NO115737B - - Google Patents

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NO115737B
NO115737B NO133325A NO13332559A NO115737B NO 115737 B NO115737 B NO 115737B NO 133325 A NO133325 A NO 133325A NO 13332559 A NO13332559 A NO 13332559A NO 115737 B NO115737 B NO 115737B
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acid
group
amino
penicillin
general formula
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NO133325A
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Norwegian (no)
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H Smith
F Doyle
J Nayler
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Beecham Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Fremgangsmåte for fremstilling av bredspektrede penicillinderivater. Process for the production of broad-spectrum penicillin derivatives.

Foreliggende oppfinnelse vedrører derivater av 6-aminopenicillansyre. The present invention relates to derivatives of 6-aminopenicillanic acid.

6-aminopenicillansyre har strukturforme-len: 6-aminopenicillanic acid has the structural formula:

Det har nu i henhold til foreliggende oppfinnelse vist seg at nye penicillinderivater med verdifull antibiotisk aktivitet kan fåes ved å innføre aminoacylsubstituentgrupper i amino-gruppen i 6-aminopenicillansyren. According to the present invention, it has now been shown that new penicillin derivatives with valuable antibiotic activity can be obtained by introducing aminoacyl substituent groups in the amino group of 6-aminopenicillanic acid.

De nye penicillinderivater fremstilt i henhold til oppfinnelsen har den generelle formel: The new penicillin derivatives produced according to the invention have the general formula:

og salter herav, hvor R betyr et hydrogenatom, en eventuelt med en hydroksygruppe substitu- and salts thereof, where R means a hydrogen atom, optionally substituted with a hydroxy group

ert alkylrest, en cykloheksyl-, furyl- eller en eventuelt med et halogenatom eller en hydrok- ert alkyl residue, a cyclohexyl, furyl or one optionally with a halogen atom or a hydroxy

sy- eller alkoksygruppe substituert arylrest eller gruppen sy or alkoxy group substituted aryl radical or the group

hvor R' har den for R angitte betydning eller er en amino- eller karboksylgruppe og n står for et helt tall, idet acylresten ikke inneholder mer enn 20 karbonatomer. where R' has the meaning given for R or is an amino or carboxyl group and n stands for a whole number, the acyl residue not containing more than 20 carbon atoms.

Forbindelsene som fremstilles i henhold til oppfinnelsen er verdifulle som antibakterielle midler, som tilskuddsnæringsstoffer i fCrstof-fer, som middel for behandling av mastitis hos kveg og som terapeutiske midler for fjærkre og dyr, innbefattet mennesker, spesielt ved behandling av infeksjonssykdommer som forårsakes av Gram-positive og Gram-negative bakterier. The compounds produced according to the invention are valuable as antibacterial agents, as supplemental nutrients in organic matter, as agents for the treatment of mastitis in cattle and as therapeutic agents for poultry and animals, including humans, especially in the treatment of infectious diseases caused by Gram- positive and Gram-negative bacteria.

En av forbindelsene som fremstilles i henhold til foreliggende fremgangsmåte, a-aminobenzylpenicillin (som dets D(-)-epimer), er av særlig stor verdi, som et bredspektret antibiotikum, særlig i betraktning av dets aktivitet like overfor Gram-negative bakterier. One of the compounds prepared according to the present process, α-aminobenzylpenicillin (as its D(-)-epimer), is of particular value as a broad-spectrum antibiotic, especially in view of its activity against Gram-negative bacteria.

Saltene er ikke-giftige salter omfattende ikke-giftige metallsalter som natrium, kalium, The salts are non-toxic salts comprising non-toxic metal salts such as sodium, potassium,

kalsium og aluminium, ammoniumsalter og sub-stituerte ammoniumsalter, f. eks. salter av slike ikke-giftige aminer som trialkylaminer innbefattet trietylamin, prokain, dibenzylamin, N-benzyl-|3-fenyletylamin, 1-efenamin, N,N'-diben-zyletylendiamin, dehydroabietylamin, N.N-bis-dehydroabietyletylendiamin og andre aminer som er blitt anvendt for å danne salter med benzylpenicillin. calcium and aluminium, ammonium salts and substituted ammonium salts, e.g. salts of such non-toxic amines as trialkylamines including triethylamine, procaine, dibenzylamine, N-benzyl-|3-phenylethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N,N-bis-dehydroabiethylethylenediamine and other amines which are have been used to form salts with benzylpenicillin.

Foreliggende oppfinnelse tilveiebringer en fremgangsmåte for fremstilling av penicillinderivater av den generelle formel I som erkarakterisert vedat 6-aminopenicillansyre kobles med en syre av den generelle formel The present invention provides a method for the production of penicillin derivatives of the general formula I which is characterized by combining 6-aminopenicillanic acid with an acid of the general formula

hvis aminogruppe eller grupper er beskyttet, eller et reaktivt derivat herav, og deretter fjer-nes den beskyttende gruppe eller grupper under tilstrekkelig milde forhold for å unngå øde-leggelse av penicillinkjernen, og eventuelt omdannes penicillinet til et ikke-toksisk salt. whose amino group or groups are protected, or a reactive derivative thereof, and then the protecting group or groups are removed under sufficiently mild conditions to avoid destruction of the penicillin core, and optionally the penicillin is converted into a non-toxic salt.

Hovedmengden av derivater som er nevnt ovenfor, inneholder i det minste et asymmetrisk karbonatom og vil foreligge i D- og L-former. Det vil forståes at foreliggende oppfinnelse omfatter både D- og L-former og DL-blandingen. Når derivatet inneholder to asymmetriske karbonatomer, vil det foreligge fire isomerer og to DL-blandinger. The bulk of derivatives mentioned above contain at least one asymmetric carbon atom and will exist in D and L forms. It will be understood that the present invention includes both D and L forms and the DL mixture. When the derivative contains two asymmetric carbon atoms, there will be four isomers and two DL mixtures.

De beskyttende, aminoacylderivater av 6-aminopenicillansyre fremstilles fortrinnsvis ved å la 6-aminopenicillansyre reagere med et blandet anhydrid fremstilt ved å la den aminosubstituerte karboksylsyre, eller et salt herav, med dens aminogruppe eller -grupper beskyttet, reagere med en ester av klorkarbonsyre, f. eks. etyl- i klorkarbonat. Alternativt kan den beskyttede aminosubstituerte karboksylsyre omdannes til et reaktivt syrehalogenid. The protected aminoacyl derivatives of 6-aminopenicillanic acid are preferably prepared by reacting 6-aminopenicillanic acid with a mixed anhydride prepared by reacting the amino-substituted carboxylic acid, or a salt thereof, with its amino group or groups protected, with an ester of chlorocarbonic acid, f e.g. ethyl- i chlorine carbonate. Alternatively, the protected amino-substituted carboxylic acid can be converted to a reactive acid halide.

Andre fremgangsmåter som anvendes for å danne det beskyttede aminoacylderivat av 6-aminopenicillansyre er standardfremgangsmåter som anvendes i peptidsyntesen og omfatter bru-ken av et reaktivt syreazid eller et karbodi-imidreagens (sml. Sheehan og Hess, J. Amer. Chem. Soc, 1955, 77, 1067). Other methods used to form the protected aminoacyl derivative of 6-aminopenicillanic acid are standard procedures used in peptide synthesis and include the use of a reactive acid azide or a carbodiimide reagent (cf. Sheehan and Hess, J. Amer. Chem. Soc, 1955 , 77, 1067).

Den påfølgende fjernelse av den beskyttende gruppe eller grupper for å danne det frie aminosubstituerte penicillin kan bevirkes ved katalytisk hydrogenering, og passende beskyttende grupper er f. eks. grupper av den generelle formel R"0. CO-, hvor R" er en allyl-benzyl-, substituert benzyl-, fenyl- eller substituert fenylgruppe, eller tritylgruppen Ph3. C-. Forkortelsen «Ph» som her anvendes, represen-terer fenylgruppen. The subsequent removal of the protecting group or groups to form the free amino-substituted penicillin can be effected by catalytic hydrogenation, and suitable protecting groups are e.g. groups of the general formula R"O.CO-, where R" is an allyl-benzyl, substituted benzyl, phenyl or substituted phenyl group, or the trityl group Ph3. C-. The abbreviation "Ph" used here represents the phenyl group.

Fjernelsen av den beskyttende gruppe eller grupper bevirkes ved å la det beskyttede aminoacylderivat reagere med hydrogen i nærvær av en katalysator. Denne hydrogenering utføres normalt ved romtemperatur og ved atmosfærisk trykk og pH i reaksjonsblandingen er fra 5 til 9. Oppløsningsmiddelet for hydrogeneringsre-aksjonen er normalt vann, men andre ikke re-duserbare oppløsningsmidler som etylalkohol eller dioksan eller blandinger av disse med vann kan anvendes. The removal of the protecting group or groups is effected by allowing the protected aminoacyl derivative to react with hydrogen in the presence of a catalyst. This hydrogenation is normally carried out at room temperature and at atmospheric pressure and the pH of the reaction mixture is from 5 to 9. The solvent for the hydrogenation reaction is normally water, but other non-reducible solvents such as ethyl alcohol or dioxane or mixtures of these with water can be used.

Den foretrukne hydrogeneringskatalysator er palladium, men andre katalysatorer som pla-tina eller rhodium kan anvendes. Katalysatoren anvendes fortrinnsvis på et inert bæremid-del, f. eks. bariumkarbonat eller kull. The preferred hydrogenation catalyst is palladium, but other catalysts such as platinum or rhodium can be used. The catalyst is preferably used on an inert carrier, e.g. barium carbonate or charcoal.

Når et karbonatom som befinner seg ved det som bærer karbobenzyloksyamingruppen, som skal reduseres, utgjør en del av en aroma-tisk ring, tilendebringes hydrogeneringstrinnet normalt ved en eneste behandling med hydrogen og katalysator. I alle andre tilfeller, dvs. når karbonatomet som befinner seg ved det som bærer karbobenzyloksyaminogruppen som skal reduseres, er av alifatisk natur, kan det imid-lertid for å bevirke en fullstendig reaksjon være nødvendig å hydrogenere i nærvær av to eller flere på hverandre følgende porsjoner av katalysator. When a carbon atom located at the carrier of the carbobenzyloxyamine group, which is to be reduced, forms part of an aromatic ring, the hydrogenation step is normally completed by a single treatment with hydrogen and catalyst. In all other cases, i.e. when the carbon atom adjacent to that bearing the carbobenzyloxyamino group to be reduced is of an aliphatic nature, however, in order to effect a complete reaction, it may be necessary to hydrogenate in the presence of two or more successive portions of catalyst.

Når den aminosubstituerte karboksylsyre inneholder mer enn én karboksylsyre, f. eks. a-aminoadipinsyre, er det i øyemed å fremstille et helt bestemt acylderivat nødvendig enten å beskytte en av karboksylgruppene før reaksjonen med 6-aminopenicillansyre eller å fremstille et helt bestemt reaktivt derivat av bare én karboksylgruppe. When the amino-substituted carboxylic acid contains more than one carboxylic acid, e.g. α-aminoadipic acid, in order to prepare a completely specific acyl derivative, it is necessary either to protect one of the carboxyl groups before the reaction with 6-aminopenicillanic acid or to prepare a completely specific reactive derivative of only one carboxyl group.

Da enkelte av de antibiotiske stoffer som fåes ved fremgangsmåten ifølge oppfinnelsen, er relativt ustabile forbindelser som lett kan bli utsatt for kjemiske forandringer resulterende i at den antibiotiske aktivitet går tapt, er det ønskelig å velge reaksjons- og isoleringsforhold som er tilstrekkelig moderate til å unngå at de spaltes. Since some of the antibiotic substances obtained by the method according to the invention are relatively unstable compounds that can easily be exposed to chemical changes resulting in the antibiotic activity being lost, it is desirable to choose reaction and isolation conditions that are sufficiently moderate to avoid that they split.

Det følgende eksempel skal tjene til å klar-gjøre oppfinnelsen. The following example shall serve to clarify the invention.

Eksempel 1.Example 1.

Fremstilling av aminometylpenicillin. Preparation of aminomethylpenicillin.

Natriumsaltet av karbobenzyloksyaminometylpenicillin ble fremstilt som følger: Etylklorkarbonat (1,9 ml) ble tilsatt dråpe-vis til en iskjølt omrørt oppløsning av N-karbo^benzyloksyglycin (4,5 g) og trietylamin (3 ml) i tørr aceton (170 ml). Etter 5 minutter ble den resulterende suspensjon som inneholdt det blandete anhydrid, behandlet langsomt med en is-kald oppløsning av 6-aminopenicillansyre (4,3 The sodium salt of carbobenzyloxyaminomethylpenicillin was prepared as follows: Ethyl chlorocarbonate (1.9 ml) was added dropwise to an ice-cooled stirred solution of N-carbo-benzyloxyglycine (4.5 g) and triethylamine (3 ml) in dry acetone (170 ml). . After 5 minutes, the resulting suspension containing the mixed anhydride was treated slowly with an ice-cold solution of 6-aminopenicillanic acid (4.3

g) i 3 pst.'s'vandig natriumbikarbonat (170 ml). Under hele tilsetningen ble blandingen holdt g) in 3% aqueous sodium bicarbonate (170 ml). During the entire addition, the mixture was maintained

ved 0°C, men deretter fikk den anledning til å anta romtemperatur i løpet av ytterligere en times omrøring. Blandingen ble vasket med eter (3 x 250 ml) og vaskevæskene ble kastet bort. Den vandige fase ble behandlet med saltsyre til pH 2 og den frie penicillinsyre ble ekstrahert i butanol (40 ml, derpå 2 x 10 ml). Natriumsaltet av karbobenzyloksyaminometylpenicillin ble utvunnet ved pånyekstrahering av den vaskete butanoloppløsning med vann (3x5 ml), og til hver av disse porsjoner var det blitt tilsatt tilstrekkelig 3 pst. vandig natriumkarbonat for å tilveiebringe den vandige fase til pH 7. De forente vandige ekstrakter ble vasket med eter og derpå inndampet under 20°C i vakuum så at man fikk et fast natriumsalt (4,7 g). at 0°C, but was then allowed to assume room temperature during a further hour of stirring. The mixture was washed with ether (3 x 250 mL) and the washings were discarded. The aqueous phase was treated with hydrochloric acid to pH 2 and the free penicillin acid was extracted into butanol (40 ml, then 2 x 10 ml). The sodium salt of carbobenzyloxyaminomethylpenicillin was recovered by re-extracting the washed butanol solution with water (3 x 5 ml), and to each of these portions sufficient 3% aqueous sodium carbonate had been added to bring the aqueous phase to pH 7. The combined aqueous extracts were washed with ether and then evaporated below 20°C in vacuum to give a solid sodium salt (4.7 g).

En suspensjon av palladium på bariumkarbonat (7,3 g, av 30 pst.) i vann (200 ml) ble rystet i en atmosfære av hydrogen ved romtemperatur og atmosfærisk trykk i 2 timer. Etter denne behandling ble katalysatoren oppsamlet og vasket med vann, idet man sørget for at den aldri ble tørr. Natriumsaltet av karbobenzyloksyaminometylpenicillin (III) (4,5 g av det materiale med en renhet av 40 pst.) ble tilsatt til den vandige suspensjon av den forbehandlete katalysator og pH regulert til 8,0 med natrium-bikarbonatoppløsning (3 pst.). Blandingen ble derpå rystet under hydrogen ved romtemperatur og atmosfærisk trykk i 45 minutter. En annen mengde av palladium på bariumkarbonat (7,3 g, av 30 pst.), på forhånd redusert som tidligere, ble tilsatt og hydrogeneringen fortsatte i ytterligere 45 minutter. Katalysatoren ble filtrert fra, vasket med vann og filtratet etter regule-ring til pH 7,0 med N-saltsyre, ble inndampet til tørrhet under redusert trykk ved en temperatur under 20°C. Aminometylpenicillinet (IV) fikk man som et gult pulver (3,0 g) som ved prøve påviste en renhet av 33 pst. Papirkromatografi viste at dette materiale inneholdt et antibiotikum som hadde en betydelig forskjellig RF verdi fra utgangsmaterialet. Produktet viste seg å være stabilt i sur oppløsning og å hemme veksten av Staph. aureus ved en konsentrasjon av 1,25 mikrogram/milliliter. A suspension of palladium on barium carbonate (7.3 g, of 30 percent) in water (200 mL) was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 2 hours. After this treatment, the catalyst was collected and washed with water, taking care that it never became dry. The sodium salt of carbobenzyloxyaminomethylpenicillin (III) (4.5 g of the material with a purity of 40 percent) was added to the aqueous suspension of the pretreated catalyst and the pH adjusted to 8.0 with sodium bicarbonate solution (3 percent). The mixture was then shaken under hydrogen at room temperature and atmospheric pressure for 45 minutes. Another amount of palladium on barium carbonate (7.3 g, of 30 percent), pre-reduced as before, was added and the hydrogenation continued for another 45 minutes. The catalyst was filtered off, washed with water and the filtrate, after adjustment to pH 7.0 with N-hydrochloric acid, was evaporated to dryness under reduced pressure at a temperature below 20°C. The aminomethylpenicillin (IV) was obtained as a yellow powder (3.0 g) which, when tested, showed a purity of 33 percent. Paper chromatography showed that this material contained an antibiotic that had a significantly different RF value from the starting material. The product proved to be stable in acidic solution and to inhibit the growth of Staph. aureus at a concentration of 1.25 micrograms/milliliter.

Eksempel 2. Example 2.

Fremstilling av a-aminopentylpenicillin. Preparation of α-aminopentylpenicillin.

a-karbobenzyloksyaminopentylpenicillin ble fremstilt med 64 pst. utbytte fra 6-aminopenicillansyre og et blandet anhydrid, fremstilt fra N-karbobenzyloksy-DL-nor-leucin og etylklorkarbonat i henhold til den generelle fremgangsmåte som er anført i eksempel 1. α-Carbobenzyloxyaminopentylpenicillin was prepared in 64% yield from 6-aminopenicillanic acid and a mixed anhydride, prepared from N-carbobenzyloxy-DL-nor-leucine and ethyl chlorocarbonate according to the general procedure set forth in Example 1.

Natriumsaltet av a-karbobenzyloksyaminopentylpenicillin (56 pst. rent) ble hydrogen ert i nærvær av tre på hverandre følgende deler av for-behandlet palladium på bariumkarbonat-katalysator, som beskrevet i eksempel 1, for å gi a-aminopentylpenicillin, som ved prøve viste seg å være 34 pst. rent og med et utbytte av 56 pst. Papirkromatografi viste bare et antibiotikum med en betydelig forskjellig RF verdi fra utgangsmaterialet. Det var stabilt i sur oppløsning og viste seg å hemme veksten av Staph. aureus ved en konsentrasjon av 0,12 mikrogram/milliliter. N-karbobenzyloksy-DL-nor-leucin, smp. 106 —107°C, ble erholdt med 70 pst. utbytte fra DL-nor-leucin og benzylklorkarbonat i kold vandig natriumhydroksydoppløsning. The sodium salt of α-carbobenzyloxyaminopentylpenicillin (56% pure) was hydrogenated in the presence of three successive portions of pretreated palladium on barium carbonate catalyst, as described in Example 1, to give α-aminopentylpenicillin, which on trial showed to be 34 percent pure and with a yield of 56 percent. Paper chromatography showed only one antibiotic with a significantly different RF value from the starting material. It was stable in acidic solution and was shown to inhibit the growth of Staph. aureus at a concentration of 0.12 micrograms/milliliter. N-carbobenzyloxy-DL-nor-leucine, m.p. 106 -107°C, was obtained in 70% yield from DL-nor-leucine and benzyl chlorocarbonate in cold aqueous sodium hydroxide solution.

Eksempel 3Example 3

Fremstilling av a-aminoheptylpenicillin. a-karboksybenzylaminoheptylpenicillin ble fremstilt med 43 pst. utbytte fra 6-aminopenicillansyre og et blandet anhydrid fremstilt fra DL-a-karbobenzyloksyamino-oktansyre og etylklorkarbonat i henhold til den generelle fremgangsmåte som er anført i eksempel 1. Preparation of α-aminoheptylpenicillin. α-Carboxybenzylaminoheptylpenicillin was prepared in 43% yield from 6-aminopenicillanic acid and a mixed anhydride prepared from DL-α-carbobenzyloxyaminooctanoic acid and ethyl chlorocarbonate according to the general procedure stated in Example 1.

Natriumsaltet av a-karbobenzyloksyamino-heptylpenicillin (68 pst. rent) ble hydrogenert i nærvær av tre på hverandre følgende deler av for-behandlet palladium på bariumkarbonatka-talysator, som beskrevet i eksempel 1, for å gi a-aminoheptylpenicillin, som ved prøve viste seg å være 47 pst. rent og med et utbytte av 44 pst. Papirkromatografi viste bare ett antibiotikum med en betydelig forskjellig R,,, verdi fra utgangsmaterialet. Det var stabilt i sur opp-løsnin og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,012 mikrogram/milliliter. DL-a-karbobenzyloksyamino-oktansyren som krevdes for denne fremstillingen, ble erholdt ved reaksjonen av benzylklorkarbonat med DL-a-amino-oktansyre i fortynnet natriumhydrok-sydoppløsning. Det ble erholdt som fargeløse krystaller (63 pst.), smp. 91—92°C. The sodium salt of α-carbobenzyloxyaminoheptylpenicillin (68% pure) was hydrogenated in the presence of three successive portions of pretreated palladium on barium carbonate catalyst, as described in Example 1, to give α-aminoheptylpenicillin, which by test showed proved to be 47 per cent pure and with a yield of 44 per cent. Paper chromatography showed only one antibiotic with a significantly different R,,, value from the starting material. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.012 micrograms/milliliter. The DL-α-carbobenzyloxyamino-octanoic acid required for this preparation was obtained by the reaction of benzyl chlorocarbonate with DL-α-amino-octanoic acid in dilute sodium hydroxide solution. It was obtained as colorless crystals (63 percent), m.p. 91-92°C.

(Funnet: 65,7 % C. 7,9 % H. 4,9 % N. C1CH,3N04krever: 65,5 % C. 7,9 % H. 4,7 %N). (Found: 65.7% C. 7.9% H. 4.9% N. C1CH,3N04 required: 65.5% C. 7.9% H. 4.7%N).

Eksempel 4Example 4

Fremstilling av a-aminocykloheksylmetylpeni-cillin. a-karbobenzyloksyaminocykloheksylmetylpe-nicillin ble fremstilt med 51 pst. utbytte fra 6-aminopenicillansyre og et blandet anhydrid fremstilt fra DL-a-karbobenzyloksyaminocyklo-heksyleddiksyre og etylklorkarbonat i henhold til den generelle fremgangsmåte som er anført i eksempel 1. Preparation of α-aminocyclohexylmethylpenicillin. α-Carbobenzyloxyaminocyclohexylmethylpenicillin was prepared in 51% yield from 6-aminopenicillanic acid and a mixed anhydride prepared from DL-α-carbobenzyloxyaminocyclohexylacetic acid and ethyl chlorocarbonate according to the general procedure stated in example 1.

Natriumsaltet av a-karbobenzyloksyamino-cykloheksylmetylpenicillin (75 pst. rent) ble hydrogenert i nærvær av tre på hverandre føl-gende deler av for-behandlet palladium på ba-riumkarbonatkatalysator, som beskrevet i eksempel 1, for å gi a-aminocykloheksylmetylpeni-cillin, som ved prøve viste seg å være 46 pst. rent og med 51 pst. utbytte. Papirkromatografi viste bare ett antibiotikum med en betydelig forskjellig RF verdi enn utgangsmaterialet. Det var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,12 mikrogram/milliliter. DL-a-karbobenzyloksyaminocykloheksyled-diksyre, smp. 136—137°C ble fremstilt med 80 pst. utbytte fra DL-a-aminocykloheksyleddiksyre og benzylklorkarbonat i natriumhydroksydopp-løsning. The sodium salt of α-carbobenzyloxyamino-cyclohexylmethylpenicillin (75% pure) was hydrogenated in the presence of three consecutive portions of pretreated palladium on barium carbonate catalyst, as described in Example 1, to give α-aminocyclohexylmethylpenicillin, which on testing proved to be 46 per cent pure and with a yield of 51 per cent. Paper chromatography showed only one antibiotic with a significantly different RF value than the starting material. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.12 micrograms/milliliter. DL-α-carbobenzyloxyaminocyclohexylacetic acid, m.p. 136-137°C was prepared with 80% yield from DL-α-aminocyclohexylacetic acid and benzyl chlorocarbonate in sodium hydroxide solution.

(Funnet: 66,2 % C. 7,5 % H. 4,6 N%. C^H^NO., krever: 65,9 % C. 7,3 % H. 4,8 %N). (Found: 66.2% C. 7.5% H. 4.6% N. C^H^NO., required: 65.9% C. 7.3% H. 4.8%N).

Eksempel, 5Example, 5

Fremstilling av a-amino-(3-fenyletylpenicillin a-karbobenzyloksyamino-p-fenyletylpenicillin ble fremstilt ved å bringe N-karbobenzyloksy-(5-fenyl-DL-alanin til reaksjon med etylklorkar- Preparation of α-amino-(3-phenylethylpenicillin α-carbobenzyloxyamino-p-phenylethylpenicillin was prepared by reacting N-carbobenzyloxy-(5-phenyl-DL-alanine) with ethylchlorocar-

bonat for å gi det reaktive blandede anhydrid. Dette ble derpå bragt til reaksjon med 6-aminopenicillansyre under de forhold som er beskrevet i eksempel 1. bonate to give the reactive mixed anhydride. This was then reacted with 6-aminopenicillanic acid under the conditions described in example 1.

Natriumsaltet av a-karbobenzyloksyamino-|3-fenyletylpenicillin (53 pst. rent) ble hydrogenert i nærvær av tre på hverandre følgende deler av for-behandlet palladium på barium-karbonatkatalysator, som beskrevet i eksempel The sodium salt of α-carbobenzyloxyamino-|3-phenylethylpenicillin (53% pure) was hydrogenated in the presence of three consecutive portions of pretreated palladium on barium carbonate catalyst, as described in Example

1, for å gi a-amino-p-fenyletylpenicillin, som 1, to give α-amino-p-phenylethylpenicillin, which

ved prøve viste seg å være 30 pst. rent og med 49 pst. utbytte. Papirkromatografi viste at dette when tested it turned out to be 30 per cent pure and with a yield of 49 per cent. Paper chromatography showed that this

materialet inneholdt bare ett antibiotikum som hadde en betydelig forskjellig RFverdi fra utgangsmaterialet. Produktet var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,6 mikrogram/milli-liter. the material contained only one antibiotic that had a significantly different RF value from the starting material. The product was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.6 micrograms/millilitre.

Eksempel 6Example 6

Fremstilling av a-amino-|3-hydroksyetylpeni-cillin a-karbobenzyloksyamino-(3-hydroksyetylpe-nicillin ble fremstilt med 67 pst. utbytte fra 6-aminopenicillansyre og et blandet anhydrid som fåes fra N-karbobenzyloksy-DL-serin og etylklorkarbonat, i henhold til den generelle fremgangsmåte som er anført i eksempel 1. Preparation of α-amino-|3-hydroxyethylpenicillin α-carbobenzyloxyamino-(3-hydroxyethylpenicillin) was prepared in 67% yield from 6-aminopenicillanic acid and a mixed anhydride obtained from N-carbobenzyloxy-DL-serine and ethyl chlorocarbonate, according to the general procedure set forth in Example 1.

Dette ble erholdt ved å hydrogenere natriumsaltet av a-karbobenzyloksyamino-p-hydroksyetylpenicillin (70 pst. rent), som beskrevet i eksempel 2, med 29 pst. utbytte og som ved prøve viste seg å være 21 pst. rent. Papirkromatografi viste bare ett antibiotikum med en betydelig forskjellig RF verdi fra utgangsmaterialet. Det var stabilt i sur oppløs-ning og viste seg å hemme Staph. aureus ved en konsentrasjon av 5,0 mikrogram/milimeter. This was obtained by hydrogenating the sodium salt of α-carbobenzyloxyamino-p-hydroxyethylpenicillin (70% pure), as described in example 2, with a yield of 29% and which by test proved to be 21% pure. Paper chromatography showed only one antibiotic with a significantly different RF value from the starting material. It was stable in acidic solution and proved to inhibit Staph. aureus at a concentration of 5.0 micrograms/millimetre.

Eksempel 7Example 7

Fremstilling av a-aminobenzylpenicillin Natriumsaltet av a-karbobenzyloksyamino-benzylpenicillin ble erholdt ved å la DL-a-karbobenzyloksyaminofenyleddiksyre (1 ekv.) reagere med etylklorkarbonat (1 ekv.) for å gi det reaktive blandete anhydrid. Dette fikk derpå anledning til å reagere med 6-aminopenicil-lanyre under de forhold som er beskrevet i eksempel 1. Det erholdtes et gult fast stoff (65 pst.) som ved prøve viste seg å være 56 pst. rent. Preparation of α-aminobenzylpenicillin The sodium salt of α-carbobenzyloxyaminobenzylpenicillin was obtained by reacting DL-α-carbobenzyloxyaminophenylacetic acid (1 eq.) with ethyl chlorocarbonate (1 eq.) to give the reactive mixed anhydride. This was then given the opportunity to react with 6-aminopenicyl-lanyre under the conditions described in example 1. A yellow solid was obtained (65 per cent) which, by test, proved to be 56 per cent pure.

En suspensjon av palladium på bariumkarbonat (3,7 g, av 30 pst.) i vann (20 ml ble rystet i en atmosfære av hydrogen ved romtemperatur og atmosfærisk trykk i iy2time. Katalysatoren ble derpå filtrert og vasket godt med vann, idet man sikret seg at den ikke ble tørr. En oppløsning av natriumsaltet av a-karbobenzyl-oksyaminobenzylpenicillin (4 g) i vann (20 ml) ble tilsatt til den for-behandlete katalysator og suspensjonen rystet i en atmosfære av hydrogen ved romtemperatur og trykk i en time. Katalysatoren ble derpå avfiltrert, vasket godt med vann og det forente filtrat og vaskevæskene regulert til pH 7,0 med saltsyre. Den resulterende oppløsning ble derpå inndampet i vakuum ved en temperatur under 20°C for å gi a-amiriobenzylpenicillin (indre salt) (2,4 g, 74 pst.) som ved prøve viste seg å være 48 pst. rent. Papirkromatografi viste at dette materiale inneholdt bare ett antibiotikum, som hadde en betydelig forskjellig RF verdi fra utgangsmate-riale. Det var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,12 mikrogram/millimeter. A suspension of palladium on barium carbonate (3.7 g, of 30 per cent) in water (20 ml) was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for iy2h. The catalyst was then filtered and washed well with water, ensuring A solution of the sodium salt of α-carbobenzyloxyaminobenzylpenicillin (4 g) in water (20 ml) was added to the pretreated catalyst and the suspension shaken in an atmosphere of hydrogen at room temperature and pressure for one hour . The catalyst was then filtered off, washed well with water and the combined filtrate and washings adjusted to pH 7.0 with hydrochloric acid. The resulting solution was then evaporated in vacuo at a temperature below 20°C to give α-amiriobenzylpenicillin (inner salt) (2.4 g, 74 per cent) which was tested to be 48 per cent pure. Paper chromatography showed that this material contained only one antibiotic, which had a significantly different RF value from the starting material. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.12 micrograms/millimetre.

Eksempel 8Example 8

Fremstilling av a-amino-p-klorbenzyipeniculin Preparation of α-amino-p-chlorobenzypeniculin

Dette ble erholdt i henhold til den fremgangsmåte som er beskrevet i eksempel 7 ved hydrogenering av natriumsaltet av a-karbobenzyloksyamino-p-klorbenzylpenicillin (42 pst. rent) med 88 pst. utbytte og som ved prøve viste seg å være 45 pst. rent. Det var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,06 mikro-gram/milliliter. DL-a-karbobenzyloksyamino-p-klorfenyleddiksyre ble erholdt fra den tilsvarende a-aminosyre med 85 pst. utbytte, smp 132—133°C. This was obtained according to the method described in example 7 by hydrogenating the sodium salt of α-carbobenzyloxyamino-p-chlorobenzylpenicillin (42% pure) with a yield of 88% and which, by test, proved to be 45% pure. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.06 microgram/milliliter. DL-α-carbobenzyloxyamino-p-chlorophenylacetic acid was obtained from the corresponding α-amino acid in 85% yield, mp 132-133°C.

(Funnet: 60,5 % C. 4,8 % H. 4,7 % N. C16HHC1N04 krever: 60,0 % C. 4,4 % H. 4,4 %N). (Found: 60.5% C. 4.8% H. 4.7% N. C16HHC1N04 requires: 60.0% C. 4.4% H. 4.4%N).

Nevnte syre ble koblet med 6-aminopenicillansyre ved fremgangsmåten som angitt i eksempel 1 under bruk av etylklorkarbonat. Said acid was coupled with 6-aminopenicillanic acid by the method indicated in example 1 using ethyl chlorocarbonate.

Eksempel 9Example 9

Fremstilling av a-amino-l-naftylmetylpenicillin Preparation of α-amino-l-naphthylmethylpenicillin

a-amino-l-naftylmetyloddliksyre, smp. 219 —220°C ble fremstilt ved Bergs-Bucherer-syn-tesen fra a-naftaldehyd (jfr. Harvill og Herbst, J. Org Chem., 1944, 9, 21). Med benzylklorkarbonat i vandig natriumhydroksydoppløsning gav det a-karbobenzyloksyamino-l-naftyleddik-syre, smp. 144—145° C med 40 pst. utbytte. Det blandete anhydrid fremstilt fra denne syre og etylklorkarbont ble koblet med 6-aminopenicillansyre i henhold til den generelle fremgangsmåte som er anført i eksempel 1, så at man fikk a-karbobenzyloksyamino-l-naftylmetylpenicillin. α-amino-l-naphthylmethyl butylic acid, m.p. 219-220°C was prepared by the Bergs-Bucherer synthesis from α-naphthaldehyde (cf. Harvill and Herbst, J. Org Chem., 1944, 9, 21). With benzyl chlorocarbonate in aqueous sodium hydroxide solution it gave α-carbobenzyloxyamino-1-naphthylacetic acid, m.p. 144-145° C with 40 percent yield. The mixed anhydride prepared from this acid and ethyl chlorocarbon was coupled with 6-aminopenicillanic acid according to the general procedure given in Example 1, so that α-carbobenzyloxyamino-1-naphthylmethylpenicillin was obtained.

a-amino-l-naftylmetylpenicillin ble erholdt i henhold til den fremgangsmåte som er beskrevet i eksempel 7, ved hydrogenering av natriumsaltet av«-karbobenzyloksyamino-l-nafitylme-tylpenicillin (64 pst. rent) med 61 pst. utbytte, og som ved prøve viste seg å være 40 pst. rent. Det var stabilt i sur oppløsning og viste seg å hemme Staph. Oxford ved en konsentrasjon av 0,025 mikrogram/milliliter. α-amino-1-naphthylmethylpenicillin was obtained according to the method described in example 7, by hydrogenating the sodium salt of α-carbobenzyloxyamino-1-naphthylmethylpenicillin (64% pure) with 61% yield, and as sample turned out to be 40 percent pure. It was stable in acidic solution and was shown to inhibit Staph. Oxford at a concentration of 0.025 micrograms/milliliter.

Eksempel 10Example 10

Fremstilling av a-amino-2-furylmetylpenicillin Preparation of α-amino-2-furylmethylpenicillin

Natriumsaltet av a-karbobenzyloksyamino-2-furylmetylpenicillin ble erholdt ved å be-handle DL-a-karb6benzyloksyamino-2-furyled-diksyre (1 ekv.) med etylklorkarbonat (1 ekv.) så at man fikk det reaktive blandete anhydrid. Dette fikk anledning til å reagere med 6-amlno-penicillansyre under de betingelser som er beskrevet i eksempel 1. Det erholdtes et utbytte av 32 pst. av et fast stoff, som var 40 pst. rent. The sodium salt of α-carbobenzyloxyamino-2-furylmethylpenicillin was obtained by treating DL-α-carb6benzyloxyamino-2-furylacetic acid (1 eq.) with ethyl chlorocarbonate (1 eq.) to give the reactive mixed anhydride. This gave the opportunity to react with 6-amlno-penicillanic acid under the conditions described in example 1. A yield of 32% of a solid was obtained, which was 40% pure.

a-amino-2-furylmetylpenicillin ble erholdt i henhold til den fremgangsmåte som er beskrevet i eksempel 7, ved hydrogenering av natriumsaltet av a-karbobenzyloksyamino-2-furylmetyl-penicillin (40 pst. rent) med 74 pst. utbytte og som ved prøve viste seg å være 32 pst. rent. Papirkromatografi viste bare ett antibiotikum med en RFverdi betydelig forskjellig fra utgangsmaterialets. Det var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,5 mikrogram/milliliter. DL-a-karbobenzyloksyamino-2-furyleddik-syre, smp. 121—122°C ble erholdt med 40 pst. utbytte ved behandling av a-amino-2-furyled-diksyre med benzylklorkarbonat i fortynnet na-triumhydroksydoppløsning. α-amino-2-furylmethylpenicillin was obtained according to the method described in example 7, by hydrogenating the sodium salt of α-carbobenzyloxyamino-2-furylmethylpenicillin (40% pure) with a yield of 74% and as in test turned out to be 32 percent clean. Paper chromatography showed only one antibiotic with an RF value significantly different from that of the starting material. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.5 micrograms/milliliter. DL-α-carbobenzyloxyamino-2-furylacetic acid, m.p. 121-122°C was obtained with 40% yield by treating α-amino-2-furylacetic acid with benzyl chlorocarbonate in dilute sodium hydroxide solution.

(Funnet: 61,3 % C. 4,7 % H. 4,9 % N. CuH13OsN krever: 61,1 % C. 4,8 % H. 5,1 %N). (Found: 61.3% C. 4.7% H. 4.9% N. CuH13OsN requires: 61.1% C. 4.8% H. 5.1%N).

Eksempel 11Example 11

Fremstilling av a,E-diaminopentylpenicillin a,e-dikarbobenzyloksyaminopentylpenicillin ble fremstilt ved å la N,N'-dikarbobenzyloksy-DL-]ysin (1 ekv.) reagere med etylklorkarbonat (1 ekv.) for å gi det reaktive blandete anhydrid. Dette fikk anledning til å reagere med 6-aminopenicillansyre under de betingelser som er beskrevet i eksempel 1. Preparation of α,E-diaminopentylpenicillin α,ε-dicarbobenzyloxyaminopentylpenicillin was prepared by reacting N,N'-dicarbobenzyloxy-DL-]ysine (1 eq.) with ethyl chlorocarbonate (1 eq.) to give the reactive mixed anhydride. This gave the opportunity to react with 6-aminopenicillanic acid under the conditions described in example 1.

Natriumsaltet avct.e-dikarbobenzyloksy-aminopentylpenicillin (2,0 g, av 68 pst. renhet) ble redusert med to deler (2 x 4,4 g) forbehand-let palladium på bariumkarbonat i vann (2 x 50 ml) ved pH 8,0 som beskrevet i eksempel 1. Den totale tid for hydrogeneringen var 2 timer og den andre mengden av katalysator ble tilsatt etter 1 time. Isolering som beskrevet i eksempel 1, gav a,e-diaminopentylpenicillin som et hygro-skopisk fast stoff (0,65 g) som ved prøve viste seg å ha en renhet av 22 pst. Papirkromatografi viste at dette materiale hadde en betydelig forskjellig RF verdi fra utgangsmaterialet. Produktet viste seg å hemme Staph. aureus ved en konsentrasjon av 1,25 mikrogram/milliliter. The sodium salt of α-dicarbobenzyloxy-aminopentylpenicillin (2.0 g, of 68% purity) was reduced with two parts (2 x 4.4 g) pretreated palladium on barium carbonate in water (2 x 50 ml) at pH 8 ,0 as described in example 1. The total time for the hydrogenation was 2 hours and the second amount of catalyst was added after 1 hour. Isolation as described in Example 1 gave a,e-diaminopentylpenicillin as a hygroscopic solid (0.65 g) which, when tested, was found to have a purity of 22 percent. Paper chromatography showed that this material had a significantly different RF value from the starting material. The product was shown to inhibit Staph. aureus at a concentration of 1.25 micrograms/milliliter.

Eksempel 12Example 12

Fremstilling av a-amino-p-metoksybenzyl-penicillin Preparation of α-amino-p-methoxybenzyl penicillin

Dette ble erholdt i henhold til den fremgangsmåte som er beskrevet i eksempel 7, ved hydrogenering av natriumsaltet av a-karbobenzyloksyamino-p-metoksybenzylpenicillin (59 pst. rent) med 58 pst. utbytte og som ved prøve viste seg å være 41 pst. rent. Papirkromatografi viste bare ett antibiotikum med en RFverdi betydelig forskjellig fra utgangsmaterialets. Det var stabilt i sur oppløsning og viste seg å hemme Staph. aureus ved en konsentrasjon av 0,025 mikrogram/milliliter. DL-a karbobenzyloksyamino-p-metoksyfenyleddiksyre ble erholdt fra den tilsvarende a-aminosyre med 60 pst. utbytte, sm.p. 105°C. This was obtained according to the method described in example 7, by hydrogenating the sodium salt of α-carbobenzyloxyamino-p-methoxybenzylpenicillin (59% pure) with a yield of 58% and which, by test, proved to be 41% pure . Paper chromatography showed only one antibiotic with an RF value significantly different from that of the starting material. It was stable in acidic solution and was shown to inhibit Staph. aureus at a concentration of 0.025 micrograms/milliliter. DL-α carbobenzyloxyamino-p-methoxyphenylacetic acid was obtained from the corresponding α-amino acid in 60% yield, m.p. 105°C.

(Funnet: 65,0 % C. 5,5 % H. 4,1 % N. (Found: 65.0% C. 5.5% H. 4.1% N.

C17H17N03krever: 64,8 % C. 5,4 % H. 4,4 %N). C17H17N03requires: 64.8% C. 5.4% H. 4.4%N).

Nevnte syre ble koblet med 6-aminopenicillansyre ved fremgangsmåten som angitt i eksempel 1 under bruk av etylklorkarbonat. Said acid was coupled with 6-aminopenicillanic acid by the method indicated in example 1 using ethyl chlorocarbonate.

Claims (2)

1. Fremgangsmåte for fremstilling av bredspektrede penicillinderivater av den generelle formel1. Process for the preparation of broad-spectrum penicillin derivatives of the general formula og salter herav, hvor R betyr et hydrogenatom, en eventuelt med en hydroksygruppe substituert alkylrest, en cykloheksyl-, furyl- eller en eventuelt med et halogenatom eller en hydroksy- eller alkoksygruppe substituert arylrest eller gruppen and salts thereof, where R means a hydrogen atom, an alkyl radical optionally substituted with a hydroxy group, a cyclohexyl, furyl or an aryl radical optionally substituted with a halogen atom or a hydroxy or alkoxy group or the group . hvor R' har den for R angitte betydning eller er en amino- eller karboksygruppe og n står for et helt tall, idet acylresten ikke inneholder mer enn 20 karbonatomer, karakterisert ved at 6-aminopenicillansyre kobles med en syre av den generelle formel . where R' has the meaning given for R or is an amino or carboxy group and n stands for a whole number, the acyl residue not containing more than 20 carbon atoms, characterized in that 6-aminopenicillanic acid is coupled with an acid of the general formula hvis aminogruppe eller grupper er beskyttet, eller et reaktivt derivat herav, og deretter fjer-nes den beskyttende gruppe eller grupper under tilstrekkelig milde forhold for å unngå øde-leggelse av penicillinkjernen, og eventuelt omdannes peinicillinet til et ikke-toksisk salt. whose amino group or groups are protected, or a reactive derivative thereof, and then the protecting group or groups are removed under sufficiently mild conditions to avoid destruction of the penicillin nucleus, and optionally the penicillin is converted into a non-toxic salt. 2. Fremgangsmåte som angitt i krav 1 for fremstilling av a-aminobenzylpenicillin, karakterisert ved at det som syre av den generelle formel II anvendes a-aminofenyled-diksyré.2. Process as stated in claim 1 for the production of α-aminobenzylpenicillin, characterized in that α-aminophenylacetic acid is used as acid of the general formula II.
NO133325A 1958-10-06 1959-10-05 NO115737B (en)

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GB960896A (en) * 1961-09-26 1964-06-17 Lepetit Spa Production of penicillins
ES284254A1 (en) * 1962-01-29 1963-07-16 Bristol Myers Co A procedure for the production of an alpha-aminobencilopeniline (Machine-translation by Google Translate, not legally binding)
GB975379A (en) * 1962-08-18 1964-11-18 Beecham Res Lab Preparation of ª‡-aminobenzylpenicillin and salts thereof
DE3936298A1 (en) * 1989-11-01 1991-05-02 Bayer Ag SUBSTITUTED AMINO ACID DERIVATIVES THE PRODUCTION AND USE THEREOF
DE4030062A1 (en) * 1990-09-22 1992-03-26 Bayer Ag SUBSTITUTED AMINO ACID DERIVATIVES THE PRODUCTION AND USE THEREOF
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