SU471715A3 - The method of obtaining - (aminophenyl) aliphatic carboxylic acids or their salts - Google Patents

Description

It is one of these, predominantly up to 4 carbon atoms of lower alkyl primers, which contains, in one of the positions, mainly at the final carbon atom, one of the cycloalkyl or cycloalkenyl groups. Such residues are, for example, cyclopropyl methyl, 2-cyclopentyl | Methyl or 3-cyclopentylmethyl groups.

Feiillo residue containing group AK

in the 2nd position, mainly in the 3rd position, primarily in the 4th position, may in other positions in the appropriate case have one or several, preferably 1 or 2, identical or different substituents. Such substituents are, for example, lower alkyl groups, for example, free, etherified, or ethoxy or mercapto groups, for example, lower alkoxy, for example methoxy, ethoxy, and propyloxy,. isopropyloxy, / z-butyloxy izobutnloksigruppy, lower alkylmercapto, such metnlme.rkapto- il.i etilmerkaptogruppy or galloidov atoms such as fluorine, chlorine, bromine or iodine, trifluoromethyl group, nitro-amino group, preferably a di-lower alkylamino, e.g. dimethylamino -, N-ethyl-N-methyl-Amino-, di tylamino, di - “- propylamino, d.iisopropylamino, di- / g-butylamino or diisobutylamino groups, lower alkyleneamine or lower alkenyleneamino-, for example, pyrrolidine, pilyridine, pyrroline, piperidine groups, monoase- myoprotein, myoprotein, myoprotein, myoprotein, myoprotein, myoprotein, pyroxylamino, diisobutylamino, diisobutylamino or diisobutylamino groups; , for example piperazine, 4-lower alkynlpinerazine, morpholino or thio.morphonol groups, or lower alkanoylamino, for example, acetylamino or pivaloyl oroglyamide groups, then in an appropriate case, functionally modified carboxyl groups, for example, carbonyls s alkoksn-, e.g., carbomethoxy or karbetoksigruppy, if appropriate N-substituted, for example lower al.kilnymi residues, carbamoyl groups, e.g., dinizschie alkylcarbamoyl, nanrimer dimethylcarbamoyl group or tsiaillnye group 1 izschie alkil.sulfonilnye, nalrimer, methylsulfonyl or ethylsulfonyl groups, or in the appropriate case functionally modified sulfo groups, for example, in the corresponding case N-substituted sulfamoyl soils, for example, the lowest alkylsulfonamyl, dimethylsulfamoyl groups. The Ph residue, in particular, means 1,3- or 1,4 phenyl, (lower alkyl) -1,3- or-1,4-phenylene (lower alkoxy) -1,3- or 1,4-phenylene, ( mono- or dihalogen) -1,3-yl-1,4-phenylene (trifluoromethyl) -1,3- or -1,4-feiylene, (nitro) -1,3- or 1,4-phenylene, (amino ) 1, 3- or 1,4-phenylene, (di-lower alkylene-amino) -1,3 - or -1,4-phenylene group.

Bicyclic alkene amino group

Preferably, this is the corresponding residue, for example, in the subgroups below, containing 5-b units in the cycle and in the isocyclic part 1–3 of double bonds. It is primarily a benzoalkenylene amine residue or the corresponding dihydro or tetrahydro benzoalkynylene amine residue, in which the alkenylene amine part contains 5-6 units per cycle, and which in the appropriate case, for example, the phenylene residue Ph can be displaced in the aromatic part, in particular, lower alkyl groups, which are free, esterified into a hollow or ester by hydroxy or mercapto groups, for example, lower alkoxy or lower alkanoyloxy groups, and also by halogen atoms, and in the aliphatic part also by oxo or thionogroup. Such groups are 1-indolinyl, 2-isoicdolinyl, 1,2,3,4-tetrahydro-1-quinolinyl or 1,2,3,4-tetrahydro-2-isoquinolinyl, as well as 4,5,6,7- tetrahydro-1-indolinyl, 4,5,6,7-tetrahydro2-isoindolinyl, 4,7-dihydro - 1 - indolinyl, 4,7-dihydro-2-isoindolinyl, 1,2,

3,4,5,6,7,8-octahydro-1-quinolinyl, 1,2,3,4,5, 6,7,8-octahydro-2-isoquinolinyl, 1,2,3,4,5, 6, 7,8-hexahydro-1-quinolinyl or 1,2,3,4,5,6, 7.8 - hexagndro-2-isoquinolinyl, which

may be as appropriate, for example, as indicated, substituted.

The proposed method consists in the fact that in the compound of the formula

(D)

Ajf-Tk-C-Xi RO

where Xi is a functionally modified carboxyl group; transform a functionally modified carboxyl group into a free carboxyl group.

The starting materials of formula II are, in particular, the corresponding esters, nanrnmer esters of lower alkyl or lower alkenyl, cycloalkyl, cycloalkyl, cycloalkyl lower alkenyl or cycloalkenyl-lower alkyl, where the cycloaliphatic residue contains 3-7 units in the ring, aryl esters or aryl-lower alkyl, where the .aromatic residue means and preferably, as for example the residue Ph, a substituted phenyl group,

 With the subsequent isolation of the target product in free form or by transferring to salt, or dividing the resulting isomeric mixture into individual isomers by known iriems.

free or esterified oxy-lower alkyl, for example, lower alkoxy-lower alkyl or cycloalkoxy, lower alkyl esters, where Celoalkyl contains 3-7 units in the ring, or Greg-amino-lower alkyl esters, where the tert-amino group means, for example, the lowest alkyl aminogroup, nalimer dimethylamino- or diethylamino group, an abundant alkylamino, for example, pyrrolidino- or pyridyridone-group, or a monoazamonoox-monothian-alKyleno-amino-, iHanpHiMcp piperazino-, 4-11 lower-alkyl-nperzino-for example 4 -methyl-piperazino-, 4-11-lower alkyl-nperazino-for example 4 -methylamino-piperazino-, 4-11-lower-alkyl-ni-pi-perazino-, for example, 4 -methyran piperazino-, 4-11-lower-alkyl-ni-pi-perazino-for example 4 -methylamino-amino-piperazino-4-11 lower-alkyl-ni-pi-perazino-4 -methyl-amino-piperazino-, 4-11-lower-alkylamino-amino-, iHanpHiMcp piperazino-, 4-11 - yl-piperazino, or morfoliio- tiomorfoliiogruppu ester residue to a heteroatom such atoms are separated from each other and the oxygen to at least two carboxyl groups preferably 2-3 carbon atoms.

Other starting materials of the formula II are, for example, such amide amides or thioamides, such as monoplace di-lower alkylamides, aryl amninds, or aryl-and-lyshl alkylamides, where the aromatic residue is preferably in the corresponding case, such as, for example, P- substituted phenyl group, or monocyclic lower alkylene-, myoaza-ness al.chylene-, monoox-lower alkylene-yln monothia-lower alkylene-amides, in addition, the corresponding thioamides, hydroxamic acids or nitriles.

The complex; ester of formula II can be hydrolyzed to free acids, for example, by treatment with appropriate basic means, for example, aqueous alkali metal hydroxides.

Amides or thioamides of formula II. Can be hydrolyzed under acidic or alkaline conditions, for example, by treatment with aqueous mineral and / or carboxylic acids, silts with alkali hydroxides: 1-th. Metals.

Nitriles of formula II. It is possible to hydrolyze, for example, by treatment with concentrated aqueous acids or alkaline agents, using sodium hydroxides with alkali metals.

The resulting compounds of Formula I can be converted to other compounds of this formula. Thus, it is possible to convert compounds with oxogrunnam by treatment with phosphorpentasulfido in the corresponding thio; 1 compounds. In the bicyclic residue A of the N- without oxo groups, we can enter such into them by means of oxidation, for example, oxygen (for example, in the form of air) or other mild oxidizing agents into the part containing a linking nitrogen atom as a link in the ring. , especially in one or both positions, in the vicinity of the nitrogen atom in the ring, moreover, the corresponding lactam or imnd compounds are obtained from the aminine compound itself.

Salts obtained in which at least one group R) and Rj denote hydrogen in the axi-positions relative to the carboxyl group, and it is possible to know the metal that is in salt form, for example, by treatment with alkali metals or their derivatives, for example, organic compounds of alkali metals. for example, sodium triphenylmethyl phenyllitne or sodium, or by treatment with alkali metal alcohols, for example, drides, amides or sodium alkoxides, and then expose it to the reactionary complex of the first ester of the formula RI-OP and / or R o-OH, (For example, with the corresponding halide, and thus introduce into the a-position the organic group RI and R2.

The compounds obtained can be halogenated in an aromatic Ph residue, for example, using halogen, preferably in the presence of a Lewis acid, for example iron -III, aluminum-, antimony III- or tin-IV- halide, or a halogenating agent, nalimeter hydrochloric acid in the presence of hydrogen peroxide, or alkali metal chlorate, napiiMep, sodium; 1N nitrosyl halide, for example, nitrosylchloride or bromide, halogen-, naimer, bromosuccinimide nly -phthalate.

 It is possible to introduce into the aromatic residue the Ph-nitro group, nanorimer, by exposure to the nitric salt, salt, or salt under acidic conditions, for example, in the presence of cepiioii or trifluoroacetic acid.

In the obtained nitrosoadia, the introgrune can be reduced to an amino group, for example, by exposure to catalytically activated hydrogen or chemical reductants (hydrogen to the release moiety).

0 Prn these ii other reactions vostagulevle; p-1I should be monitored to maintain iieiiacbiHieiDibiA. Alkenylamino residue.

The obtained compounds with the primary amino group can be reacted with the reactive esters of alcohols of h; 1 coli, as well as the reaction of 1Mn are functional functional derivatives, for example, halo-peptides, nanodimeric chloride or angdromine acids and thus be converted into compounds nor with secondary or tertiary amino or quaternary ammonium groups, or acyl alcohol; 1 groups 1. After treatment with nitric acid, the compounds obtained with the free amino group give the diazonium salts, which. can be translated into the corresponding OCs; | -, halogen, cyanic, lower alkoxy-nylmer-mercitol compounds; 1i by the reaction; n1 Zandmeysr, nanrn0. lger, by hydrolysis np) j at elevated temperatures, affected by the halide amide (II) nli equivalent znand, nln lower alkanol or 1} 1; 1mg alkyl, mercaptaio, predominantly in neutral or

5 slightly acid or alkaline conditions.

In the resulting phenolic compounds, phenolic hydroxyl mercaptogrug groups can be etherified from ether downtime, for example, by using corresponding metal phenolates and thiophoiolates, for example, alkali acids, by reacting esters of "ester alkanols or cycloalkanols, and, for example, I can use the same I-words or I or a few. sulphates or sulphonates, as well as diazo-compounds, such as diazo-containing alcaia. The resulting feiol esters can be cleaved, for example, by exposure to strong acids or acid salts, for example, hydrobromic acid and acetic acid, as well as nrpdiphydrochloride. Aliphatic hydroxyl compounds, as described above, can be dehydrated.

The resulting unsaturated compounds can be saturated, for example, by exposure to catalytically activated hydrogen or chemical reducing agents (hydrogen at the moment of isolation) with removal of double bonds, for example, in R2 and / or ester group.

In the resulting compounds with cleavable, if appropriate, esterified with ester gpdroxyl

A- these groups can

groups in the balance

in this case, ptp1, co-dissolve with hydrogen, i.e., when a double bond is introduced.

The production of the free acid can, for example, by reacting with an appropriately stoichiometric amount of an appropriate salt-forming agent such as ammonia, ammonia or carbonate hydroxide or alkali or alkaline earth metal bicarbonate. The ammonium or metal salts thus obtained can be unreacted into the free acid by the action of an acid, such as hydrochloric, sulfuric, or acetic acid, to the extent required by the i: h ipH.

The resultant compound can be converted into a salt with an acid, for example, by reacting with a perorganic or organic acid or an appropriate anion-metaboliser and isolating the resulting salt. The preparation of the salt with acids can be converted into a free compound by the action of a base, for example, an alkali metal hydroxide, ammonia or hydroxy. Solvents with acids, for example, pharmaceutically-used and toxic salts with acids are, for example, those with such inorganic acids as hydrochloric acid, hydrobromic acid 1a, sulfuric, phosphoric, nitric or chlorine, or organic acids, in particular with organic carboxylic acids. or sulfonic as formic, acetic, propnonova, succinic, glycolic, molochial, malic, tartaric, citric, ascorbic, maleiYuva, oksimaleiiova, iirovipogradna, phenylacetic, benzoic, 4-amiiobenzoy 1a antrannlova, 4-oksiben oyna, salntsnlova, aminosalntsilova, embonic NLI ikotiiova and metansulfopova, etansulfopova, oksietansulfonova, etilensulfopova, beizolsulfonova, galogepbenzolsulfonova, toluenesulfonic, naphthalenesulfonic, sulfanilic or tsnklogeksilsul4) amiiova acid.

Etna and other salts, for example, n; -1crats, are used for purification and are definite; free compounds, free compounds CHIII, can be converted into their salts, separated from the crude mixture, and then free compounds can be obtained from the isolated salts. Due to the close ties between new compounds in the free

in the form of salts in the form of salts below and above, free compounds or salts should, in appropriate cases, be imbued with appropriate salts or liberated compounds. The resulting isomeric mixtures can be divided, for example, by fractional distillation or crystallization and / or chromatography, into individual isomers. The racemic products. Can be divided into the individual antipodes, and appr. Measures, by means of divided 1: for example, fractional crystallization, mixtures d; .yyi, yu nli 1-vopnaya acid ill1 d-a-phenylsminyl amine, ya-1- (1-naphthyl) -ethylamine or 1-cciioi.idina and the release of free

antipodes nz salts.

Reactions are carried out, for example, in the presence or absence of diluents, predominantly such that are inert according to the 1H; s reaction lids and can dissolve them, if at least in the presence of catalysts, condiscine or neutralized means, in an inert atmosphere, in an inert atmosphere. nitrogen, iri okhgazhideiii or heating; | / or higher pressure.

P p i:, 1 e p 1. A mixture of 1 g of ethyl ester of p-3-chloro-4- (2-isoindolyiyl) -feC1 l -nropionic acid, 50 l / l of ethanol and 15 l; l 20% - Hydrochloric acid carbonate i-cip t t for 1 hour under reflux and evaporated under reduced pressure. The residue is dissolved in water and the mixture is adjusted to pH 3 with 6 g of hydrochloric acid and extracted with ethyl ethyl acetate. The organic extract is dried, they are fired. Recrystallized residue; lz lz ethyl acetate

li get cc-3-chloro-4- (2-isoidiol) 1iyl) -phen l-prop; ionic acid with m. pl. 148-150 C.

The starting material can be obtained in the following manner.

4.8 g of 50% sodium hydride slurry in linear oil under stirring and under nitrogen atmosphere is added to 100 ml of hexamethylphosphoric acid triamide. Then, 17.1 g of a-methyl diethyl ether are added.

malonic acid, slowly warm the mixture to 100 ° and then a solution of 19.2 g of 2,4-dichloronitrobepzol in 20 ml of hexmethylphosphoric acid, which is added within 30 minutes, is added dropwise. The temperature is maintained at 100 hours for 7 hours, then the mixture is cooled and diluted with water, co-collected under reduced pressure, the residue is dissolved in water and extracted with benzene. The organic extract is sieved with water, dried, filtered and evaporated. The residue is distilled; kinia at 147 -14870.25 l; lg. Hg Art. Fraction 1 represents a- (3-chloro-4-pntrofepyl) -a-mystyl-malonic acid diethyl ester.

For 5 minutes, 4 g of a- (3-chloro-4-nitrophe; 1yl) -a-methyl-malonic acid diethyl ether, dissolved in 50 ml of anhydrous ethanol, are passed through hydrochloric gas, then 0.5 g of 10% is added. a catalyst (palladium on carbon), the mixture is hydrogenated at an initial pressure of 3 ° g and then filtered, evaporated under reduced pressure. The residue is dissolved in a 5% aqueous solution of sodium hydroxide and extracted with diethyl ether. The organic extract is dried, filtered and evaporated. A- (4-amino3-chloro-phenyl) -a-methyl-maldioic acid diethyl ester is obtained with characteristic bands in the HP spectrum npi-; 1720, 3370 and 3460 cm.

A mixture of 75 g of diethyl ether gx- (4amio-3-chlorofelp1l) a-methyl malonic acid and 150 ml of 50% aqueous sodium hydroxide solution was heated under reflux for 16 hours, cooled, diluted with water and washed with diethyl simple: ether, zat.m acidified by concentrating with hydrochloric acid. The mixture was again boiled under reflux for 16 hours and evaporated under reduced pressure. The residue is dissolved in an anhydrous hydrochloride solution in ethanol. The mixture was boiled under cold for 6 hours; the mixture was evaporated. The residue after recrystallization from the mixture of ethanol and diethyl ether gives a- (4-amino-3-chlorophenyl) -propionic acid ethyl ester hydrochloride with mp. 164-168 °, which can be converted into a free compound in a known manner, using exposure by such a basic agent as sodium hydroxide, and extraprosy with an organic solvent: as d; -: ethyl. Ether.

A mixture of 12 g of ethyl ester of a- (4-am: 103-chloro-phenyl) -propionic acid, 11.6 g of a, a-dibromo-o-xylene. 17 g of carbo: ata natrn and 250 ml of dimethylforma, and for 6 hours, boil with reverse cold: vinegar in a nitrogen atmosphere. After cooling, the reaction was performed: 1: the mixture was filtered, the filtrate was diluted with water, and the diet was extracted: -1l ether.

The organic extract is washed with water, dried, filtered and evaporated. Osta10

CURRENT is distilled boiling at 190–200 ° / 0.4 LHH. Art. gives ethyl effr a-3-chloro-4- (2-isoindinnyl) -phenyl-prone :: o: 1-acid.

Example 2. A mixture of 4.5 g of ethyl (1-oxo-2-isoindole: 1Nyl) phenyl propionate: new acid and 1.6 g of hydroxide: 1 in 2 ml of WATER i 250 ml of ethanol are heated 2 hours in the atmosphere: a:; oa with reverse; 1 ;; m cold; -0 dilnom n evaporates n. p, :: reasonably: L daEle: il. The residue is dissolved in water, washed with chloroform, added: salt: OH with acid, and extracted with ethyl acetate. Organic extract Vy: 11vayut and evaporated: the residue of unrecr: steel: 13vv watered from this ethical effect: 1p of acetic acid. In this way, a-4- {1oxo-2-30 iidolyl) -phenyl-propiopic acid is obtained. m.p. 208-210 °.

Primeny eGGy as the source: ater :: ala ethyl ester (1-oxo-2-: 3: 3dol ::: n: l) -phenyl-prop: new acid with t. Il. 104-106 ° can be obtained, naprnmer, but OH: Ica and: io: y method.

i I r n m e r 3. out of 4.5 g of ethyl (2-isoindolinyl) -fe: 1: 1 l -xus: 1st acid: and 80 ml of a 25% aqueous solution of g :: droo:: 1si 1 atri The mixture is refluxed for 1 hour with cold: 1, then cooled and diluted with water. The mixture is acidified with hydrochloric acid, the precipitate is filtered and cross-precipitated from this: ethyl ester of acetic acid (2-isonndol-1P1l) -fe: p1l -acetic to: the slot of the structural formula

G, H2

SNO-ON

, /

with t. il. 237-239 ° C.

Original mater: 1al noluchayut sleduny M way.

A mixture of 5000 ml of anhydrous ethanol and 1000 g of 4-aminophenylacetic acid for 5 hours and 30 minutes np: i stirring under reflux: a dry chlorine: hydrogen chloride. Then, for 4 hours, the mixture is stirred; distance: it is then cooled for 16 hours at 10 °. The f: lt mixture, the rest of the iia filter was washed with cold water, diluted with anhydrous ethanol, and diluted in 8,000 "l of water. By adding porcelain in 50 ml of 50Sj-Horo aqueous solution of hydroxyn liaTp :: solution with agitated :. Allow to alkaline reaction; then stir for another 1 hour at coma temperature. The result is: the precipitate is filtered off; or: it is water; ethyl complex: 1b eff: 1p 4-aminesBe: il-acetic acid melt: 1 tc at 47-49 ° C

C. a mixture of 10 g of ethyl ester 4-aminophene:; l-xacetic acid, 16.4 g o, a-dpbromo-oxylol, 17.8 g sodium carbonate, n 250 ml d; Methylformamnd at 6 g stirrer boiling is refluxed. After cooling, it is diluted with water and extracted with ether; the organic extract is washed with water, dried, filtered and evaporated, the residue is recrystallized from ether. Ethyl eff, ir (2-isoindolyl) -phenyl-acetic-1-th acid is obtained, which melts at 118-120 ° C. Example 4. A mixture of 1.8 g of ethyl ester of (2-isoindolyiyl) -phenyl-nrop, ionic acid, 5 ml of a 50% aqueous solution of sodium hydroxide, 25 ml of water and 100 ml of ethanol 1 hour 30 min kilotons reflux and concentrate under reduced pressure. The concentrate is diluted with water, the resulting suspension is acidified with 6N. hydrochloric acid to pH 3 and extracted with ethyl acetate. The organic extract is dried, filtered and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate and a-4-2 isoindolinyl) -phenyl-propionic structural formula cn-c is C. m.p. 247-250 ° C. The starting material is obtained in the following manner. To a solution of 52 g of ethyl 4-; i iTraphenyl acetic acid in 350 ml of a mixture (1: 1) of dimethylformamide and toluene while stirring in portions, add 9.5 g of a 50% suspension of sodium hydride in mineral oil After 1 hour and 30 minutes of stirring at room temperature, 26 g of methyl iodide is added to the callae at room temperature and the mixture is stirred at room temperature for 16 hours. Water is then carefully added and the ether is extracted. The organic extract is dried, filtered and evaporated. The residue is dissolved in 100 ml of this 1 liter, the solution is charged with several crystals of the starting material and settled in the cold. The resulting precipitate is filtered, the filtrate is evaporated. The residue is a- (4-Nitrophenyl) -propio: hydroxy acid ethyl ester. A mixture of 50 g of a- (4-i; iTraphenyl) propionic acid ethyl ester in 200 ml of 95% pure aqueous ethanol in the presence of 0.4 g of catalyst (palladium on carbon) is hydrogenated until the end of the hydrogen absorption. The mixture is filtered, the filtrate is evaporated. The ethyl ester is a- (4-aminophene; 1l) -propionic acid, the hydrochloride of which melts at 137-140 °. A mixture of 10 g of a- (4-amyiophenyl) -propionic acid ethyl ester hydrochloride, 15 g a, a-dibro.m-xylene, 16.5 g of sodium carbonate and 250 ml of dimethylformamide is boiled for 5 hours with stirring reverse fridge. After cooling, it is filtered, the filtrate is concentrated under reduced pressure, diluted with water and extracted with ether.m. The organic extract is washed with water, dried, filtered and concentrated under reduced pressure. The precipitate is filtered off, recrystallized from ethanol and dissolved in a minimum amount of bezzol. The solution was applied to a small silica gel column and eluted with benzene. The first eluate is evaporated, the residue is recrystallized from ethanol. (2-Isoindolinyl) -phenyl pronionic acid ethyl ester is obtained, which melts at 111-113 °. By using suitable substances, the following compounds can be obtained in a similar way: (l-OKco-2-isoindolinyl) -phenyl-acetic acid, m.p. 206-208 °; a-3-chloro-4- (1-oxo-2-isoindolinyl) - fep-1l-butyl acid, so pl. 191 -193 °; a-13-chloro-4- (1-oxo-2-isoindolinyl) -phenyl-a-c-cyclopropyl acetic acid, so pl. 242-245 °; a-cyclopropyl-4-oxo-2-isoindolinyl) - phenyl - acetic acid, so pl. 186-188 °; a-3-methyl-4- (1-oxo-2-isoindolinyl) -phenyl - pronionic acid, so pl. 203-207 ° after recrystallization from a mixture of ethanol and diethyl ether; .methoxy-4- (1 - oxo - 2 - isoindolinyl) - propanoic acid, so pl. 221 - 224 ° after recrystallization from ethanol; a-3-methyl-4- (1-OXO-2 - isoindolinyl) phenyl propionic acid, m.p. 214-217 ° after recrystallization from ethyl acetate; a-3-trifluoro.1ethyl-4 - (1-oxo-2-isoindolinyl) -fe 1il-propiopic acid, so pl. 181-184 ° after recrystallization from diethyl ether. The subject matter of the invention is 1. A method for producing a- (aminopepyl) -aliphatic carboxylic acids of the formula - (jt-Ph-CO-OH) where the group AN-oz: starts a bicyclic alkylene-amino group with 1-3 double bonds and 5-6 links in each ring; Ph - in the appropriate case, substituted fe} 1ylene residue; RI - hydrogen or a lower alkyl group; 1 R2 - hydrogen or lower al-kil, lower alky}, or cycloalkyl, cycloalkenyl, cycloalkyl, lower alkyl or cycloalkenyl-lower alkyl group .

13

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

A N-Pfi-C-X, (P)

Kg,

where Xi means function; modally modified carboxyl primer,

this group is converted into a free carboxyl group, followed by dividing the target product in free form or salt conversion, or by dividing the resulting isomeric mixture into separate: isomers by known methods.

2. A method according to claim 1, wherein the compound of formula II, wherein Xi is an ester, is subjected to hydrolysis by treatment with, for example, an alkali metal hydroxide.

3. The method according to claim 1, distinguishes in that the compound of formula II, where Xj is amide

14

whether thioamide, undergo hydrolysis under acidic 11h alkaline conditions.

4. The method according to claim 1, characterized in 11 (ice in that the compounds of the formula II, where X is a nitrile, are treated with acids or alkalis.

Priority by featured;

07.07.69 -4 l -

bicyclic alkeot

a nilenamino group with 1 to 3 double bonds and 5 to 6 units in each ring, which can be substituted in the appropriate case by lower alkyl groups that are free from esterified to the ether or hydroxy or mercapto group; or oxogruns;

from 12.09.69 —An-bicyclic 1-ches of alkenylapaminogruppa with 1–3 double bonds and 5–6 units in each ring, which, if appropriate, can be replaced by a thionogroup.