SU455529A3 - The method of obtaining - (aminophenyl) -aliphatic carboxylic acids or their derivatives or their salts - Google Patents

Description

The invention relates to the field of production of the starting a- (aminfeiyl) -aliphatic carboxylic acids or their derivatives used in the pharmaceutical industry. A known method is the formation of a- (a.minophenyl) a. Schphatic carbopic acids, in which ammonium is a cyclic tertiary amino group. Odiaco in the literature there is no information about the method of obtaining y- (aminophenyl) aliphatic carboxylic acids, which are the subject of this invention, and have high biological activity. According to the present invention, a method for the preparation of compounds of the general formula II is defined. N-Ph-C-C-OH R 2 means where the oicyclic alkenylene amino group with 1 to 3 double bonds and 5 to 6 elements in each ring; Ph - substituted in appropriately. phenylene residue; RI is hydrogen or lower alkylgrune; and R2 is hydrogen or-i-lower alkyl, lower alkenyl, cycloalkyl-. ts 1kloalkey; 1l. cycloalkyl lower alkyl or cycloalkyl lower alkyl group. The lower alkyl residue is, for example, methyl-, ethyl-, n-nronyl-, isonroni., N-butn.1, 130butyl-. vgOu-butyl, greg-butnl-, k-nentyl-, isopeitnl-, neonentyl-. n-hexyl-, pzohexyl-, n-gentil- or isogentillo residue. Lower alkyloxy is, for example, vicyl, allyl, letallyl, 3-butenyl or pentenyl. The lower alkaline residue is. Iapr 1mer, vinyl-, alli.t-, metallic-, 3-butenyl or ienteiylgruin. Cycloalkyl- or cycloalkenylgruyia contains, and preferably 3-7 units in the ring, and can be replaced by a maximum of 4 lower alkylgruynes in the appropriate case. Such residues are, for example, cyclonronyl, cyclobutyl, cyclopethyl, cyclohexnyl or cycloheptyl-, 2-cyclocloityl-, 2-cycloiropyl-, 1-, 2-or 3-cycloieteyl or 1-, 2- or 3- cyclohexeylgroups containing up to 4, preliminarily 1 or 2 and from the outside alkyl-, in particular, methyl residues. Cycloalkyl-lower alkyl- or cy: a clo-alkenyl-lower alkyl-residue is one of the above, containing preferably up to 4 C atoms and one of the alkyl groups containing in some position, and counts, of a carbon atom, one of the above cycloalkyl or cycloalkyl groups; such residues are, for example, cycloirmethyl, 2-cyclopethylethyl- or 3 and 1 -kloieenyl, methyl rruits. Pli, co; i, epi Kaiij, f | nniiy is in position 2. Preferably, in position 3 and first of all in position 4, it may in appropriate case contain other laws and OD1I1-or substitute, if appropriate, 1, preferably 1 or 2, which are the same or different. Such substituents are lower alkylgrines, such as the aforementioned groups, free radicals, esterifi- cations in the growth or ester, hydroxy or merciphenyl groups, such as lower alkoxy, for example, methoxy, ethoxy, and -nropoxy-. isopropyloxy, w.-butyloxy- or isobutyloxngrunium, lower alkyl mercanto, naimer meth. mercapto, na merimer methyl mercant or ethyl mercaptogruip, or halogen atoms, fluorine, chlorine, bromine or iodine atoms, trifluoromethyl groups. preferably dimethyl alkyl UIAO-, for example, dimethyl-amino-, N-STH.TN-Methyl. amino-, diethylamino, di-β-nroyilamino-, diisopropylam.iio-, di-n-butylaminio, or dsbutylamino groups, lower alkeiyl and amidno-n. - for example, pyrROLIDINO-, neridinogroup, moioaza, monoox- or monothialkynechrophysiao-, nenperazino-, 4-: lower alkylierazino-, morpholio- or thiomorpholino-gruiii, or lower a.cioiomino-, Fia-npHi-mathyneminogruiiy, or lower a.cioiomino-, Fia-npHi –mathyne-morphological, or lower a.cioiomino-, Fia-npHi ––––––––––––––––––––––– case of functionally modified carboxy nye group as karboiiz Chiyah-alkoxy, carbomethoxy or -naprimer karbetoksigruiiy substituted where appropriate for example 1P zshpmi alki.tostatkami. N-substitution; carbamyl - lower alkylsulfamoyl-, as dnmethyls-lfamoylgruny. The remainder of Pli means, in particular, 1,3- or 1,4-feiylene- (lower alkyl) -1,3- or -1,4-phenylene-, (lower alkoxy) -1,3- or -1,4 -fennlen-, (MONO- or dihalogen) -1,3- or -1,4-feiilen, (trifluoromethyl) -1,3- or -1,4-feiilen, - (nitro) -1,3- or - 1,4-phenylene-, (amine) -1,3 or 1,4-phenyle-i, (di-lower alkylamino) -1, 3-or-1,4-phenylene-, or (lower alkpleiamino) -1.3 - or -1,4-pileygruit1u. A bicyclic alkenyleneamine is substituted as appropriate, for example, the following group residue, soda cup is always 5-6 c: -11 in the ring and in the isocyclic part 1-3 double bonds. In the first place, it is represented by a beisoalkenylene and amino or an appropriate dihydro- or tetrahydrobenzoalkenyleneaminostat, in which the alkenyleneamino moiety contains 5-6 units in the ring and which can be in the corresponding aroma in the aroma. xiep Phenylestatis Pli, In particular, lower alkylgruine free esterified to an ether or ester of hydroxy or mercantogruine, such as lower alkoxy or lower alkanoyl oxygrutine, as well as halogen atoms, which can be in al of the phytic part, the oxonli are also substituted by tonogroups. Such groups are, for example, 1-indolpyl-, 2-isoindoli-IL, 2, 3, 4-tetrahydro-1-quinolinyl or 1, 2,3, 4-tetrahydro-2-isochipolinyl, as well as 4, 5 , 6, 7 -tetrahydro-1-indolinyl-, 4, 5, 6, 7-tetrahydro-2-isoindolinyl-, 4,7 - dihydro - 1 INDOLIIL-, 4,7-dihydro-2-isoindolinyl, 1, 2, 3,4, 5, 6, 7, 8-octahydro-1-hiiolinyl-, 1, 2, 3, 4,5, 6, 7, 8-octahydro-1-hiiolinyl-1, 2, 3, 4, 5 , 6-7, 8-octahydro-2-isoquinolinyl, 1, 2, 3, 4, 5, 8-hexahydro-1-hiiolinyl- or 1, 2, 3, 4, o, 8-hexanidro-2-isoquinolipylgroup. which, if appropriate, should be ignored; Fuiccio | alnymp acid derivatives are, in particular, pharmaceutically primeiimye, non-toxic derivatives of such acids, preferably their esters, nanrimer iizshy alkyl or lower alkenyl esters, cycloalkyl, cycloalkenyl, tsikloalhil- lower alkyl or cycloalkenyl nizschy alkyl esters, wherein the residue tsi.kloalifatichesky contains 3-7 ring animals, aryl or aryl lower alkyl esters, where the aromatic residue means a phenyl group substituted in the appropriate case, and as an example, as a Ph residue, free or Crester esterified into a ester is oxp-lower alkyl-, for example, lower alkoxy-lower alkyl or cycloalkoxyalkyl alkyl ester, where cycloalkyl contains 3-7 animals in the ring, or greg-amio lower alkyl ester, where tert-amino group represents, for example, , day-lysing by alkylamino-, for example, dimethylamino or diethylamino group, lower alkenylamine, for example, pyrrole dinone or iperdniogroup, or monoaza, monoox-or monothia-lower alkylenamio, or naimimer ieprazino-, 4-i-iso, and iprazino-, 4-iyo-monoia-lower alkylenamio-, monomea- 4-methylylmerase or 4-ethylyiline, mor folio or thiomorphic folinogroup. In the ester residues containing their heteroatoms, the latter are separated from each other and from the oxygen of the caroxyl group of at least two, preferably by 2-3 carbon atoms. Further functional derivatives of the acids of Formula I are, for example, the amides replaced, if appropriate, or: ii:; iM; i; ib. as mono- or di-lower alkyl lllides. 1 p1 l :: 1mides or aryl-and-lower alkyl; p., Where the aromatic residue is coGoii lredgyuchtitelio substitution in the appropriate case, for example, as a residue of P. feilyl group, or l oncyclic alkylene, mozoase-lower alkylene, moio-izshig alkylep-or monothia-izlie alky. chemiamides, then the corresponding thioamides, hydroxamoic acids or} nitriles. Fu; | kc} onalmic ammonium derivatives are, on aIIpi ep, N-oxides, iot and a lower alkyls aryl-yisis, alkyl-chegovertic ammonium salts, where aryl is preferably substituted, iaryimer as a residue of Ph, feNIl group. Salts are E, airimer, ammonium salts or metal salts, as well as acid addition salts. According to the invention, compounds I are obtained if a compound of the formula-Ph-Xi where X | means acetylgrunpa, treated with sulfur in the presence of ammonia, or a primary, or secondary amine. The reaction is carried out according to the Willgrodt-Kimdler reaction by treating cepoii in the presence of ammonia or a primary or secondary amine, in particular morpholine, and preferably sulfonic acid, and, for example, l-toluenesulfonic acid. The resulting compounds can not be interconnected by known techniques. The resulting amides or thioamides can be hydrolyzed, as well as alcoholized or re-minimized under acidic or alkaline conditions, for example, by treatment with aqueous mieralised or "arbonic acid or alkali metal hydroxides, then desulfated, and, for example, by treatment with mercury oxide (I) and lower alkali metal hydroxides, then desulfi- subsequent hydrolysis. Further, for example, the resulting free acids obtained can be esterified into an ester, using alcohols in the presence of etternafacacin, as strong acids, for example hydrochloric, sulfuric, benzene sulfonic or p-toluenesulfonic, and dicyclohexylcarbodiimide, diazo compounds, or transhydrated into hydrochloride acid halogenating agents such as t) unhalogenides, for example thioyl chloride or phosphorus halides or phosphorus oxyhalides, for example phosphorus chloride or phosphorus oxychlorides. The resulting esters can be hydrolyzed to free acids, for example, by treating with suitable basic means as aqueous hydroxylating alkali metals, or to transesterify to other esters with alcohols in the presence of hydrochloric or alkaline agents, like mineral acids, or complex acids; Calcium metals, as well as iwijidoiiaTOB or alcoholic alkali metals. By treatment with ammonia or the corresponding Amshi sl1) g; | th esters can be converted to amides. In the esters, halides, anhydrides, amides, thioa.mides or nitriles), but the choice of starting materials and the use of jiekKtivs) can be converted to the resulting acid hydroxyls with nomop1, yew alcohols, as well as ammonia and amnpoz, and nolchspys solpa retalla Ammonium iLiii with 11omo; cyyu cniqiTOB or corresponding halogenides, for example, chlorides or bromides, or the corresponding f.yu.chfitov, thiopylhalogen, nanpiiMeii thionyl chloride, phosphorus nioxin, pfacus —funorum, thiopylhalogen, nanopiiMeii thionyl chloride, n-phosphorus thioxin; for example, phosphorus nentachloride, or phosphorus oxyhalides, for example, phosphorus oxychloride, or other acid halides, for example, acyl chlorides. The resulting amides or thioamides can be hydrolyzed, alcoholized or reconnected with acidic or alkaline chemicals, for example, by treatment with water and () carboxylic acids, or alkaline meta hydroxides, 1l, then they can be desulfurized, for example, by treatment with mercury oxide (II) and the latter. alkyl halide. mi, with nosleduyupshm gid.shzom. The resulting nitriles can be hydrolyzed or alcoholized, for example, using co-citrated aqueous or sulfuric acids or alkaline agents, such as alkali metal hydroxides, as well as hydrolysis | 1 is not hydrogen. Compound; 1N, containing oxogruns, can be converted to the corresponding thionic compounds, for example, by treatment with phosphorus abutasulfide. The latter can be introduced into oxidative oxidants, for example, oxygen (in the form of air) or other oxidative oxidants, into the binder containing nitrogen atom as a ring member, in particular at one or both of the cyclic nitrogen atoms, to get from the amip, the corresponding lactam or imidose compounds. The resulting esters, nitrile salts of nitriles, in which at least one of the primers RI and Ro means hydrogen, can be metallized to form a functionally modified carboxyl group, paprpmer by treating electrolyte metals or their derivatives as organic compounds of alkali metals , for example, fepplitity or triphenylmethylsodium, or alkali metal alkoxides, such as hydrides, amides or sodium alkoxides, and then iodiergate interaction) with an alcohol ester of the formula RI-OH and (Il and) Rj-OH, as the corresponding halide, and thus to introduce into the a-position the organic group R, and Rg.

The resulting compounds can be halogenated in the aromatic residue of Pli by using chemical measures, halogens, preferably in the presence of Lewis acid, naimer iron (IH) halides, aluminum halide, antimony (III) or tin llV, or halogenating agents, hydrochloric acid in the presence of v-hydrogen, or chlorate nj, of the metal, nanochmer of sodium chlorate, litrosylhalogen., for example, nitrosyl chloride or bromide, halogiiminda, and: for example, bro. msuckindimide or bromophthalimide.

13, the aromatic residue of Pb can be further introduced into nitrogruium, iarymer, by treatment with nitric acid or nitrate salts under difficult conditions, for example, in the presence of sulfuric or trifluoroacetic acid, in order to obtain iio .M litromediay can be reduced to nitrogroup, nanorimeter, catalytically activated hydrogen .mi chimes reducing agents (formed at the time of release of hydrogen), to obtain an amino group.

In these or other reduction operations, care must be taken to maintain the unsaturated; e11 alkenyleneamine residue.

The resultant lERBIC-containing amino-group compounds can be reacted with reactive esters of alcohols or glycols, as well as reactive fuics and derivatives, such as haloids, for example chlorides or acid anhydrides, and thus can be converted into secondary compounds or tertiary amino or quaternary ammonium groups, as well as acylated a.MnIogrupny. If the obtained compounds with free aminogruyl are treated with nitric acid, diazonium salts are obtained, which according to Zandmeier's reaction, are obtained by hydrolysis at elevated temperature, by treatment with copper (II) halide or copper (II) acid, or copper (P) alkanol or cyanide Copper (II), or a lower alkanol or lower alkyl mercaptan, preferably neutral or weakly acidic or alkaline conditions, can be converted to the corresponding oxp, halogen, cpan, alkoxy or lower alkaline alkyl mercapto compounds.

In tyulucheNNyh fepolnyh nroduktah oksiili merkaptogruniy can eterifitsprovat in ether pashrimer using appropriate phenol comrade metals such as phenates and thiophenol of alkali metal by treatment with reactive esters of alkanols or cycloalkanols nizschih as pizschih alkpl- or tsikloalkilgalogenidov, sulfates or sulfonates, and also diazo compounds as diazo-hiiannix alkanes.

The resulting phenol ethers can be cleaved, for example, by treatment with strong acids with N-salts with acidic salts, such as hydrobromic and acetic acids, and also pyridine hydrochloride. Aliphatic oxo compounds can be dehydrated by the offer ;; e. In my own way.

The resulting unsaturated com pounds of lujio saturate, iairimer, treatment with catalysts, and active hydrogen or pliable mixtures (formed at the time of hydrogen release), with removal of double bonds, nalriem in Rj group or complex group. the ether.

In the resulting compounds with the appropriately cleaved etherifuged ester oxygranes in the residue

And N can be split such groups in

appropriate case in place with hydrogen, i.e., by introducing a double bond, for example, according to the method described above.

The resulting free acid MOHiriO is converted into a salt by a known method, for example, by interacting with a stoichiometric amount of a suitable salt-forming agent, such as ampak, amine or hydroxide, carbonate or alkali carbonate or alkaline earth metal.

The salts of am.mopi or -metal that can be obtained in the same way can be converted into free acid by adjusting the pH to the desired pH by treatment with an acid, for example, hydrochloric, sulfuric or acetic.

The resulting compound can be converted to an acid-additive salt, for example, by interacting with an inorganic or organic acid; or by an anionite, followed by isolation of the salt formed. The resulting acid additive salt can be transferred into a free compound by treating the base metal, iagaric meter with hydroxide alkaline} of the 10th metal, ammonia or oxyion-exchange metal. Pharmaceutically applied, non-toxic acid addition salts are, for example, acid addition salts with inorganic acids, as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric, or organic acids, in particular -picheskimi "arbonovymi-sulfonic acids and the like .muravinoy, acetic, pronionovoy, succinic, glycolic, .molochnoy, malic, tartaric, citric, ascorbic, maleic, oksimaleinovoy, nirovinogradnoy, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-oksib enzoic, salicylic, a. minosalicylic, and also methanesulfonic, ethanesulfonic, oxyethanesulfonic, ethylene sulfonic, benzenesulfonic, halogenobenzenesulfonic, toluene sulfopic, naphthalpsulfonic, sulfapic9

Loboi plc cyclohexanesulfamic acids.

These and other salts, such as nicrates, can also be used for purification, as can the definition of free compounds. Thus, the free compounds can be converted to their salts, separated from the crude mixture, and then isolated compounds can be obtained from the isolated salts. In view of the close connection between the new-n connected ML in free form and in the form of their salts, the following should be understood as free, compounds or salts, depending on the meaning and purpose, the corresponding salts are free compounds.

The resulting mixtures of isomers can be separated into individual isomers in a known manner, for example, by fractional distillation or crystallization and chromatography. Racemic products can be split into oltic antipodes by separation of diastereoisomeric salts, such as fractionated crystallization of mixtures of diureoisomeric salts, for example, d- or / -vino acid, or c-a-fen.ylethylamine, -o- (1-naphthyl) -Egylamine or / -tsinchonidine and, if desired, the release of free antipodes from salts.

The reactions described above are carried out according to known methods, nalimer in the presence or absence of diluents, preferably inert to the reaction participants or dissolving THEIR diluents, if necessary, in the presence of catalysts, condensation or neutralizing agents, in an inert atmosphere, for example nitrogen, with cooling or heating and (or) under elevated pressure.

Example 1. A mixture of 5 g of 4- (2-isoiidolinyl) acetophenone, 20 ml of morpholine, 1 g of sulfur and 0.25 and -toluenesulfonic acid is boiled for 16 hours under reflux and evaporated under reduced pressure. The residue containing 4- (2-isoindolinyl) thio-acetic acid morpholide is dissolved in 100 ml of 8% potassium hydroxide solution in standard, and the mixture is boiled for 4 hours under reflux and then evaporated. The residue is dissolved in 100 ml of water, the solution is washed with diethyl ether and hydrochloric acid to pH 4. Extract with diethyl ether; The organic extractor is washed with water, dried and evaporated, and the residue is recrystallized from ethyl acetate. In this manner, 4- (2-.isoipdolinyl) -phenylacetic acid is obtained; m.p. 237-239 ° C.

The starting material is prepared as follows.

A mixture of 15.5 g of 4-chloroacetophenone, 27 g of nzoindoILine and 60 ml of dimethyl sulfoxide is heated for 36 hours on a steam bath, then poured onto ice. The mixture is filtered, the residue is dissolved in diethyl ether, the solution is distilled, filtered and evaporated. So about 10

at once, 4- (2-isoipdol-1P1 l) -acetophilol is obtained.

In a similar manner, it is possible to obtain, when selecting suitable starting materials and after additional transformation, the following compounds:

ethyl ether) ((2-pzo P1dolinyl) -phenyl-acid acid; mp. 118-120 ° C after; trans; cf. from ether;

ethyl ester "- 3-chloro-4- (1,3-dioxo-2nzoindoline") -felpronionic acid; m.p. 107-100 ° C after recrystallization from ether;

(2-isoipdolinol) phenyl-proniopic acid ethyl ester; m.p. 111 - 13 ° C after recrystallization from ethanol;

(1,3-dioxo-1. 2, 3, 4 tetrahydro-2-isohioylinyl) phenyl acetic acid ethyl ester; T. Il. 89-9GS norele ikrkptililizatsii ethanol;

ethyl ester (4- 3-Chlo-4- (1-OXO-2-ZOINdolyl) -phenyl-pro-iion clumps; so pl. 111-113 ° C;

chloro-4- (1-OXO-2-Isoyl-11-diol-yl) -phenyl propiopic acid; T. Il. 178-180 ° C;

a-4-1-oxo-2-iso-11Dolyl) phenyl-acetic acid; m.p. 206-208 ° С:

these, a-4- (1-oxo-2-iso11Hdo.1inyl) -phenyl acetic acid ester; m.p. 111 -114 ° C;

methyl ester of (1-oxo-2-iso1P1dolinpl) -phenyl-iropiopic acid; T. Il. 129- 13: 2 ° C;

ETPLOV ester ((- -1- (1 -ОКСО-2-130ПНДОЛ11Н11л) -Fefflpl-nrop11opo ;; acid acid; t.ch. 104-106 ° С;

/ g-Nropyl ether (1-OXO-2-Isoiiidolpi) -phenyl-iropiopova

acids; T. Il. 87--89 ° C;

isopropyl ester of (1-OXO-2-1130P11Donyl) -hepple-iroionic acid; t. and, t. 118-121 ° C;

GZOB T 1LOVY1 ether (t-4- (1-OXO-2-ISOPNYdolyl) -fepl-iroppone to 1slot; mp 110-113 ° С;

a-3-chloro-4- (2-pzoyidolpiyl) ethyl-propionic acid ethyl ester; m.p. 67-70 ° C ii t. Kip. 190--200 ° C (0.4 mm Hg. Art.);

a-3-chloro-4- (1-oxo-2-isoindolp1P1l) -fe1P1.-1-butyric acid; m.p. 191 - 193 ° C;

ethyl ester of n-3-chloro-4-11-OXO-2-1130 (yapdolinyl) -phenyl-butyl acid; m.p. 230-240 ° C (0.35 mm Hg. Art.);

a-3-chloro-4- (1-OXO-2-IZOIPDOLII peel) -phenyl a-cyclopropylacetate sour, tota; T. n, i. 242-245 ° C;

a-3-chloro-4- (1-OXO-2-isoprotein) ethyl-phenyl-a-cyclopropylene acetic acid ethyl ester; m.p. 225-235 ° C (0.33 mm Hg. Art.);

(1,3-dioxo-4, 5, 6, 7-tetrachloro-2-iso-dipdolinyl) phenyl acetic acid ethyl ester; m.p. 197--199 ° C;

a-cyclopropyl-a 4-1-oxo-2-isoindolipyl) feiyl acetic acid; m.p. 186-188 ° C;

a-cyclonropyl-o-4- (1-oxo2-iso) 1 methyl ester-phenyl acetic acid methyl ester km / uyatt pl. 98-101 ° C; This is methyl a-cyclopropyl-a-4- (1-oxo2-isoindolipyl) -phenyl-acetic acid, m.p. II1 - 113 ° C; Ex. 2. A mixture of 1 g of ethyl ester and 3-chloro-4- (2-iso-iidolinyl) -phenyl-propionic acid, 50 ml of ethanol and 15 ml of 20% -iioro aqueous potassium carbonate is boiled under reflux for 1 hour. and evaporated under partial pressure. The residue is dissolved in water and the mixture is adjusted to pH 3 with 6 hydrochloric acid and extracted with ethyl acetate. The organic extract is dried, filtered and evaporated. The residue is recrystallized from ethyl acetate and a-3-.-Chloro-4- (2-isoindolyiyl) pepyl-nroniopic acid is obtained; T. Il. C. Example 3. A mixture of 4.5 g of ethyl ester (1-oxo-2-isoindolinyl) -phenyl-iroi-tolic acid and 1.6 g of hydroxide or 2 ml of water and 250 ml of etaiol are boiled under reflux. in nitrogen atmosphere for 2 hours and evaporated. at) low pressure. The residue is dissolved in water, treated with chloroform, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic extract is dried and evaporated and the residue is recrystallized from ethyl acetate. Thus, (1-oxo-2-nzoindolyl) -phenyl propionic acid is obtained; T. Il. 208-210 ° C. Example 4. C. a mixture of 2.1 g of the acid chloride (l-OKCo-2-isoidiol)) phenyl propionic acid, 0.9 g of 4-chloro-ylip and 1.5 g of triethylap in 100 ml of benzene bale t for 1 hour under reflux, filtered and the filtrate is washed with water, dried: and evaporated. The residue is recrystallized from acetonitrile to give a- 4- (1-oxo-2-isoindolinyl) phenyl-ironionic acid M- (4-chlorophenyl) -amide; m.p. 240-242 ° C. The starting material can be obtained as follows. A mixture of 2.0 g (1-oxo-2-iso and 1dol: Ipil) phenyl-propionic acid and 25 ml of thiopyl chloride is refluxed for half an hour under a nitrogen atmosphere and evaporated under partial pressure. The residue is evaporated twice to dryness, he added 13ol; the anhydride of (1-oxo-2-isoindolyiyl) -feiyl-propionic acid thus obtained is ilavites at a temperature of 129-132 ° C. Example 5. A mixture of 4.6 g of a-4- (2-iso-iidol-yl) ethyl ester The acids and 80 ml of a 25% aqueous solution of sodium hydroxide are boiled for 3 hours under reflux, then cooled and diluted with water. The mixture is acidified with hydrochloric acid, the precipitate is filtered off and recrystallized from ethyl acetate. Thus obtained (2-isoplindyl) -phenyl-acetic acid; T. Il. 237--239 ° C. Example 6. A mixture of 1.8 g of ethyl ester ((2 - isoidiolium.) -Phenyl-iropioic acid, 5 ml of a 50% aqueous solution of sodium hydroxide, 25 Mi of water and 100 ml of ethanol boil t for V /: an hour with reverse hoto. The garden is co-nitrated and co-nitrated. The concentrate is diluted with water, but the suspension is adjusted to pH 3 with 6N hydrochloric acid and extracted with ethyl ester of acetic acid. the extract is dried, filtered, and evaporated at a low pressure, the residue is crystallized from ethyl ester -110th acid and sex (2-isoindolinyl) -phenylnronioic acid; mp. 247-250 ° C. Example 7: To a solution of 0.5 g of 2-iso-ethylnyl) -phenyl-eronionic acid ethyl ester in 50 ml Ice and acetic acid is added dropwise but with 6 ml of a saturated solution of chlorine in glacial acetic acid, and the mixture is not stirred, and the mixture is then evaporated under reduced pressure. The residue is dissolved in an aqueous solution of sodium bicarbonate and extracted with growth solution; the organic extract is chromatographed over silica gel (benzene-hexane 1: 1). Ethyl ester of i-3-chloro-4 - (2-isoindolyiyl) -feiyl-niropiopic acid with an Rt of 0.30 (starting material: RI 0.26) and ethyl ester, 5-dichloro-4- (2-isoindolipyl) -feiyl-propionic acid of the formula with a value of Rs 0.395. PRI me R 8. If ironed for 2 hours with stirring, air through a concentrated solution of ethyl ester a-3-chloro-4- (2-isoindolinyl) -phenyl-iropiopic acid in dimethylformamide and withstand temperatury and 60 ° C, U-3-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-tfonioic acid ethyl ester is obtained, which is isolated by evaporation of the reaction mixture under pressure and followed by non-residue of the residue. The compounds are obtained in the form of a boiling Iranian 200-210 ° C (0.4 mmHg) fraction. According to the above methods, a-3-chloro-4- (5-chloro-1-oxo-2n-zoindolinyl) -phenyl-neopioic acid, as its methyl and ethyl esters, or sodium or potassium salts, can also be obtained using the approach of the original substance. PRESENTATION DUTY 1. Procedure for the preparation of " - (amyiophenyl) -aliphatic carboxylic acids of the general form R. ABOUT

  II

, A N-Plv-C -C-OH

R7

where the group D i means bntsnklitskuyu

alkenelene amino group with 1-3 double bonds and 5-6 links in each ring;

Ph is a substituted phenyl residue;

An RI is hydrogen or a lower alkyl group; and R2 is a hydrogen or lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower, alkyl or cycloalkenyl lower alkyl group, or their derivatives, or their salts, different the fact that the compound of the formula

or by transferring it to the corresponding derivative, or salt, or 1) separate isomers by known isomers.

2. A method according to claim 1. wherein a morpholip is used as a secondary ampa.

3. A method according to claim 1. wherein the reaction is carried out in the presence of sulfoxylotes, paprpmer, p-toluenesulfopic acid.

Priority on the tricks: 18.07.69; R, Ra, Ra and Ph no p. 1;

. represents a cyclic oocyclic

a group with 1-3 double bonds and 5-6 links in each ring, which can be replaced by lower alkyl groups and free, esterified into an ether or ester of hydroxy or .MepKanTorp HnaNrn i oxogruip;

-Nl

12.09.69

representing soooi

where Xi means acetyltrupnuyu, treated with sulfur in the presence of ammonia or a primary or secondary amine, followed by release of the desired product in free form

bicyclic alkenylempampogun with 1-3 double bonds and o-6 stars in each ring, which can be replaced with a thionogroup.