SU471714A4 - The method of obtaining - (aminophenyl) -aliphatic carboxylic acids or their derivatives, or their salts - Google Patents

Description

methyl-, 2-cyclopentyl-ethyl-or 3-cyclopeitol H 1 and l of m of l l pr y p p.

Phenylene residue Ph containing group

And N in position 2, (preferably in position 3 and primarily in position 4, may in appropriate case contain in other positions one or more substituents, preferably 1 or 2, which are odd or different. Ta-qmi substituents are lower alkyl groups that are free, esterificic to the oKiCH- or .merpaphon ether or ester, such as the lower algioioi, for example, metaxy, ethoxy, n-trapyloxy, isapro / piloxy, n-butylaxy, or iso-butyloxy; merka1pto-, for example methylmercapto-, or ethyl-mer halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, trifluoromethyl groups, nitro groups, amino groups, preferably d-and lower allylamides, for example dimethylamino, N-ethylN-methyl-amino, diethylamino , di-n-propyl. ino, di-isopropylamine-, di-n-butylaminoyl or di-isobutylam 1 inogroup, lower alkydols in inino or lower in alkenylene, uranymer pyrrolidino, piperidine, pyrrolino or .piperidine inylpropyl , LMOHoa3a-, LMOHOOKca- 1IL Or Mono-thialkylene-a) mino, for example, Piprazino-, 4-: poor alkylpiperaZINO-, morphol no- or thiomorpholino groups, or lower alkanoylamino, for example, acetylamino or pivaloylamino groups, then, in appropriate cases, functionally modified ones “ar1bo1K1C1IlNIe” groups, as well as carboxylic acid alkoxy, n1p; - substituted -carbamoyl groups, such as di-lower alkylcarbamoyl-, for example, di methyl-1-carboxymethyl groups, or cyanogroups, lower alkyl-O-sulfonyl, for example,

appropriate (case of fuccionically modified sulfate groups, each in the corresponding case substituted sulfamoyl groups, for example, di-lower alkylsulfamoIL-, such as dimethyl Il-1 sulfimoyl 1G (hp1PY. Ph residue means, in particular, 1,3- or 1,4-phenylene-, ((LOW alzhil) - 1,3- or 1,4- | phenylene, (lower al1Coc1si) -1,3- or 1,4-1fcn1Ilen-, (mono- or di (halogen) -1,3- or 1,4-phenylene- , (trifluoro (methyl) -1,3- or 1,4nphenylene-, (| nitro) -1,3 or 1,4-fvvilen, (amino) -1,3- or 1,4-phenylene-, (di- lower al "ylami1) -1,3- or 1,4-fe1Nilenyl (lower alkyleneamino) -1,3- or 1,4-phenylgrutpu.

B and the cyclic alkenylene-amino group is (Preferably the corresponding, substituted IB appropriate case, for example, 1 of the above indication.): Residue and groups containing Always 5-6 units in the ring and in the cyzyl-part 1-3 double bonds. , first of all, benzoalkenylene, but a residual or corresponding (dihydro- or tetrahydro-benzoalkenyleneamine residue, in which al; the kienylene-amino-part contains 5-b units in the ring, and which can be replaced in the corresponding case in (a) of the romatic part, for example Phenylene residue Ph, in particular, lower alkyl groups that are free esterified to an ether or ester of: x-or-OR groups, for example, lower alkoxy or lower alkanoyloxy groups, as well as halogen atoms, and which can be substituted in the aliphatic part also oxo- or thionogr (p: pami. TIPI) Groups are

for example, 1-indolinyl-, 2-isoindolinyl-, 1,2,3,4-tetrahydro-1-quinolinyl- or 1,2,3,4teta HL | I1 cro-2-isoquinOninyl- and that (kzhe 4, 5,6,7tenrahydro- - Indolinyl-, 4,5,6,7-tetrapidro-2-isoindolinyl-4, 7-digi-Dro-2-isoindoline-NIL-, 1,2,

3,4,5,6,7,8-octahydro-1 - quinolyl-, 1,2,3,4,5,6, 7,8-octaH: Id: ro-2 - isoquinolinyl-, 1,2, 3,4,5,8-hexahydro-1-quinolinyl or 1,2,3,4,5,8-hexaHydro-2-isoquinolinyl1Group (Peaks that IB can be substituted for, for example, as indicated.

The FDI proprietary acids. Are, in particular, pharmaceutically acceptable, non-toxic essential acids of such acids, preferably their complex esters (eg, for example (lower alkyl or lower alkenyl esters, cycloalkyl, cycloalkenyl, cyclic alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkenyl -lower alkylose effdry, where

cycloaliphatic residue contains 3-7 units in the ring, aryl or aryl-lower al (acid esters, where the aromatic residue means the phenyl group substituted in the appropriate case, for example, as the Ph residue,

free or esteri fi ed oxy-lower alkyl- ether, for example (lower alkoxy-lower alkyl or cycloalkoxy-lower alkyl ethers, where cycloalkyl contains 3-7 units, in kilo, or treg-am-INO lower alkyl ether, where the warm-amino group means , for example, di-lower alkyl-amino-, for example dimethyl-amino- or diethyl (inogroup (p, LOW alkylenam-i.e., for example, shirrolidine- or (piperidiol group, or monoazy,

monoox- or monothia-lower alkylenamino-, for example, piperazino, 4-lower alkyl-piperazino, for example, 4-methyl piperazino or 4-ethyl-piperazino, morphol o- or thiomorpholino group. In ester residues,

containing heteroatoms, (the latter are separated from each other and from the oxygen of the carboxyl group of at least two, preferably 2-3 carbon atoms.

Further functional carbohydrate acids of formula I are, for example, suitably substituted amides OR thioamides, such as adono-or di-lower alkyl amides, aryl amides or aryl lower alkyl amides, where a | aromatic residue is irrely substituted in the corresponding case, for example, as Ph residue, phenylgroup-poo, ILI MONO-SECONDARY ALKYLENE, MONOAUSE-EXCESS ALKYLENE, MYOXA-OTHER ALKYLENE- or (molimo-lower alkyleneamides, further corresponding thioamides, hydroxyamino acids or nitriles. u1Nktsi0 "cial; amIN01Proiz.vod.ny n) MI are, for example, N-oxy or lower alkilily nizschy aryl-alkyl-quaternary ammonium salts, where aryl is preferably substituted, for example, as a residue OC phenyl group. Layers are. For example, an ammonium salt, and or metal salts, as well as acid addition salts. The proposed method for the preparation of compounds of the formula I consists in the fact that the compound of the formula Xi-Ph-0 - (- OH I where Xi is lergic and a minogroup, or its functional acid P. derivative. It is reacted with a compound of the formula HO-A-OH or its reactive As the L-derivative of glycol compounds, glycols; oh acid or dicarboxylic acid of formula III, preferably, a reactively capable complex eff, ir, nalimer, with a strong mineral acid or sulfonic acid, iB in particular, a halo acid; gray bourbon bourbon or glycolic acid. It is also possible to use as a starting material of the formula: And lactane, a compound of hydroxy acid III or a halide, an ester or an acid anhydride of the same formulas. The reaction is carried out preferably in the presence of water or an acid binding agent, such as an alkali metal or an alkali metal alcohol or carbonate, and (Addition of an unsaturated compound, preferably in the presence of a catalyst as a catalyst, copper, cobalt or molybdenum, and / or acids fixed assets. The obtained compounds can be converted into each other in a known manner. Thus, the resulting free acids can be esterifldi ester, and almen alcohols in the presence of esterifikats and, as : x ACID, hydrochloric, ernary, nimbly, benzenesulfonic or / g-toluenesulfonyl, and dicyclohexylcarbodiimide, diaosoconiations, or .to convert them to acid halides by treatment with the approach they use: I used my own part. In particular, thion and lhl oridol phosphorus halogen or phosphorus oxyhalides, for example, 1. phosphorus oxychloride or phosphorus oxychloride. The esters obtained can be hydrolyzed to free acids, for example, by treatment with suitable basic agents such as aqueous hydroxy acids. 1, and then the alkali metal or pereeterif.itsirovat to other esters via apirtov knslyh 1 or in the presence of alkali oredstv as mineral acids or acid kom.pleksnyh heavy metals, and carbonates or alcoholates of alkali metals. By treatment with ammonia or the corresponding am.min.MY and LESS esters can be converted to am.idy. The complex esters, halides, anhydrides, amides, thioMides, ILs, and nitriles (review of the choice of starting materials and the use of reagents) can be used to convert the resulting acid halides using spirts, as well as ammonia or amines, and the resulting metal or ammonium salts using alcohols or appropriate Halides, for example, chlorides OR bromide, or the corresponding chlorofluids, thion and liter of halides, n a / thc of thionyl chloride, pentoxide, pentasulfide, phosphorus halides, eg, pentachloride or oxychloride phosphorus phosphorus, phosphorus halides, for example, pentachloride or oxychloride phosphorus phosphorus, phosphorus halides, eg. for example measures of phosphorus oxychloride, or other acyl halides, such as acyl chlorides. The resulting am; l (dy or thioamic acid can be hydrolyzed, alcoholized or altered under acidic or alkaline conditions, for example, by treatment with aqueous mineral and / or carbonic acids, or alkali metal hydroxide, then they can be desulfIdated, for example, by treating oxides -syro mercury and (lower alkyl halides followed by hydrolysis. The resulting nitriles can be hydrolyzed or alcoholized, either impregnated using concentrated aqueous or alcoholic acids or alkaline agents such as alkali metal hydroxides, Also alkaline hydrogen peroxide. Compounds containing oxo groups can be converted to the corresponding thionic compounds, "APImer, by treatment with phosphorus pentasulfide. In a bicyclic residue, without oxo groups, the latter can be introduced by oxidation, for example with oxygen (in example, in the form of air) or by other mild oxidants to the containing nitrogen atom as part of the ring ring, in particular in

one or both (positions at the cyclic nitrogen atom, like it is obtained from amy, on the corresponding lactamavs, o.vie compounds.

The resulting esters, salts or nitriles, in which 1U at least one RI and R2 grin shines hydrogen, can be metallized in a-oligarch and functionally modified 1-carbo: xyl group, for example, by treatment with alkali metals or, and, by production. as or, ra.nyvsk / their compounds of alkali metals, for example, phenyl lithium or triphenylmethyl sodium, or alkali metal alcohols, such as hydrades, amides or alcohols, and then react with reactive COMPLEX Ether of opi formulas .and / and and R2-OH as € ootvetst1vuyuschim halide, thus "driving position and .in orgaiicheskuyu Ri or R2.

The obtained compounds can be halogenated in the aromatic Ph residue, trimer, for example, halogen, preferably in the presence of Lewis acid, for example, iron halide, aluminum halide, antimony, or tin, or halogenation agents, for example, hydrogen, hydrogen chloride, and acid. in the presence of, and hydrogen peroxide, or an alkali metal chlorate, for example, sodium chlorate, nitrosyl halide, for example nitrosyl chloride or bromide, a haloimide, for example bromosuccinimide or bromophthalimide.

The aromatic residue Ph can be further iodized by the “itro group, and for example, by treatment with nitric acid or nitrite salts (in various conditions, for example, in the absence of sulfur trifluoroacetic acid, in the resulting nitro compound. It can be reduced to nitrocarin, for example, by treatment with catalytically Tiv1Ilpovanoi voddo.dorom or chemical reductants (formed during the release of hydrogen), to obtain an amino group.

With these .IL | And other restoration operations it is necessary to ensure that the unsaturated alkenylamino residue remains. The obtained compounds containing the first primary AMI 1 Nogroup can be reacted with the reaction of the reactive esters of esters and alcohols or glycols, as well as the reaction of the NITs of the CCA bn M and fu N. CZI he al B H M and Pr O and Z. O. DNY My, as halides, for example, chlorides or anhydrides of 1 acid, and thus o6ipa30M is preferred to form compounds containing secondary or tertiary amino groups or quaternary, ammonium groups, and also acylated amino groups. If the compounds obtained with the free amino group are treated with a nitrogen acid, then diazonium salts are obtained, which according to the Schmalndmeier reaction, for example, by hydrolysis with three high temperatures, by treatment with copper halogenide or copper nucleate, or with a lower alkanol or lower alkyl mercaptan, preferably when neutral. x or weakly. black or alkaline conditions: and. ., .can be converted to the corresponding oxy-, galegen-c, lower alkoxy- or n, eminent al.c1 mercapto compounds.

In the resulting phenolic products of the oxy or MeipiKanTorpynnbi, we can esterify | I | CI1 in simple EF.IR, for example, using the corresponding metal phenols, for example, alkali metal, phenol and thiophenol, by treatment with reactive esters of fused alkanols. cycloalka “OL01B, as .n. isomer al: kil-, or cycloalkylthalogenides, -sulfates or -sulfonates, as well as diazo-compounds of diazo-lowering alkanes. The resulting simple phenol can be cleaved, for example, by treating with strong acids or acid acids, hydrochloric and acetic acids, as well as hydrochloric acid and pyridine. Aliphatic o: xysoedepenia can be dehydrated. The resulting unsaturated compounds can be saturated, for example, by treatment with catalytically activated hydrogen or chemical reducing agents (formed at the time of hydrogen evolution), with the removal of double bonds, for example, in R2-rpynne and / or group complex ef.ira.

In the resulting compounds with split, if appropriate, etherified esteric oxy groups in residue A, N- can be split such groups.

in the appropriate case, in combination with hydrogen, i.e. by means of a new one for a double bond.

The resulting free acid can be converted into a salt with a known cp. As an example, for example, by reaction with a stoichiometric amount of an appropriate salt-forming agent, such as ammonia, an amine or

alkali or alkaline earth metal hydroxide, carbonate or bicarbonate.

The ammonium or metal salts thus obtained can be converted into the free acid, bringing them to the required pH value.

acid treatment, for example, hydrochloric, sulfuric or acetic acid.

The resulting basic compound can be converted to an acid addition salt, for example, by reacting with a nonorganic, organic or anion exchanger, followed by isolation of the salt formed. The resulting acid additive salt can be converted into the free compound by treatment with an anhydrous, for example, alkali metal hydroxide, ammonia or hydroxy-ionic exchange agent. Pharmaceutically used, non-toxic acid-and-additive. Salts are, for example, acid-addition salts with inorganic acids, acidic salts like hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, in particular, organic carboxylic or sulfonic acids, like formic, acetic, propionic,

Amber, glycolic, dairy, block.

zinoa, limoana, asvdryinovoy, malepnozoy, oximeleinovoy,; pyroinog, radnoy, phenyuksuonoy, | be, nzoynoy, 4-am; but.benzoYi, anthranilova, 4-oxybeizoy, saliciloi, amine, 4, Also methanesulfonic, etaysulfovy, oxyethanesulfonic, ethylene sulfonic, non-sulfosonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfonic, or cyclohexyl sulfonic acid | ACID.

ET | And other salts, for example, tkrakraty, you can use the same for cleaning, as well as the definition of free compounds. Thus, free compounds can be converted into their salts, separated from the crude mixture and their isolated salts, then the free compounds can be obtained. By free compounds or - salts, is meant the corresponding salts or the free compounds. The resulting mixtures of isomers can be divided into individual isomers; measures in a known manner, for example, by means of: racrocylite or distillation or crystallization and / or chromatography. Racemic products can be applied to the optical antipodes, for example, by separation of the diasteroisomer salts, as fractionated installation of mixtures of diastereomeric salts, adrimer, d-, silt, and / -wartic acid, or rf-and feiylethylamine, th - {1-naphthyl) -ethiyl1.m.in -or / -ci chionijum and, ifL: 11 preferably, (isolation of free aliptypes from salts.

The described reactions are carried out according to known methods, for example, in the presence or presence of a worker, preferably inert: in relation to participants of the reaction or dissolving the latter diluents, if necessary, in the presence of catalysts that are suitable. neutralizing; their means, IB at a non-atmospheric atmosphere, at a nitrogen atmosphere, when cooled or heated, and / or 1–1 under elevated pressure.

Example 1. A mixture of 10 g of ethyl 4-amI1nophenyl acetic acid, 16.4 g of a.a.-Dibromo-o-zsilol, 17.8 g of sodium carbonate and 250 ml of dimethylphomamide is boiled for 6 hour with reflux. cooling is diluted with water and extracted with ether. The organic extract is washed with water, dried, filtered; and the residue is evaporated; and the residue is recrystallized from ether. As a result, ethyl α-4- {2-isoindoly1nyl) -phenyl-acetic acid ethyl ester is obtained, which is: water-oil and 118-120 ° C.

The starting material can be obtained by the following METHOD.

A mixture of 5000 ml of anhydrous ethanol and 1000 g of 4-amino; the phenyl acetic acid OH is treated for 5 hours and 30 minutes with stirring and boiling with reverse hydrochloric acid with dry hydrochloric gas, stirred and then left for another 4 hours and then cooled for 16 hours to 10 °. The mixture is filtered, the residue on the filter is washed with cold, anhydrous ethanol, and dissolved 5 in 8000 ml of water. By adding portions of 50 ml of a 50% aqueous solution of sodium hydroxide and the solution should be stirred to the basic state and continue to stir for an hour at room temperature. The residue obtained is filtered and washed with water. The resulting 4-aminophenylacetic acid ethyl ester melts at 47-49 ° C.

Example 2. A mixture of 13.2 g of hydrochloride of ethyl a- (4-amino-3-chloro. N, yl) -proshylic acid ethyl ester, 7.4 g of a. Phthalic acid hydride, 10.1 g of triethnlamine and 200 ml The toluene is refluxed for 6 hours and evaporated at ionic pressure. The residue is dissolved in water. And the aqueous mixture is extracted with ether. The organic extract is dried, filtered and evaporated. And the residue is recrystallized from a simple eff.. So

5 a-3-chloro-4- (1,3-dioxy-CO-2-isoindolinyl) -phenyl propionic acid ethyl ester is obtained, which melts at 107-110 ° C.

The starting material can be obtained as follows.

To a solution of 52 g of ethyl eff. 4-nitrophenyl acetic acid,. In 350 ml of a mixture of dimethylformamide and toluene (1: 1), add in portions of 1 Jan 1 and cooling 5 of the scientific research institute 9.5 g of 50% hydride suspension. Sodium in mineral oil. After stirring for 1 hour 30 minutes at room temperature, 26 g of methyl iodide-ida is added dropwise. And the mixture is stirred IB for 16 hours

 at room temperature. Water is added carefully and extracted with ether; the organic extract is dried, filtered, and w.parised. The residue is dissolved in 100 ml of ethanol, the solution is contaminated with several crystals of the starting material and left to stand at a low temperature. The resulting precipitate is filtered off and the filtrate is taken up; the residue (is a- (4-n. nitrophenyl) propionic ethyl ester

 acid. A mixture of 50 g of a- (4-nitrophenyl) -propionavalent ethyl ester ether in 200 ml of 95% aqueous ethanol is hydrogenated with iB in the presence of 0.4 g of catalyst — palladium on carbon — until the absorption of hydrogen ceases. The mixture was filtered and the filtrate was evaporated. In this way, a- (4-amino-phenyl) -1P | ropionic acid ethyl ester is obtained, the hydrochloride of which is melt at 37-140 ° C.

The mixture of 25 g of a- (4-aminophenyl) propionic acid ethyl ester and 25 ml of acetic anhydride obtained by stirring and cooling is left to stand for one hour at room temperature and

then evaporated under reduced pressure.

AND

The residue is recrystallized from ether. So o.brazom. Get this ether a- (4-acetylamino-fvnil) - propionic KjHiCvTOTbi with t.: Pl. 88-90 ° C.

A solution of 25 g of enyl ether with a- (4-acetylamines of G-feiil) -proionic acid in 100 ml of acetic acid is passed through a re-mash into aj l of cooling and gas: oo | 5 times chlorine, and the course of chlorinating and matting is carried out using thick layer chromatography (silica gel: hexane. Simple: 4). After the starting material has disappeared, the mixture is evaporated. The solution is evaporated and, under pressure, the residue is dissolved, the residue is dissolved in 150 ml of ethalol and the gaseous chlorine is passed through for 45 hours. The mixture is then boiled for 15 hours with an abratny fridge and up; balance, to: p1kistall izvyvayut, from ethanol and ether. In this way, a- (4-amino-3-CHLOROF1SYL) -PrO ethyl ester lidhrochloride; PIO | BUT: VOY acids with t. TTL are obtained.

164-16 ° C.

The source material can be obtained as follows.

A solution of 5000 ml of non-precipitated ethanol and 1000 g of 4-amino-phenylacetic acid boiling with a condensed refrigerator and boiling dry hydrogen chloride gas for 5 hours and 30 hours; stirred and boiled for 4 hours. After cooling for 16 hours at 10 °, the mixture is filtered and the residue on the filter is chromicized with cold ethanol and dissolved in 8000 ml of water. A 50% aqueous solution of sodium hydroxide is added in 50 ml portions with stirring until the solution becomes basic and Continue mixing for another hour at Room temperature. The precipitate obtained is filtered off and washed with water. In this way, 4-aiMscho-phenylacetic acid ethyl ester is obtained with t. Il. 47-49 ° C.

A solution of 200 g of ethyl 4-aminophenylacetic acid ester in 250 ml of acetic anhydride is allowed to stand for 10 minutes, then poured with stirring on 1500 ml of a mixture of ice and water. The precipitate obtained is filtered and washed with water. 4-acetylamino-phenylacetic acid ethyl ester is obtained with m.p. 75-78 ° C.

RacTiBop 170 g of ethyl 4-acetyl-minyl-phenyl-acetic acid in 25 ml of ether. Add IB for 25 minutes to a mixture of 20, 38 g of sodium, 2000 ml of anhydrous ammonia and several crystals of nitrate-iron hydrate, stirring the solution. . Then a mixture of 120, 28 g of methyl iodide and 50 ml of ether is added dropwise over 20 minutes and stirred for an hour. The mixture is treated with 50 g of Ammanium chloride, then evaporated, and the residue is dissolved with IB ether and a dilute aqueous solution of sodium hydroxide. The base solution is extracted with ether and the combined organic phases are evaporated. Get

12

a- (4-acetyl-amio-phenyl) -: 1-propionic acid ethyl ester with m.p. 84-86 °. The material containing approximately 10% of the mixtures is subjected to a molecular conversion. N1ke and caught, roll the fraction boiling at 170-183 ° / 0.15 hr. Art. A solution of 72 g of a- (4-acetylamino-phenyl) -protic ionic acid ethyl ester with 200 ml of acetic acid is treated with chloro gaseous gas, which is passed through

solution with stirring and ta.mperature 15-20 °. The course of the reaction is monitored using thin layer chromatography. Moreover, a mixture of simple ether and hexane (4: 1) is used as the subshining phase, in which

 product is 0.8, the starting material is 0.51. When the chlorination is complete, the mixture is evaporated and the O1 residue is distilled. An apical lrp 155-160 ° / 0.7 mm Hg. Art. the fraction is ethyl ethe ether of a- (4-acetylamino-3chloro-phenyl) -propionic acid.

A mixture of 60 g of a- (4-acetylmino-3-chlorophenyl) -propionic acid ethyl ester in 200 ml of ethanol is saturated with chlorine gas and boiled iB for one hour.

with reverse refrigerators, and then evaporated under reduced pressure. The residue is dissolved in an aqueous solution of sodium hydroxide and the mixture is extracted with ether. The limited extract is evaporated and the residue

chromatographic on oxide alu | Mini, p.hrbbm elute a mixture of cyclohexane and ethyl ester of acetic acid (95: 5). The a- (4-amino-3-chloro-phenyl) -; ethyl ester ethyl ester obtained in this way melts

at 168-170 ° and it can be translated according to the specific method IB hydrochloride.

Example 3. A mixture of 10 g of a- (4-aminophenyl) -propionic acid ethyl ester hydrochloride, 15 g of a, o / -dibromo-o-xylene, 16.5 g

sodium carbonate and 250 ml of dimethylformamide are refluxed for 5 hours with stirring. After cooling, filter; the filtrate is concentrated under reduced pressure, diluted with water

and extracted with ether. The organic extract is washed with scrub, dried, F. | Yltruyut and concentrated under reduced pressure. The precipitate is filtered off, -crystallized from ethanol and dissolved in

-minimal amount of benzene. The solution fell onto a column (silica gel) and eluted with benzene. The first eluate is evaporated and the residue is converted from ethanol. Thus, (2-isoindolinyl) -phenyl-propionic acid ethyl ester is obtained with m.p. 111 -113 ° C.

Example 4. A mixture of 5 g of 4-amino ethyl ester, phenylacetic acid, 4.9 g of gogmophthalic anhydride, 100 ml of toluene and 0.5 ml of triethylamine is boiled for 16 hours with a 01 fridge, and the resulting water is collected in a water separator . It is evaporated under reduced pressure and the residue is crystallized from ethanol with the use of active carbon. Thus polucha13

ethyl (1,3-d -1Oxo-1,2,3,4-tetra-hydro-2-isoquinolinyl) -phenyl-acetic acid ethyl ester with m. pl. 89-91 ° C.

Example 5. A mixture of 12 g of a- (4-amino-3-chloro-phenyl) -1-propionic acid ethyl ester, 11.6 g a, a-dibrO M-o-, xylene, 17 g sodium carbonate and 250 ml of dimethylformamide are boiled for 6 hours with inverse: m under reflux in a nitrogen atmosphere. After cooling, the reaction mixture is filtered; the filtrate is diluted with water and the mixture is extracted with diethyl ether. The organic extract is washed with water, dried, filtered and evaporated. The residue is distilled: boiling at 190 mm, 4 mm. Hg Art. the fraction gives a-3-chloro-4- (2-isoindolinyl) -phenyl propionic acid ethyl ester.

Example 6. A mixture of 22.8 g of a- (4-amino-3-chloro-phenyl) -propionic acid ethyl ester, 19.8 g of 2-chloromethyl-benzoic acid ethyl ester, 15 ml of triethylamine and 300 ml of ethanol is left stand for 16 hours and slowly evaporated. The residue is dissolved in water and extracted with diethyl ether; the organic extract is washed with 5% hydrochloric acid and water, filtered and evaporated. The residue is dissolved in 250 ml of ethanol; 100 ml of a 10% potassium carbonate aqueous solution are added and the mixture is slowly evaporated under reduced pressure. The residue containing a-3-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-propionic acid ethyl ester with mp. 111 -113 °, dissolved in water; the solution is filtered, the filtrate is adjusted to pH 4 with hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic extract is washed with water, dried and concentrated. In this way, a-3-chloro-4- (1-oxo-2-isoindolinyl) feiyl - propionic acid with m.p. 178-180 ° C. In the process described here, it is possible to use 2-chloromethylbenzoic acid chlorohydrite instead of ethyl 2-chloromethylbenzoate.

The source material can be obtained in the following way.

4.8 g of 50% sodium hydride slurry in mineral oil is added with stirring under a nitrogen atmosphere to 100 ml of hexamethylphosphoric acid triamide. 17.1 g of a-methylmalonic acid diethyl ether are added, the mixture is slowly heated to 100 ° and treated dropwise with a solution of 19.2 g of 2,4-dichloronitrobenzene in 20 ml of hexamethylphosphoric triamide, which is added within 30 minutes. The temperature is maintained at 100 ° for 7 hours. The mixture is cooled and diluted with water, evaporated under reduced pressure, the residue is dissolved in water and extracted with benzene. The organic extract is washed with water, dried, filtered and evaporated. The residue is distilled; boiling at 147-148 ° / 0.25 mm Hg. Art. the fraction is a- (3chloro-4-nitrophenyl) -a-methylmalonic acid diethyl ether

you. Through a solution of 4 g of diethyl ether and (3-chloro-4-nitrophenyl) -a-methyl-malonic acid in 50 ml of anhydrous ethanol, hydrogen chloride gas is passed through for 5 minutes; then 0.5 g of a 10% catalyst is added — palladium on carbon — the mixture is hydrogenated for 10 minutes at an initial pressure of 3 atm and then filtered. The filtrate is evaporated under reduced pressure; the residue is dissolved in a 50% aqueous solution of sodium hydroxide and extracted with diethyl ether-M. The organic extract is dried, filtered and evaporated. A- (4-amino-3-chloro-phenyl) -methyl-malonic acid diethyl ester is obtained, having characteristic bands in the IR absorption spectrum at 1720, 3370 and 3460 cm. A mixture of 75 g of a- (4-amino- The 3-chloro-phenyl) -a-methylmalonic acid and 150 ml of a 50% aqueous solution of sodium hydroxide are boiled for 16 hours with a refluxing cooler, cooled, diluted with water and washed with diethyl ether, then acidified with concentrated hydrochloric acid. The mixture is boiled

again for 16 hours under reflux and evaporated under reduced pressure. The residue is dissolved in an anhydrous solution of hydrogen chloride in ethanol; the mixture was boiled for 6 hours under reflux and evaporated. The residue is recrystallized from a mixture of ethanol and diethyl ether to obtain ethyl ester a- (4-amino-3-chloro-phen, yl) -propionic acid hydrochloride with mp. 164-168 °, which can be re

let loose

method, for example, treatment with a basic agent, such as sodium hydroxide, and extraction with an organic solvent, as

diethyl ether.

Example 7. Similarly, you can

receive when choosing the appropriate source

substances and in the appropriate case after

additional transformation c. the following compounds:

 (l-OKCO-2-isoiidolinyl) -phenyl - acetic acid, so pl. 206-208 °;

(1-oxo-2-isoindolinyl) phenyl acetic acid ethyl ester, m.p. 111 -114;

(1-oxo-2-isoindolinyl) phenyl propionic acid methyl ester, mp. 129-

132 °;

ethyl ester (1-oxo-2-isoindolinyl) -phenyl-propionic to 1slota, so pl. 104-106 °;

P-PROPYL ester - 4 - (1-OXO-2-isoindoyl) -phenyl-propionic acid, so pl. 87-89 °;

(1-oxo-2-isoindolinyl) phenyl propionic acid isopropyl ester, m.p. 118-12G;

(1-oxo-2-isoindolinyl) phenyl propionic acid isobutyl ester, m.p. 110-113 °; a-3-chloro-4- (2-isoindolinyl) -phenyl-propionic acid ethyl ester, m.p. 67-70 ° and so on. Kip. 190-200 ° / 0.4 mmHg v .; a-3-chloro-4- (1-oxo-2-iso.indolinyl) -fe11yl butyric acid, m.p. 191 - 193 °; a-3-chloro-4- (1-oxo-2-isonndol, inyl) -phenyl-butylic acid ethyl ester, so pl. 230-240 ° / 0.35 mm Hg. v .; a-3-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-a-cyclopropylacetic acid, so pl. 242-245 °; a-3-chloro-4- (1-oxo-2-isoindolinyl) phenyl-a-cyclopropyl-acetic acid ethyl ester, m.p. 225-235 ° / 0.33 ML1. Hg v .; (1,3-dioxo-4,5,6,7-tetrachloro-2-isoindolinyl) -phenyl-acetic acid ethyl ester, so pl. 197-199 °; a-cyclopropyl-a - 4. (1-oxo-2-isoindolinyl) -phenyl-acetic acid, so pl. 186-188 °; methyl ef.ir a-cyclopropyl-a-4- (1-oxo-2-isoindolinyl) -phenyl-acetic acid, so pl. 98-101 °; a-cyclopropyl-a-4- (1-oxo2-isoindolinyl-phenyl-acetic acid ethyl ester, mp 111-113 °. Example 8. A mixture of 1 g of a-3-chloro-4- ethyl ester (2 -isoindolin.il) -phenyl-propionic acid, 50 ml of ethanol — 5 ml of 20% aqueous potassium carbonate are boiled for one hour under reflux and evaporated under reduced pressure. The residue is evaporated in water — and the mixture is made up to 6 n hydrochloric acid to pH 3 and extracted with ethyl acetate. The organic extract is dried, filtered and evaporated. The residue is recrystallized from ethyl ether of acetic acid and get a-3-chloro-4 - (2 - isoindolinyl) phenyl propionic acid, mp 148-150 °. EXAMPLE 9 A mixture of 4.5 g of ethyl ester (1 -OXO-2-IZOINDOL ynyl) -phenyl-propionic acid and 1.6 g of potassium hydroxide in 2 liters of water and 250 ml of ethanol were heated under reflux B under nitrogen for 2 hours and evaporated under reduced pressure. The residue was dissolved in water, washed with chloroform, acidified with hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and evaporated and the residue is recrystallized from ethyl acetate. This way (1oxo-2-isoindolinyl) -phenyl is obtained. propionic acid, so pl. 208-210 ° c. Example 10. A mixture of 2.1 g of the acid chloride (1-0; KCO-2-isoindolinyl) phenylpropionic acid, 0.9 g of 4-chloroaniline and 1.5 g of triethylamine in 100 ml of benzene is boiled for one hour refluxed, filtered and the filtrate washed with water, dried and evaporated. The residue is recrystallized from acetonitrile to obtain N- (4-chlorophenyl) -amide - (1-o-co-2-isoindo-ylnyl) -phenyl-propionic acid, m.p. 240-242 ° C. The starting material can be obtained as follows. A mixture of 2.0 g (1 o.xo-2-ionndol Inyl) phenylpropion and 25 ml of thionyl chloride is refluxed for half an hour under a nitrogen atmosphere and evaporated under reduced pressure. The residue is twice evaporated to dryness, added benzene. The anhydride (2oxo-2-isoindolinyl) -phenyl-propionic acid thus obtained melts at 129-132 ° C. Example I. A mixture of 4.6 g of (2-isoindolivyl) ethyl ester of phenyl acetic acid and 80 ml of 25% The aqueous solution of sodium hydroxide is boiled under reflux for 3 hours, then cooled and diluted with water. The mixture is acidified with hydrochloric acid, the precipitate is filtered off and recrystallized from ethyl acetate. Receive (2-isoindolinyl) -phenyl-acetic acid with so pl. 237-239 ° C. Example 12. A mixture of 1.8 g of ethyl ester of (2-isoindolinyl) phenyl propionic acid, 5 ml of a 50% aqueous solution of sodium hydroxide, 25 ml of water and 100 ml of ethanol is boiled in for 1 hour 30 minutes under reflux and concentrated under reduced pressure. The concentrate is diluted with water, the resulting suspension is adjusted to 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 ethyl acetate and the (2-isoindolinyl) -feEl-propionic acid is obtained with m.p. 247-250 ° C. Example 13. To a solution of 0.5 g of (2-isoindolinyl) -phenyl-propionic acid ethyl ester in 50 ml of hydrochloric acetic acid is added dropwise 6 ml of a saturated solution of chlorine in glacial acetic acid at stirring, and the mixture is then evaporated under reduced pressure. The residue is dissolved in an aqueous solution of sodium bicarbonate and extracted with ether; the organic extract is dried, filtered and evaporated. The residue is chromatographed on silica gel (benzene / hexane-1: 1). As the main product, a-3chloro-4- (2-isoindolinyl) -phenyl propionic acid Rf-Q, 3Q ethyl ester is obtained (source material 0.26) and, as a second product, ethyl a- (3 , 5-dichlar-2- (2-iso-ndolinyl) phenyl -Po: pyo, new acid € 0.395. Example 14. If air is passed through a concentrated solution of ethyl ether а-: 3-chloro for 2 hours while stirring -4- (2-isoindolI; H, yl) -phenyl-propionic acid in dimethylformamide and withstand the temperature at 60 °, then a-3-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-ethyl ester is obtained propion acid, which is separated by evaporation of the reaction mixture under reduced pressure, followed by distillation of the residue. The compound is obtained as a fraction boiling at 200–210 ° / 0.4 mm Hg. - (5-chloro-1-oxo-2-isoindole, inyl) -phenyl - propionic acid, its methyl and ethyl esters, or sodium or potassium salts, using suitable starting materials. Subject of the invention. Method of obtaining compounds a- (aminocarboxylic acids, phenyl) -aliphatic formulas RjO Ml 4jf-Ph.-C - (- OH where the group A N means bicyclic alkenylene a group with 1-3 twins, and 5-6 links in each ring; Ph is a substituted phenyl residue; RI is hydrogen or a lower alkyl group; Rg is hydrogen or lower alkyl-, lower alkenyl-, cycloalkyl-, cycloalkenyl-, cycloal: kil-lower-al "yl- or cycloalkenyl-lower alkylgroup", or their derivatives, or their salts, characterized in that the compound of the formula Xi-Ph-C- (i-OH where X, means the primary amino group, or its functional acid derivative, is reacted with a compound of the formula HO-A-OH or its reactive derivative, followed by isolation of the target product in free form or by transferring it to functional derivative or in salt, or by separation of p of the resulting isomeric mixture to the individual isomeoids known to MI.Priority according to the following signs: 07/18/1969 - A means a bicyclic alkenylene amino group with 1–3 double bonds and 5–6 units in each ring, which can be displaced as necessary. alkyl groups, esterified into simple il and ester, are permeable by measuring with phenyl or phenyl groups; 12.09.69 - Ov is a biclical alkenylene amino group with 1–3 double bonds and 5–6 links in each ring , which of necessity MAY be replaced by a thionogroup.