NO155066B - DEVICE BY FORK BOILER. - Google Patents
DEVICE BY FORK BOILER. Download PDFInfo
- Publication number
- NO155066B NO155066B NO84845230A NO845230A NO155066B NO 155066 B NO155066 B NO 155066B NO 84845230 A NO84845230 A NO 84845230A NO 845230 A NO845230 A NO 845230A NO 155066 B NO155066 B NO 155066B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- ester
- lysine
- basic
- residue
- Prior art date
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Landscapes
- Control Of Steam Boilers And Waste-Gas Boilers (AREA)
Description
Fremgangsmåte til fremstilling av estere av basiske aminosyrer med antibakteriell virkning. Process for the production of esters of basic amino acids with antibacterial action.
Nærværende oppfinnelse vedrører en fremgangsmåte til fremstilling av estere med den generelle formel I The present invention relates to a process for the production of esters with the general formula I
hvor R betyr en minst 8 og fortrinnsvis høyst 20 C-atomer inneholdende langkjedet alkylrest og Ac acylresten av en basisk a-amino-monokarboxylsyre eller av et di- eller tripeptid som inneholder minst en basisk a-amino-monokarboxylsyre, where R means a at least 8 and preferably at most 20 C atoms containing a long-chain alkyl residue and Ac the acyl residue of a basic α-amino-monocarboxylic acid or of a di- or tripeptide containing at least one basic α-amino-monocarboxylic acid,
såvel som syreaddisjonssalter av slike estere. as well as acid addition salts of such esters.
Den med symbolet R angitte langkjedete, i det minste 8 C-atomer inneholdende alkylrest kan være rettkjedet eller forgrenet. Fortrinnsvis oppviser den en kjedelengde på 10—20, i særdeleshet 10—16 C-atomer. Eksempler på foretrukne R-res-ter er følgende alkylgrupper: n-decyl, n-do-decyl, n-octadecyl, n-eicosyl og i særdeleshet n-tetradecyl og n-hexadecyl eller også n-octyl. The long-chain, at least 8 C atoms-containing alkyl residue indicated by the symbol R can be straight-chain or branched. Preferably, it exhibits a chain length of 10-20, in particular 10-16 C atoms. Examples of preferred R residues are the following alkyl groups: n-decyl, n-do-decyl, n-octadecyl, n-eicosyl and in particular n-tetradecyl and n-hexadecyl or also n-octyl.
Basiske a-am|inokarboxylsyrer i nærværende oppfinnelses betydning er slike a-aminomonokarboxylsyrer som foruten a-aminogruppen ennu i det minste inneholder en ytterligere basisk gruppe, som f. eks. en iminogruppe (f. eks. 1 histidin), i særdeleshet en ytterligere aminogruppe, som i diaminomonokarboxylsyrene. Eksempler på slike diaminomonokarboxylsyrer er: a,(3-diamiinopropionsyre, a.y-diamino-smørsyre, ornithin, lysin og arginin. I arginin forelig-ger den ene aminogruppe som del av guani-dlnogruppen (-NH-C(NH)-NH2). Foretrukne representanter for slike basiske a-aminomonokarboxylsyrer er de native aminosyrer av proteiner, i særdeleshet lysin. Basic α-aminocarboxylic acids in the sense of the present invention are such α-aminomonocarboxylic acids which, in addition to the α-amino group, still contain at least one further basic group, such as e.g. an imino group (e.g. 1 histidine), in particular a further amino group, as in the diaminomonocarboxylic acids. Examples of such diaminomonocarboxylic acids are: a, (3-diaminopropionic acid, a.y-diaminobutyric acid, ornithine, lysine and arginine. In arginine the one amino group is present as part of the guanido group (-NH-C(NH)-NH2) Preferred representatives of such basic α-aminomonocarboxylic acids are the native amino acids of proteins, in particular lysine.
De basiske a-aminomonokarboxylsyrer kan foreligge i racemisk (D, L) eller i optisk aktiv (D- eller L-form). Foretrukne er de naturlige representanter med L-konfigura-tion. The basic α-aminomonocarboxylic acids can exist in racemic (D, L) or in optically active (D or L form). Preferred are the natural representatives with L-configuration.
Foretrukne eksempler på langkjedete estere med formel I, hvor Ac betyr acylresten av en basisk a-aminomonokarboxylsyre, er Preferred examples of long-chain esters of formula I, where Ac means the acyl residue of a basic α-aminomonocarboxylic acid, are
L-lysin-n-octylester L-ornithin-n-dodecylester L-lysin-n-decylester L-lysin-n-tetradecylester L-lysine-n-octyl ester L-ornithine-n-dodecyl ester L-lysine-n-decyl ester L-lysine-n-tetradecyl ester
L-lysin-n-hexadecylester. L-lysine-n-hexadecyl ester.
En annen gruppe av fremgangsmåteproduktene danner de langkjedete estere av basiske dipeptider, d.v.s. slike forbindelser med formel I, i hvilke symbolet Ac betyr acylresten av et av en basisk a-aminomonokarboxylsyre avledet dipeptid. Eksempler på slike dipeptider er: seryl-lysin, lysyl-serin, lysyl-lysin. Ifølge defini-sjonen skal i det minste en byggesten av peptidet være av basisk natur. Den annen byggesten kan være en nøytral (d.v.s. en i ovenfor nevnte definisjons betydning ikke-basisk a-aminomonokarboxylsyre) eller eventuelt en basisk a-amlnomonokarboxyl-syre. Som nøytrale a-aminomonokarboxylsyrer kommer i betraktning særlig de naturlige i proteinene foreliggende representanter for denne forbindelsesklasse, som alanin, fenylanalin, cystein, cystin, methio-nin, glycin, leucin, isoleucin, valin, norva-lin, prolin, serin, threonln og tyrosin. Another group of process products forms the long-chain esters of basic dipeptides, i.e. such compounds of formula I, in which the symbol Ac means the acyl residue of a dipeptide derived from a basic α-aminomonocarboxylic acid. Examples of such dipeptides are: seryl-lysine, lysyl-serine, lysyl-lysine. According to the definition, at least one building block of the peptide must be of a basic nature. The second building block can be a neutral (i.e. a non-basic α-aminomonocarboxylic acid in the sense of the above-mentioned definition) or possibly a basic α-aminomonocarboxylic acid. As neutral α-aminomonocarboxylic acids, the natural representatives of this class of compounds present in proteins, such as alanine, phenylalanine, cysteine, cystine, methionine, glycine, leucine, isoleucine, valine, norvaline, proline, serine, threonine and tyrosine.
Som de basiske komponentene kan As the basic components can
også de nøytrale komponentene (i det minste de med et asymmetrisk sentrum) foreligge såvel i racemisk som i optisk aktiv form. also the neutral components (at least those with an asymmetric centre) exist both in racemic and in optically active form.
Ved de fra en nøytral og en basisk a-aminomonokarboxylsyre oppbygde dipeptider kan skilles mellom dipeptider, ved hvilke karboxylfunksjonen i endestilling danner del av den nøytrale syrekomponen-ten (som f. eks. i lysyl-serin) og slike dipeptider, ved hvilke karboxylfunksjonen i endestilling danner del av den basiske syre-komponenten (som f. eks. i seryl-lysin). I sistnevnte tilfelle er det videre å skille mellom a-amid og co-amidlignende for-bundne dipeptider. (Eksempler: Na-seryl-lysin henholdsvis N^-seryl-lysin). Den sistnevnte inndeling er naturlig også å ta hen-syn til ved de av to basiske komponenter oppbygde dipeptider (eksempler: Na-lysyl-lysin henholdsvis Ne-lysyl-lysin). In the dipeptides built up from a neutral and a basic α-aminomonocarboxylic acid, a distinction can be made between dipeptides, in which the carboxyl function in the terminal position forms part of the neutral acid component (such as, for example, in lysylserine) and such dipeptides, in which the carboxyl function in end position forms part of the basic acid component (as e.g. in seryl-lysine). In the latter case, it is further possible to distinguish between α-amide and α-amide-like linked dipeptides. (Examples: Na-seryl-lysine and N-seryl-lysine respectively). The latter division is naturally also to be taken into account in the case of dipeptides made up of two basic components (examples: Na-lysyl-lysine and Ne-lysyl-lysine respectively).
Som eksempler på langkjedete estere fra denne andre gruppen av fremgangsmå-teprodukter (dipeptidestere) kan nevnes: Na-L-arginyl-L-arginin-n-decylester N"-D-seryl-L-lysin-n-hexadecylester NE-L-fenylal'anyl-L-lysin-n-tetradecylester L-lysyl-L-fenylalanin-n-hexadecylester Na-L-lysyl-L-lysin-n-dodecylester. Examples of long-chain esters from this second group of process products (dipeptide esters) can be mentioned: Na-L-arginyl-L-arginine-n-decyl ester N"-D-seryl-L-lysine-n-hexadecyl ester NE-L- phenylal'anyl-L-lysine-n-tetradecyl ester L-lysyl-L-phenylalanine-n-hexadecyl ester Na-L-lysyl-L-lysine-n-dodecyl ester.
For enkelthets skyld betegnes i det føl-gende og i særdeleshet i utførelseseksemp-lene den a-amidlignende sammenknytning ikke spesielt som en slik. For the sake of simplicity, in the following and in particular in the exemplary embodiments, the α-amide-like linkage is not specifically designated as such.
En tredje gruppe av fremgangsmåteproduktene danner de langkjedete estere av basiske tripeptider, dvs. slike forbindelser med formel I, i hvilke symbolet Ac betyr acylresten av et av en basisk a-arai-nomonokarboxylsyre avledet tripeptid. Det gjelder for disse forbindelsesgrupper det samme oppbygningsprinsipp, som foran er blitt drøftet for dipeptidesterne. Ved siden av den ene (ifølge definisjon beskyttet) a-aminokarboxylsyre-komponenten kan således den andre og den tredje komponenten av basiske og/eller nøytrale a-amino-rrionokarboxylsyrer være avledet. Videre er det også ved tripeptidesterne å skille mellom forbindelser, ved hvilke estergruppen er bundet til en basisk syrekomponent og slike, ved hvilke estergruppen er bundet til en nøytral syrekomponent. Mang-foldigheten som gir seg fra de forskjellige muligheter av sammenknytning av peptid-byggstenene (a-amid- og/eller co-amidlignende), er her naturlig nok større enn ved dipeptidesterne. Eksempler på langkjedete estere av denne tredje gruppen av fremgangsmåte-produkter (tripeptidestere) er: A third group of process products form the long-chain esters of basic tripeptides, i.e. such compounds of formula I, in which the symbol Ac means the acyl residue of a tripeptide derived from a basic α-arai-nomonocarboxylic acid. The same structural principle that has been discussed above for the dipeptide esters applies to these connecting groups. Next to the one (according to definition protected) α-aminocarboxylic acid component, the second and third components of basic and/or neutral α-aminorionocarboxylic acids can thus be derived. Furthermore, with the tripeptide esters, a distinction can be made between compounds in which the ester group is bound to a basic acid component and those in which the ester group is bound to a neutral acid component. The diversity that results from the different possibilities of connecting the peptide building blocks (α-amide- and/or co-amide-like) is naturally greater here than with the dipeptide esters. Examples of long-chain esters of this third group of process products (tripeptide esters) are:
L-lysyl-L-lysyl-L-lysin-n-hexadecylester Na-L-lysyl- (Ne-L-lysyl) -L-lysin-n- tetradecylester glycyl-L-lysyl-L-lysin-n-dodecylester Fremgangsmåten etter oppfinnelsen for fremstilling av forbindelser med formel I, karakteriseres ved at man forestrer en forbindelse med formel II hvor Ac betyr det samme som ovenfor, eller et reaksjonsdyktig derivat av en slik forbindelse, med en alkohol med formel III hvor R betyr det samme som ovenfor, eller med et reaksjonsdyktig derivat av en slik alkohol, eller at man for utvinning av di- og tripeptidesterne med formel I N-acylerer en ester med formel IV hvor Ac* betyr acylresten av en nøytral eller basisk a-aminomonokarboxylsyre eller et av slike syrer oppbygd dipeptid og R betyr det samme som ovenfor, med en forbindelse med formel V L-lysyl-L-lysyl-L-lysine-n-hexadecyl ester Na-L-lysyl-(Ne-L-lysyl)-L-lysine-n- tetradecyl ester glycyl-L-lysyl-L-lysine-n-dodecyl ester The method according to the invention for producing compounds of formula I is characterized by esterifying a compound of formula II where Ac means the same as above, or a reactive derivative of such a compound, with an alcohol of formula III where R means the same as above, or with a reactive derivative of such an alcohol, or that to obtain the di- and tripeptide esters of formula I N-acylate an ester of formula IV where Ac* means the acyl residue of a neutral or basic α-aminomonocarboxylic acid or a dipeptide made up of such acids and R means the same as above, with a compound of formula V
hvor Ac2 betyr acylresten av en a-aminokarboxylsyre eller et fra a-amino-monokarboxylsyrene oppbygget dipeptid, where Ac2 means the acyl residue of an α-aminocarboxylic acid or a dipeptide built from the α-amino-monocarboxylic acids,
eller med et reaksjonsdyktig derivat av en slik forbindelse, idet Ac2-resten minst skal inneholde en basisk a-aminokarboxylsyre-komponent, ifall Ac i-resten ikke inneholder en slik komponent, idet basiske grupper som ikke skal reagere, beskyttes intermediært, og at man, hvis ønsket, overfører de erholdte estere til syreaddisjonssalter. or with a reactive derivative of such a compound, since the Ac2 residue must contain at least one basic α-aminocarboxylic acid component, if the Ac i residue does not contain such a component, since basic groups that are not supposed to react are protected intermediately, and that one , if desired, transfer the obtained esters to acid addition salts.
Samtlige sluttprodukter med formel I, altså såvel esterne av aminosyrene som esterne av di- og tripeptidene lar seg ut-vinne ved forestring av tilsvarende uforest-rete utgangsforbindelser. Di- og tripeptidesterne lar seg for øvrig oppnå ved forlen-gelse av kjeden av aminokarboxylsyre- og dipeptidesterne med en henholdsvis to ami-nosyrerester ved hjelp av N-acylering. All end products with formula I, i.e. the esters of the amino acids as well as the esters of the di- and tripeptides can be recovered by esterification of corresponding unesterified starting compounds. The di- and tripeptide esters can also be obtained by extending the chain of the aminocarboxylic acid and dipeptide esters by one or two amino acid residues using N-acylation.
Forestringsoperasjonen kan foretas etter i og for seg kjent metode. Således kan man f. eks. omsette en N-beskyttet basisk a-aminokarboxylsyre eller et N-beskyttet i det minste en basisk a-amlnomonokar-boxylsyre som byggsten inneholdende di-eller tripeptid med formel II i nærvær av en tertiær base (som et trialkylamin, f. eks. triethylamin) med en reaktiv ester av en alkohol med formel III. Som reaktive estere er halogenldene (f. eks. kloridene, bromidene eller jodidene) særlig egnet. The esterification operation can be carried out according to a method known per se. Thus, one can e.g. react an N-protected basic α-aminocarboxylic acid or an N-protected at least one basic α-aminomonocarboxylic acid as the building block containing the di- or tripeptide of formula II in the presence of a tertiary base (such as a trialkylamine, e.g. triethylamine ) with a reactive ester of an alcohol of formula III. The halogens (e.g. the chlorides, bromides or iodides) are particularly suitable as reactive esters.
De frie aminogrupper i utgangsmate-rialene kan blokkeres med de vanlige beskyttelsesgrupper. Slike N-beskyttelsesgrupper er f. eks. karbobenzoxy-, tosyl-, fthalyl-, trityl-, formyl-, trifluoracetyl- og tert. butyloxykarboxylgruppen. For argini-nets guanidinogruppe kommer som bekjent også nitrogruppeni i betraktning som be-skyttelsesgruppe. Som oppløsnings- henholdsvis som fortynnings-midler kommer f. eks. dioxan, dimethylformamid etc. på tale. Hensiktsmessig finner omsetningen sted ved forhøyet temperatur, f. eks. ved til-bakeløpstemperatur. Etter denne forest-ringsvariant kan f. eks. n-hexadecylesteren av L-lysin oppnås, ved at man oppvarmer en oppløsning av N«, N6-dikarbobenzoxy-L-lysin i dioxan i nærvær av triethylamin sammen med omtrent 1 molekvivalent 1-brom-hexadecan til koking under tilbake-løp og deretter fjerner begge karbobenzoxy-beskyttelsesgruppene hydrogenolytisk. På tilsvarende måte lar f. eks. L-lysyl-L-lysin eller L-lysyl-L-lysyl-L-lysin seg forestre, idet man omsetter disse peptider (under beskyttelse av amlnogruppene) med et langkjedet alkylhalogenid og til slutt avspalter beskyttelsesgruppen igjen. The free amino groups in the starting materials can be blocked with the usual protective groups. Such N-protecting groups are e.g. carbobenzoxy, tosyl, phthalyl, trityl, formyl, trifluoroacetyl and tert. the butyloxycarboxyl group. For the guanidino group of the arginine, as is known, the nitro group also comes into consideration as a protecting group. As solvents or as diluents, e.g. dioxane, dimethylformamide etc. in speech. Appropriately, the reaction takes place at an elevated temperature, e.g. at supply-reflux temperature. According to this esterification variant, e.g. The n-hexadecyl ester of L-lysine is obtained by heating a solution of N, N6-dicarbobenzoxy-L-lysine in dioxane in the presence of triethylamine together with about 1 molar equivalent of 1-bromohexadecane to reflux and then removes both carbobenzoxy protecting groups hydrogenolytically. In a similar way, lets e.g. L-lysyl-L-lysine or L-lysyl-L-lysyl-L-lysine are esterified by reacting these peptides (while protecting the amlno groups) with a long-chain alkyl halide and finally cleaving off the protecting group again.
For forestringsoperasjonen lar som ut-gangsstoffer også reaksjonsdyktige deriva-ter av syrer med formel II på den ene side og langkjedete alkoholer med formel III på den andre side seg anvende. Således kan man omsette f. eks. anhydridet eller et blandet anhydrid av en syre med formel II (hensiktsmessig under beskyttelse av en aminogruppe) med en langkjedet alkohol, f. eks. med cetylalkohol. For the esterification operation, reactive derivatives of acids with formula II on the one hand and long-chain alcohols with formula III on the other hand can also be used as starting materials. Thus, one can convert e.g. the anhydride or a mixed anhydride of an acid of formula II (suitably under the protection of an amino group) with a long-chain alcohol, e.g. with cetyl alcohol.
Videre lar forestringen seg også oppnå ved syrekatalysert omsetning av en syre med formel II med en alkohol med formel III. Som syrekatalysator kommer f. eks., p-toluolsulfonsyre i betraktning. Ved denne forestringstype er en beskyttelse av aminogruppen ikke nødvendig. Furthermore, the esterification can also be achieved by acid-catalyzed reaction of an acid of formula II with an alcohol of formula III. As an acid catalyst, for example, p-toluenesulfonic acid comes into consideration. With this type of esterification, protection of the amino group is not necessary.
Langkjedete estere av dipeptider lar seg ifølge oppfinnelsen også oppnå fra langkjedete estere av basiske eller nøytrale According to the invention, long-chain esters of dipeptides can also be obtained from long-chain esters of basic or neutral
a-aminomonokarboxylsyrer ved a- eller a-aminomonocarboxylic acids by a- or
eventuelt to-amidlignende sammenknytning med en ytterligere a-aminokarboxylsyre-byggsten. Går man ut fra en langkjedet ester av en basisk a-aminokarboxylsyre, f. eks. n-dodecylesteren av ornithin, så kan optionally two-amide-like linkage with a further α-aminocarboxylic acid building block. Starting from a long-chain ester of a basic α-aminocarboxylic acid, e.g. The n-dodecyl ester of ornithine, so can
den til peptidoppbygning bestemte andre aminosyrekomponent være av basisk eller nøytral natur, som f. eks. ornithin eller threonin. Anvender man derimot som ut-gangsstoff en ester av en nøytral a-amino-monokarboxylsyre, som f. eks. en leucin-ester, så kommer som annen peptidbygg-sten bare en basisk a-aminomonokarboxylsyre i betraktning, da i det minste en aminosyrekomponent i molekylet for sluttpro-duktet skal være av basisk natur. the second amino acid component determined for peptide structure be of a basic or neutral nature, such as e.g. ornithine or threonine. On the other hand, an ester of a neutral α-amino-monocarboxylic acid is used as starting material, such as e.g. a leucine ester, then as another peptide building block only a basic α-aminomonocarboxylic acid comes into consideration, as at least one amino acid component in the molecule for the end product must be of a basic nature.
Oppbygningen av dipeptidestere fra de tilsvarende estere av a-aminomonokarboxylsyrer kan iverksettes etter de vanlige metoder for peptidkjemi ved N-acylering av aminokarboxylsyreesterne med en forbindelse som avgir den ønskede acylrest. Således kan man f. eks. omsette en a-aminomonokarboxylsyre med en langkjedet ester av en a-aminokarboxylsyre i nærvær av et kondensasjonsmiddel (som et ka-rbo-diimid, f. eks. dicyklohexylkarbodiimid, eller av karbonyldiimidazol eller 2-ethyl-5-metasulfonato-fenylisoxazol). Omsetningen finner fortrinnsvis sted ved lavere temperatur (f. eks. i området fra ca. 0—20°C) i nærvær av et oppløsningsmiddel, som di-methylformaml, kloroform, methylenklorid, eddikester, tetrahydrofuram, etc. The construction of dipeptide esters from the corresponding esters of α-aminomonocarboxylic acids can be carried out according to the usual methods for peptide chemistry by N-acylation of the aminocarboxylic acid esters with a compound which releases the desired acyl residue. Thus, one can e.g. reacting an α-aminomonocarboxylic acid with a long-chain ester of an α-aminocarboxylic acid in the presence of a condensing agent (such as a carbodiimide, e.g. dicyclohexylcarbodiimide, or of carbonyldiimidazole or 2-ethyl-5-metasulfonato-phenylisoxazole). The reaction preferably takes place at a lower temperature (e.g. in the range from about 0-20°C) in the presence of a solvent, such as dimethylformamide, chloroform, methylene chloride, acetic ester, tetrahydrofuram, etc.
Man kan videre til acylering av ester-komponentene anvende som acylerings-middet et i karboxylgruppen funksjonelt modifisert derivat av en a-aminomonokarboxylsyre, f. eks. azidet, et halogenid (som kloridet), en energirik ester (som p-nitro-fenylesteren, thiofenylesteren eller cyan-methylesteren), eliler et blandet anhydrid med en uorganisk syre (som karbonsyre, svovelsyre, fosforsyre). Omsetningen kan finne sted ved værelsestemperatur eller lavere temperatur. A derivative of an α-aminomonocarboxylic acid functionally modified in the carboxyl group can also be used as the acylation agent for acylation of the ester components, e.g. the azide, a halide (such as the chloride), an energetic ester (such as the p-nitro-phenyl ester, the thiophenyl ester or the cyano-methyl ester), or a mixed anhydride with an inorganic acid (such as carbonic acid, sulfuric acid, phosphoric acid). The reaction can take place at room temperature or a lower temperature.
En metode som tillater såvel en akti-vering av karboxylgruppen i acylerings-midlet som aminogruppen i esterkompo-nenten, er den etter Anderson, ved hvilken karboxylgruppen overføres til en -COOP-(OC2H5)2 gruppe og aminogruppen til en A method that allows activation of the carboxyl group in the acylating agent as well as the amino group in the ester component is the one according to Anderson, in which the carboxyl group is transferred to a -COOP-(OC2H5)2 group and the amino group to a
-NHP(OC2H5)2 gruppe ved hjelp av tetra-ethylpyrofosfit [(C^O), = POP = -NHP(OC2H5)2 group by means of tetra-ethylpyrophosphite [(C^O), = POP =
(<O>C2<H>5)2]. (<O>C2<H>5)2].
Estere av basiske a-aminomonokarboxylsyrer, som av a,co-diaminokarboxylsyrer kan acyleres i a- og/eller co-aminogruppen. Acyleringen i N« (henholdsvis Na>) kan oppnås ved blokkering av co- henholdsvis a-) aminogruppen. For blokkering av aminogruppen egner seg de allerede ovenfor nevnte beskyttelsesgrupper som karbobenzoxy- eller formylgruppen. Beskyttes ingen av aminogruppene i den basiske esterkom-ponenten, så kan Na, N">-diacylderivater (tripeptidester) oppnås. Esters of basic a-aminomonocarboxylic acids, which of a,co-diaminocarboxylic acids can be acylated in the a- and/or co-amino group. The acylation in N« (respectively Na>) can be achieved by blocking the co- or a-) amino group. For blocking the amino group, the already mentioned protective groups such as the carbobenzoxy or formyl group are suitable. If none of the amino groups in the basic ester component is protected, Na, N">-diacyl derivatives (tripeptide esters) can be obtained.
Foruten på den ovenfor nevnte måte kan følge oppfinnelsen langkjedete estere av tripeptlder også oppnåes ved kondensasjon av en a-aminomonokarboxylsyreester med et dipeptid eller ved kondensasjon av en ddpeptidester med en a-aminokarboxylsyre. Således kan f. eks. n-dicylesteren av lysyl-lysyl-lysin oppnås ved at man acy-lerer N-beskyttet n-decylester av lysin med et i samtlige aminogrupper beskyttet lysyl-lysin-azid og deretter avspalter beskyttelsesgruppene. Til den samme tripeptidester når man også ved Na-acylering av en i e-aminogruppene beskyttet lysyl-lysin-n-decylester med eventuelt N-beskyttet lysin og deretter avspaltning av beskyttelsesgruppene. In addition to the above-mentioned method, according to the invention, long-chain esters of tripeptylder can also be obtained by condensation of an α-aminomonocarboxylic acid ester with a dipeptide or by condensation of a ddpeptide ester with an α-aminocarboxylic acid. Thus, e.g. The n-dicyl ester of lysyl-lysyl-lysine is obtained by acylating the N-protected n-decyl ester of lysine with a lysyl-lysine azide protected in all amino groups and then removing the protective groups. The same tripeptide ester is also reached by Na-acylation of a lysyl-lysine-n-decyl ester protected in the ε-amino groups with possibly N-protected lysine and then removal of the protective groups.
Avspaltningen av beskyttelsesgruppene etter inntrått forestring henholdsvis N-acylering kan finne sted på i og for seg kjent måte, f. eks. ved hydrogenolyse eller hydrolyse. Karbobenzoxy-beskyttelsesgruppen kan f. eks. avspaltes ved hjelp av ka-talytisk aktivert hydrogen (under anvendelse av f. eks. palladium som katalysator) eller ved hjelp av HBr/iseddik. Formyl-beskyttelsesgruppen kan avspaltes med mi-neralsyre i kulde. The removal of the protective groups after esterification or N-acylation has taken place can take place in a manner known per se, e.g. by hydrogenolysis or hydrolysis. The carbobenzoxy protecting group can e.g. is split off with the help of catalytically activated hydrogen (using e.g. palladium as a catalyst) or with the help of HBr/glacial acetic acid. The formyl protecting group can be removed with mineral acid in the cold.
Som baser oppnådde fremgangsmåte-produkter lar seg etter kjente metoder overføre til syreaddisjonssalter, fra hvilke basene kan frisettes på likeså kjent måte. Til dannelse av syreaddisjonssalter kan de vanligvis for dette formål anvendte uorga-niske og organiske syrer anvendes, f. eks. sovelsyre, fosforsyre, halogenhydrogensyre (som saltsyre, bromhydrogensyre), oxalsy-re, eddiksyre, citronsyre, vinsyre, sorbin-syre, p-toluolsulfonsyre etc. Process products obtained as bases can be transferred by known methods to acid addition salts, from which the bases can be liberated in an equally known manner. For the formation of acid addition salts, the inorganic and organic acids usually used for this purpose can be used, e.g. sulfuric acid, phosphoric acid, hydrohalic acid (such as hydrochloric acid, hydrobromic acid), oxalic acid, acetic acid, citric acid, tartaric acid, sorbic acid, p-toluenesulfonic acid, etc.
De etter fremgangsmåten etter oppfinnelsen oppnåelige produkter utmerker seg med lavere toksisitet ved høy antibakteriell virkning mot grampositive bakterier (som pneumokokker, streptokokker, miltbrandbasiller, stafylokokker, entero-kokker) og gramnegative bakterier (som Escherichia coli, Salmonella typhi murium, Shigella, Klebsiella pneumoniae, i særdeleshet også Pseudomonas aeruginosa). Fremgangsmåteproduktene kan på tilsvarende måte anvendes som desinfeksjons-middel for medisinske og ikke-medisinske formål, f. eks. til desinfeksjon av værelser, apparaturer og redskap i meierier. De kan videre finne anvendelse som antiseptika for mennesker og dyr (f. eks. for profylakse og bekjempelse av mastitis hos pattedyr, i særdeleshet storfe). The products obtainable according to the method according to the invention are characterized by lower toxicity with high antibacterial action against gram-positive bacteria (such as pneumococci, streptococci, anthrax bacilli, staphylococci, enterococci) and gram-negative bacteria (such as Escherichia coli, Salmonella typhimurium, Shigella, Klebsiella pneumoniae, in particular also Pseudomonas aeruginosa). The process products can similarly be used as disinfectants for medical and non-medical purposes, e.g. for disinfection of rooms, equipment and tools in dairies. They can also be used as antiseptics for humans and animals (e.g. for prophylaxis and combating mastitis in mammals, particularly cattle).
En spesielt høy antibakteriell aktivitet viser bl. a. de følgende forbindelser: L-lysin-n-decylester, L-lysin-n-dodecylester, L-lysin-n-tetradecylester og deres syreaddisjonssalter. A particularly high antibacterial activity shows, among other things, a. the following compounds: L-lysine-n-decyl ester, L-lysine-n-dodecyl ester, L-lysine-n-tetradecyl ester and their acid addition salts.
Det er kjent (sml. f. eks. de bekjent-gjorte dokumenter i det belgiske patent nr. 618 417 eller det i mellomtiden offentlig-gjorte norske patent nr. 106 035), at N-acyl-derivater av basiske di-, tri- og tetrapepti-der med langkjedet N-acylgruppe frem-viser antibakteriell virkning. Derimot dreier det seg ved de nærværende fremgangsmå-teprodukter om1 langkjedete estere av basiske aminosyrer, såvel som av di- og tripeptider, som er billigere fremstillbare enn de tidligere kjente N-acylpeptider. I mot-setning f. eks. til langkjedete N-acylderi-vater av basiske aminosyrer oppviser de ifølge oppfinnelsen oppnålige langkjedete estere av basiske aminosyrer overraskende et optimalt antibakterielt spektrum. Således hemmer f. eks. den ifølge oppfinnelsen oppnålige L-lysin-n-dodecylester (i form av dihydrokloridet) Klebsiella pneum. DHD, Shighella flexneri, Staphylokokker og miltbrandbasiller i konsentrasjoner på ca. 10 y/ml og Salminella typhi murium, Streptokokker og Pneumokokker i konsentrasjoner på ca. 5 y/ml- Lignende tall gjelder for L-lysin-n-tetradecylester (i form av dihydrokloridet) . L-lysyl-L-lysin-n-hexadecylesteren (i form av trihydrokloridet) hemmer Klebsiella pneum. DHD, Shighella, Streptokokker og Pneumokokker i konsentrasjoner på ca. 10 y/ ml. Bestemmelsen av den akutte toksisitet, f. eks. av L-lysin-n-dodecylester-dihydroklorid, på mus p.o. ga føl-gende verdier: DL 10: 2900 mg/kg, DL 50: 3500 mg/kg, DL 90: 4300 mg/kg. It is known (cf. e.g. the disclosed documents in the Belgian patent no. 618 417 or the meanwhile published Norwegian patent no. 106 035) that N-acyl derivatives of basic di-, tri - and tetrapeptides with a long-chain N-acyl group exhibit antibacterial action. In contrast, the present process products are long-chain esters of basic amino acids, as well as of di- and tripeptides, which are cheaper to produce than the previously known N-acyl peptides. In contrast, e.g. to long-chain N-acyl derivatives of basic amino acids, the long-chain esters of basic amino acids obtainable according to the invention surprisingly exhibit an optimal antibacterial spectrum. Thus inhibits e.g. the L-lysine-n-dodecyl ester obtainable according to the invention (in the form of the dihydrochloride) Klebsiella pneum. DHD, Shighella flexneri, Staphylococci and anthrax bacilli in concentrations of approx. 10 y/ml and Salminella typhi murium, Streptococci and Pneumococci in concentrations of approx. 5 y/ml - Similar figures apply to L-lysine-n-tetradecyl ester (in the form of the dihydrochloride). The L-lysyl-L-lysine-n-hexadecyl ester (in the form of the trihydrochloride) inhibits Klebsiella pneum. DHD, Shighella, Streptococci and Pneumococci in concentrations of approx. 10 y/ml. The determination of the acute toxicity, e.g. of L-lysine-n-dodecyl ester dihydrochloride, on mice p.o. gave the following values: DL 10: 2900 mg/kg, DL 50: 3500 mg/kg, DL 90: 4300 mg/kg.
Fremgangsmåteproduktene kan finne anvendelse som legemiddel f. eks. i form av farmasøytiske preparater, som inneholder den eller deres salter i blanding med et for den enterale eller parenterale admini-strasjon egnet farmasøytisk, organisk eller uorganisk inert bæremateriale, som f. eks. vann, gelatin, melkesukker, stivelse, mag-nesiumstearat, talkum, vegetabilske oljer, gummi, polyalkylenglykoler, vaselin osv. De farmasøytiske preparatene kan foreligge i fast form f. eks. som tabletter, dragéer, suppositorier, kapsler eller i flytende form, f. eks. som oppløsninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og/ eller inneholder hjelpestoffer som konser-verings-, stabiliserings-, fuktnings- eller emulgeringsmiddel, salter til forandring av det osmotiske trykk eller puffer. De kan også inneholde andre terapeutisk verdifulle stoffer. The process products can be used as medicine, e.g. in the form of pharmaceutical preparations, which contain one or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.
I de etterfølgende eksempler er tempe-raturene angitt i Celsiusgrader. Symbolet Z betyr karbobenzoxygruppen. In the following examples, the temperatures are given in degrees Celsius. The symbol Z means the carbobenzoxy group.
Eksempel 1. Example 1.
41,4 g N«-Z(Ne-Z)-L-lysin, 200 ml dioxan, 14,7 ml triethylamin og 30,5 g 1-brom-hexadecan oppvarmes 20 timer under tilbakeløp ved 95—100°. Man nutsjer av det utfelte triethylamin-hydrobromid, inndamper filtratet i våkum, opptar resten i eddikester og vasker eddikesterekstraktet nøytralt med 1 n saltsyre, 5 pst.-ig NaCl-oppløsning, 1 n ammonisk og 5 pst.-ig Na-Cl-oppløsning. Etter tørking over Na2SO,, inndampes oppløsningen i vakuum og den således erholdte N«-Z(NE-Z)-L-lysin-n-hexadecylester krystalliseret fra ether/pet-rolether. Smeltepunkt 70—72°, [a]<2>D<n> = h-9,0° (c = 21 methanol). 41.4 g of N«-Z(Ne-Z)-L-lysine, 200 ml of dioxane, 14.7 ml of triethylamine and 30.5 g of 1-bromo-hexadecane are heated for 20 hours under reflux at 95-100°. The precipitated triethylamine hydrobromide is filtered off, the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate and the ethyl acetate extract is washed neutrally with 1 N hydrochloric acid, 5% NaCl solution, 1N ammonium and 5% Na-Cl solution . After drying over Na 2 SO 3 , the solution is evaporated in vacuo and the N-Z(NE-Z)-L-lysine-n-hexadecyl ester thus obtained is crystallized from ether/petroleum ether. Melting point 70-72°, [a]<2>D<n> = h-9.0° (c = 21 methanol).
Den erholdte N-beskyttede aminosyreester dekarbobenzoxyleres i iseddik med 5 pst.-ig palladiumkull og hydrogen. Katalysatoren skilles så fra, filtratet inndampes i vakuum, resten inndampes ennå en gang med 4 n salfcsyre/methanol og blandes deretter med aceton. Det således erholdte L-lysin-n-hexadecylester-dihydroklorid nutsjes fra, vaskes med aceton og omkrystalliseres fra ethanol. Smeltepunkt 108—110° The N-protected amino acid ester obtained is decarbobenzoxylated in glacial acetic acid with 5% palladium charcoal and hydrogen. The catalyst is then separated, the filtrate is evaporated in vacuo, the residue is evaporated once more with 4 N sulfuric acid/methanol and then mixed with acetone. The L-lysine-n-hexadecyl ester dihydrochloride thus obtained is filtered off, washed with acetone and recrystallized from ethanol. Melting point 108-110°
(spaltning); [a] y = +6,9° (c = 2 i methanol). (fission); [a] y = +6.9° (c = 2 in methanol).
Eksempel 2. Example 2.
18,2 g cetylalkohol, 14,25 g p-toluolsulfonsyre-monohydrat, 9,1 g L-lysinmono-hydroklorid og 200 ml benzol kokes 20 timer under tilbakeløp. Vannet som danner seg, fjernes fortløpende med en vannavskiller. Reaksjonsblandingen inndampes i vakuum. Resten ekstraheres for fjerning av den overskytende cetylalkohol med en blanding av vann og eddikester, den vandige fase 18.2 g of cetyl alcohol, 14.25 g of p-toluenesulfonic acid monohydrate, 9.1 g of L-lysine monohydrochloride and 200 ml of benzene are boiled for 20 hours under reflux. The water that forms is continuously removed with a water separator. The reaction mixture is evaporated in vacuo. The residue is extracted to remove the excess cetyl alcohol with a mixture of water and acetic acid, the aqueous phase
innstilles med konsentrert ammoniak på en pH = 9—10, ekstraherer med eddikester, eddikesteroppløsningen tørkes over Na2S04 og inndampes. Den tilbakeblivende olje nøytraliseres med ln HCL/methanol, opp-løsningen inndampes, resten blandes med aceton og krystallgrøten nutsjes fra. Til slutt omkrystalliseres det således erholdte L-lysin-n-hexadecylester-dihydroklorid fra ethanol. Smeltepunkt 108—110° (spaltning); [a] <2>D° = +6,9° (c = 2 i methanol). adjusted with concentrated ammonia to a pH = 9-10, extracted with ethyl acetate, the ethyl acetate solution is dried over Na2SO4 and evaporated. The remaining oil is neutralized with ln HCL/methanol, the solution is evaporated, the residue is mixed with acetone and the crystal slurry is filtered off. Finally, the L-lysine-n-hexadecyl ester dihydrochloride thus obtained is recrystallized from ethanol. Melting point 108-110° (decomposition); [a] <2>D° = +6.9° (c = 2 in methanol).
Eksempel 3. Example 3.
29,8 g n-eicosanol, 200 ml absolutt tetrahydrofuran og 115 mg pulverisert natri-um kokes 3 timer under tilbakeløp under CaCl2-lås. N-eicosanol/Na-n-eicosanolat-blandingen helles fra en liten mengde nat-rium. 29.8 g of n-eicosanol, 200 ml of absolute tetrahydrofuran and 115 mg of powdered sodium are boiled for 3 hours under reflux under a CaCl2 lock. The N-eicosanol/Na-n-eicosanol mixture is poured from a small amount of sodium.
Imidlertid oppløser man 41,4 g N«-Z(Ne-Z)-L-lysin i 200 ml tetrahydrofuran, avkjøler til 4-10°, tilsetter 16,7 g karbonyldiimidazol og rører en time ved -=-10°. Deretter tildryppes den ovenfor nevnte n-eicosanol/Na-n-eicosanolat-blandingen ved en temperatur på 0° under røring. Man rører videre 30 minutter ved 0° og 24 timer ved 20°. Oppløsningen inndampes deretter i vakuum, resten i eddikester nøytralvaskes med 1 n saltsyre, 5 pst.-ig NaCl-oppløsning, 1 n ammoniakk og 5 pst.-ig NaCl-oppløs-ning, tørkes over Na2S04, inndampes og resten krystalliseres fra ether/petrolether. However, 41.4 g of N«-Z(Ne-Z)-L-lysine are dissolved in 200 ml of tetrahydrofuran, cooled to 4-10°, 16.7 g of carbonyldiimidazole are added and stirred for one hour at -=-10°. The above-mentioned n-eicosanol/Na-n-eicosanol mixture is then added dropwise at a temperature of 0° while stirring. Stirring continues for 30 minutes at 0° and 24 hours at 20°. The solution is then evaporated in vacuo, the residue in acetic acid is washed neutrally with 1 N hydrochloric acid, 5% NaCl solution, 1 N ammonia and 5% NaCl solution, dried over Na2SO4, evaporated and the residue crystallized from ether/ petroleum ether.
Den således erholdte voksaktige N-beskyttede aminosyreester [N«-Z(NE-Z)-L-lysin-n-eicosylester] hydrogenolyseres i iseddik med 5 pst.-ig palladiumkull og hyd-rogengass. Katalysatoren skilles fra, filtratet inndampes i vakuum, resten inndampes ennå en gang med 4 n HCl/methanol og blandes deretter med aceton. Det således erholdte L-lysin-n-eicosylesterdihydroklo-rid nutsjes fra og utfelles flere ganger fra methanol under inndrypning i eddikester. Smeltepunkt 107—109°; [a] V = +7,0°, (c = 2 i methanol). The thus obtained waxy N-protected amino acid ester [N«-Z(NE-Z)-L-lysine-n-eicosyl ester] is hydrogenolysed in glacial acetic acid with 5% palladium charcoal and hydrogen gas. The catalyst is separated, the filtrate is evaporated in vacuo, the residue is evaporated once more with 4 n HCl/methanol and then mixed with acetone. The L-lysine-n-eicosyl ester dihydrochloride thus obtained is extracted from and precipitated several times from methanol while dipping in acetic acid. Melting point 107-109°; [a] V = +7.0°, (c = 2 in methanol).
Eksempel 4. Example 4.
Etter de i de foranstående eksempler beskrevne metoder lar følgende forbindelser seg fremstille: Using the methods described in the preceding examples, the following compounds can be prepared:
Eksempel 5. 23 g N«-Z(N'-Z)-L-lysyl-(N*-Z)-L-lysin omsettes ifølge eksempel 1 i nærvær av 100 ml dioxan og 5,2 ml triethylamin med 11,4 g 1-brom-hexadecan. Den N-beskyttede dipeptidester [N«-Z (N*-Z) -L-lysyl- (N*-Z) - L-lysin-n-hexadecylester] omkrystalliseres flere ganger fra eddikester/petrolether, [smeltepunkt 100—102°] og dekarbobenzoxyleres så i iseddik med hydrogen under anvendelse av 5 pst.-ig palladiumkull. Etter avskilling av katalysatoren destilleres iseddiken fra, resten inndampes med 4 n HCl/methanol og omfelles flere ganger fra ethanol/aceton. Det således erholdte L-lysyl-L-lysin-n-hexadecylester-trihydro-klorid smelter ved 234° (spaltning); [a] y = +3° (c = 2 i methanol). Example 5. 23 g of N«-Z(N'-Z)-L-lysyl-(N*-Z)-L-lysine is reacted according to example 1 in the presence of 100 ml of dioxane and 5.2 ml of triethylamine with 11.4 g 1-bromohexadecane. The N-protected dipeptide ester [N«-Z (N*-Z)-L-lysyl-(N*-Z)-L-lysine-n-hexadecyl ester] is recrystallized several times from acetic ester/petroleum ether, [melting point 100—102° ] and then decarbobenzoxylated in glacial acetic acid with hydrogen using 5% palladium charcoal. After separation of the catalyst, the glacial acetic acid is distilled from, the residue is evaporated with 4 n HCl/methanol and reprecipitated several times from ethanol/acetone. The L-lysyl-L-lysine-n-hexadecyl ester trihydrochloride thus obtained melts at 234° (decomposition); [a] y = +3° (c = 2 in methanol).
Eksempel 6. Example 6.
19 g (Nc-Z)-L-lysin-n-hexadecylester og 11,3 g Z-L-fenylalanin oppløses i 50 ml dimethylformamid avkjøles til -=-10°, tilsettes 7,7 g dicyklohexylkarbodiimid og står til henstand 20 timer ved 0°. Den full-stendig størknede reaksjonsblanding fly-tendegjøres ved kort oppvarming, avkjøles raskt og det oppståtte dicyklohexylkarba-mid skilles fra ved nutsjing. Filtratet utfelles i 1 n saltsyre, omfelles fra dimethylformamid/1 n ammoniak, nutsjes fra og tørkes. Den således erholdte rå N-beskyttede dipeptidester [Z-L-fenylalanyl-(Ne-Z)-L-lysyl-n-hexadecylester] omkrystalliseres fra ethanol og dekarbobenzoxyleres med 33 pst.-ig HBr/iseddik i 3 timer under CaCl2-tillukning. Det derved erholdte L-fenylalanyl-L-lysin-n-hexadecylester-di-hydrobromld utfelles med absolutt ether, nutsjes fra, vaskes med ether, tørkes og omkrystalliseres fra ethanol. Smeltepunkt 145—147°; [a]2Dft = -f3° (c = 2 i methanol). 19 g of (Nc-Z)-L-lysine-n-hexadecyl ester and 11.3 g of Z-L-phenylalanine are dissolved in 50 ml of dimethylformamide, cooled to -=-10°, 7.7 g of dicyclohexylcarbodiimide are added and allowed to stand for 20 hours at 0 °. The fully solidified reaction mixture is volatilized by brief heating, cooled rapidly and the resulting dicyclohexylcarbamide is separated by decantation. The filtrate is precipitated in 1 N hydrochloric acid, reprecipitated from dimethylformamide/1 N ammonia, filtered off and dried. The thus obtained crude N-protected dipeptide ester [Z-L-phenylalanyl-(Ne-Z)-L-lysyl-n-hexadecyl ester] is recrystallized from ethanol and decarbobenzoxylated with 33% HBr/glacial acetic acid for 3 hours under CaCl2 closure. The L-phenylalanyl-L-lysine-n-hexadecyl ester dihydrobromide thus obtained is precipitated with absolute ether, filtered off, washed with ether, dried and recrystallized from ethanol. Melting point 145-147°; [a]2Dft = -f3° (c = 2 in methanol).
Den som utgangsmateriale anvendte (Ne-Z)-L-lysin-n-hexadecylester kan oppnås på følgende måte: 61,6 g N«-formyl-(N<=-Z)-L-lysin, 200 The (Ne-Z)-L-lysine-n-hexadecyl ester used as starting material can be obtained in the following way: 61.6 g of N«-formyl-(N<=-Z)-L-lysine, 200
ml dioxan, 29 ml triethylamin og 61 g 1-brom-hexadecan oppvarmes 20 timer under ml of dioxane, 29 ml of triethylamine and 61 g of 1-bromohexadecane are heated for 20 hours under
tilbakeløp ved 95—100°. Triethylamin-hyd-robromidet nutsjes fra, filtratet inndampes i vakuum, resten i eddikester nøytralvaskes med 10 pst.-ig eddiksyre, 5 pst.-ig NaCl-oppløsning, i n ammoniak og 5 pst.-ig NaCl-oppløsning, tørkes over NagSOj, inndampes og krystalliseres fra ethanol. Den således erholdte Na-formyl-(Ne-Z)-L-lysin-n-hexadecylester smelter ved 86—88°. reflux at 95—100°. The triethylamine hydrobromide is distilled off, the filtrate is evaporated in vacuo, the residue in acetic acid is washed neutrally with 10% acetic acid, 5% NaCl solution, in n ammonia and 5% NaCl solution, dried over NaSOj, evaporated and crystallized from ethanol. The Na-formyl-(Ne-Z)-L-lysine-n-hexadecyl ester thus obtained melts at 86-88°.
Denne N-beskyttede aminosyreester deformyleres i 2 n HCl/methanol i 16 timer, oppløsningen inndampes og krystalliseres fra methanol/ether. Det således erholdte (Ne-Z)-L-lysin-n-hexadecylester-hydro-klorid smelter ved 88—90°; [a] <2>Dn = +6,5°, (c = 2 i methanol). This N-protected amino acid ester is deformylated in 2 n HCl/methanol for 16 hours, the solution is evaporated and crystallized from methanol/ether. The (Ne-Z)-L-lysine-n-hexadecyl ester hydrochloride thus obtained melts at 88-90°; [a] <2>Dn = +6.5°, (c = 2 in methanol).
Den frie esterbase oppnår man, idet man fordeler hydrokloridet mellom kloroform og ammoniak, vasker kloroformfasen med vann, tørker over Na2S04 og inndamper i vakuum. Den frie (Ne-Z)-L-lysin-n-hexadecylester faller så ut som olje, som størkner ved avkjøling. The free ester base is obtained by dividing the hydrochloride between chloroform and ammonia, washing the chloroform phase with water, drying over Na2S04 and evaporating in a vacuum. The free (Ne-Z)-L-lysine-n-hexadecyl ester then precipitates as an oil, which solidifies on cooling.
Eksempel 7. Example 7.
6,8 g L-fenylalanin-n-hexadecylester og 7,2 g N«-Z(NE-Z)-L-lysin oppløses i 40 ml dimethylformamid, tilsettes ved 0° 3,55 g dicyklohexylkarbodiimid og står til henstand i 20 timer ved 0°. Ved kort oppvarming flytendegjøres den størknende masse, avkjøles raskt og dicyklohexadecylkarba-mid nutsjes fra. Filtratet fortynnes med eddikester, nøytralvaskes så med 1 n saltsyre, 5 pst.-ig NaCl-oppløsning, 1 n ammoniak og 5 pst.-ig NaCl-oppløsning, tørkes over Na2S04, inndampes og resten krystalliseres fra eddikester/petrolether. Den erholdte N-beskyttede dipeptidester dekarbobenzoxyleres i iseddik med hydrogen i nærvær av 5 pst.-ig palladiumkull, katalysatoren skilles fra, filtratet inndampes, resten inndampes med 4 n HCl/methanol og blandes med aceton. Det således erholdte L-lysyl-L-fenylalanin-n-hexadecylester-dihydroklorid nutsjes fra og omkrystalliseres fra ethanol. Smeltepunkt 160— 162°; [a] = +20,4°, (c = 2 i methanol). 6.8 g of L-phenylalanine-n-hexadecyl ester and 7.2 g of N«-Z(NE-Z)-L-lysine are dissolved in 40 ml of dimethylformamide, 3.55 g of dicyclohexylcarbodiimide are added at 0° and allowed to stand for 20 hours at 0°. Upon brief heating, the solidifying mass liquefies, cools quickly and dicyclohexadecylcarbamide is distilled off. The filtrate is diluted with ethyl acetate, then neutral washed with 1 N hydrochloric acid, 5% NaCl solution, 1 N ammonia and 5% NaCl solution, dried over Na2SO4, evaporated and the residue crystallized from ethyl acetate/petroleum ether. The N-protected dipeptide ester obtained is decarbobenzoxylated in glacial acetic acid with hydrogen in the presence of 5% palladium charcoal, the catalyst is separated, the filtrate is evaporated, the residue is evaporated with 4 n HCl/methanol and mixed with acetone. The thus obtained L-lysyl-L-phenylalanine-n-hexadecyl ester dihydrochloride is distilled off and recrystallized from ethanol. Melting point 160— 162°; [a] = +20.4°, (c = 2 in methanol).
Eksempel 8. Example 8.
23 g N«-formyl-(NY-Z)-L-a,y-diamino-smørsyre-n-hexadecylester (smeltepunkt 89—91°; [a]\3 = -4-12,1°; c = 2 i methanol) dekarbobenzoxyleres i iseddik med 5 pst.-ig palladiumkull og hydrogen. Katalysatoren nutsjes så fra, filtratet inndampes i vakuum, resten utrystes med vann, eddikester og overskytende ammoniakk, eddikesterfasen vaskes med vann, tørkes over NajSO,, og inndampes i vakuum. Man oppnår således N«-formyl-L-a, y-diaminosmør-syre-n-hexadecylester som seig olje, som krystalliserer ved avkjøling. 23 g of N«-formyl-(NY-Z)-L-a,y-diamino-butyric acid-n-hexadecyl ester (melting point 89-91°; [a]\3 = -4-12.1°; c = 2 in methanol ) is decarbobenzoxylated in glacial acetic acid with 5% palladium charcoal and hydrogen. The catalyst is then removed, the filtrate is evaporated in vacuo, the residue is shaken off with water, acetic acid and excess ammonia, the acetic acid phase is washed with water, dried over Na 2 SO 4 , and evaporated in vacuum. N-formyl-L-a,y-diaminobutyric acid-n-hexadecyl ester is thus obtained as a viscous oil, which crystallizes on cooling.
Til en oppløsning av 15 g av den erholdte ester og 15,7 g N«-Z(Nv-Z)-D-a, y-diaminosmørsyre i 70 ml dimethylformamid tilsettes ved 0° en oppløsning av 8,4 g dicyklohexylkarboimid og står til henstand i 20 timer ved 0°. Deretter nutsjes det utskilte dicyklohexylcarbamid fra. Filtratet fortynnes med 500 ml eddikester, nøytralvaskes med 1 n ammoniakk, vann og 1 n eddiksyre, og eddikesteroppløsnin-gen tørkes over Na2S04 og inndampes deretter i vakuum. Den således erholdte Na-f ormyl-Nv- [N«-Z(Nv-Z) -D-a,y-diamino-butyryl]-L-a,y-diaminosmørsyre-n-hexadecylester krystalliseres fra eddikester/- petrolether. Smeltepunkt 114—116°; [a] 2Dn To a solution of 15 g of the ester obtained and 15.7 g of N«-Z(Nv-Z)-D-a,y-diaminobutyric acid in 70 ml of dimethylformamide, a solution of 8.4 g of dicyclohexyl carboimide is added at 0° and allowed to stand for 20 hours at 0°. The separated dicyclohexylcarbamide is then filtered off. The filtrate is diluted with 500 ml of acetic acid, washed neutrally with 1 N ammonia, water and 1 N acetic acid, and the acetic acid solution is dried over Na 2 SO 4 and then evaporated in vacuo. The thus obtained Na-formyl-Nv-[N«-Z(Nv-Z)-D-a,y-diamino-butyryl]-L-a,y-diaminobutyric acid-n-hexadecyl ester is crystallized from acetic ester/petroleum ether. Melting point 114-116°; [a] 2Dn
-4-6,9° (c = 2 i dimethylformamid). -4-6.9° (c = 2 in dimethylformamide).
5 g av den erholdte N-beskyttede dipeptidester dekarbobenzoxyleres i iseddik med hydrogen i nærvær av 5 pst.-ig palladiumkull. Deretter nutsjes katalysatoren fra, filtratet inndampes i vakuum og resten deformyleres med 30 ml 4 n HCl/methanol i 5 timer ved 20°. Man inndamper deretter oppløsningen i vakuum, blander resten med aceton, nutsjer fra, feller om fra methanol/aceton og methanol/eddikester og tør-ker i vakuum ved 60°. Det således erholdte Ny- (D-a,y-diaminobutyryl) -L-a,y-di-aminosmørsyre-n-hexadecylester-trihyd-roklorid smelter ved 190—193° (spaltning); [a] V = -4-15,7° (c = 3 i methanol). 5 g of the N-protected dipeptide ester obtained is decarbobenzoxylated in glacial acetic acid with hydrogen in the presence of 5% palladium charcoal. The catalyst is then removed, the filtrate is evaporated in vacuo and the residue is deformylated with 30 ml of 4 n HCl/methanol for 5 hours at 20°. The solution is then evaporated in a vacuum, the residue is mixed with acetone, filtered off, precipitated from methanol/acetone and methanol/acetic ester and dried in a vacuum at 60°. The N-(D-a,y-diaminobutyryl)-L-a,y-diaminobutyric acid-n-hexadecyl ester trihydrochloride thus obtained melts at 190-193° (decomposition); [a] V = -4-15.7° (c = 3 in methanol).
Eksempel 9. Example 9.
32 g N«-formyl-(Ne-Z)-L-lysin-n-hexadecylester dekarbobenzoxyleres i iseddik med palladiumkull og hydrogen. Katalysatoren nutsjes fra, filtratet inndampes i vakuuum, resten oppløses med en blanding av vann og eddikester, oppløsningen innstilles med konsentrert ammoniakk på en pH lik 9—10, ektraheres deretter med 32 g of N«-formyl-(Ne-Z)-L-lysine-n-hexadecyl ester are decarbobenzoxylated in glacial acetic acid with palladium charcoal and hydrogen. The catalyst is discarded, the filtrate is evaporated in vacuo, the residue is dissolved with a mixture of water and vinegar, the solution is adjusted with concentrated ammonia to a pH equal to 9-10, then extracted with
eddikester, eddikesterfasen tørkes over Na,S04 og inndampes i vakuum. Den som rest inneholdende Na-formyl-L-lysin-n-hexadecylester størkner ved avkjøling. acetic acid, the acetic acid phase is dried over Na, SO 4 and evaporated in vacuo. The remaining Na-formyl-L-lysine-n-hexadecyl ester solidifies on cooling.
22 g av den således erholdte amlnosyre-ester og 22,9 g N«-Z(Ne-Z)-L-lysin oppløses i 50 ml dimethylformamid, tilsettes ved 0° en oppløsning av 11,3 g dicyklohexylkarbodiimid og står til henstand i 24 timer ved 0°. Det erholdte tykke gel flytendegjøres ved oppvarming, deretter nutsjes dicyklohexylcarbamidet fra, og filtratet utfelles i 1 n eddiksyre. Man nutsjer bunnfallet fra 22 g of the amino acid ester thus obtained and 22.9 g of N«-Z(Ne-Z)-L-lysine are dissolved in 50 ml of dimethylformamide, a solution of 11.3 g of dicyclohexylcarbodiimide is added at 0° and allowed to stand in 24 hours at 0°. The thick gel obtained is liquefied by heating, then the dicyclohexylcarbamide is filtered off, and the filtrate is precipitated in 1 N acetic acid. The sediment is skimmed off
og omfeller det fra dimethylformamid/- 1 n ammoniakk. Den således erholdte N"-formyl-Ne-[N«-Z(Ne-Z)-L-lysyl]-L-lysin-n-hexadecylester nutsjes fra, vaskes med vann, tørkes i vakuum og omkrystalliseres fra eddikester/petrolether. Smeltepunkt 102—104°; [a]2D<s> = -4-10,2° (c = 2 i methanol). 15 g av den således erholdte dipeptidester dekarbobenzoxyleres i iseddik med palladiumkull og hydrogen. Katalysatoren nutsjes fra, filtratet inndampes i vakuum og resten deformyleres med 100 ml 2 n HCl/methanol i 5 timer ved 20°. Ved inn-dampning oppstår en krystallinsk rest som omkrystalliseres fra ethanol. Det således erholdte Ne-L-lysyl-L-lysin-n-hexadecylester-trihydroklorid smelter ved 220—222° and reprecipitate it from dimethylformamide/- 1 N ammonia. The N"-formyl-Ne-[N"-Z(Ne-Z)-L-lysyl]-L-lysine-n-hexadecyl ester thus obtained is filtered off, washed with water, dried in vacuum and recrystallized from ethyl acetate/petroleum ether. Melting point 102-104°; [a]2D<s> = -4-10.2° (c = 2 in methanol). 15 g of the dipeptide ester thus obtained is decarbobenzoxylated in glacial acetic acid with palladium charcoal and hydrogen. The catalyst is removed, the filtrate is evaporated in vacuum and the residue is deformylated with 100 ml of 2 n HCl/methanol for 5 hours at 20°. Upon evaporation, a crystalline residue is formed which is recrystallized from ethanol. The Ne-L-lysyl-L-lysine-n-hexadecyl ester thus obtained trihydrochloride melts at 220—222°
(spaltning); [a] y - +18,9° (c = 2 i methanol). (fission); [a] y - +18.9° (c = 2 in methanol).
Eksempel 10. Example 10.
9 g Z-D-serin og 19 g (NE-Z)-L-lysin-n-hexadecylester oppløses i 70 ml dimethylformamid og avkjøles til -4-10°, tilsettes deretter 7,7 g dicyklohexylkarbodiimid og står til henstand 20 timer ved 0°. Den størknede masse flytendegjøres ved kort oppvarming, avkjøles raskt og skilles fra dicyklohexylcarbamidet ved nutsj ing. Filtratet utfelles i 1 n saltsyre og omfelles fra dimethylformamid/1 n ammoniakk. Etter tørking krystalliserer man den erholdte Z-D-seryl- (N6-Z) -L-lysin-n-hexadecylester fra ethanol. Den erholdte N-beskyttede dipeptidester dekarbobenzoxyleres i iseddik med 5 pst.-ig palladiumkull og hydrogen. Katalysatoren skilles fra filtratet inndampes og inndampes med 4 n HC1/- ethanol1. Det således erholdte D-seryl-L-lysin-n-hexadecylester-dihydroklorid blandes med aceton, står til henstand 3 timer ved 0°, nutsjes fra og krystalliseres fra 9 g of Z-D-serine and 19 g of (NE-Z)-L-lysine-n-hexadecyl ester are dissolved in 70 ml of dimethylformamide and cooled to -4-10°, then 7.7 g of dicyclohexylcarbodiimide are added and allowed to stand for 20 hours at 0 °. The solidified mass is liquefied by brief heating, cooled quickly and separated from the dicyclohexylcarbamide by nutting. The filtrate is precipitated in 1 N hydrochloric acid and reprecipitated from dimethylformamide/1 N ammonia. After drying, the obtained Z-D-seryl-(N6-Z)-L-lysine-n-hexadecyl ester is crystallized from ethanol. The N-protected dipeptide ester obtained is decarbobenzoxylated in glacial acetic acid with 5% palladium charcoal and hydrogen. The catalyst is separated from the filtrate, evaporated and evaporated with 4 n HC1/- ethanol1. The D-seryl-L-lysine-n-hexadecyl ester dihydrochloride thus obtained is mixed with acetone, allowed to stand for 3 hours at 0°, filtered off and crystallized from
ethanol. Smeltepunkt 120°; [<x]2D<ft> = -4-15°, (c = 2 i methanol). ethanol. Melting point 120°; [<x]2D<ft> = -4-15°, (c = 2 in methanol).
Eksempel 11. Example 11.
17 g L-lysin-n-hexadecylester og 34,6 g Na-Z(NE-Z)-L-lysin oppløses i 150 ml dimethylformamid, tilsettes ved -f-10° 17 g dicyklohexylkarbodiimid og står til hen- 17 g of L-lysine-n-hexadecyl ester and 34.6 g of Na-Z(NE-Z)-L-lysine are dissolved in 150 ml of dimethylformamide, 17 g of dicyclohexylcarbodiimide are added at -f-10° and allowed to stand until
stand i 24 timer ved 0°. Det tykke gel fly- stand for 24 hours at 0°. The thick gel fly-
tendegjøres ved oppvarming, avkjøles raskt og befries ved nutsj ing fra dicyklohexyl- becomes tenacious by heating, cools quickly and is freed by nutting from dicyclohexyl-
carbamidet. Filtratet fortynnes med 800 the carbamide. The filtrate is diluted with 800
ml eddikester og nøytralvaskes med 1 n saltsyre, vann, 1 n ammoniakk og vann. ml of acetic acid and neutral washed with 1 n hydrochloric acid, water, 1 n ammonia and water.
Etter tørking over Na2S04 avdestilleres After drying over Na2S04, distill off
eddikester en i vakuum og resten omkry- acetic acid one in vacuum and the rest in circu-
stalliseres først fra ethanol, så fra metha- is stabled first from ethanol, then from meth-
nol. Den således erholdte N-beskyttede Na,Ne-Di-L-lysyl-L-lysin-n-hexadecyles- nil The thus obtained N-protected Na,Ne-Di-L-lysyl-L-lysine-n-hexadecyles-
ter smelter ved 131—132°. ter melts at 131—132°.
Denne N-beskyttede tripeptidester dekarbobenzoxyleres i iseddik med 5 pst.-ig palladiumkull og hydrogen, katalysatoren skilles fra og iseddiken destilleres av i vakuum. Resten inndampes med 4 n HC1/- This N-protected tripeptide ester is decarbobenzoxylated in glacial acetic acid with 5% palladium charcoal and hydrogen, the catalyst is separated and the glacial acetic acid is distilled off in a vacuum. The residue is evaporated with 4 n HC1/-
methanol i vakuum, blandes med aceton, methanol in vacuum, mix with acetone,
nutsjes fra, tørkes og omfelles flere ganger fra ethanol/aceton. Det således erholdte Na-L-lysyl-(Ne-L-lysyl)-L-lysin-n-hexadecylester-tetrahydroklorid smelter ved 240° (spaltning); [a] y = +12,9° (c = Nuts are removed, dried and reprecipitated several times from ethanol/acetone. The thus obtained Na-L-lysyl-(Ne-L-lysyl)-L-lysine-n-hexadecyl ester tetrahydrochloride melts at 240° (decomposition); [a] y = +12.9° (c =
2 i methanol). 2 in methanol).
Eksempel 12. Example 12.
20,9 g N«-Z(N*-Z)-L-lysyl-(N<=-Z)-L-lysinhydrazin oppløses i 120 ml 80 pst.-ig eddiksyre og 13 ml konsentrert saltsyre, 20.9 g of N«-Z(N*-Z)-L-lysyl-(N<=-Z)-L-lysine hydrazine is dissolved in 120 ml of 80% acetic acid and 13 ml of concentrated hydrochloric acid,
tilsettes 150 ml eddikester og avkjøles til add 150 ml of vinegar and cool to
-=-10°. Ved denne temperatur tildrypper man en oppløsning av 2,2 g natriumnitrit i 10 ml vann under røring, ekstraherer etter 20 minutter azidet ved 0° med 150 -=-10°. At this temperature, a solution of 2.2 g of sodium nitrite in 10 ml of water is added dropwise while stirring, after 20 minutes the azide is extracted at 0° with 150
ml eddikester, vasker eddikesterekstraktet med vann, 1 n natriumbikarbonatoppløs- ml acetic acid, wash the acetic acid extract with water, 1 n sodium bicarbonate solution
ning og tørker ved 0° over natriumsulfat. ning and drying at 0° over sodium sulfate.
Den ennu eddiksure azidoppløsning tilset- The still acetic acid azide solution added
tes porsjonsvis under røring ved 0° med en oppløsning av 15,6 g (Ne-Z)-L-lysin-hexa- portionwise while stirring at 0° with a solution of 15.6 g of (Ne-Z)-L-lysine-hexa-
decylester i 50 ml eddikester og står til henstand 48 timer ved 0°. Den således erholdte N-beskyttende tripeptidester [N«-Z (N*-Z) -L-lysyl- (N<=-Z) -L-lysyl- (N*-Z) - decylester in 50 ml of acetic acid and leave to stand for 48 hours at 0°. The thus obtained N-protecting tripeptide ester [N«-Z (N*-Z)-L-lysyl-(N<=-Z)-L-lysyl-(N*-Z)-
L-lysin-n-hexadecylester] nutsjes fra, vas- L-lysine-n-hexadecyl ester] nutsjes from, vas-
kes med ether, utfelles fra dimethylform- kes with ether, is precipitated from dimethylform-
amid i 1 n saltsyre, og omfelles fra dimethylformamid/1 n ammoniakk, nutsjes fra, amide in 1 N hydrochloric acid, and reprecipitated from dimethylformamide/1 N ammonia, evaporated from,
tørkes og omkrystalliseres fra dimethylformamid/alkohol. Smeltepunkt 151—153°, dried and recrystallized from dimethylformamide/alcohol. Melting point 151—153°,
[a] V = -=-8,3° (c = 2 i dimethylform- [a] V = -=-8.3° (c = 2 in dimethylform-
amid). amide).
15 g av den erholdte N-beskyttede tri- 15 g of the obtained N-protected tri-
peptidester dekarbobenzoxyleres i iseddik med palladiumkull og hydrogen. Kataly- peptide esters are decarbobenzoxylated in glacial acetic acid with palladium charcoal and hydrogen. Cataly-
satoren skilles så fra og filtratet inndam- the sator is then separated and the filtrate
pes i vakuum1. Resten oppløses i 60 ml 4 n HCl/methanol, inndampes straks i vakuum, pes in vacuum1. The residue is dissolved in 60 ml of 4 n HCl/methanol, immediately evaporated in vacuo,
blandes så med aceton, nutsjes fra og om- then mixed with acetone, sprinkled off and on
telles flere ganger fra methanol/eddik- counted several times from methanol/acetic
ester. Man oppnår så L-lysyl-L-lysyl-L-lysin-n-hexadecylester-tetrahydrokloridet med smeltepunkt 275° (spaltning). ester. The L-lysyl-L-lysyl-L-lysine-n-hexadecyl ester tetrahydrochloride with a melting point of 275° (decomposition) is then obtained.
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE8302335A SE436298B (en) | 1983-04-26 | 1983-04-26 | DEVICE WITH A VEHICLE DEVICE DEVICE WITH A VEHICLE |
PCT/SE1984/000145 WO1984004374A1 (en) | 1983-04-26 | 1984-04-16 | A means in a heating boiler |
Publications (3)
Publication Number | Publication Date |
---|---|
NO845230L NO845230L (en) | 1984-12-21 |
NO155066B true NO155066B (en) | 1986-10-27 |
NO155066C NO155066C (en) | 1987-02-04 |
Family
ID=26658463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO845230A NO155066C (en) | 1983-04-26 | 1984-12-21 | DEVICE BY FORK BOILER. |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO155066C (en) |
-
1984
- 1984-12-21 NO NO845230A patent/NO155066C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO155066C (en) | 1987-02-04 |
NO845230L (en) | 1984-12-21 |
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