NO135938B - - Google Patents

Abstract

Analogous process for the preparation of isoindolinyl-phenyl-propionic acid compounds.

Description

The subject of patent no. 132,199 are α-(aminophenyl)-aliphatic carboxylic acids in which the amino group is a cyclic tertiary amino group and their acid derivatives. These compounds show anti-inflammatory properties and can be used accordingly.

It has now been found that isoindolinyl-phenyl-propionic acids of formula

in which the group \^ Jfi means an isoindolino group, which can optionally be substituted with 1 oxo group, R-^ means hydrogen or optionally halogen, or esters or salts of such compounds, have particularly pronounced anti-inflammatory properties or can easily be transferred into corresponding pharmacological active compounds.

The expression "lower" used above and below together with organic radicals, groups or compounds means that organic radicals thus designated in groups and compounds contain up to 7, preferably up to k carbon atoms.

Esters are e.g. lower alkyl esters, salts are e.g. ammonium or metal salts, as well as acid addition salts.

The anti-inflammatory properties can be demonstrated using animal experiments, for which mammals such as rats are preferably used as experimental animals. According to the test method that e.g. is described by Winter and co-workers in Proe.Soc.Exptl.Biol.

& Med., volume 111, page 5^4 (1962), the compounds according to the present invention are provided in the form of aqueous solutions or suspensions containing e.g. carboxymethylcellulose or

Polyethylene glycol as dissolution mediators, using gastric tubes to adult male and female rats in daily doses of approx. 0.0001 to approx. 0.075 g/kg, preferably in doses of between 0.0005 and 0.05 g/kg and primarily in doses of between approx. 0.001 and about 0.025 g/kg. Approximately one hour later, 0.06 ml of a 1% carrageenan suspension in aqueous physiological salt solution is injected into the left hind leg of the experimental animal. After 3-4 hours, the volume and/or weight of the edematous left hind leg is compared with these data for the right hind leg. The difference between the two extremities is compared with the differences between the sizes for untreated control animals, and the comparison serves as a benchmark for the anti-inflammatory effect of the test compounds.

The anti-inflammatory effect of the following compounds was examined and compared: acid (according to the invention)

II α-[4-(1-oxo-2-isoindolinyl)-phenylZ-propionic acid

(according to the invention)

III a-//~3~chloro-4-(2-isoindolinyl)-phenylj-propionic acid

(according to the invention)

IV 2-/~p-(1-pyrryl)-phenyl7-propionic acid (known)

The therapeutic index of the compounds I - III which can be prepared according to the invention is clearly significantly greater than that of the comparison compound IV. Reference can be made to a superior anti-inflammatory effect compared to the known compound.

According to the developed adjuvant arthritis test described by Newbould, Brit.J. PharmacolChemotherap., vol. 21, page 126 (1963), sensitized 1 rats under ether anesthesia with 0.05 ml 1#-ig aqueous carrageenin suspension on all 4 legs. After 24 hours, 0.1 ml of a 1% suspension of mycobacterium butyricum is injected under the tail skin. The test compounds are given after 7 days in the above-mentioned manner for 1k days by means of gastric tubes. The rats are weighed once a week, and the secondary arthritic lesions are determined three times a week in number and size.

The compounds of the present invention can thus be used as anti-inflammatory agents in the treatment of arthritic and dermatopathological diseases.

The method according to the invention is characterized in that

a) a compound with formula

wherein Xp means a primary amino group or an ester thereof,

is reacted with a compound of formula

in which the bivalent residue A with a nitrogen atom has the meaning given in the group A^^N above, or a reactive derivative thereof or a corresponding dehydrated derivative thereof, or

b) a compound of formula

in which X^ denotes a hydrogen atom, is reacted by Friedel-Crafts reaction with a compound of formula

or an ester in which Y-^ means a halogen atom, or

c) a compound of formula IV is reacted with a compound of formula

or an ester, wherein one of the groups X-, and means a halogen atom and the other means an alkali metal or organometallic grouping, or d) a compound of formula IV, in which X-^ means the grouping with formula in which Y£ means a metallic residue, is reacted with a metal-free, reactive derivative of carbonic or formic acid, or e) a compound of formula IV, in which X.^ means the grouping of formula in which Y2 means an ammonium group or a free hydroxy group or a halogen atom is reacted with a metal cyanide, or f) in a compound of formula IV, in which X.^ means the grouping of formula in which means a methyl group, Y^ is converted by oxidation or rearrangement into a free carboxy group, or g) in a compound of formula IV, in which X]_ means a free or a group with formula present in ester form

in which Yjj means a carboxy group, Y^ is split off by pyrolysis, or

h) a compound of formula IV, in which X^ represents an acetyl group, is treated with sulfur in the presence of ammonia or

a primary or secondary amine, or

i) a compound of formula IV, wherein X-^ means a grouping of formula

converted by hydrolysis, alcoholysis, ammonolysis or aminolysis, or j) a compound of formula IV, in which X-^ means a grouping of formula

wherein Hal means a halogen atom, is treated with a strong alkaline agent or a soluble silver salt,

and/or a formed ester or a formed salt with a hydrogen atom in the α-position is metallized or reacted with a reactive ester of an alcohol of the formula R^-OH and/or compounds formed halogenate the aromatic residue Ph and/or, if desired, a formed free compound is transferred into a salt or a formed salt in the free compound and/or, if desired, a formed isomer mixture is divided into the individual isomers.

A metal-containing group or metal group is e.g. of an alkali metal atom such as a lithium atom, or a substituted alkaline earth metal, zinc or cadmium atom such as a halogen-magnesium group, or a lower alkyl zinc or lower alkyl cadmium, e.g. chlorine, bromine or iodomagnesium or also methyl or ethyl zinc or methyl or ethyl cadmium group. A reactively esterified hydroxyl group is preferably formed by a hydroxyl group which is esterified with a strong mineral acid or sulphonic acid, e.g. hydrohalic acid, sulfuric acid, 1 valcanesulfonic acid or benzenesulfonic acid, e.g. hydrochloric acid, bromic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

The Priedel-Crafts reaction is carried out in the presence of a Lewis acid such as e.g. an aluminum salt, or boron, antimony-V, iron-II or zinc salt, especially chlorides, or in the presence

of hydrofluoric acid, sulfuric acid or preferably polyphosphoric acid, whereby the latter is primarily used together with compounds of formula IVb or derivatives thereof where, Y-^ denotes a hydroxyl group.

In a grouping with the formula -CHCCH^O-Yg (IVc), a metallic residue Yg-e.g. means one of the above-mentioned residues, further means an ammonium group e.g. a tri-lower alkyl-ammonium or di-lower alkyl-aryl-lower alkyl-ammonium, e.g. trimethylammonium or dimethylbenzylammonium group, while a functionally modified hydroxy group, e.g. an esterified hydroxy group such as one of the above-mentioned esterified hydroxy groups, an esterified hydroxy group e.g. a hydroxy group etherified with a lower alkanol or an aryl-lower alkanol or a hydroxy group present in salt form, e.g. one with an alkali or alkaline earth metal, e.g. sodium, potassium or calcium, in a corresponding salt group converted hydroxy group.

A metal or Grignard compound of formula IV can be reacted with a suitable metal-free carboxylic acid derivative or formic acid derivative, preferably with carbon dioxide, or with a corresponding carbonate or halogen formic acid ester such as e.g. diethyl carbonate, orotformic acid-lower alkyl-, such as e.g. -ethyl ester or -propyl ester, haloformic acid-lower alkyl-, -phenyl- or -phenyl-lower alkyl ester, in which a lower alkyl phenyl or phenyl lower alkyl ester may optionally be substituted, such as e.g. chloroformic acid ethyl ester, -t-butyl ester, -allyl ester, -2-methoxyethyl ester, -phenyl ester or -benzyl ester, or with halocyano or carbamoyl halide, e.g. cyanogen bromide or diethylcarbamoyl chloride.

A starting material of formula IV with a group of formula IVc, in which Y2 denotes an ammonium group or a free or reactively functionally converted hydroxyl group, in particular an esterified or etherified hydroxyl group, is reacted with a metal cyanide such as an alkali metal cyanide of the sodium or potassium cyanide type. A starting substance in which Y2 in a group of formula IVc is a free esterified or salted hydroxyl group or a corresponding dehydrated compound with formula IV in which X-^ denotes a 1-alkenyl residue can also be reacted with carbon monoxide. The latter turnover takes place in a neutral, basic or acidic environment, and e.g. in the presence of sulfuric acid and under high pressure and temperature, e.g. at up to 400 atmospheres and 300°C, and preferably in the presence of heavy metal catalyst such as nickel or cobalt salts or a carbonyl derivative thereof. carbon monoc-

syd can also be developed by suitable reagents such as e.g. formic acid in the presence of high-boiling mineral acids such as sulfuric and phosphoric acid.

In a corresponding starting material of formula IV with a grouping of formula IVd, in which Y^ constitutes a potential carboxyl group, Y^ can be transferred to a free or functionally converted carboxyl group by means of standard oxidation methods, e.g. by treatment with oxygen (either in pure form or in the form of air), preferably in the presence of a suitable catalyst such as a silver, manganese, iron or cobalt catalyst, or with oxidizing agents such as hydrogen peroxide, or with a nitrogen oxide, oxy - , derating acids or salts thereof such as e.g. oxyhalogenic acids, periodic acid, nitric acid or percarboxylic acids or corresponding salts such as e.g. alkali metal salts of the type sodium hypochlorite or sodium periodate, peracetic acid, perbenzoic acid or raonoperphthalic acid, heavy metal salts or oxides such as alkali metal-e.g. sodium or potassium chromates or permanganates, chromium III or copper II salts, e.g. -halides or -sulphates, or silver, mercury, vanadium-V, chromium-VI or manganese-IV oxides, in acidic or alkaline medium. Generally, according to the above oxidation methods, the free acids of formula I or their salts are obtained as products.

A starting material with the above group of formula IVd in which Y-j denotes an optionally functionally converted and particularly esterified carboxycarbonyl such as carbo-la carboxycarbonyl group, can be transferred to the desired compound of formula I by oxidation with e.g. hydrogen peroxide in an acidic environment, e.g. with the addition of mineral acid, or by decarbonylation primarily by means of pyrolysis, preferably in the presence of copper or glass powder.

In such a residue of formula -C(CH5) (Y4)-C(=0)-OH (IVf) the residue Yj| to the group CH-j together with hydrogen, by reduction, decarboxylation, deacylation or desulphurisation.

If Yfj denotes a carboxyl group and if the starting material is a corresponding malonic acid derivative, such a starting material can be decarboxylated by pyrolysis, preferably in an acidic environment. If Yjj stands for another acyl group such as lower alkanoyl, aroyl or aryl alkanoyl, e.g. acetyl or benzoyl group, the corresponding B-keto acid starting material can be cleaved by acid under the influence of a strong alkaline reagent such as e.g. one of the above alkali metal hydroxides.

In a starting substance with formula III, Xn can e.g. denote a hydrogen atom, or a metal-containing group or an optionally reactive esterified hydroxyl group such as the groups defined above, preferably for an alkali metal or halogen atom. The corresponding starting material of formula III can be reacted with a compound of formula r\~ Yc (Ula), whereby one of the residues Xg and Yg denotes a hydrogen atom or said metal-containing group, e.g. lithium or sodium., and the other stands for a free or reactively esterified hydroxyl group,. e.g.

a fluorine or chlorine atom.

If X2 denotes hydrogen and Yg stands for a halogen atom, the reaction is carried out analogously to the above Friedel-Crafts reaction, e.g. in the presence of a Lewis acid, or if Yg denotes a hydroxyl group in the presence of an alkaline reagent such as potassium hydroxide. If X2 means a hydroxy or lower alkanoyloxy group, work is preferably carried out in the presence of a dehydrating or dehydrogenating agent, such as e.g. a mineral acid or a mineral acid salt, for example hydrochloric acid, ammonium sulphite or sodium hydrogen sulphite, activated aluminum oxide, Raney nickel or palladium/coal. A halogen atom X2 is preferably constituted by a fluorine atom.

A starting substance of formula II in which X2 denotes a primary amino group can be reacted with a glycol, glycolic acid

or dicarboxylic acid compound of formula HO-A-OH (III)

or preferably with a reactive derivative such as e.g. a reactive ester, for example halohydrogen acid, or a cyclic ether of a hydroxyl compound of formula III, or with a corresponding dehydrated derivative of such a compound, further with a lactone of a hydroxy acid compound of formula III

or a halide or anhydride of an acid of formula III. The reaction is preferably carried out in the presence of water or an acid-attracting reagent, e.g. an alkali metal carbonate, the addition of an unsaturated compound is preferably carried out in the presence of a catalyst such as a copper, cobalt or molybdenum catalyst, or in the presence of an alkali metal or corresponding hydroxide.

Prepared free acids with alcohols in the presence of esterification reagents such as strong acids, e.g. hydrochloric acid, sulfuric acid, benzenesulfonic acid or p-toluenesulfonic acid, or dicyclohexylcarbodiimide or with diazo compounds, or transfer the compounds to acid halides, e.g. by treatment with thionyl halides such as thionyl chloride or phosphorus halides or -oxy-halides such as -chloride or -oxychloride.

Produced esters can be hydrolysed to free acids, e.g. by treatment with suitable basic reagents such as aqueous alkali metal hydroxide, or transesterified with alcohols in the presence of acids or alkalis such as mineral acids or complex heavy metal acids, or with alkali metal carbonates or alcoholates. When treated with ammonia or similar amines, esters can over-

is led to amides.

Produced acid halides can, depending on the choice of starting materials and reaction participants, be transferred to esters, halides, anhydrides, amides, thioamides or nitriles by treatment with alcohols with ammonia or amines, and prepared metal or ammonium salts with alcohols or corresponding halides such as chlorides or bromides, or corresponding chlorosulfites, thionyl halides such as thionyl chloride, phosphorus pentoxide, phosphorus pentasulfide, phosphorus halides such as phosphorus pentachloride or phosphorus oxyhalides such as phosphorus oxychloride, or other acyl halides such as e.g. -chlorides.

Produced amides or thioamides (products of the Will-gerodt-Kindler reaction) can be hydrolysed, alcoholized or transaminated in an acidic or alkaline environment, e.g. by treatment with aqueous mineral acids and/or carboxylic acids or with alkali metal hydroxides, and further desulphurised by treatment with mercury II oxide and lower alkyl halides followed by hydrolysis.

Manufactured nitriles can be hydrolyzed or alcoholized, e.g. by treatment with concentrated aqueous or alcoholic acids or alkaline reagents such as alkali metal hydroxides or with alkaline hydrogen peroxide.

The produced esters, salts or nitriles where a group R-|_ stands for a hydrogen atom, can be metallized in the a-position to the free or functionally converted carboxyl group, e.g. by treatment with alkali metals or alkali metal derivatives such as organic alkali metal compounds, e.g. phenyllithium or tri-phenylmethyl sodium, or with alkali metals such as sodium hydrides, amides or alcoholates, and then reacted with a reactive ester of an alcohol of the formula R-^-OH, e.g., a corresponding halide, whereby an organic group R-^ is introduced in a-position.

Compounds produced can be halogenated in the aromatic residue, preferably with halogen and in the presence of a Lewis acid such as e.g. iron III, aluminium, antimony III or tin IV halides, or a halogenating agent such as hydrochloric acid - in the presence of hydrogen peroxide, or with an alkali metal chlorate such as sodium chlorate, a nitrosyl halide such as nitrosyl chloride or

-bromide, halogen-, e.g. bromosuccinimide or -phthalimide.

In manufactured phenolic products, the phenolic hydroxy or mercapto groups can be preferred, e.g. with the corresponding metal phenolates such as alkali metal phenolates and -thiophenolates, by treatment with lower alkyl or cycloalkyl halides, -sulfates or -sulfonates. Produced phenol ethers can be split, e.g. by treatment with strong acids or acid salts such as bromic acid and acetic acid, or acid salts such as bromic acid and acetic acid, or with pyridine hydrochloride.

A free acid can be transferred to a salt in otherwise known manner, e.g. by reaction with approximately stoichiometric amounts of suitable salt-forming reagents such as ammonia, an amine or an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate. Ammonium or metal salts of this type can be transferred to the free acid by treatment with an acid such as hydrochloric acid, sulfuric acid or acetic acid until the necessary pH is achieved.

A basic compound produced can be transferred to

an acid addition salt, e.g. by reaction with an organic or inorganic acid or a corresponding ion exchanger and isolation of the formed salt. A prepared acid addition salt can be transferred to the free compound, e.g. by treatment with a base such as alkali metal hydroxide, ammonia or a hydroxyl ion exchanger.

Jr

Acid addition salts which are pharmaceutically usable are e.g. those with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid or with organic acids and--especially organic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid . ,. sulfanilic acid or cyclohexylsulfamic acid.

These and other salts, such as the picrates, can also be used for purification of the free compounds, as the free compounds can be transferred to their salts, these are separated from the mother liquor and processed from the isolated salts by releasing the compounds. Due to the close connection between the new compounds in free form and in the form of salts, the one designation also possibly includes the other in the present description and claims.

The produced isomer mixtures can be separated into the individual isomers in otherwise known manner, e.g. by fractional distillation or crystallization and/or chromatography. Racemic products can be separated in the optical antipodes by fractional crystallization of mixtures of the diastereoisomeric salts, e.g. with d- or 1-tartaric acid or with d-α-phenylethylamine, d-α-(l-naphthyl)ethylamine or 1-cinchonidine, and eventual liberation of the antipodes from the salts.

The above reactions are carried out on otherwise known ways, e.g. with or without diluents, and preferably those which are inert towards the reaction participants and dissolve these, if necessary in the presence of catalysts, condensation or neutralizing agents, under an inert gas atmosphere such as a nitrogen atmosphere, during cooling or heating and/or under elevated pressure and temperature.

The invention also includes such modifications of the above methods whereby one uses as a starting material a compound that appears at one or other of the intermediate steps of the process as an intermediate product, and carries out the remaining step or steps with this intermediate product, or interrupts the method at one or other step, or methods whereby the starting substances are formed in the reaction environment or used in the form of salts or reactive derivatives. In most of the above oxidation methods where Y-j is transferred to a free or functional converted carboxyl group, the corresponding aldehydes where Y-j stands for a formyl group will thus be formed as intermediate products. Furthermore, the trihalomethyl compounds which are formed as intermediate products can e.g. by the haloform reaction, are hydrolyzed to the corresponding salts of acids of formula I under the prevailing alkaline conditions. Quaternary o- or p-quinone methide compounds can likewise be formed during the reaction as intermediate products from the corresponding starting materials where Y^ constitutes a group of formula Ilf containing a free or reactive esterified hydroxyl group, e.g. in strongly acidic or alkaline environments. Furthermore, the α-diazo-ketones which are prepared according to the Arndt-Eistert method from the acid halides by reaction with diazo compounds can be used directly for the Wolff rearrangement without isolation. Furthermore, different intermediate products can be formed from the different starting materials when building up. the group A^ 11- . If e.g. the group X2 constitutes a primary amino group, and a corresponding starting substance is reacted with a glycol of formula III or a reactive functional derivative of the latter, an intermediate product with a secondary amino group X2 of the formula -NH-A-OH (Ille) is usually obtained, or a reactive derivative of this.

According to the method, starting materials are preferably used which lead to the compounds of the invention which are described as particularly valuable.

The starting materials are known or, when they are new, can be produced in known ways. If X-^ e.g. denotes a reactive esterified hydroxyl group, this can be introduced by halogenation or nitration, followed by reduction, diazosation and the Sandmeyer reaction. The manufactured starting material can then be transferred to a metal compound, e.g. by reaction with an alkali or alkaline earth metal such as lithium or magnesium,

or with a dialkyl zinc or cadmium.

Starting substances where Y2 denotes a metal group can be prepared in an analogous way, e.g. by reaction of the reactive esters of a corresponding benzyl alcohol compound with an alkali metal or alkaline earth metal or with dilower alkyl zinc or

- cadmium. Starting substances where Y2 denotes an ammonium group,

can be prepared from the above reactive esters by reaction with tertiary amines or with secondary amines, followed by quaternization of the produced tertiary amines according to usual methods, e.g. by reaction with lower alkyl or aryl lower alkyl halides.

Starting material with a group Y-j can be produced from

from the above starting materials with metal group Y2 by treatment with a methyl halide, formaldehyde, formyl halide, laval channel, low alkenal or hydroxy-laval channel, or a low alkanoyl, low alkenoyl or oxalyl halide, whereby the produced alcohols can be dehydrated if desired, e.g. by treatment with acidic reagents such as sulfuric acid or phosphorus pentoxide, and transfer these to the corresponding unsaturated compounds. The latter, e.g. methylene compounds can be converted with boranes into boryl-methyl compounds, while aldehydes when treated with hydroxylamine give the corresponding hydroxyiminomethyl, i.e. oxime compounds.

Intermediates prepared by the above methods

and based on the aforementioned starting substances can also be transferred to each other within the specified framework.

The pharmacologically usable compounds of the present invention can e.g. is used for the production of pharmaceutical preparations in which an effective amount of the active compound is present together with inorganic or organic, solid or liquid, pharmaceutically usable carrier materials and drench agents suitable for enteral, parenteral or topical administration.

The pharmaceutical preparations are produced in otherwise known ways, using usual mixing, granulating,

and coating methods, and contains between approx. 0.1 and 75$, especially between approx. 1 and 50% of the active compounds and can, if desired, contain other pharmaceutically active compounds.

The following examples shall illustrate the invention further, and the temperatures are indicated in degrees Celsius.

Example 1.

A mixture of 10 g of α-(4-aminophenyl)-propionic acid ethyl ester hydrochloride, 15 g of α,α'-dibromo-o-xylene, 16.5 g of sodium carbonate and 250 ml of dimethylformamide is boiled with stirring and refluxed for 5 hours. After cooling, it is filtered, the filtrate is evaporated under vacuum, diluted with water and extracted with ether. The organic extract is washed with water, dried, filtered and evaporated in vacuo. The precipitate is filtered off, recrystallized from ethanol and taken up in a minimal amount of benzene. The solution is loaded onto a small silica gel column and eluted with benzene. The first eluate is evaporated and the residue recrystallized from ethanol to give α-£~4-(2-isoindolino)-phenyl-17-propionic acid ethyl ester

with formula

which melts at 111 - 113°C.

Example 2.

A mixture of 1.8 g α-_/~4-(2-isoindolino)-phenyl7-propionic acid ethyl ester, 5 ml 50% aqueous sodium hydroxide solution, 25 ml water and 100 ml ethanol, is boiled for 1.5 hours by reflux and concentrated under reduced pressure. The concentrate is diluted with water, the suspension is acidified with 6 N hydrochloric acid to pH = 3 and extracted with ethyl acetate. The organic extract is dried, filtered and evaporated under reduced pressure. The residue is crystallized from acetic acid ethyl ester and you get a-

which melts at 247 - 250°C.

Example 3-

A solution of 0.5 g of a-/_ 4-(2-isoindolino)-phenyl/-propionic acid ethyl ester in 50 ml of glacial acetic acid is added dropwise to 6 ml of a saturated solution of chlorine in glacial acetic acid with stirring, and the mixture is evaporated under reduced pressure. The residue is taken up in aqueous sodium bicarbonate solution and extracted with ether, the organic extract is dried, filtered and evaporated. The evaporation residue is chromatographed on silica gel with a 1:1 mixture of benzene and hexane as mobile phase. As the main product, α-/~3-chloro-4-(2-isoindolino)-phenyl7-propionic acid ethyl ester is obtained with the formula

which has an Rf value of 0.30 (starting substance: Rf = 0.26), and as a secondary product a-/_ 3,5-dichloro-4-(2-isoindolino)-phenyl/-propionic acid ethyl ester with formula

with Rf = 0.395-

Example 4.

In an analogous manner, the following compounds can be prepared using the starting materials used and, if necessary, after additional conversion: α-[3-chloro-4-(1-oxo-2-isoindolinyl)-phenyl7-propionic acid, melting point 178-180°C,

α-/_~4-(1-oxo-2-isoindolinyl)-phenyl7-propionic acid methyl ester, melting

point 129-132°C,

α-/ 4-(1-oxo-2-isoindolinyl)-phenyl-17-propionic acid ethyl ester, melting point 104-106°C,

α-/_ 4 - (1-oxo-2-isoindolinyl)-phenyl_1/-propionic acid-n-propyl ester, melting point 87-89°C,

α-/_ 4-(1-oxo-2-isoindolinyl)-phenyl7-propionic acid isopropyl ester, melting point 118-121°CJ

ot-/~4-(1-oxo-2-isoindolinyl)-phenyl7-propionic acid isobutyl ester, melting point 110-113°C,

a-/_ 3~Chloro-4-(2-isoindolinyl)-phenyl3,7-propionic acid ethyl ester, melting point 67-70°C and boiling point 190-200°C/0.4 mm Hg.

Example 5 -

A mixture of 0.25 g of magnesium, 10 ml of tetrahydrofuran and 1 drop of methyl iodide is mixed dropwise with stirring with a solution of 3 g of α-£~4-(2-isoindolinyl)-phenyl7-ethyl bromide in 5 ml of tetrahydrofuran and the mixture is boiled during return until the reaction ceases. Carbon dioxide is then allowed to bubble through with vigorous stirring for 5 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 evaporated. The residue is recrystallized from acetic acid ethyl ester and gives <x-/"~2t (4-isoindolinyl)-phenyl_1/-propionic acid, melting point 247-250°C.

The starting material can be prepared as follows: A solution of 2.4 g of 4-(2-isoindolinyl)-acetophenone in 30 ml of ethanol is mixed with 0.75 g of sodium borohydride and refluxed for 2 hours, then diluted with water and evaporated under reduced pressure. Dilute again with water and extract with diethyl ether, the organic extract is dried and evaporated under reduced pressure. Thus α-/_ 4-(2-isoindolinyl)-phenyl/- ethanol is obtained.

A solution of 2.5 g α-/_ 4-(2-isoindolinyl)-phenyl7-ethanol in 20 ml benzene is treated with 0.43 g phosphorus pentachloride and the mixture is boiled for 2 hours under reflux and cooled. Wash with water, dry and evaporate under reduced pressure. One thus obtains ot-[4-(2-isoindolinyl)-pheny3/7-ethyl bromide, which is further processed without purification.

Example 6.

A mixture of 2.7 g of N,N-dimethyl-N-a-/~4-(2-isoindolinyl)-phenyl7-ethylamine, 1.6 g of methyl iodide and 30 ml of anhydrous ethanol is boiled for 15 minutes under reflux and diluted with diethyl ether . The precipitate containing N,N,N-trimethyl-N-a-/~4-(2-isoindolinyl)-phenyl/-ethyl-ammonium iodide is filtered off and dissolved in the minimum amount of 50% aqueous ethanol. The solution is mixed with 6.6 g of potassium cyanide, the mixture is heated for 8 hours at 160°C in a closed vessel. After cooling, extract with diethyl ether, the organic extract is dried, filtered and evaporated. One thus obtains α-_/~4-(2-isoindolinyl)-phenyl7-propionitrile. Infrared absorption spectrum: prominent band at 2110 cm^.

The above-mentioned product is taken up in 25 ml of ethylene glycol and

9 ml of a 50 µg aqueous sodium hydroxide solution and the mixture is boiled for 24 hours under reflux. Cool, dilute with water, wash with diethyl ether and adjust the pH with hydrochloric acid to 4. One extracts with acetic acid ethyl ester, the organic extract is dried, filtered and evaporated and the residue is recrystallized from acetic acid ethyl ester. One thus obtains ct-£~4-(2-isoindolinyl)-phenyl7-propionic acid, melting point 247-250°C.

The starting material can be prepared as follows: A solution of 2.4 g of 4-(2-isoindolinyl)-acetonephenone in 30 ml of ethanol is mixed with 0.75 g of sodium borohydride and refluxed for 2 hours, then diluted with water and evaporated under reduced pressure. Dilute again with water and extract with diethyl ether, the organic extract is dried and evaporated under reduced pressure. One thus obtains α-[<->4-(2-isoindolinyl)-phenyl]-ethanol.

A solution of 2.5 g of α-[4-(2-isoindolinyl)-phenyl]-ethanol in 20 ml of benzene is treated with 0.43 g of phosphorus pentachloride and the mixture is boiled for 2 hours under reflux and cooled. Wash with water, dry and evaporate under reduced pressure. One thus obtains α-[<->4-(2-isoindolinyl)-phenyl-17-ethyl bromide, which is processed further without purification.

A mixture of 3 g of α-(2-isoindolinyl)-phenyl-7-ethyl bromide, 4.1 g of dimethylamine hydrochloride and 12 ml of triethylamine is heated for 3 hours in a closed vessel at 100°C. It is cooled and filtered, the filtrate is evaporated under reduced pressure. The concentrate is diluted with an aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract is dried and evaporated under reduced pressure. N,N-dimethyl-N-a-[4-(2-isoindolinyl)-phenyl]-ethylamine is thus obtained.

Example 7.

A mixture of 5 g of 2-_/ 4-(2-isoindolinyl)-phenyl_1/- propanol, 4 g of sodium hydroxide and 50 ml of water is stirred into a suspension of 6.5 g of silver nitrate, 1.8 g of sodium hydroxide and 60 ml water. After 3 hours, the mixture is filtered, the pH of the filtrate is adjusted to 5.5 with hydrochloric acid and extracted with diethyl ether. The organic extract is washed with water, filtered and evaporated. The residue is recrystallized from acetic acid ethyl ester,

one thus obtains α-/~4-(2-isoindolinyl)-phenyl].7-propionic acid, melting point 247-250°C.

The starting material can be produced in the following way:

A solution of 89 g of 4-acetylamino-acetophenone i

200 ml of tetrahydrofuran is added dropwise in a nitrogen atmosphere to a magnesium iodide solution, formed from 13.4 g of magnesium and 78.1 g of methyl iodide in 300 ml of tetrahydrofuran. The reaction mixture is boiled for 18 hours under reflux and, after cooling, is mixed with 200 ml of 10% aqueous hydrochloric acid, heated for a further two hours, then evaporated and the residue taken up in water. The mixture is extracted with diethyl ether and the organic extract is dried and evaporated. The residue is mixed with 100 ml of acetic anhydride and heated on the steam bath for one hour. The solvent is azeotropically evaporated together with toluene and thus 2-(4-acetylamino-phenyl)-propene is obtained.

A solution of 67 g of 2-(4-acetylamino-phenyl)-propene

in 100 ml diethylene glycol dimethyl ether is mixed at 0°C and under a nitrogen atmosphere with a mixture of 15 g sodium borohydride, 61 g boron trifluoride diethyl etherate and 100 ml diethylene glycol methyl ether. The mixture is heated to 25°C, stirred for 2 hours and mixed with ice cubes. 100 ml of a 3 N aqueous sodium hydroxide solution is added, mixed over the course of an hour with 50 ml of a 30% aqueous hydrogen peroxide solution and stirred for 2 hours at room temperature. The layers are separated, the aqueous phase is extracted with diethyl ether and the combined organic solutions are evaporated under reduced pressure. The residue is dissolved in 100 ml of ethanol and 100 ml of a 3 N aqueous sodium hydroxide solution is added, the mixture is boiled for 2 hours under reflux, cooled and extracted with diethyl ether. The organic extract is dried and evaporated to give 2-(4-amino-phenyl)-propanol.

A mixture of 15.1 g of 2-(4-amino-phenyl)-propanol,

26.4 g of a,a'-dibromo-o-xylene, 30 g of sodium carbonate and 200 ml of dimethylformamide are heated with stirring for 4 hours at 100°C. After cooling, filter, the filtrate is evaporated under reduced pressure

pressure and dilute with water. Extract with diethyl ether, wash the organic extract with water, dry and evaporate.

2-1-4-(2-isoindolinyl)-phenyl-17-propanol is thus obtained. Example 8.

A mixture of 5 g of cc-/_ 4-(2-isoindolinyl)-phenyl7-a-jnethyl-malonic acid diethyl ester, 50 ml of ethanol and 40 ml of a 25% aqueous potassium hydroxide solution is boiled for 4 hours under reflux and evaporated under reduced pressure. The residue is taken up in 50 µg aqueous sulfuric acid and the mixture is heated on a steam bath for 10 minutes, the pH is adjusted to 4 with aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract is washed with water, dried and evaporated. The residue is recrystallized from acetic acid ethyl ester and 2-[4-(2-isoindolinyl)-phenyl-17-propionic acid is thus obtained, melting point 247-250°C.

The starting material can be prepared as follows: A mixture of 25 g of 4-chloronitrobenzene, 12.6 g of a 50% suspension of sodium hydride in mineral oil, 50 g of a-methyl-malonic acid diethyl ester and 150 ml of hexamethyl-phosphorus triamide is heated for 2 \ day at 100°C. After cooling, it is poured onto water and extracted with diethyl ether, the extract is dried and evaporated to give α-methyl-α-(4-nitrophenyl)-malonic acid diethyl ester.

A solution of 28 g of α-methyl-α-(4-nitrophenyl)-malonic acid diethyl ester in 150 ml of a saturated solution of hydrogen chloride in ethanol is mixed with 1.5 g of a 10# palladium -on-charcoal catalyst and is hydrated at 3 atmospheres of pressure. After the hydrogen absorption has ceased, the catalyst is filtered off, the filtrate is evaporated under reduced pressure and the residue is taken up in water. The mixture is basified with an aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract is dried and evaporated, thus obtaining ot-(4-aminophenyl)-a-methyl-malonic acid diethyl ester.

A mixture of 5 g of ot-(4-aminophen<y>l)-α-methyl-malonic acid diethyl ester, 5.3 g of α,α'-dibromo-o-xylene, 5 g of sodium carbonate and 120 ml of dimethylformamide is heated in 5 hours with stirring at 100°C. After cooling, it is filtered, the filtrate is evaporated under reduced pressure, the concentrate is diluted with water and extracted with diethyl ether. The organic extract is washed with water, dried

and evaporated. One thus obtains o-[<->4-(2-isoindolinyl)-phenyl-17-malonic acid diethyl ester.

Example 9-

A mixture of 10 g of α-(4-aminophenyl)-propionic acid ethyl ester hydrochloride, 15 g of α,α'-dibromo-o-xylene, 16.5 g of sodium carbonate and 250 ml of dimethylformamide is boiled without stirring and refluxed for 5 hours. After cooling, it is filtered, the filtrate is evaporated under reduced pressure, diluted with water and extracted with ether. The organic extract is washed with water, dried, filtered and evaporated under reduced pressure. The precipitate is filtered off, recrystallized from ethanol and taken up in a minimal amount of benzene. The solution is drawn up on a small column of silica gel and eluted with benzene. The first eluate is evaporated and the residue is recrystallized from ethanol and one thus obtains α-£~ h-(2-isoindolinyl)-phenyl-1/-propionic acid ethyl ester of the formula

which melts at 111-113°C.

Example 10.

A solution of 27.3 g of 2-(4-bromophenyl)-isoindoline i

25 ml of diethyl ether are added dropwise with stirring in a nitrogen atmosphere to a suspension of 1.4 g of lithium in 100 ml of diethyl ether. After consumption of lithium, the mixture is filtered through glass wool and the filtrate is added dropwise with stirring in a nitrogen atmosphere to a solution of 18 g of α-bromo-propionic acid ethyl ester in 100 ml of diethyl ether. After boiling under reflux for 3 hours, treat with 100 ml of a saturated, aqueous ammonium chloride solution, the organic solution is separated, dried and evaporated. The residue is crystallized from ethanol and gives α-[4-(2-isoindolinyl)-phenyl]-propionic acid ethyl ester, melting point 111-113°C.

The starting material can be prepared as follows: A mixture of 5 g of 4-bromoaniline, 8 g of ct,a'-dibromo-o-xylene, 9 g of sodium carbonate and 130 ml of dimethylformamide is boiled with stirring for 5 hours under reflux. After cooling, it is evaporated under reduced pressure and the concentrate is diluted with water and extracted with diethyl ether. The organic extract is washed with water, dried and evaporated, the 2-(4-bromophenyl)-isoindoline thus formed is further processed without purification.

Example 11.

A mixture of 22.8 g of ethyl α-(4-amino-3-chlorophenyl)-propionate, 19.8 g of ethyl 2-chloromethylbenzoate, 15 ml of triethylamine and 100 ml of <p>tannl is prepared overnight p>r ner fn-prtamnps 1 nnersnmf.. The R<p>sidue is taken up in water, the mixture is extracted with diethyl ether, the extract is washed with 5% hydrochloric acid and water, dried, filtered and evaporated. The residue is taken up in 250 ml of ethanol, 100 ml of 10% aqueous potassium carbonate is added and the mixture is slowly evaporated in vacuo. The residue is taken up in water, the solution is filtered, the pH of the filtrate is adjusted to 4 with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give α-[<_>—3-chloro-4-(1-oxo-isoindolino;-phenyl7-propionic acid of formula

Melting point at l6l-l63°C.

The ethyl ester thereof boils at 200-210°C70.4 mm Hg. Example 12.

A mixture of 7.9 g of ethyl α-(4-aminophenyl)-propioate and 8.3 g of ethyl 2-chloromethylbenzoate is refluxed under nitrogen for 1 hour. The residue is recrystallized from hexane to give ethyl α-jf~4-(1-oxoisoindolino)-phenyl7-propionate of the formula

Melting point 104-106°C.

A mixture of 4.5 g of this, 1.6 g of potassium hydroxide,

2 ml of water and 250 ml of ethanol are refluxed under nitrogen i

2 hours and evaporate under reduced pressure. The residue is taken up in water, the solution is washed with chloroform, acidified with hydrochloric acid and extracted with ethyl acetate. The extract is dried, evaporated and the residue recrystallized from ethyl acetate to give the corresponding free acid with a melting point of 208-210°C,

Ethyl 4-(1-oxoisoindolino)-phenylacetate, melting point 11-114°C and the corresponding free acid with melting point 206-208°C are prepared in an analogous manner,

Claims (1)

Analogy method for the production of those according to Norwegian patent no. 132,199 produced isoindolinyl-phenyl-propion- swear by formula wherein the group means an isoindolino group, which optionally may be substituted with 1 oxo group, R-j_ means hydrogen or optionally halogen, or esters or salts of such compounds elsers, characterized in that a) a compound with formula wherein X2 means a primary amino group or an ester thereof, is reacted with a compound of formula in which the bivalent residue A with a nitrogen atom has the meaning given in the group A^N above, or a reactive therein- vat thereof or an equivalent dehydrated derivative thereof, or b) a compound of formula in which X^ means a hydrogen atom, is reacted according to the Friedel-Crafts- reaction with a compound of formula or an ester in which Y-^ means a halogen atom, or c) a compound of formula IV is reacted with a for- bindIse with formula or an ester, wherein one of the groups X^ and Y-^ means a halogen atom and the other means an alkali metal or organometallic grouping, or d) a compound of formula IV, in which X-^ means the grouping of formula in which Y2 means a metallic residue,, is reacted with a metal-free, reactive derivative of carbonic or manric acid, or e) a compound of formula IV, in which X-^ means the grouping of formula in which Y2 means an ammonium group or a free hydroxy group or a halogen atom is reacted with a metal cyanide or f) in a compound of formula IV, in which X^ means the grouping of formula in which Y-j means a methyl group, Y-j is converted by oxidation or rearrangement into a free carboxy group. or g) in a compound of formula IV, in which X-^ denotes a free or a group of formula present in ester form wherein Yjj represents a carboxy group, Y^ is cleaved off by pyrolysis, or h) a compound of formula IV, wherein X-^ represents an acetyl group, is treated with sulfur in the presence of ammonia or a primary or secondary amine, or i) a compound of formula IV, where X-^ means a grouping by formula converted by hydrolysis, alcoholysis, ammonolysis or aminolysis, or j) a compound of formula IV, in which X-^ means a grouping of formula wherein Hal means a halogen atom, is treated with a strong alkaline agent or a soluble silver salt, and/or a formed ester or a formed salt with a hydrogen atom in the α-position is metallized or reacted with a reactive ester of an alcohol of the formula R^-OH and/or compounds formed halogenate the aromatic residue Ph and/or, if desired, a formed free compound is transferred into a salt or a formed salt in the free compound and/or, if desired, a formed isomer mixture is divided into the individual isomers.