SK98594A3 - Asymetric substituted derivatives diaminodicarboxylic acids and method of their preparation - Google Patents

Asymetric substituted derivatives diaminodicarboxylic acids and method of their preparation Download PDF

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SK98594A3
SK98594A3 SK985-94A SK98594A SK98594A3 SK 98594 A3 SK98594 A3 SK 98594A3 SK 98594 A SK98594 A SK 98594A SK 98594 A3 SK98594 A3 SK 98594A3
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Johann Hiebl
Franz Rovenszky
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Hafslund Nycomed Pharma
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/20—Processes
    • C25B3/29—Coupling reactions

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Abstract

The invention relates to novel asymmetrically substituted diaminodicarboxylic acid derivatives of the formula <IMAGE> and to a process for their preparation by mixed Kolbe synthesis.

Description

Asymetricky substituované deriváty diamínokorkovej kyseliny sú cennými medziproduktmi na syntézu peptidov.Asymmetrically substituted diaminoic acid derivatives are valuable intermediates for peptide synthesis.

V J. Org. Chem. 1980, 45, 3078-3080 sú popísané asymetricky substituované deriváty kyseliny diamínokorkovej, ktoré boli pripravené kombinovanou Kolbeho syntézou. Pritom sa neoddeľujú vedľajšie symetrické produkty. Ďalej je z Tetrahedron Lett. 30, 1982, 33, 4727-4730 známa príprava asymetricky substituovaných derivátov diamínopimelovej kyseliny zložitou 9-stupňovou enantioselektívnou syntézou.J. Org. Chem. 1980, 45, 3078-3080 discloses asymmetrically substituted diamineocorkic acid derivatives prepared by the combined Kolbe synthesis. The symmetric by-products are not separated. Next is from Tetrahedron Lett. 30, 1982, 33, 4727-4730, a known preparation of asymmetrically substituted diaminopimelic acid derivatives by complex 9-step enantioselective synthesis.

Nečakane boli nájdené nové asymetricky substituované deriváty diamínodikarboxylových kyselín, ktoré sú cenným medziproduktom pri syntéze peptidov a zlúčenín s obsahom syntetických aminokyselín.Unexpectedly, novel asymmetrically substituted diamine dicarboxylic acid derivatives have been found, which are valuable intermediates in the synthesis of peptides and compounds containing synthetic amino acids.

Podstata vynálezuSUMMARY OF THE INVENTION

Predmetom vynálezu sú preto asymetricky substituované deriváty diamínodikarboxylových kyselín, vzorca IThe invention therefore provides asymmetrically substituted diamine dicarboxylic acid derivatives of formula I

OABOUT

II II (OII

A - C - CH - (CH2)n - CH - C - BA - C - CH - (CH 2 ) n - CH - C - B

E-NHE-NH

F-NH kdeF-NH where

A a B znamená nezávisle na sebe skupinu -OR, pričom R môže prípadne znamenať alifatickú nerozvetvenú alebo rozvetvenú alebo cyklickú alkylovú skupinu, ktorá obsahuje 1 až 10 atómov uhlíka, ktorá je substituovaná jedným alebo viacerými atómami halogénu, fenylovú skupinu alebo skupinu -CH2~X, pričom X môže znamenať 9-fluorenylovú, fenylovú skupinu, skupinu -OCH3-, -CH2SO2CH2, -CF^SC^CgH^, -CCI3, -CH2Y, kde Y môže znamenať halogén, -p-tosylovú, prípadne fenylovú alebo fenylalkylovú skupinu, ktorá je substituovaná jedným alebo viacerými atómami halogénu, jednou alebo viacerými skupinami -N02 alebo jednou alebo viacerými alkoxyskupinami, difenylmetylovú, trifenylmetylovú, 2-pyridylovú skupinu alebo skupinu SÍR1R2R3’ Pričom skupiny ^^2^3 vždy nezávisle na sebe môžu znamenať nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka alebo fenylovú skupinu,A and B are each independently -OR, wherein R may optionally be an aliphatic unbranched or branched or cyclic alkyl group having 1 to 10 carbon atoms substituted with one or more halogen atoms, a phenyl group, or -CH 2 - X, wherein X may be 9-fluorenyl, phenyl, -OCH 3 -, -CH 2 SO 2 CH 2, -CF 2 SC 2 C 8 H 4, -CCl 3, -CH 2 Y, where Y may be halogen, -p-tosyl, optionally phenyl or phenylalkyl a group which is substituted by one or more halogen atoms, one or more -NO 2 groups or one or more alkoxy groups, diphenylmethyl, triphenylmethyl, 2-pyridyl or a S 1 R 1 R 2 R 3 group, each being independently of one another may be straight-chained or a branched alkyl group having 1 to 4 carbon atoms or a phenyl group,

E,F prípadne znamená nerozvetvenú, rozvetvenú alebo cyklickú skupinu, ktorá obsahuje 1 až 10 atómov uhlíka, ktorá je substituovaná halogénom, alebo skupinu o oE, F optionally represents an unbranched, branched or cyclic group containing 1 to 10 carbon atoms which is substituted by halogen, or a group o

A alebo A0-b pričom V môže znamenať 9-fluorenylmetylovú skupinu alebo prípadne benzylovú skupinu, substituovanú jedným alebo viacerými halogénmi, jednou alebo viacerými skupinami -NO2, jednou alebo viacerými alkoxyskupinami, jednou alebo viacerými skupinami -CN, alebo ich kombináciou, alebo substituenty E, prípadne F tvoria po odbúraní atómu vodíka spolu s dusíkom jeden z nasledovných kruhových systémovA or A 0 - b wherein V may be a 9-fluorenylmethyl group or optionally a benzyl group substituted with one or more halogens, one or more -NO 2 groups, one or more alkoxy groups, one or more -CN groups, or a combination thereof, or substituents E and / or F form one of the following ring systems after the hydrogen atom has been removed with nitrogen

X / si ’n si \X / si 'n \

pričom, ak sú skupiny A a B odlišné, E a F môžu byť rôzne alebo rovnaké, na druhej strane ak sú zvyšky A a B rovnaké, E a F musia byť odlišné, a n je celé číslo od 2 do 10, pričom stredy asymetrie molekúl sú dané použitými eduktami a obidve musia mať konfiguráciu L alebo D alebo D,L, prípadne L,D.wherein, if the groups A and B are different, E and F may be different or the same, on the other hand if the residues A and B are the same, E and F must be different and n is an integer from 2 to 10, the centers of asymmetry of molecules they are given by the starting materials used and both must have the configuration L or D or D, L or L, D respectively.

Ďalším predmetom vynálezu je spôsob prípravy takýchto asymetricky substituovaných derivátov diamínodikarboxylových kyselín kombinovanou Kolbeho syntézou, ktorého podstatou je, že chránený derivát aminokyseliny vzorcaA further object of the invention is a process for the preparation of such asymmetrically substituted diamino-dicarboxylic acid derivatives by combined Kolbe synthesis, which is characterized in that the protected amino acid derivative of the formula

IIII

A - C - CH - (CH2)k - COOH (II)A - C - CH - (CH 2 ) k - COOH (II)

II

E-NH kde A a E majú vyššie uvedený význam a k je celé číslo, je podrobený elektrolýze na platinových elektródach spolu s derivátom aminokyseliny vzorcaE-NH where A and E are as defined above and k is an integer, is subjected to electrolysis on platinum electrodes together with an amino acid derivative of the formula

IIII

HOOC - (CH2)i - CH - C - B (III)HOOC - (CH 2 ) i - CH - C - B (III)

F-NH kde B a F majú vyššie uvedený význam a 1 je celé číslo, pričom kal dávajú spolu číslo n.F-NH wherein B and F are as defined above and 1 is an integer, the sludge together being the number n.

Vo vzorcoch I, II a III znamená A a B skupinu -OR, pričom R znamená prípadne nerozvetvenú alebo rozvetvenú alebo cyklickú alkylovú skupinu, ktorá obsahuje 1 až 10 atómov uhlíka, ktorá je substituovaná jedným alebo viacerými halogénmi, napríklad halogénovanú metylovú, etylovú, i-propylovú, n-butylovú, i-butylovú, t-butylovú skupinu a podobne, cyklohexylovú, cyklopentylovú alebo cyklobutylovú alebo fenylovú skupinu.In formulas I, II and III, A and B are -OR, wherein R is an optionally branched or branched or cyclic alkyl group containing 1 to 10 carbon atoms substituted with one or more halogens, for example halogenated methyl, ethyl, i a propyl, n-butyl, i-butyl, t-butyl group and the like, a cyclohexyl, cyclopentyl or cyclobutyl or phenyl group.

Ďalej môže R znamenať skupinu -CH2~X, pričom X znamenáFurther, R can be -CH 2 -X, wherein X is

9-fluorenylovú, fenylovú skupinu, skupinu -OCH^,9-fluorenyl, phenyl, -OCH3,

-CI^SC^CHj, -Cl^SÍ^CgHg, -CCI3, -CH2-Y, kde Y je halogén,-CI ^ SC ^ CH, Cl ^ Si ^ CgHg, -CCl 3, -CH 2 Y, wherein Y is halogen,

-p-tosylová, prípadne fenylová, fenacylová, napríklad p-brómfenacylová, p-chlórfenacylová skupina a podobne, ktorá je substituovaná jedným alebo viacerými halogénmi a jednou alebo viacerými skupinami -N02 alebo alkoxyskupinami, difenylmetylovú, trifenylmetylovú, 2-pyridylovú skupinu alebo skupinu -SiR-^R2R3, pričom skupiny ^^^2^3 nezávisle znamenajú nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka alebo fenylovú skupinu.-p-tosyl, optionally phenyl, phenacyl, for example p-bromophenacyl, p-chlorophenacyl and the like, which is substituted with one or more halogens and one or more -NO 2 or alkoxy groups, diphenylmethyl, triphenylmethyl, 2-pyridyl or a group -SiR 1 R 2 R 3, wherein the groups R 1, R 2, R 3, independently represent a straight or branched alkyl group having 1 to 4 carbon atoms or a phenyl group.

A a B znamená výhodne skupinu -OR, pričom R znamená 9-fluorenylmetylovú, substituovanú alebo nesubstituovanú fenylovú, benzylovú alebo fenakrylovú skupinu alebo prípadne halogénovanú nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka.A and B are preferably -OR, wherein R is a 9-fluorenylmethyl, substituted or unsubstituted phenyl, benzyl or phenacrylic group, or an optionally halogenated linear or branched alkyl group having 1 to 4 carbon atoms.

Skupiny E a F znamenajú prípadne halogénovanú nerozvetvenú, rozvetvenú alebo cyklickú alkylovú skupinu, ktorá obsahuje 1 až 10 atómov uhlíka, napríklad metylovú, etylovú, n-propylovú, i-propylovú, n-butylovú, i-butylovú, t-butylovú, pentylovú, hexylovú skupinu a podobne, ktorá môže byť prípadne substituovaná jedným alebo viacerými halogénmi.Groups E and F are optionally halogenated unbranched, branched or cyclic alkyl groups having 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl and the like, which may be optionally substituted with one or more halogens.

Ďalej môžu skupiny E a F znamenať skupinu o oFurther, groups E and F may be a group o o

A. alebo Ao-« pričom V znamená 9-fluorenylmetylovú skupinu alebo prípadne benzylovú skupinu, ktorá je substituovaná jedným alebo viacerými halogénmi, skupinou N02, alkoxyskupinou alebo skupinou -CN alebo ich kombináciou, napríklad brómbenzylovú, dibrómbenzylovú, chlórbenzylovú, dichlórbenzylovú, nitrobenzylovú, metoxybenzylovú, cyanobenzylovú skupinu a podobne.A and A o - 'wherein W is 9-fluorenylmethyl radical or a benzyl group optionally substituted by one or more halogen, N0 2, alkoxy or -CN or combinations thereof, e.g., bromobenzyl, dibrómbenzylovú, chlorobenzyl, dichlorobenzyl, nitrobenzyl , methoxybenzyl, cyanobenzyl, and the like.

Ďalej môžu substituenty A, prípadne F tvoriť po odbúraní atómu vodíka jeden z uvedených kruhových systémov.Further, the A and F substituents may form one of the above ring systems after the hydrogen atom has been removed.

Výhodne znamenajú skupiny E a FThey are preferably E and F

aleboor

skupinu, pričom V znamená 9-fluorénmetylovú skupinu, prípadne substituovanú benzylovú skupinu alebo nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka.wherein V represents a 9-fluorenomethyl group, an optionally substituted benzyl group or a straight or branched chain alkyl group having 1 to 4 carbon atoms.

Ak sú skupiny A a B odlišné, môžu byť substituenty na funkčnej amínoskupine dikarboxylovej kyseliny buď rovnaké alebo rôzne. Ak sú skupiny A a B rovnaké, potom musia byť substituenty na funkčnej amínoskupine dikarboxylovej kyseliny odlišné.If the groups A and B are different, the substituents on the functional amino group of the dicarboxylic acid can be either the same or different. If the groups A and B are the same, then the substituents on the functional amino group of the dicarboxylic acid must be different.

Centrá asymetrie dikarboxylových kyselín sú dané voľbou použitých eduktov. Môžu mať obidve buď konfiguráciu D alebo obidve L alebo D,L, prípadne L,D, napríklad nI-E-nH-F-2,7-D,L-2,7-mono-A-ester-mono-B-ester kyseliny diamínokorkovej, keď sa vychádza z A-esteru kyseliny N-E-D-glutamínovej a B-esteru N-F-L-glutamínovej.The centers of dicarboxylic acid asymmetry are determined by the choice of the starting materials used. They may have either the D configuration or both L or D, L or L, D, for example nI-E-nH-F-2,7-D, L-2,7-mono-A-ester-mono-B- a diamine cork ester when starting from NED-glutamic acid A-ester and NFL-glutamic acid B-ester.

Asymetricky substituované deriváty diamínodikarboxylových kyselín podľa vynálezu sa pripravujú kombinovanou Kolbeho syntézou.The asymmetrically substituted diamine dicarboxylic acid derivatives of the invention are prepared by a combined Kolbe synthesis.

Pritom sa príslušné chránené deriváty aminokyselín podrobia elektrolýze na platinových elektródach.The respective protected amino acid derivatives are electrolyzed on platinum electrodes.

Východiskové zlúčeniny sú známe z literatúry alebo sa dajú odborne pripraviť bežnými metódami.The starting compounds are known from the literature or can be prepared by conventional methods.

Deriváty aminokyselín sa pritom rozpustia v rozpúšťadle, ktoré je za podmienok reakcie inertné. Ako rozpúšťadlá prichádzajú do úvahy napríklad nižšie alifatické alkoholy, napríklad metanol, etanol, propanol alebo i-propanol, alebo heterocyklické rozpúšťadlo, ako napríklad pyridín alebo dimetylformamid, acetontril, nitrometán alebo kombinácie takýchto rozpúšťadiel.The amino acid derivatives are dissolved in a solvent which is inert under the reaction conditions. Suitable solvents are, for example, lower aliphatic alcohols, for example methanol, ethanol, propanol or i-propanol, or a heterocyclic solvent such as pyridine or dimethylformamide, acetontril, nitromethane or combinations of such solvents.

V elektrolyzačnej komore sa do rozpúšťadla pridá zásada, napríklad alkalický kov v alkoholovom roztoku, napríklad metoxid sodný v metanole, alebo metoxid draselný v etanole.In the electrolysis chamber, a base such as an alkali metal in an alcohol solution such as sodium methoxide in methanol or potassium methoxide in ethanol is added to the solvent.

Následne prebehne počas chladenia elektrolýza na platinových elektródach, pričom sa teplota prednostne udržiava na hodnote 18 až 25 °C. Intenzita prúdu počas elektrolýzy je približne 5 až 15 A pri napätí 60 až 120 V a v ostatnom závisí od geometrie použitej elektródy.Subsequently, electrolysis is carried out on the platinum electrodes during cooling, the temperature being preferably maintained at 18-25 ° C. The current intensity during electrolysis is approximately 5 to 15 A at a voltage of 60 to 120 V and, in other cases, depends on the geometry of the electrode used.

Priebeh elektrolýzy sa ukončí, len čo sa z elektrolyzovaného roztoku stratí edukt.The electrolysis process is terminated as soon as the starting material is lost from the electrolysed solution.

Elektrolyzovaný roztok sa potom prípadne zahustí pri zníženom tlaku, zvyšok sa rozpustí vo vhodnom rozpúšťadle, napríklad v etylacetáte, a tento roztok sa postupne premyje zriedenou kyselinou, napríklad zriedenou kyselinou soľnou, nasýteným roztokom soli, napríklad nasýteným roztokom hydrouhličitanu sodného, a nasýteným roztokom chloridu sodného.The electrolysed solution is then optionally concentrated under reduced pressure, the residue is dissolved in a suitable solvent, for example ethyl acetate, and this solution is successively washed with dilute acid, for example dilute hydrochloric acid, a saturated salt solution, for example a saturated sodium bicarbonate solution, and a saturated sodium chloride solution. .

Roztok sa potom vysuší vhodným vysušovacím prostriedkom, napríklad síranom sodným alebo síranom horečnatým, prefiltruje a znovu sa prípadne zahustí pri zníženom tlaku.The solution is then dried with a suitable drying agent, for example sodium sulphate or magnesium sulphate, filtered and again optionally concentrated under reduced pressure.

Zvyšok sa prečistí chromatograficky, napríklad cez silikagél, pričom sa môžu symetricky substituované vedľajšie produkty oddeliť. Reakcia prebieha s dobrým 10 až 15 % výťažkom oproti vypočítanej hodnote požadovaného symetricky substituovaného konečného produktu.The residue is purified by chromatography, for example through silica gel, whereby symmetrically substituted by-products can be separated. The reaction proceeds with a good 10 to 15% yield over the calculated value of the desired symmetrically substituted end product.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklad 1:Example 1:

29,41 g (96 mmólu) alfa-t-butylesteru kyseliny N-t-bu tyloxykarbonylglutamínovej a 35,63 g (96 mmólu) alfa- benzylesteru kyseliny N-benzyloxykarbonylglutamínovej sa rozpustí v 240 ml MeOH a 80 ml pyridínu, pričom sa bankou krúži. Reakčný roztok sa prenesie do elektrolyzačnej komory s valcovitými platinovými elektródami. Opláchne sa MeOH a elektrolyzačná komora sa tak naplní s MeOH, aby boli obidve elektródy úplne ponorené.29.41 g (96 mmol) of N-t-butyloxycarbonylglutamic acid alpha-t-butyl ester and 35.63 g (96 mmol) of N-benzyloxycarbonylglutamic acid alpha-benzyl ester are dissolved in 240 ml of MeOH and 80 ml of pyridine while swirling. The reaction solution is transferred to an electrolysis chamber with cylindrical platinum electrodes. The MeOH is rinsed and the electrolysis chamber is filled with MeOH to completely immerse both electrodes.

Pridá sa 0,8 ml NaOCH^ (30% v MeOH) a elektrolyzačná komora sa začne výdatne chladiť. Keď je reakčný roztok ochladený na 15θ0, zapne sa prístroj na sieť. Reakčná teplota sa udržuje na hodnote medzi +18 “C a +24 “C reguláciou teploty, prípadne regulovaním intenzity prúdu (5 až 15 A, 60 až 120 V).0.8 ml of NaOCH 2 (30% in MeOH) was added and the electrolysis chamber began to be vigorously cooled. When the reaction solution is cooled to 15θ0, the instrument is switched on. The reaction temperature is maintained between +18 ° C and +24 ° C by controlling the temperature or by adjusting the current intensity (5 to 15 A, 60 to 120 V).

Priebeh reakcie sa kontroluje jednosmerným prúdom.The progress of the reaction is controlled by direct current.

Po ukončení reakcie sa reakčný roztok stiahne pri 40 C.After completion of the reaction, the reaction solution was withdrawn at 40 ° C.

Zvyšok z Kolbeho syntézy sa rozpustí v 500 ml etylacetátu, najprv v zriedenom roztoku HC1 (25 ml kone. HC1, doplnené vodou do objemu 250 ml, potom sa premyje s celkovým množstvom 250 ml NaHCO^ a napokon viacnásobne s celkovým množstvom 250 ml NaCl až do neutrálnej hodnoty vodnej fázy.The residue from Kolbe synthesis is dissolved in 500 ml of ethyl acetate, first in dilute HCl solution (25 ml of conc. HCl, made up to 250 ml with water), then washed with a total of 250 ml of NaHCO 3 and finally several times with a total of 250 ml of NaCl to to the neutral value of the aqueous phase.

Organická fáza sa vysuší pomocou Na2S04> odfiltruje a odparí. Odparok: 58,17 g.The organic phase is dried over Na2SO4, filtered off and evaporated. Evaporation: 58.17 g.

Odparok sa prefiltruje cez silikagél a potom sa rozdelí metódou HPLC.The residue is filtered through silica gel and then separated by HPLC.

Výťažok: 4,5 g monobenzylesteru-mono-t-butylesteru kyseliny N1-benzoyloxykarbonyl-N11-t-butyloxykarbonyl-2,7-diamínokorkovej:Yield: 4.5 g of N 1 -benzoyloxycarbonyl-N 11 -t-butyloxycarbonyl-2,7-diamino-cork monobenzyl ester-mono-t-butyl ester:

10% z vypočítanej hodnoty10% of the calculated value

Teplota topenia 51 až 56 ’C, [alfa]D= -21,5Mp 51 DEG-56 DEG C., [.alpha.] D = -21.5

Analogickým spôsobom sa pripravujú nasledovné zlúčeniny:The following compounds are prepared in an analogous manner:

-i--------1--------------------1------------------1------------------n-i -------- 1 1 -------------------- ------------------ 1 n ------------------

Č. No. A A B B E E F F n n 2 2 0-benzyl 0-benzyl 0-metyl 0-methyl t-butyloxykarbonyl t-butyloxycarbonyl t-butyloxykarbonyl t-butyloxycarbonyl 4 4 3 3 0-benzyl 0-benzyl 0-benzyl 0-benzyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 4 4 4 4 0-benzyl 0-benzyl 0-2-tosyletyl 0-2-tosylethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 4 4 5 5 0-benzyl 0-benzyl Ο-2-tosyletyl Ο-2-tosylethyl t-butyloxykarbonyl t-butyloxycarbonyl t-butyloxykarbonyl t-butyloxycarbonyl 4 4 6 6 0-benzyl 0-benzyl Ο-2-tosyletyl Ο-2-tosylethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3 7 7 0-benzyl 0-benzyl 0-2-tosyletyl 0-2-tosylethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 2 2 8 8 0-benzyl 0-benzyl 0-metyl 0-methyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3 9 9 0-benzyl 0-benzyl 0-fenacyl 0-phenacyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3 10 10 0-benzyl 0-benzyl O-trimetylsilyletyl O-trimethylsilylethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3 11 11 0-benzyl 0-benzyl 0-benzyl 0-benzyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3 12 12 0-benzyl 0-benzyl 0-2,2,2-trichlóretyl 0-2,2,2-trichloroethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 2 2 13 13 0-benzyl 0-benzyl 0-benzyl 0-benzyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 2 2 14 14 0-benzyl 0-benzyl 0-2-tosyletyl 0-2-tosylethyl t-butyloxykarbonyl t-butyloxycarbonyl benzyloxykarbonyl benzyloxycarbonyl 3 3

V príkladoch 5 a 14 boli použité príslušné D- a L- deriváty aminokyselín.In Examples 5 and 14, the respective D- and L- derivatives of amino acids were used.

Chemické údaje vyššie uvedených zlúčenín, pričom použité skratky majú nasledovný význam:Chemical data of the above compounds, where the abbreviations used are as follows:

Skratka In short Význam meaning OBn OBn 0-benzyl 0-benzyl OMe OMe O-metyl O-methyl OEtTos OEtTos O-etyltosyl O-ethyl tosylate OtBu OtBu O-terc-butyl O-tert-butyl Boe Boe t-butyloxykarbony1 t-butyloxykarbony1 Z FROM benzyloxykarbony1 benzyloxykarbony1 SUB SUB n = 4 n = 4 PI M PI M n = 3 n = 3 ADI ADI n = 2 n = 2

Príklad 1: Boc-Z-SUB-OtBu-OBn 13C(CDC13, 100 MHz): 24.80(CH2), 24.82(CH2), 28.02 (O-t-Bu-CH3), 28.34(Boc-CH3), 32.52(CH2), 32.72(CH2),Example 1: Boc-Z-SUB-OtBu-OBn 13 C (CDCl 3 , 100 MHz): 24.80 (CH 2 ), 24.82 (CH 2 ), 28.02 (Ot-Bu-CH 3 ), 28.34 (Boc-CH 3) ), 32.52 (CH 2 ), 32.72 (CH 2 ),

53.82(CH), 67.00 a 67.12(benzyl-CH2), 79.62((CH3)3C z Boe), 81.57((CH3)3C z OtBu), 128.09-128.63(aromáty-C), 135.36,53.82 (CH), 67.00 and 67.12 (CH2 benzyl), 79.62 ((CH 3) 3 C from Boc), 81.57 ((CH 3) 3 C z O t Bu), 128.09-128.63 (aromatic C), 135.36,

136.30, 155.34 a 155.87(karbamát-CO), 171.86 a 172.22(CO). Teplota topenia 51-56¾ [alfa]p= -21,5136.30, 155.34 and 155.87 (carbamate-CO), 171.86 and 172.22 (CO). Melting point 51-56¾ [alpha] p = -21.5

Príklad 2: Di-Boc-SUB-OBn-OMe 13C(CDC13, 100 MHz): 24.82(2CH2), 28.32(2(CH3)3C),Example 2: Di-Boc-SUB-OBn-OMe 13 C (CDCl 3 , 100 MHz): 24.82 (2CH 2 ), 28.32 (2 (CH 3 ) 3 C),

32.49(CH2), 32.54(CH2), 52.18(OCH3), 53.38(br s, 2CH),32.49 (CH 2 ), 32.54 (CH 2 ), 52.18 (OCH 3 ), 53.38 (br s, 2CH),

66.99(benzyl-CH2), 138.31, 128.42, 128.59, 135.46 a 155.32(2 karbamát-CO), 172.57 a 173.20(ester-CO).66.99 (CH2-benzyl), 138.31, 128.42, 128.59, 135.46 and 155.32 (2-carbamate CO), 172.57 and 173.20 (ester CO).

Teplota topenia 55-59¾ [alfa]D= -24,9 (1% v DMF)Melting point 55-59¾ [alpha] D = -24.9 (1% in DMF)

Príklad 3: Boc-Z-SUB-Di-OBn 13C(CDC13, 100 MHz): 24.68(CH2), 24.81(CH2), 28.32 (2(CH3)3C), 32.47(2CH2), 53.37(CH), 53.83(CH), 66.99 (benzyl-CH2), 67,13(benzyl-CH2), 79.90((CH3)C),Example 3: Boc-Z-SUB-Di-OBn 13 C (CDCl 3 , 100 MHz): 24.68 (CH 2 ), 24.81 (CH 2 ), 28.32 (2 (CH 3 ) 3 C), 32.47 ( 2 CH 2 ) , 53.37 (CH), 53.83 (CH), 66.99 (CH2 benzyl), 67.13 (CH2 benzyl), 79.90 ((CH3) C),

128.10-128.63(aromáty-C), 135.33, 135.46, 136.28, 155.30 a 155.83(karbamát-CO), 172.17 a 172.56(ester-CO).128.10-128.63 (aromatics-C), 135.33, 135.46, 136.28, 155.30 and 155.83 (carbamate-CO), 172.17 and 172.56 (ester-CO).

Teplota topenia 65-67θϋ [alfa]D= -1,4 (5% v CHC13)Melting point 65-67 ° C [alpha] D = -1,4 (5% in CHCl 3 )

Príklad 4: Boc-Z-SUB-OBn-OEtTos 13C(CDC13, 100 MHz): 21.65(tolyl-CH3), 24.65(CH2), 24.81 (CH2), 28.32((CH3)3C), 32.06(CH2), 32.38(CH2), 53.12(CH),Example 4: Boc-Z-SUB-OBn-OEtTos 13 C (CDCl 3 , 100 MHz): 21.65 (tolyl-CH 3 ), 24.65 (CH 2 ), 24.81 (CH 2 ), 28.32 ((CH 3 ) 3 C) ), 32.06 (CH 2 ), 32.38 (CH 2 ), 53.12 (CH),

53.80(CH), 54.94(OCH2CH2SO2C7H7), 58.27(OCH2CH2SO2C7H7),53.80 (CH), 54.94 (OCH 2 CH 2 SO 2 C 7 H 7 ), 58.27 (OCH 2 CH 2 SO 2 C 7 H 7 ),

67.01(benzyl-CH2), 67.17(benzyl-CH2), 80.05((CH3)3C),67.01 (benzyl-CH 2 ), 67.17 (benzyl-CH 2 ), 80.05 ((CH 3 ) 3 C),

128.12-128.65(aromáty-C), 130.08, 135.32, 136.27, 145.23,128.12-128.65 (aromatics-C), 130.08, 135.32, 136.27, 145.23,

155.26 a 155.90(karbamát-CO), 172.15(ester-CO).155.26 and 155.90 (carbamate-CO), 172.15 (ester-CO).

olej [alfa]D= +4,45 (5% v CHC13)oil, [alpha] D = +4.45 (5% in CHC1 3)

Príklad 5: Di-Boc-D,L-SUB-OBn-OEtTos 13C(CDC13, 100 MHz): 21.63(tolyl-CH3), 24.79(CH2), 24.84 (CH2), 28.31((CH3)3C), 32.13(CH2), 32.52(CH2), 53.23(brs,Example 5: Di-Boc-D, L-SUB-OBn-OEtTos 13 C (CDCl 3 , 100 MHz): 21.63 (tolyl-CH 3 ), 24.79 (CH 2 ), 24.84 (CH 2 ), 28.31 ((CH) 3 ) 3 ( C), 32.13 (CH 2 ), 32.52 (CH 2 ), 53.23 (brs,

2CH) , 54.99(OCH2CH2SO2C7H7), 58.28(OCH2CH2SO2C7H7), 67.01 (benzyl-CH2), 79.98(2(CH3)3C), 128.13-128.61(aromáty-C),2CH), 54.99 (OCH 2 CH 2 SO 2 C 7 H 7 ), 58.28 (OCH 2 CH 2 SO 2 C 7 H 7 ), 67.01 (benzyl-CH 2 ), 79.98 (2 (CH 3 ) 3 C), 128.13-128.61 (aromatic C);

135.45, 136.35, 145.21, 155.30 a 155.83(karbamát-CO),135.45, 136.35, 145.21, 155.30 and 155.83 (carbamate-CO),

172.11(2 ester-CO).172.11 (2-ester-CO).

Príklad 6: Boc-Z-PIM-OBn-OEtTos 13C(CDC13, 100 MHz): 21.10(CH2), 21.60(tolyl-CH3),Example 6: Boc-Z-PIM-OBn-OEtTos 13 C (CDCl 3 , 100 MHz): 21.10 (CH 2 ), 21.60 (tolyl-CH 3 ),

28.31((CH3)3C), 31.62(CH2), 31.90(CH2), 52.85(CH),28.31 ((CH 3) 3 C), 31.62 (CH2), 31.90 (CH2), 52.85 (CH);

53.55(CH), 54.93(OCH2CH2SO2C7H7), 58.32(OCH2CH2SO2C7H7), 67.05 a 67.22(benzyl-CH2), 80.08((CH3)3C), 138.11-128.66 (aromáty-C), 130.05, 135.31, 136.25, 145.21, 155.45 a 155.83(karbamát-CO), 171.97 a 172.08(ester-CO).53.55 (CH), 54.93 (OCH 2 CH 2 SO 2 C 7 H 7 ), 58.32 (OCH 2 CH 2 SO 2 C 7 H 7 ), 67.05 and 67.22 (benzyl-CH 2 ), 80.08 ((CH 3 ) 3 C, 138.11-128.66 (aromatics-C), 130.05, 135.31, 136.25, 145.21, 155.45 and 155.83 (carbamate-CO), 171.97 and 172.08 (ester-CO).

Príklad 7: Boc-Z-ADI-OBn-OEtTos 13c(cdci3,Example 7: Boc-Z-ADI-OBn-OEtTos 13 C (CDCl 3,

28.29(CH2), 58.29(0CH2CH2S02C7H7)28.29 (CH 2 ), 58.29 (0CH 2 CH 2 SO 2 C 7 H 7 )

100 MHz):100 MHz):

52.79(CH),52.79 (CH);

21.60(tolyl-CH3), 28.17((CH3)3C),21.60 (tolyl-CH3), 28.17 ((CH 3) 3 C);

53.61(CH), 54.87(OCH2CH2SO2C7H7),53.61 (CH), 54.87 (OCH 2 CH 2 SO 2 C 7 H 7 ),

67.04 a 67.31(benzyl-CH2),67.04 and 67.31 (CH 2 benzyl);

80.18((CH3)3C), 128.05-128.67(aromáty-C), 130.09, 135.24,80.18 ((CH 3) 3 C), 128.05-128.67 (aromatic C), 130.09, 135.24,

136.20, 136.26, 145.27 a 156.00(2 karbamát-CO), 171.59 a 171.75(ester-CO).136.20, 136.26, 145.27 and 156.00 (2 carbamate-CO), 171.59 and 171.75 (ester-CO).

Príklad 8: Boc-Z-PIM-OBn-OMe 13C(CDC13, 100 MHz): 20.82(CH2), 21.16(CH2), 28.31 ((CH3)3C), 31.97(CH2), 32.17(¾) , 52.53(OMe), 52.93(CH), 53^61(CH), 67.07(benzyl-CH2), 80.01((CH3)3C), 128.17-128.64 (aromáty-C), 135.29, 136.23, 155.55 a 156.06(karbamát-CO), 172.12 a 173.06(ester-CO).Example 8: Boc-Z-PIM-OBn-OMe 13 C (CDCl 3 , 100 MHz): 20.82 (CH 2 ), 21.16 (CH 2 ), 28.31 ((CH 3 ) 3 C), 31.97 (CH 2 ), 32.17 (¾), 52.53 (OMe), 52.93 (CH), 53 ^ 61 (CH), 67.07 (CH2 benzyl), 80.01 ((CH 3) 3 C), 128.17-128.64 (aromatic C), 135.29 , 136.23, 155.55 and 156.06 (carbamate-CO), 172.12 and 173.06 (ester-CO).

Príklad 9: Boc-Z-PIM-OBn-OCH2COC6H5 13C(CDC13, 100 MHz): 20.82(2CH2), 28.33((CH3)3C), 31.86 (CH2), 32.16(CH2), 53.08(CH), 53.69(CH), 66.35(OCH2COC6H5),Example 9: Boc-Z-PIM-OBn-OCH 2 COC 6 H 5 13 C (CDCl 3 , 100 MHz): 20.82 ( 2 CH 2 ), 28.33 ((CH 3 ) 3 C), 31.86 (CH 2 ), 32.16 (CH 2 ), 53.08 (CH), 53.69 (CH), 66.35 (OCH 2 COC 6 H 5 ),

66.97(benzyl-CH2), 67.13(benzyl-CH2), 80.05((CH3)3C),66.97 (CH2 benzyl), 67.13 (CH2 benzyl), 80.05 ((CH 3) 3 C);

127.77-128.89(aromáty-C), 139.99, 135.43, 136.36, 155.51 a 156.17(karbamát-CO), 172.16(2 ester-CO), 191.61 (och2coc6h5).127.77-128.89 (aromatic C), 139.99, 135.43, 136.36, 155.51 and 156.17 (carbamate CO), 172.16 (-CO 2 ester), 191.61 (s 2 COC 6 H 5).

Príklad 10: Boc-Z-PIM-OBn-OCH2CH2Si(CH3)3 13C(CDC13, 100 MHz): -1.54((CH3)3Si), 17.42(OCH2CH2Si (CH3)3), 21.22(CH2), 22.20(CH2), 28.32((CH3)3C),Example 10: Boc-Z-PIM-OBn-OCH 2 CH 2 Si (CH 3 ) 3 13 C (CDCl 3 , 100 MHz): -1.54 ((CH 3 ) 3 Si), 17.42 (OCH 2 CH 2 Si ( CH 3 ) 3 ), 21.22 (CH 2 ), 22.20 (CH 2 ), 28.32 ((CH 3 ) 3 C),

31.91(CH2), 32.34(CH2), 53.01(CH), 53.73(CH),31.91 (CH 2 ), 32.34 (CH 2 ), 53.01 (CH), 53.73 (CH),

63.74(OCH2CH2Si(CH3)3), 67.05(benzyl-CH2), 67.17 (benzyl-CH2), 79.89((CH3)3C), 128.14, 128.26, 128.50,63.74 (OCH 2 CH 2 Si (CH 3 ) 3 ), 67.05 (benzyl-CH 2 ), 67.17 (benzyl-CH 2 ), 79.89 ((CH 3 ) 3 C), 128.14, 128.26, 128.50,

128,64, 135.32, 136.25, 155.58 a 156.06(karbamát-CO),128.64, 135.32, 136.25, 155.58 and 156.06 (carbamate-CO),

172.17 a 172.68(2 ester-CO).172.17 and 172.68 (2 ester-CO).

Príklad 11: Boc-Z-PIM-Di-OBn 13C(CDC13, 100 MHz): 21.14(CH2), 28.30((CH3)3C), 31.92 (CH2), 32.16(CH2), 53.07(CH), 53.64(CH), 67.06(2 benzyl-CH2), 67.18(benzyl-CH2), 79.98((CH3)3C), 128.16, 128.29, 128.44, 128,50, 128,61, 128,63, 135,30, 135,40, 136,24, 155.53 a 156.04(karbamát-CO), 172.09 a 172.41(2 ester-CO).Example 11: Boc-Z-PIM-Di-OBn 13 C (CDCl 3 , 100 MHz): 21.14 (CH 2 ), 28.30 ((CH 3 ) 3 C), 31.92 (CH 2 ), 32.16 (CH 2 ), 53.07 (CH), 53.64 (CH), 67.06 (2-benzyl-CH 2 ), 67.18 (benzyl-CH 2 ), 79.98 ((CH 3 ) 3 C), 128.16, 128.29, 128.44, 128.50, 128.61 , 128.63, 133.30, 133.40, 136.24, 155.53 and 156.04 (carbamate-CO), 172.09 and 172.41 (2 ester-CO).

Príklad 12: Boe-Z-ADI-OBn-OCH2CC13 13C(CDC13, 100 MHz): 28.60((CH3)3C), 29.25(CH2), 30.00 (CH2), 53.34(CH), 53.78(CH), 74.67(OCH2CC13), 67.47 (benzyl-CH2), 67.72(benzyl-CH2),Example 12: Boe-Z-ADI-OBn-OCH 2 CCl 3 13 C (CDCl 3 , 100 MHz): 28.60 ((CH 3 ) 3 C), 29.25 (CH 2 ), 30.00 (CH 2 ), 53.34 (CH ), 53.78 (CH), 74.67 (OCH 2 CCl 3 ), 67.47 (benzyl-CH 2 ), 67.72 (benzyl-CH 2 ),

80.69((CH3)3C), 94.79(OCH2CC13), 128.42,80.69 ((CH 3) 3 C), 94.79 (OCH 2 CC1 3), 128.42,

128.87, 128.96, 129.02, 135.43,128.87, 128.96, 129.02, 135.43,

74.67(OCH2CC13),74.67 (OCH 2 CC1 3 )

128.54, 128.74,128.54

143.46, 155.53 a 156.17(karbamát-CO), 171.09 a 171.96(2CO).143.46, 155.53 and 156.17 (carbamate-CO), 171.09 and 171.96 (2CO).

Príklad 13: Boc-Z-ADI-Di-OBn 13C(CDC13, 100 MHz): 21.22(CH2), 22.20(CH2), 28.32 ((CH3)3C), 31.91(CH2), 32.34(CH2), 53.01(CH), 53.73(CH), 63.74(OCH2CH2Si(CH3)3), 67.05(benzyl-CH2), 67.17 (benzyl-CH2), 79.89((CH3)3C), 128.14, 128.26, 128.50, 128,64, 135.32, 136.25, 155.58 a 156.06(karbamát-CO), 172.17 a 172.78(ester-CO).Example 13: Boc-Z-ADI-Di-OBn 13 C (CDCl 3 , 100 MHz): 21.22 (CH 2 ), 22.20 (CH 2 ), 28.32 ((CH 3 ) 3 C), 31.91 (CH 2 ), 32.34 (CH 2 ), 53.01 (CH), 53.73 (CH), 63.74 (OCH 2 CH 2 Si (CH 3 ) 3 ), 67.05 (benzyl-CH 2 ), 67.17 (benzyl-CH 2 ), 79.89 ((CH) 3 ) 3 C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06 (carbamate-CO), 172.17 and 172.78 (ester-CO).

Príklad 14: Boc-Z-D,L-PIM-OBn-ORtTos 13C(CDC13, 100 MHz): 20.98(CH2), 21.58(tolyl-CH3),Example 14: Boc-ZD, L-PIM-OBn-ORtTos 13 C (CDCl 3 , 100 MHz): 20.98 (CH 2 ), 21.58 (tolyl-CH 3 ),

28.29((CH3)3C), 31.77(CH2), 31.93(CH2), 52.98(CH),28.29 ((CH 3) 3 C), 31.77 (CH2), 31.93 (CH2), 52.98 (CH);

53.73(CH), 54.94(OCH2CH2SO2C7H7), 58.25(OCH2CH2SO2C7H7), 67.00 a 67.15(benzyl-CH2), 80.10((CH3)3C), 128.09-128.64 (aromáty-C), 135.05, 135.01, 136.32, 145.19, 155.28 a 156.02(karbamát-CO), 171.87 a 171.94(ester-CO).53.73 (CH), 54.94 (OCH 2 CH 2 SO 2 C 7 H 7 ), 58.25 (OCH 2 CH 2 SO 2 C 7 H 7 ), 67.00 and 67.15 (benzyl-CH 2 ), 80.10 ((CH 3 ) 3 C), 128.09-128.64 (aromatics-C), 135.05, 135.01, 136.32, 145.19, 155.28 and 156.02 (carbamate-CO), 171.87 and 171.94 (ester-CO).

Claims (4)

1. Asymetricky substituované deriváty diamino- dikarboxylových kyselín, vzorca I 0n1. Asymmetrically substituted diamino dicarboxylic acid derivatives of the formula I 0 n IIII A - C - CH - (CH2)n - CH - C - BA - C - CH - (CH 2 ) n - CH - C - B I II I E-NH F-NH kdeE-NH F-NH where A a B znamená nezávisle na sebe skupinu -OR, pričom R môže prípadne znamenať alifatickú nerozvetvenú alebo rozvetvenú alebo cyklickú alkylovú skupinu, ktorá obsahuje 1-10 atómov uhlíka, ktorá je substituovaná jedným alebo viacerými atómami halogénu, fenylovú skupinu alebo skupinu -CH2-X, pričom X môže znamenať 9-fluorenylovú, fenylovú skupinu, skupinu -0CH3-, -CH2SO2CH3, -CH2SO2C6Hs, -CC13, -CH2Y, kde Y môže znamenať halogén, -p-tosylovú, prípadne fenylovú alebo fenylalkylovú skupinu, ktorá je substituovaná jedným alebo viacerými atómami halogénu, jednou alebo viacerými skupinami -N02 alebo jednou alebo viacerými alkoxyskupinami, difenylmetylovú, trifenylmetylovú, 2-pyridylovú skupinu alebo skupinu SiR3R2R3, pričom skupiny R^R2R3 vždy nezávisle na sebe môžu znamenať nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka alebo fenylovú skupinu,A and B are each independently -OR, wherein R may optionally be an aliphatic unbranched or branched or cyclic alkyl group containing 1-10 carbon atoms substituted with one or more halogen atoms, a phenyl group or a -CH 2 -X group wherein X may be 9-fluorenyl, phenyl, -OCH 3 -, -CH 2 SO 2 CH 3 , -CH 2 SO 2 C 6 H s , -CCl 3 , -CH 2 Y, where Y may be halogen , -p-tosyl, optionally phenyl or phenylalkyl, which is substituted by one or more halogen atoms, one or more -NO 2 or one or more alkoxy, diphenylmethyl, triphenylmethyl, 2-pyridyl or SiR 3 R 2 R 3 wherein the groups R 1, R 2, R 3 may in each case independently represent a straight or branched alkyl group containing 1 to 4 carbon atoms or a phenyl group, E,F prípadne znamená nerozvetvenú, rozvetvenú alebo cyklickú skupinu, ktorá obsahuje 1 až 10 atómov uhlíka, ktorá je substituovaná halogénom, alebo skupinu alebo pričom V môže znamenať 9-fluorenylmetylovú skupinu alebo prípadne benzylovú skupinu, substituovanú jedným alebo viacerými halogénmi, jednou alebo viacerými skupinami -N02, jednou alebo viacerými alkoxyskupinami, jednou alebo viacerými skupinami -CN, alebo ich kombináciu, alebo substituenty E, prípadne F tvoria po odbúraní atómu uhlíka spolu s dusíkom jeden z nasledovných kruhových systémov pričom, ak sú skupiny A a B odlišné, E a F môžu byť odlišné alebo rovnaké, na druhej strane, ak sú skupiny A a B rovnaké, E a F musia byť odlišné, a n je celé číslo od 2 do 10, pričom stredy asymetrie molekúl sú dané použitými eduktami a obidva musia mať konfiguráciu L alebo D alebo D,L, prípadne L,D.E, F optionally represents a straight, branched or cyclic group containing 1 to 10 carbon atoms which is substituted by halogen or a group or wherein V may be 9-fluorenylmethyl or optionally benzyl substituted by one or more halogens, one or more -NO 2 groups, one or more alkoxy groups, one or more -CN groups, or a combination thereof, or the E or F substituents, after removal of the carbon atom together with the nitrogen, form one of the following ring systems wherein, if A and B are different, E and F may be different or the same, on the other hand, if the groups A and B are the same, E and F must be different and an is an integer from 2 to 10, the centers of asymmetry of the molecules being given by the starting materials used and both L or D or D, L and L, D, respectively. 2. Asymetricky substituované deriváty diamínodikarboxylových kyselín vzorca I podľa nároku 1, kde A a B znamená skupinu -OR, pričom R znamená 9-fluorenylmetylovú skupinu, substituovanú alebo nesubstituovanú fenylovú, benzylovú alebo fenacylovú skupinu, 2-(2-pyridyl)-etylovú,The asymmetrically substituted diamine dicarboxylic acid derivatives of formula I according to claim 1, wherein A and B are -OR, wherein R is 9-fluorenylmethyl, substituted or unsubstituted phenyl, benzyl or phenacyl, 2- (2-pyridyl) -ethyl, 2-p-tosyletylovú skupinu, alebo prípadne halogenizovanú nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka, E a F znamená skupinu oA 2-p-tosylethyl group, or an optionally halogenated unbranched or branched alkyl group containing from 1 to 4 carbon atoms, E and F being o alebo oor o pričom V znamená 9-fluorenylmetylovú skupinu, prípadne substituovanú benzylovú skupinu alebo nerozvetvenú alebo rozvetvenú alkylovú skupinu, ktorá obsahuje 1 až 4 atómy uhlíka wherein V represents a 9-fluorenylmethyl group, an optionally substituted benzyl group or a straight or branched chain alkyl group containing 1 to 4 carbon atoms 3. Spôsob prípravy asymetricky substituovaných derivátov diamínodikarboxylových kyselín kombinovanou Kolbeho syntézou, vyznačujúci sa tým, že chránený derivát aminokyseliny, vzorca a n je celé číslo od 2 do 10.A process for the preparation of asymmetrically substituted diamine-dicarboxylic acid derivatives by combined Kolbe synthesis, characterized in that the protected amino acid derivative of formula a n is an integer from 2 to 10. IIII Ä - C - CH - (CH2)k - COOH IÄ - C - CH - (CH 2 ) k - COOH I E-NH (II)E-NH - B (III) v ktorom A a E má vyššie uvedený význam a k je celé číslo, sa podrobí elektrolýze na platinových elektródach spolu s derivátom aminokyseliny, vzorca- B (III) wherein A and E are as defined above and k is an integer, are subjected to electrolysis on platinum electrodes together with an amino acid derivative of the formula IIII HOOC - (CH2)i - CH - CHOOC - (CH 2 ) i - CH - C F-NH v ktorom B a F majú vyššie uvedený význam a 1 je celé číslo, pričom kal spolu dávajú číslo n.F-NH wherein B and F are as defined above and 1 is an integer, the sludge together giving the number n. 4. Spôsob podľa nároku 3,vyznačuj úci sa tým, že teplota pri elektrolýze sa chladením udržiava na hodnote 18 až 25 ’C.Method according to claim 3, characterized in that the electrolysis temperature is maintained at a temperature of 18 to 25 ° C by cooling.
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