-Methyl-4-isoindolino-phenyl) -butyric acid amide 2- (3-fluoro-4-isoindolino-phenyl) -butyric acid amide 2- (3-chloro-4-isoindolino-phenyl) -butyric acid amide 2- (3-bromo-4-isoindolino-phenyl) butyric acid amide the corresponding Carboxylic acids.

Example 21 20 g of 3-chloro-4-isoindolino-phenylthioacetic acid morpholide (obtainable from 3-chloro-4-isoindolino-acetophenone by reacting with morpholine and Sulfur) are boiled in 100 ml of concentrated HCl for 2 hours. Tan leaves 15 hours stand at room temperature, evaporate, work on as usual (plf 5) and receive 3-chloro-4-isoindolinophenylacetic acid, mp 175-1770.

Analogously, morpholide is obtained from 4-isoindolino-phenylthioacetic acid 3-methyl-4-isoindolino-phenylthioacetic acid morpholide, 3-fluorine-4-isoindolino-phenylthioacetic acid morpholide 3-Bromo-4-isoindolino-phenylthioacetic acid morpholide with HCl the corresponding phenylacetic acids.

Example 22 10 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid chloride (obtainable from the acid and SOC12) with 100 ml of absolute n-propanol for 3 hours heated to 95. It is evaporated, worked up as usual and obtained 2- (3-chloro-4-isoindolinophenyl) propionic acid n-propyl ester, Kp. 200 t 2050 / 0.05 mm.

Analogously, one obtains from the acid chlorides according to the formula I. (COCl in place of Z) with the corresponding alcohols the corresponding esters.

Example 23 9 g of 2- (3-1yromo-4-isoindolino-phenyl) -propionic acid ellloride are dissolved in 100 ml of absolute tetrahydrofuran and treated with 3 g of potassium tert-butoxide offset. The mixture is stirred for 30 minutes at room temperature, filtered off with suction, evaporated and worked as usual and receives 2- (3-bromo-4-isoindolino-phenyl) -propionic acid. -butyl ester, Bp. 208 - 218 ° / 0.01 mm.

Example 24 10.5 g of 2- (3-chloro-4-isoindolino-phenyl) -propionic acid-iminoethyl ether hydrochloride (available from the nitrile and ethanol / HCl) are boiled with 250 ml of water for 1 hour. Customary work-up gives ethyl (2- (3-chloro-4-isoindolinophenyl) propionate, F. 70-72 °.

Example 25 17.6 g of ethyl 2- (3-fluoro-4-isoindolino-phenyl) acrylic acid are dissolved (obtainable by reaction of 2-fluoroaniline with o-xylylene bromide to form 2-isoindolino-fluorobenzene, Acylation with ethoxalyl chloride / AlCl3 to give 3-fluoro-4-isoindolino-phenylglyoxylic acid ethyl ester vom F. 122-1230, reaction with CH3MgJ and hydrolysis to ethyl 2-hydroxy-2- (3-fluoro-4-isoindolinophenyl) propionate vom F. 83 - 850 and elimination of water with polyphosphoric acid) in 200 ml of methanol and 100 ml of ethyl acetate, hydrogenated on 8 g of palladium carbon (5%) at room temperature and 1 at until hydrogen uptake ceases, the catalyst is filtered off and evaporated hurries, the residue is distilled and receives ethyl 2- (3-fluoro-4-isoindolino-phenyl) propionate, P. 60-620.

Analogously, 2- (4-isoindolino-phenyl) -acrylic acid gives 2- (3-methyl-4-isoindolino-phenyl) -acrylic acid 2- (3-Fluoro-4-isoindolino-phenyl) -acrylic acid 2- (3-chloro-4-isoindolino-phenyl) -acrylic acid 2- (3-Bromo-4-isoindolino-phenyl) -acrylic acid 2- (4-isoindolino-phenyl) -2-butenoic acid 2- (5-E.Iethyl-4-isoindolino-phenyl) -2-butenoic acid 2- (3-fluoro-4-isoindolino-phenyl) -2-butenoic acid 2- (3-Chloro-4-isoindolino-phenyl) -2-butenoic acid 2- (3-Bromo-4-isoindolino-phenyl) -2-butenoic acid 2- (4-isoindolino-phenyl) -3-butenoic acid 2- (3-methyl-4-isoindolino-phenyl-3-butenoic acid 2- (3-Fluoro-4-isoindolino-phenyl) -3-butenoic acid 2- (3-chloro-4-isoindolino-phenyl) -3-butenoic acid 2- (3-Bromo-4-isoindolino-phenyl) -3-butenoic acid or from the esters, especially the lower alkyl esters, e.g. B. the methyl, ethyl or n-propyl esters of these acids the corresponding 2-arylpropionic or butyric acids by catalytic hydrogenation or their esters.

Example 26 Crude 2- [2-chloro-4- (1-ethoxycarbonyl-ethyl) -phenyl] -1H-isoindolium bromide [Obtained by boiling 22 g of ethyl 2- (3-chloro-4-aminophenyl) propionate for 3 hours with 20 g of o-bromomethyl-benzaldehyde in 300 ml of toluene under N2 and evaporation dissolved in 400 ml of ethanol and added to 1 g of platinum until 1 mol of H2 is absorbed at 250 and normal pressure hydrogenated. It is filtered, evaporated, worked up as usual and receives ethyl 2- (3-chloro-4-isoindolino-phenyl) propionate, P. 70 - 720.

Similarly, 2- (4-ethoxycarbonyl-methyl) -phenyl-1H-isoindolium bromide is obtained 2- (2-methyl-4-ethoxycarbonyl-methyl) -phenyl-1H-isoindolium bromide 2- (2-fluoro-4-ethoxycarbonyl-methyl) -phenyl-1H-isoindolium bromide 2- (2-chloro-4-rithoxyearbonyl-methyl) -phenyl-1lL-isoindolium bromide 2- (2-bromo-4-ethoxycarbonyl-methyl) -phenyl-1H-isoindolium bromide 2- [4- (1-ethoxycarbonyl-ethyl) -phenyl] -1H-isoindolium bromide 2- [2-methyl-4- (1-ethoxycarbonyl-ethyl) -phenyl] -1H-isoindolium bromide 2- [2-Fluoro-1- (1-ethoxycarbonyl-ethyl) -phenyl] -1H-isoindolium bromide 2- [2-Bromo-4- (1-ethoxycarbonyl-ethyl) -phenyl] -1H-isoindolium bromide 2- [4- (1-ethoxycarbonyl-propyl) -phenyl] -1H-isoindolium bromide 2- [2-methyl-4- (1-ethoxycarbonyl-propyl) -phenyl] -1H-isoindolium bromide 2- [2-Fluoro-4- (1-ethoxycarbonyl-propyl) -phenyl] -1H-isoindolium bromide 2- [2-chloro-4- (1-ethoxycarbonyl-propyl) -phenyl] -1H-isoindolium bromide 2- [2-Bromo-4- (1-ethoxycarbonyl-propyl) -phenyl] -1H-isoindolium bromide or the corresponding Methyl ester salts by catalytic hydrogenation the corresponding isoindoline derivatives.

Example 27 20 g of 2- (3-chloro-4-aminophenyl) propionic acid and 14 g of phthalaldehyde are boiled in 200 ml of benzene for 30 minutes. The solvent is removed and dissolved the residue in 200 ml of acetic acid, hydrogenated on 1 g of 10% Pd-charcoal to a standstill, filtered, evaporated, worked up as usual and obtained after chromatographic Purification on silica gel 2- (3-chloro-4-isoindolino-phenyl) propionic acid, mp 148 °.

Example 28 15 g of 3-chloro-4-isoindolino-phenylglyoxy acid (available by reaction of 2-o-clilorphenyl-isoindoline with ethoxalyl chloride / AlCl3 and then Saponification of the ester) with 2 g of red phosphorus and 200 ml of 57% HJ for 1 hour cooked under N2. It is cooled, worked up as usual (pH 5.5) and obtained 3-chloro-4-isoindolino-phenylacetic acid, 175-177 ° F.

Analogously, 3-methyl-4-isoindolino-phenylglyoxylic acid is obtained from 4-isoindolino-phenylglyoxylic acid 3-Fluoro-4-isoindolino-phenylglyoxylic acid 3-Bromo-4-isoindolino-phenylglyoxylic acid with HJ / P the corresponding 4-isoindolino-phenylacetic acids.

Example 29 A solution of 7 g of 3-chloro-4-isoindolino-mandelic acid (obtainable by reducing 3-chloro-4-isoindolino-phenylglyoxylic acid ethyl ester with NaBH4 and subsequent saponification) in 75 ml of acetic acid added to a solution of 7 g of SnCl2 in 25 ml of concentrated hydrochloric acid. I.Xn the mixture boils below 2 for 3.5 hours, sodium hydroxide solution is added to pJI 2 and the mixture is passed H2S until the end of the precipitation. Obtained after filtration and customary work-up one 3-chloro-4-isoindoiinophenylessigsäure, mp 175-1770.

Similarly, maui is obtained by reducing 4-isoindolino-almond acid 3-methyl-4-isoindolino-mandelic acid 3-fluoro-4-isoindolino-mandelic acid 3-bromo-4-isoindolino-mandelic acid 2-Hydroxy-2- (4-isoindolino-phenyl) -propionic acid, 2-Hydroxy-2- (3-methyl-4-isoindolino-phenyl) -propionic acid 2-Hydroxy-2- (3-fluoro-4-isoindolinophenyl) propionic acid, 2-Hydroxy-2- (3-chloro-4-isoindolinophenyl) propionic acid 2-Hydroxy-2- (3-bromo-4-isoindolino-phenyl) -propionic acid, 2-Hydroxy-2- (4-isoindolino-phenyl) -butyric acid 2-Hydroxy-2- (3-methyl-4-i-soindolino-phenyl) -butyric acid 2-Hydroxy-2- (3-fluoro-4-isoindolino-phenyl) -butyric acid 2-Hydroxy-2- (3-chloro-4-isoindolinophenyl) butyric acid the corresponding 4 - isoindolino-phenyl-acetic, propionic or. -butyric acids.

Claims (33)

P a t e n t a n s p r ü c h e 1. Isoindoline derivatives of the general formula I wherein Z is a free or esterified carboxyl group, R¹2 is H, CH3 or C2H5, R2 is H, CfI3, F, Cl or Br, and their physiologically acceptable salts. 2. Compounds of the general formulas Ia to Ih. 3. 4-isoindolino-phenylacetic acid. 4. 3-methyl-4-isoindolino-phenylacetic acid. 5. 3-Fluoro-4-isoindolino-phenylacetic acid. 6. 3-chloro-4-isoindolino-phenylacetic acid. 7. 3-Bromo-4-isoindolinophenylacetic acid. 8. 2- (4-Isoindolinophenyl) propionic acid. 9. 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid. 10. 2- (3-Fluoro-4-isoindolino-phenyl) -propionic acid. 11. 2- (3-Chloro-4-isoindolino-phenyl) -propionic acid. 12. 2- (3-Bromo-4-isoindolino-phenyl) -propionic acid. 13. 2- (4-Isoindolino-phenyl) -butyric acid. 14. 2- (3-Methyl-4-isoindolino-phenyl) -butyric acid. -15 ;. 2- (3-Fluoro-4-isoin (loLirlo-phenyl) -butyric acid. 16. 2- (3-Chloro-4-isoinclolinophenyl) -butyric acid. 17. 2- (3-Bromo-4-isoindolino-phenyl) -butyric acid. 183. 3-Chloro-4-isoimdolinophenylacetic acid ethyester. 19. 3-Bromo-4-isoindolino-phenylacetic acid ethyl ester. 20. Ethyl 2- (4-isoindolino-phenyl) propionate. 21. 2- (3-Methyl-4-isoindolino-phenyl) -propionic acid, ethyl ester. 22. 2- (3-Fluoro-4-isoindolino-phenyl) -propionic acid, ethyl ester. 23. Methyl 2- (3-chloro-4-isoinclolinophenyl) propionate. 24. Ethyl 2- (3-chloro-4-isoindolino-phenyl) propionic acid. 25. 2- (3-Chloro-4-isoindolino-phenyl) -propionic acid n-propyl ester. 26. 2- (3-Chloro-4-isoindolino-phenyl) -propionic acid- (2-diethylamino-ethyl ester). 27. Ethyl 2- (3-bromo-4-isoindolino-phenyl) propionate. 28. Ethyl 2- (3-fluoro-4-isoindolino-phenyl) -butyric acid. 29. Ethyl 2- (3-chloro-4-isoindolino-phenyl) -butyric acid. 30. Process for the preparation of isoindoline derivatives of the formula I wherein Z is a free or esterified carboxyl group, R1 is H, CH3 or C2H5 and R² is H, CH3, F, Cl or Br, as well as their physiologically acceptable salts, characterized in that a compound of the formula II in which L is CHO or CH2OM and R1 and R2 have the meaning given above, treated with oxidizing agents, or that a compound of the formula III in which one equivalent of Metal atoms or Mg-Hal and Hal are Cl, Br or J and R1 and R2 have the meaning given above, are reacted with C02, or a compound of the formula IV in which RI, R2 and Z have the abovementioned Have given meaning, treated with decarboxylating agents, or that a compound of the formula V wherein R3 denotes H, alkyl with up to 4 carbon atoms or phenyl and R1, R2 and Z have the meanings given above, treated with a strong base or a compound of the formula VI in which Y is Hal, NH2, an optionally reactive esterified or etherified hydroxyl group, and R1, R2 and Z have the meanings given above, treated with cyclizing agents, or in a compound of the formula VII in which R¹ and Z are as indicated above Have meaning, the amino group exchanges for the radical R2 after diazotization, or that a compound of the formula VIII with a compound of the formula IX R¹ - X² IX wherein one of the radicals X1 or x2 is an equivalent of a metal atom, MgHal, CdR4 or ZnR4, the other is Hal and R4 CH3 or C2H5 and R¹, R² and Z have the meaning given above, or that one in a compound of the formula X wherein Q is an optionally is a functionally modified COOH group and R1 and R2 have the meaning given above, the radical Q is converted into the Res-t Z by treatment with solvolysing, thermolysing or ester-forming agents, or another compound corresponding to the formula I, in which however, there are also one or more reducible and / or hydrogen-replaceable groups and / or CC multiple bonds and / or a C = N double bond, treated with reducing agents and / or a compound of the formula I in its racemates and / or optical Antipodes cleaves and / or a compound of the formula 1 is converted into its physiologically acceptable salts by treatment with an acid or base and / or a compound of the formula I is liberated from its salts by treatment with a base or acid. 71. Process for the manufacture of pharmaceutical preparations, thereby characterized in that at least one compound of the general formula I, optionally together with at least one solid, liquid or semi-liquid auxiliary or carrier and optionally together with at least one other active ingredient into a suitable one Brings dosage form. 32. A pharmaceutical preparation containing an effective dose of a Compound of the formula I in addition to at least one solid, liquid or semi-liquid Carrier or additive. 33. Pharmaceutical preparation containing 1 to 500 mg of a compound of formula 1 in addition to at least one solid, liquid or semi-liquid carrier or additive.