HRP940472A2 - Asymmetrically substituted diaminodicarboxylic acid derivatives and process for their preparation - Google Patents

Asymmetrically substituted diaminodicarboxylic acid derivatives and process for their preparation Download PDF

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HRP940472A2
HRP940472A2 HRA1683/93A HRP940472A HRP940472A2 HR P940472 A2 HRP940472 A2 HR P940472A2 HR P940472 A HRP940472 A HR P940472A HR P940472 A2 HRP940472 A2 HR P940472A2
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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
    • C—CHEMISTRY; METALLURGY
    • 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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Description

Izum se odnosi na nove asimetrično supstituirane derivate diaminokarbonske kiseline i postupak njihovog dobivanja. The invention relates to new asymmetrically substituted derivatives of diaminocarboxylic acid and the process for their preparation.

Asimetrično supstituirani derivati diaminodikarbonske kiseline su vrijedni međuproizvodi za sintezu peptida. Asymmetrically substituted diaminodicarboxylic acid derivatives are valuable intermediates for peptide synthesis.

U J. Org. Chem. 1980., 45, 3078-3080 opisani su asimetrično supstituirani derivati diaminosuberinske kiseline, koji se dobivaju miješanom KJolbe-sintezom. No, tamo nije uspjelo odvajanje simetričnih nusproizvoda. Nadalje je iz Tetrahedron Lett. 30, 1982, 33, 4724-4730 poznato dobivanje asimetrično supstituiranih derivata diaminopimelinske kiseline kompliciranom 9-stepenom enantioselektivnom sintezom. In J. Org. Chem. 1980, 45, 3078-3080 described asymmetrically substituted derivatives of diaminosuberic acid, which are obtained by mixed KJolbe synthesis. However, the separation of symmetrical by-products failed there. It is further from Tetrahedron Lett. 30, 1982, 33, 4724-4730 known to obtain asymmetrically substituted derivatives of diaminopimelic acid by a complicated 9-step enantioselective synthesis.

Na neočekivan način pronađeni su asimetrično supstituirani derivati diaminokarbonske kiseline, koji predstavljaju vrijedne međuproizvode za sintezu peptida i spojeve koji sadrže neprirodne aminokiseline. In an unexpected way, asymmetrically substituted derivatives of diaminocarbonic acid were found, which represent valuable intermediates for the synthesis of peptides and compounds containing unnatural amino acids.

Predmet izuma su stoga asimetrično supstituirani derivati diaminokarbonske kiseline The subject of the invention is therefore asymmetrically substituted diaminocarboxylic acid derivatives

[image] [image]

u kojoj A i B neovisno jedan od drugog znače ostatak -OR, pri čemu R znači eventualno jedno- ili višestruko halogenirani ravnolančani, razgranati ili ciklički alkilni ostatak sa 1-10 C-atoma, fenil ili ostatak -CH2-X, X znači ostatke 9-fluorofenil-, fenil-, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, sa Y halogen, -p-tosil, eventualno jedno- ili višestruko halogen, -NO2 ili alkoksilom supstuirani ostatak fenila ili fenacila, difenilmetil, trifenilmetil, 2-piridil ili ostatak SiR1 R2 R3, pri čemu ostaci R1 R2 R3 neovisno jedan od drugoga znače ravnolančani ili razgranati alkilni ostatak sa 1-4 C-atoma ili fenil, in which A and B independently of each other mean the residue -OR, where R means an optionally mono- or multiply halogenated straight-chain, branched or cyclic alkyl residue with 1-10 C-atoms, phenyl or the residue -CH2-X, X means residues 9-fluorophenyl-, phenyl-, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, with Y halogen, -p-tosyl, optionally mono- or multiple halogen, -NO2 or phenyl or phenacyl substituted by alkyl , diphenylmethyl, triphenylmethyl, 2-pyridyl or the residue SiR1 R2 R3, whereby the residues R1 R2 R3 independently of each other mean a straight-chain or branched alkyl residue with 1-4 C-atoms or phenyl,

E,F znače eventualno halogenirani ravnolančani, razgranati ili ciklički alkilni ostatak sa 1-10 C-atoma ili ostatak E, F mean a possibly halogenated straight-chain, branched or cyclic alkyl residue with 1-10 C-atoms or a residue

[image] [image]

pri čemu W 9-fluoremlmetil može značiti eventualno jedno- ili višestruko ili miješano halogenom, -NO2, alkoksilom ili -CN supstituirani benzilni ostatak ili supstituenti E odn. F, kod otpadanja atoma vodika, zajedno sa atomom dušika čine jedan od sljedećih prstenastih sistema where W 9-fluoroemlmethyl may mean possibly a single or multiple or mixed halogen, -NO2, alkyl or -CN substituted benzyl residue or substituents E or F, when the hydrogen atom is removed, together with the nitrogen atom they form one of the following ring systems

[image] [image]

pri čemu, ako su ostaci A i B različiti, E i F mogu biti različiti ili jednaki, a ako su ostaci A i B jednaki, E i F moraju biti različiti, a n znači cijeli broj od 2 do 10, pri čemu se središta kiraliteta u molekulama određuju korištenim eduktima, a oba L ili oba D ili D,L odn. L,D mogu biti konfigurirani. where, if the residues A and B are different, E and F can be different or the same, and if the residues A and B are the same, E and F must be different, and n means an integer from 2 to 10, where the centers of chirality in molecules are determined by the educts used, and both L or both D or D,L resp. L,D can be configured.

Daljnji predmet izume je postupak za dobivanje takvih asimetrično supstituiranih kerivata diaminokarbonske kiseline, miješanom Kolbe-sintezom, naznačeno time, da se zaštićeni derivat aminokiseline formule A further object of the invention is a process for obtaining such asymmetrically substituted derivatives of diaminocarboxylic acid, by mixed Kolbe synthesis, characterized by the fact that the protected amino acid derivative of the formula

[image] [image]

u kojoj A i E imaju gornje značenje, a k znači cijeli broj, sa derivatom aminokiseline formule in which A and E have the above meaning and k means an integer, with the amino acid derivative of the formula

[image] [image]

u kjoj B i F imaju gornje značenja, A 1 znači cijeli broj, pri čemu d i 1 zajedno daju broj n, podvrgne elektrolizi na platinskim mrežnim elektrodama. in which B and F have the above meanings, A 1 means an integer, where d and 1 together give the number n, subjected to electrolysis on platinum network electrodes.

U formulama I, II i III A i B znače ostatak -OR, pri čemu R znači eventualno jedno, ili višestruko halogeniram ravnolančani ili razgranati ili ciklički alkilni ostatak sa 1-10 C-atoma, primjerice eventualno halogenirani metilni, etilni, i-propilni, n-butilni, i-butilni, t-butilni ostatak i sl., cikloheksilni, ciklopentilni ili ciklobutilni ostatak ili fenil. In formulas I, II and III, A and B mean the residue -OR, where R means possibly one or more halogenated straight-chain or branched or cyclic alkyl residue with 1-10 C-atoms, for example optionally halogenated methyl, ethyl, i-propyl , n-butyl, i-butyl, t-butyl residue, etc., cyclohexyl, cyclopentyl or cyclobutyl residue or phenyl.

Nadalje R može značiti ostatak -CH2-X, pri čemu X znači ostatke 9-fluorofenila, fenila, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, sa Y halogen, -p-tosil, eventualno jedno- ili višestruko halogenom –NO2 ili alkoksilom supstituirani fenilni ili fenacilni ostatak, primjerice p-bromfenacil, p-klorfenacil i sl., difenilmetil, trifenilmetil, 2-piridil ili ostatak –SiR1 R2 R3, pri čemu ostaci R1 R2 R3 neovisno jedan od drugoga znače ravnolančani ili razgranati alkilni ostatak sa 1-4 C-atoma ili fenil. Furthermore, R can mean the residue -CH2-X, where X means the residues of 9-fluorophenyl, phenyl, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, with Y halogen, -p-tosyl, possibly one- or a phenyl or phenacyl radical substituted multiple times by halogen -NO2 or alkoxyl, for example p-bromophenacyl, p-chlorophenacyl, etc., diphenylmethyl, triphenylmethyl, 2-pyridyl or the residue -SiR1 R2 R3, where the residues R1 R2 R3 independently of each other mean straight-chain or branched alkyl radical with 1-4 carbon atoms or phenyl.

A i B uglavnom znače ostatak -OR, pri čemu R znači ostatak 9-fluorenilmetila, supstituirani ili nesupstituirani ostatak fenila, benzila, fenacila ili eventualno halogenirani ravnolančani ili razgranati alkilni ostatak sa 1-4 C-atoma. A and B mainly mean the residue -OR, where R means the residue 9-fluorenylmethyl, substituted or unsubstituted phenyl, benzyl, phenacyl or optionally halogenated straight-chain or branched alkyl residue with 1-4 C-atoms.

Ostaci E i F znače eventualno halogenirani ravnolančani, razgranati ili ciklički alkilni ostatak sa 1-10 C-atoma, primjerice ostatak metila, etila, n-propila, i-propila, n-butila, i-butila, t-butila, pentila, heksila i sl, koji eventulano jedno-ili višestruko može biti halogeniran. Residues E and F mean an optionally halogenated straight-chain, branched or cyclic alkyl residue with 1-10 C-atoms, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, etc., which may be halogenated one or more times.

Nadalje E i F mogu značiti ostatak Furthermore, E and F can mean the remainder

[image] [image]

pri čemu W znači ostatak 9-fluorenilmetila ili eventualno jedno- ili višestruko miješani halogenom, NO2, alkoksilom ili -CN supstituirani ostatak benzila, primjerice ostatak brombenzila, dibrombenzila, klorbenzila, diklorbenzila, nitrobenzila, metoskibenzila, cijanobenzila. where W means a 9-fluorenylmethyl residue or optionally a benzyl residue substituted with halogen, NO2, alkoxyl or -CN, for example, a bromobenzyl, dibromobenzyl, chlorobenzyl, dichlorobenzyl, nitrobenzyl, methoxybenzyl, cyanobenzyl residue.

Nadalje mogu supstituenti E odn. F kod otpadanja atoma vodika, činiti jedan od navedenih prstenastih sistema. Furthermore, the substituents E or F when a hydrogen atom falls off, to form one of the mentioned ring systems.

Ostaci E i F uglavnom znače ostatak The residues E and F generally mean the remainder

[image] [image]

pri čemu W znači ostatak 9-fluorenilmetila, eventualno supstituirani ostatak benzila ili ravnolančani ili razgranati ostatak alkila sa 1-4 C-atoma. where W means a 9-fluorenylmethyl residue, an optionally substituted benzyl residue or a straight-chain or branched alkyl residue with 1-4 C atoms.

Ako su ostaci A i B različiti, supstituenti na aminofunkciji dikarbonske kiseline mogu biti isti ili različiti. Ako su ostaci A i B isti, supstituenti na aminofunkciji dikarbonske kiseline moraju biti različiti. If residues A and B are different, the substituents on the amino function of the dicarboxylic acid can be the same or different. If residues A and B are the same, the substituents on the amino function of the dicarboxylic acid must be different.

Središta kiraliteta dikarbonske kiseline određuju se odabirom korištenih edukta. Oni mogu ili oba biti D ili oba L ili D,L, odn. L,D, primjerice mono-A-ester-mono-B-ester-N'-E-N"-F-2,7-D,L-2,7-diaminosubermske kiseline kod korištenja A-estera N-E-D-glutaminske kiseline i B-estera N-F-L-glutaminske kiseline mogu biti konfigurirani. The chirality centers of the dicarboxylic acid are determined by the selection of the educts used. They can either be D or both L or D,L, respectively. L,D, for example mono-A-ester-mono-B-ester-N'-E-N"-F-2,7-D,L-2,7-diaminosubermic acid when using A-ester N-E-D-glutamic acid and B -esters of N-F-L-glutamic acid can be configured.

Asimetrično supstituirani derivati dikarbonske kiseline prema izumu mogu se dobiti miješanom Kolbe-sintezom. Asymmetrically substituted dicarboxylic acid derivatives according to the invention can be obtained by mixed Kolbe synthesis.

Pri tome se odredjeni zastićeni derivati aminokiseline podvrgavaju elektrolizi na platinskim mrežnim elektrodama. In doing so, certain protected amino acid derivatives are subjected to electrolysis on platinum network electrodes.

Polazni spojevi poznati su u literaturi ili se mogu dobiti metodama koje su stručnjaku poznate. The starting compounds are known in the literature or can be obtained by methods known to the person skilled in the art.

Pri tome se derivati aminokiseline raastvore u otapalu pod reakcijskim uvjetima. In doing so, the amino acid derivatives are dissolved in the solvent under the reaction conditions.

Kao otapala u obzir dolaze primjerice niski alifatski alkoholi, primjerice metanol, etanol, propanol ili i-propanol ili heterocikličko otapalo kao primjerice piridin ili dimetilformamid, acetonitril, nitrometan ili mješavine takovih otapala. 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, acetonitrile, nitromethane or mixtures of such solvents.

U elektrolitnoj ćeliji otopini se doda baza, primjerice alkalni metal u alkoholnoj otopini, kao natrijum metoksid u metanolu ili kalijum etoksid u etanolu. In the electrolytic cell, a base is added to the solution, for example an alkali metal in an alcoholic solution, such as sodium methoxide in methanol or potassium ethoxide in ethanol.

Na kraju se na platinskim mrežnim elektrodama uz hlađenje elektrolizira uz održavanje temperature na 18°-25°C. Jačina struje kod elektrolize iznosi oko 5-15 A kod napona od 60-120 V, a inače ovisi o geometriji korištene elektrode. At the end, it is electrolyzed on platinum network electrodes with cooling, maintaining the temperature at 18°-25°C. The current strength during electrolysis is about 5-15 A at a voltage of 60-120 V, and otherwise depends on the geometry of the electrode used.

Postupak elektrolize je završen, čim se u elektroliznoj otopini više ne može naći nikakav edukt. The electrolysis process is completed as soon as no educt can be found in the electrolysis solution.

Elektrolizna otopina se na kraju eventualno zgusne pod niskim pritiskom, ostatak se stavi u prikladno otapalo primjerice etilacetat i ta otopina se ispire prvo sa razrijeđenom kiselinom, primjerice razrijeđenom solnom kiselinom, zasićenom solnom otopinom, primjerice zasićenom otopinom natrijumhidrogenkarbonata i zasićenom otopinom natrijum klorida. At the end, the electrolysis solution is eventually thickened under low pressure, the residue is placed in a suitable solvent, for example ethyl acetate, and this solution is washed first with dilute acid, for example dilute hydrochloric acid, saturated salt solution, for example saturated sodium hydrogencarbonate solution and saturated sodium chloride solution.

Otopina se na kraju suši prikladnim sredstvom za sušenje, primjerice natrijum sulfatom ili magnezijum sulfatom, filtrira i ponovno zguzsnem, eventualno pod niskim pritiskom. Finally, the solution is dried with a suitable drying agent, for example sodium sulfate or magnesium sulfate, filtered and thickened again, possibly under low pressure.

Ostatak se kromatografski pročiščava, primjerice preko silika gela, pri čemu se simetrično substituirani nusproizvodi mogu odvojiti. Nakon reakcije dobiva se 10-15% teorije prema željenom asimetrično supstituiranom krajnjem proizvodu. The residue is chromatographically purified, for example over silica gel, whereby the symmetrically substituted by-products can be separated. After the reaction, 10-15% of theory is obtained according to the desired asymmetrically substituted end product.

Primjer 1 Example 1

29,41 g (96 mmol) a-t-butilestera N-t-butiloksikarbonilglutaminske kiseline i 35,63 g (96 mmol) a-benzilestera N-benziloksikarbonilglutaminske kiseline rastvori se mućkanjem u 240 MeOH i 80 ml piridina. Reakcijska otopina prenese se u elektrolitsku ćeliju sa cilindrično poredanim platinskim mrežnim elektrodama. Ispere se sa MeOH i elektrolitska ćelija napuni se toliko sa MeOH, da su obje elektrode potpuno uronjene. 29.41 g (96 mmol) of a-t-butyl ester of N-t-butyloxycarbonylglutamic acid and 35.63 g (96 mmol) of a-benzyl ester of N-benzyloxycarbonylglutamic acid were dissolved by shaking in 240 MeOH and 80 ml of pyridine. The reaction solution is transferred to an electrolytic cell with cylindrical platinum network electrodes. It is washed with MeOH and the electrolytic cell is filled with MeOH so much that both electrodes are completely immersed.

Sad se doda 0.8 ml NaOCH3 (30% u MeOH) i elektrolitska ćelija se dobro rashladi. Kad je reakcijska mješavina ohlađena na 15°C uključi se mrežni uređaj. Reguliranjem temperature, odn. reguliranjem jačine struje odn. napona struje (5-15 A, 60-120V), temperatura se održava između +18°C i 24°C. Now add 0.8 ml of NaOCH3 (30% in MeOH) and cool the electrolytic cell well. When the reaction mixture has cooled to 15°C, turn on the mains device. By regulating the temperature, or by regulating the current or current voltage (5-15 A, 60-120V), the temperature is maintained between +18°C and 24°C.

Tok reakcije kontrolira se pomoću DC-a. Nakon potpune reakcije reakcijska otopina se rotira kod 40°C. The reaction flow is controlled by DC. After the complete reaction, the reaction solution is rotated at 40°C.

Ostatak Kolbe-sinteze se rastvori u 500 ml etilacetata, ispere prvo sa razrijeđenom HCl-otopinom (25 ml HCl konc. sa H2O napunjeno do 250 ml), potom sa 250 ml NaHCO3 i na kraju sa po 250 ml NaCl do neutralnosti vodene faze. The Kolbe-synthesis residue is dissolved in 500 ml of ethyl acetate, washed first with a diluted HCl solution (25 ml of concentrated HCl with H2O filled to 250 ml), then with 250 ml of NaHCO3 and finally with 250 ml of NaCl until neutrality of the aqueous phase.

Organska faza se suši sa Na2SO4, filtrira i upari. Ostatak nakon uparavanja:58,17 g. The organic phase is dried with Na2SO4, filtered and evaporated. Remainder after pairing: 58.17 g.

Ostatak uparavanja filtrira se preko dijatomejske zemlje i na kraju podijeli pomoću HPLC. The residue of the evaporation is filtered through diatomaceous earth and finally separated by HPLC.

Dobivena količina: 4,5 g čistog mono-t-butilestera monobenzilestera N'-benziloksikarboml-N"-t- butiiloksi karbonil- 2,7-diaminosuberinske kiseline (10% teorije). Amount obtained: 4.5 g of pure mono-t-butyl ester of monobenzyl ester of N'-benzyloxycarboml-N"-t-butyloxycarbonyl-2,7-diaminosuberic acid (10% of theory).

Točka tečenja 51-56 C, (α)D=21,5°. Pour point 51-56 C, (α)D=21.5°.

Na analogan način dobivaju se sljedeći spojevi: The following compounds are obtained in an analogous way:

[image] [image]

Kod primjera 5 i 14 miješano su stavljeni odgovarajući D- i L- derivati aminokiseline. In examples 5 and 14, the corresponding D- and L-derivatives of the amino acid were mixed.

Kemijski podaci gore navedenih spojeva, pri čemu korištene skraćenice imaju sljedeća značenja: Chemical data of the above-mentioned compounds, where the abbreviations used have the following meanings:

Skraćenica Značenje Abbreviation Meaning

OBn O-benzil OBn O-benzyl

OMe O-metil OMe O-methyl

OEtTos O-etiltosil OEtTos O-ethyltosyl

OtBu O-tert-butil OtBu O-tert-butyl

Boc t-butiloksikarbonil Boc t-butyloxycarbonyl

Z benziloksikarbonil Z benzyloxycarbonyl

SUB n=4 SAT n=4

PIM n=3 PIM n=3

ADI n=2 ADI n=2

Primjer 1: Boc-Z-SUB-OtBu-OBn Example 1: Boc-Z-SUB-OtBu-OBn

13C(CDCl3 100MHz) : 24.80(CH2), 24.82(CH2), 28.02(0-t-Bu-CH3), 28,34(Boc-CH3), 32.52(CH2), 32.72(CH2), 53.82(CH), 67.00 i 67.12 (benzil-CH2), 79.62 ((CH3)3C od Boc), 81.57((CH3)3C od OtBu), 128.09 - 128.63 (aromatski-C), 135.36, 136.30, 155.34 i 155.87 (karbamat-CO), 171.86 i 172.22(CO). 13C(CDCl3 100MHz) : 24.80(CH2), 24.82(CH2), 28.02(0-t-Bu-CH3), 28.34(Boc-CH3), 32.52(CH2), 32.72(CH2), 53.82(CH) . ), 171.86 and 172.22(CO).

Točka tečenja 51°-56°C. Pour point 51°-56°C.

(α)D = 21.5 (α) D = 21.5

Primjer 2: Di-Bos-SUB-OBn-OMe Example 2: Di-Bos-SUB-OBn-OMe

13C(CDCl3, 100MHz) : 24.82(2CH2), 28.31 (2(CH3)3C), 32.49(CH2), 32.54(CH2), 52.18(OCH3), 53.38(br s, 2CH), 66.99(benzil-CH2), 128.31, 128,42, 128.59, 135.46', i 155.32 (2 karbamat-CO), 172.57 i 173.20 (ester-CO). 13C(CDCl3, 100MHz) : 24.82(2CH2), 28.31 (2(CH3)3C), 32.49(CH2), 32.54(CH2), 52.18(OCH3), 53.38(br s, 2CH), 66.99(benzyl-CH2) , 128.31, 128.42, 128.59, 135.46', and 155.32 (2 carbamate-CO), 172.57 and 173.20 (ester-CO).

Točka tečenja 55°-590°C Pour point 55°-590°C

(α)D=24.9 (1% u DMF) (α)D=24.9 (1% in DMF)

Primjer 3: Boc-Z-SUB-Di-OBn Example 3: Boc-Z-SUB-Di-OBn

13C(CDCl3, 100MHz) : 24.68(CH2), 24.81(CH2), 28.32(2 (CH3)3C), 32.74(2CH2), 53.37(CH), 53.88(CH), 66.99(benzil-CH2), 67.13(benzil-CH2), 79.90((CH3)3C), 128.10-128.63(aromatski-C), 135.33 135.46, 136.28, 155.30 i 155.83(karbamat-CO), 172.17 i 172.56(ester-CO) 13C(CDCl3, 100MHz) : 24.68(CH2), 24.81(CH2), 28.32(2(CH3)3C), 32.74(2CH2), 53.37(CH), 53.88(CH), 66.99(benzyl-CH2), 67.13( benzyl-CH2), 79.90((CH3)3C), 128.10-128.63(aromatic-C), 135.33 135.46, 136.28, 155.30 and 155.83(carbamate-CO), 172.17 and 172.56(ester-CO)

Točka tečenja 65° - 67°C Pour point 65° - 67°C

(α)D=1.4 (5% u CHCl3) (α)D=1.4 (5% in CHCl3)

Primjer 4: Boc-Z-SUB-OBn-OEtTos Example 4: Boc-Z-SUB-OBn-OEtTos

13C(CDCl3, 100MHz): 21.65(tolil-CH3), 24.65(CH2), 24.81(CH2), 28.32((CH3)3C), 32.06(CH2), 32.38(CH2), 53.12(CH), 53.80(CH), 54.94(OCH2CH2SO2C7H7), 58.27(OCH2CH2SO2C7H7), 67.01 (benzil-CH2), 67.17(benzil-CH2), 80.05((CH3)3C), 128.12-128.65(aromatski-C), 130.08, 135.32, 136.27, 145.23, 155.26 i 155.90 (karbamat-CO), 172.15 (2 ester-CO) 13C(CDCl3, 100MHz): 21.65(tolyl-CH3), 24.65(CH2), 24.81(CH2), 28.32((CH3)3C), 32.06(CH2), 32.38(CH2), 53.12(CH), 53.80(CH ), 54.94(OCH2CH2SO2C7H7), 58.27(OCH2CH2SO2C7H7), 67.01 (benzyl-CH2), 67.17(benzyl-CH2), 80.05((CH3)3C), 128.12-128.65(aromatic-C), 130.08, 135.32, 136.272, 145. , 155.26 and 155.90 (carbamate-CO), 172.15 (2 ester-CO)

Ulje Oil

(α)D=+3.45 (5% u CHCl3) (α)D=+3.45 (5% in CHCl3)

Primjer 5: Di-Boc-D,L-SUB-OBn-OEtTos Example 5: Di-Boc-D,L-SUB-OBn-OEtTos

13C(CDCl3, 100MHz): 21.63(tolil-CH3), 24.79(CH2), 24.84(CH2), 28.31(2(CH3)3C), 32.13(CH2), 32.52(CH2), 53.23(br s, 2CH), 54.99(OCH2CH2SO2C7H7), 58.28(OCH2CH2SO2C7H7), 67.01(benzil-CH2), 79.98(2(CH3)3C), 128.13-128.61(aromatski-C), 135.45, 136.35, 145.21, 155.30 i 155.83 (karbamat-CO), 172.11 (2 ester-CO) 13C(CDCl3, 100MHz): 21.63(tolyl-CH3), 24.79(CH2), 24.84(CH2), 28.31(2(CH3)3C), 32.13(CH2), 32.52(CH2), 53.23(br s, 2CH) . , 172.11 (2 ester-CO)

Primjer 6: Boc-Z-PIM-OBn-OEtTos Example 6: Boc-Z-PIM-OBn-OEtTos

13C(CDCl3, 100MHz): 21.10(CH2), 21.60(tolil-CH3), 28.31((CH3)3C), 31.62(CH2), 31.90(CH2), 52.85(CH), 53.55(CH), 54.93(OCH2CH2SO2C7H7), 58.32(OCH2CH2SO2C7H7), 67.05 i 67.22(benzil-CH2), 80.08 ((CH3), 128.11-128.66 (aromatski-C), 130.05, 135.31, 136.25, 145.21, 155.45 i 155.83 (karbamat-CO), 171.97 i 172.08(ester.CO). 13C(CDCl3, 100MHz): 21.10(CH2), 21.60(tolyl-CH3), 28.31((CH3)3C), 31.62(CH2), 31.90(CH2), 52.85(CH), 53.55(CH), 54.93(OCH2CH2SO2C7H7 ), 58.32(OCH2CH2SO2C7H7), 67.05 and 67.22(benzyl-CH2), 80.08 ((CH3), 128.11-128.66 (aromatic-C), 130.05, 135.31, 136.25, 145.21, 155.45 and 155.83 (carbamate-CO), 17.97 and 17.97 172.08(ester.CO).

Primjer 7: Boc-Z-ADI-OBn-OEtTos Example 7: Boc-Z-ADI-OBn-OEtTos

13C(CDCl3, 100MHz): 21.60(tolil-CH3), 28.17((CH3)3C), 28.29(CH2), 52.79(CH), 53.61(CH), 54.87(OCH2CH2SO2C7H7), 58.2(OCH2CH2SO2C7H7), 67.04 i 67.31(benzil-CH2), 80.18((CH3)3C), 128.05-128.67(aromatski-C), 130.09, 135.24, 136.20, 136.26, 145.27 i 156.00(2 karbamat-CO), 171.59 i 171.75(ester-CO) 13C(CDCl3, 100MHz): 21.60(tolyl-CH3), 28.17((CH3)3C), 28.29(CH2), 52.79(CH), 53.61(CH), 54.87(OCH2CH2SO2C7H7), 58.2(OCH2CH2SO2C7H7), 67.04 and 67.31 (benzyl-CH2), 80.18((CH3)3C), 128.05-128.67(aromatic-C), 130.09, 135.24, 136.20, 136.26, 145.27 and 156.00(2 carbamate-CO), 171.59 and 171.75(ester-CO)

Primjer 8: Boc-Z-PIM-OBn-OMe Example 8: Boc-Z-PIM-OBn-OMe

13C(CDCl3, 100MHz): 20.82(CH2), 21.16(CH2). 28.31((CH3)3C), 31.97(CH2), 32.17(CH2), 52.23(OMe), 52.93(CH), 53.61(CH), 67.07(benzil-CH2), 80.01 ((CH3)3C), 128.17-128.64(aromatski-C). 135.29, 136.23, 155.55 i 156.06(karbamat-CO), 172.12 i 173.06(ester-CO) 13C(CDCl3, 100MHz): 20.82(CH2), 21.16(CH2). 28.31((CH3)3C), 31.97(CH2), 32.17(CH2), 52.23(OMe), 52.93(CH), 53.61(CH), 67.07(benzyl-CH2), 80.01 ((CH3)3C), 128.17- 128.64 (aromatic-C). 135.29, 136.23, 155.55 and 156.06 (carbamate-CO), 172.12 and 173.06 (ester-CO)

Primjer 9: Boc-Z-PIM-OBn-OCH2COC6H5 Example 9: Boc-Z-PIM-OBn-OCH2COC6H5

13C(CDCl3, 100MHz): 20.82(2CH2), 28.33((CH3)3C, 31.86(CH2), 32.16(CH2), 53.08(CH), 53.69(CH), 66.35(OCH2COC6H5), 66.97(benzil-CH2), 67.13(benzil-CH2). 80.05((CH3)3C), 127.77 - 128.89(aromatski-C), 133.99, 135.43, 136.36, 155.51 i 156.17(karbamat-CO), 172.16(2 ester-CO), 191.61(OCH2COC6H5) 13C(CDCl3, 100MHz): 20.82(2CH2), 28.33((CH3)3C, 31.86(CH2), 32.16(CH2), 53.08(CH), 53.69(CH), 66.35(OCH2COC6H5), 66.97(benzyl-CH2) , 67.13(benzyl-CH2). 80.05((CH3)3C), 127.77 - 128.89(aromatic-C), 133.99, 135.43, 136.36, 155.51 and 156.17(carbamate-CO), 172.16(2 ester-CO), 191.61( OCH2COC6H5)

Primjer 10: Boc-Z-PIM-OBn-OCH2CH2Si(CH3)3 Example 10: Boc-Z-PIM-OBn-OCH2CH2Si(CH3)3

13C(d6-DMSO, 100 MHz): -1.54(CH3)3Si), 17.42(OCH2CH2Si(CH3)3), 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(benzil-CH2), 67.17(benzil-CH2), 79.89((CH3)3)C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 i 156.06(karbamat-CO), 172.17 i 172.68(2 ester-CO). 13C(d6-DMSO, 100 MHz): -1.54(CH3)3Si), 17.42(OCH2CH2Si(CH3)3), 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)3)C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carbamate-CO), 172.17 and 172.68(2 ester-CO).

Primjer 11: Boc-Z-PIM-Di-OBn Example 11: Boc-Z-PIM-Di-OBn

13C(CDCl3, 100MHz): 21.14(CH2), 28.20((CH3)3C), 31.92(CH2), 32.16(CH2), 53.07(CH). 53.64(CH), 67.06(2 benzil-CH2), 67.18(benzil-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 i 156.04(karbamat-CO), 172.09 i 172.41(2 ester-CO). 13C(CDCl3, 100MHz): 21.14(CH2), 28.20((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, 136.25, 156.3 and 156.0( carbamate-CO), 172.09 and 172.41(2 ester-CO).

Primjer 12: Boc-Z-ADI-OBn-OCH2CCl3 Example 12: Boc-Z-ADI-OBn-OCH2CCl3

13C(CDCl3, 100MHz): 28.60((CH3)3C), 29.25(CH2), 30.00(CH2), 30.00(CH2), 53.34(CH), 53.78(CH), 74.67(OCH2CCl3, 67.72(benzil-CH2), 74.67(OCH2CCl3), 80.69((CH3)3C), 94.79(OCH2CCl3), 128.42, 128.54, 128.74, 128.87, 128.96, 129.02, 135.43, 136.46, 155.53 i 156.17(karbamat-CO), 171.09 i 171.96(2 CO). 13C(CDCl3, 100MHz): 28.60((CH3)3C), 29.25(CH2), 30.00(CH2), 30.00(CH2), 53.34(CH), 53.78(CH), 74.67(OCH2CCl3, 67.72(benzyl-CH2) . ).

Primjer 13: Boc-Z-ADI-Di-OBn Example 13: Boc-Z-ADI-Di-OBn

13C(CDCl3, 100MHz): 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(benzil-CH2), 79.89((CH3)3C), 128.14, 128.26, 128.50, 128,64, 135.32, 136.25, 155.58 i 156.06(karbamat-CO), 172.17 i 172.68(2 ester-CO). 13C(CDCl3, 100MHz): 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), 79.89((CH3)3C), 128.14, 128.26, 128.50, 128.64, 135.32, 136.25, 155.58 and 156.06(carbamate-CO), 172.17 and 172.68(2 ester-CO ).

Primjer 14: Boc-Z-D,L-PIM-OBn-OEtTos Example 14: Boc-Z-D,L-PIM-OBn-OEtTos

13C(CDCl3, 100MHz): 20.98(CH2), 21.58(tolil-CH3), 28.29((CH3)3C), 31.77(CH2), 31.93(CH2), 52.98(CH), 53.73(CH), 54.94(OCH2CH2SO2C7H7), 58.25(OCH2CH2SO2C7H7), 67.00 i 67.15(benzil-CH2), 80.10((CH3)3C), 128.09 -128.64(aromatski-C), 130.05, 135.31, 136.32, 145.19, 155.28 i 156.02(karbamat-CO), 171.87 i 171.94(ester-CO). 13C(CDCl3, 100MHz): 20.98(CH2), 21.58(tolyl-CH3), 28.29((CH3)3C), 31.77(CH2), 31.93(CH2), 52.98(CH), 53.73(CH), 54.94(OCH2CH2SO2C7H7 ), 58.25(OCH2CH2SO2C7H7), 67.00 and 67.15(benzyl-CH2), 80.10((CH3)3C), 128.09 -128.64(aromatic-C), 130.05, 135.31, 136.32, 145.19, 155.28 and 156.02), (carbamate-CO 171.87 and 171.94 (ester-CO).

Claims (4)

1. Asimetrično supstituirani derivati diaminokarbonske kiseline formule [image] naznačeni time, da A i B neovisno jedan od drugoga znače ostatak -OR, pri čemu R predstavlja eventualno jedno- ili višestruko halogenirano ravnočlani, razgranati ili ciklički alkilni ostatak sa 1 - 10 C-atoma, fenil ili ostatak - CH2-X, pri čemu X znači ostatke 9-fluorfenila, fenila, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, sa Y halogen, -p-tosil, eventualno jedno- ili višestruko halogenom, -NO2 ili alkoksilom supstituirani ostatak fenila ili tenacila, digenilmetil, trifenilmetil, 2-piridil ili ostatak SiR1 R2 r3, pri čemu ostaci R1 R2 R3 neovisno jedan od drugoga znače ravnočlani ili razgranati aliklni ostatak sa 1-4 C-atoma ili fenil, E, F znače eventualno halogenirani ravnočlani, razgranati ili ciklički ostatak alkila sa 1-10 C-atoma ili ostatak [image] pri čemu W može značiti 9-fluorenilmetil ili eventualno jedno- ili višestruko ili miješano halogenom, -NO2, alkoksilom ili -CN supstituirani ostatak benzila, ili supstituenti E odnosno F kod smanjenja atoma ugljika, zajedno s atomom dušika čine jedan od sljedećih prstenastih sistema, [image] pri čemu ako su ostaci A i B različiti, E i F mogu biti različiti ili isti, a ako su ostaci A i B isti, E i F moraju biti različiti, a n znači cijeli broj od 2 do 10, pri čemu se središta kiraliteta u molekulama određuju korištenim eduktima, a oba L ili oba D ili D,L odnosno L,D mogu biti konfigurirani.1. Asymmetrically substituted diaminocarboxylic acid derivatives of the formula [image] indicated by that A and B independently of each other mean the residue -OR, where R represents a possibly single- or multiply halogenated straight-membered, branched or cyclic alkyl residue with 1 - 10 C-atoms, phenyl or the residue - CH2-X, where X means the residues 9-fluorophenyl, phenyl, -OCH3, -CH2SO2CH3, -CH2SO2C6H5, -CCl3, -CH2-Y, with Y halogen, -p-tosyl, possibly mono- or multi-halogen, -NO2 or alkyl substituted phenyl or tenacyl residue, digenylmethyl , triphenylmethyl, 2-pyridyl or the residue SiR1 R2 r3, whereby the residues R1 R2 R3 independently of each other mean a straight or branched alkyl residue with 1-4 C-atoms or phenyl, E, F mean a possibly halogenated straight-membered, branched or cyclic alkyl residue with 1-10 C-atoms or a residue [image] where W can mean 9-fluorenylmethyl or possibly a single or multiple or mixed halogen, -NO2, alkoxyl or -CN substituted benzyl residue, or the substituents E or F when the carbon atom is reduced, together with the nitrogen atom form one of the following ring systems, [image] where if residues A and B are different, E and F can be different or the same, and if residues A and B are the same, E and F must be different, and n means an integer from 2 to 10, where the centers of chirality in molecules are determined by the educts used, and both L or both D or D,L or L,D can be configured. 2. Asimetrično supstituirani derivati diaminokarboksne kiseline formule I. prema zahtjevu 1, naznačeni time, da A i B znače ostatak -OR, a R znači ostatak 9-fluorenilmetila, supstituirani ili nesupstituirani ostatak fenila, benzila ili fenacila, ostatak 2-(2-piridil)-etila, ostatak 2-p-tosiletila ili eventualno halogenirani ravnočlani ili razgranati ostatak alkila sa 1-4 C-atoma, E i F znače ostatak [image] pri čemu W znači ostatak 9-fluorenilmetila, eventualno supstituirani ostatak benzila ili ravnočlani ili razgranati ostatak alkila sa 1-4 C-atoma, a n znači cijeli broj od 2 do 10.2. Asymmetrically substituted diaminocarboxylic acid derivatives of formula I according to claim 1, characterized in that A and B mean the -OR residue, and R means the 9-fluorenylmethyl residue, substituted or unsubstituted phenyl, benzyl or phenacyl residue, 2-(2- pyridyl)-ethyl, a 2-p-tosylethyl residue or an optionally halogenated straight-membered or branched alkyl residue with 1-4 C-atoms, E and F mean the remainder [image] where W means a 9-fluorenylmethyl residue, possibly a substituted benzyl residue or a straight or branched alkyl residue with 1-4 C-atoms, and n means an integer from 2 to 10. 3. Postupak za dobivanje takvih asimetrično supstituiranih derivata diaminodikarbonske kiseline miješanom Kolbe-sintezom, naznačen time, da se zaštićeni derivat aminokiseline formule [image] u kojoj A i E ima gore navedeno značenje, a k znači cijeli broj, sa derivatom aminokiseline formule [image] u kojoj B i F imaju gore navedeno značenje, a 1 znači cijeli broj, pri čemu k i 1 zajedno daju broj n, postupkom elektrolize platinastom mrežastom elektrodom.3. Process for obtaining such asymmetrically substituted diaminodicarboxylic acid derivatives by mixed Kolbe synthesis, characterized in that the protected amino acid derivative of the formula [image] wherein A and E have the above meanings and k means an integer, with an amino acid derivative of the formula [image] in which B and F have the above meanings and 1 means an integer, where k and 1 together give the number n, by the process of electrolysis with a platinum mesh electrode. 4. Postupak prema zahtjevu 3, naznačen time, da se temperatura za vrijeme elektrolize hlađenjem drži između 18-25°C.4. The method according to claim 3, characterized in that the temperature during electrolysis is kept between 18-25°C by cooling.
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