DK142702B - Process for the preparation of isoclavulanic acid derivatives. - Google Patents
Process for the preparation of isoclavulanic acid derivatives. Download PDFInfo
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- DK142702B DK142702B DK574875AA DK574875A DK142702B DK 142702 B DK142702 B DK 142702B DK 574875A A DK574875A A DK 574875AA DK 574875 A DK574875 A DK 574875A DK 142702 B DK142702 B DK 142702B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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Description
V R^Bby (11) FREMLÆGGELSESSKRIFT 142702 DANMARK m-a-s c 07 D 498/04 §(21) Ansøgning nr. 57^8/75 (22) Indleveret den 17· &eC. 1975 (24) Løbedag 17. deC. 1975 (44) Ansøgningen fremlagt og „V R ^ Bby (11) SUBMISSION WRITING 142702 DENMARK m-a-s c 07 D 498/04 § (21) Application No. 57 ^ 8/75 (22) Filed on 17 · & eC. 1975 (24) Race day 17. deC. 1975 (44) The application presented and "
fremlasggelsesskriftet offentliggjort den 22. aeC. lyOUthe writ of publication published on the 22nd aeC. Lyou
DIREKTORATET FOR ._u .. .DIRECTORATE OF ._u ...
PATENT-OG VAREMÆRKEVÆSENET ™ 1g?^ ^jQQ/^ GBPATENT AND TRADEMARKET ™ ™ 1g? ^^ jQQ / ^ GB
14. apr. 1975a 15211/75, GBApr 14 1975a 15211/75, GB
(71) BEECHAM GROUP LIMITED, Beecham House, Great West Road, Brentford,(71) BEECHAM GROUP LIMITED, Beecham House, Great West Road, Brentford,
Middlesex TW8 9^D, GB.Middlesex TW8 9 ^ D, GB.
(7¾ Opfinder: Thomas Trefor Howarth, Little Yard Cottage, North Breache Lane, Ewhurst, Surrey, GB: Irene Stirling, 147 Vale Road, Worcester Park, Surrey, GB.(7¾ Inventor: Thomas Trefor Howarth, Little Yard Cottage, North Breache Lane, Ewhurst, Surrey, GB: Irene Stirling, 147 Vale Road, Worcester Park, Surrey, GB.
(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:
Plougmann & Vingtoft Patentbureau._ (54) Fremgangsmåde til fremstilling af isoclavulansyrederivater.Plougmann & Vingtoft Patentbureau._ (54) Process for producing isoclavulanic acid derivatives.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af hidtil ukendte (3-lactamholdige forbindelser med Ø-lac-tamase-inhiberende virkning og, i en vis udstrækning, antlbakteriel virkning.The present invention relates to a particular process for the preparation of novel (3-lactam-containing compounds with β-lac-tamase inhibitory activity and, to some extent, antibacterial activity.
I dansk patentansøgning nr. 1672/75 er beskrevet clavulansyre, som er en forbindelse med formlenDanish Patent Application No. 1672/75 discloses clavulanic acid, which is a compound of the formula
HH
iin
! CH„0H! CH "0H
i ii i
COOHCOOH
2 142702 eller salte eller estere deraf. Clavulansyre er en β-lactamase--inhibitor og et antibakterielt middel.2 142702 or salts or esters thereof. Clavulanic acid is a β-lactamase inhibitor and an antibacterial agent.
Der er nu fundet en yderligere gruppe forbindelser, som har |3-lactamase-inhiberende virkning og antibakterielle egenskaber.An additional group of compounds having β-lactamase inhibitory activity and antibacterial properties has now been found.
Den foreliggende opfindelse bygger på denne erkendelse og angårThe present invention is based on this recognition and relates to
en fremgangsmåde til fremstilling af en forbindelse med formlen Ia process for preparing a compound of formula I
HH
<-4λ ' / λ N . ch2oh 1<-4λ '/ λ N. ch2oh 1
COOHCOOH
©Her et salt deraf med en base eller en hydrogenolyserbar eller hydrolyserbar ester heraf, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse med formlen VIHere, a salt thereof having a base or a hydrogenolysable or hydrolysable ester thereof, the process of which is characterized in that a compound of formula VI
HH
_U CH20H_U CH20H
VIWE
COOHCOOH
eller et salt eller en ester af den ovenfor angivne art iso-meriseres ved at blive bragt i kontakt med en overgangsme-talkatalysator i nærværelse af hydrogen eller ved ultraviolet bestråling.or a salt or ester of the above type is isomerized by contacting with a transition metal catalyst in the presence of hydrogen or by ultraviolet radiation.
hvorefter, om ønsket, den carboxylsyreafledte funktion i 2-stil-lingen omdannes til en anden carboxylsyreafledt funktion af den ovenfor angivne artwhereupon, if desired, the carboxylic acid-derived function in the 2-position is converted to another carboxylic acid-derived function of the above-mentioned kind.
En særlig velegnet gruppe af de omhandlede forbindelser udgøres af de farmaceutisk tolerable salte og estere.A particularly suitable group of the subject compounds are the pharmaceutically tolerable salts and esters.
142702 3142702 3
Sådanne salte er f.eks. natrium-, kalium-, calcium-, magnesium-, aluminium- og sædvanlige substituerede ammoniumsalte, især salte, som har den almene formel IIISuch salts are e.g. sodium, potassium, calcium, magnesium, aluminum and usual substituted ammonium salts, especially salts having the general formula III
0^—NV ch2oh t COO" M+ hvor M+ er en natrium- eller kaliumion.O + --NV ch 2 H t COO + M + where M + is a sodium or potassium ion.
Sådanne salte kan danne hydrater.Such salts can form hydrates.
Estere af forbindelsen med formlen I er sådanne, som har den almene formel IVEsters of the compound of formula I are those of general formula IV
rfVRFV
CH0OH IVCHOOH IV
o' ; lo '; l
COOACOOA
hvor A er en sådan gruppe, at COOA er en hydrogenolyserbar eller hydrolyserbar estergruppe.wherein A is such a group that COOA is a hydrogenolysable or hydrolysable ester group.
A er hensigtsmæssigt en inert organisk gruppe med højst 16 carbonato-mer og især en inert organisk gruppe med højst 12 carbonatomer.A is suitably an inert organic group having a maximum of 16 carbon atoms and in particular an inert organic group having a maximum of 12 carbon atoms.
Egnede substituenter A er alkyl, alkenyl, alkynyl, aryl eller aralkyl, som alle, om ønsket, kan være substitueret.Suitable substituents A are alkyl, alkenyl, alkynyl, aryl or aralkyl, all of which, if desired, can be substituted.
Egnede substituenter, som kan forekomme i gruppen A, er halogenatomer eller Cj_y-alkoxy, hydroxy, C^y-acyloxy eller Cg _y-aryloxy.Suitable substituents which may be present in group A are halogen atoms or C 1-6 alkoxy, hydroxy, C 1-6 acyloxy or C 1-6 aryloxy.
4 142702 A kan således være methyl, ethyl, n-propyl, isopropyl, ligekædet eller forgrenet butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclo-pentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthyl-methyl, phenyl, naphthyl, propynyl, tolyl, 2-chlorethyl, 2,2,2-tri-chlorethyl, 2,2,2-trifluorethyl, acetylmethyl, benzoylmethy1, 2-me-thoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidino-ethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorbenzyl, p--methoxybenzyl, p-nitrobenzyl, p-brombenzyl, m-chlorbenzyl, 6-metho-xynaphthyl-2-methyl, p-chlorphenyl eller p-methoxyphenyl.Thus, A can be methyl, ethyl, n-propyl, isopropyl, straight or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chloroethyl, 2,2,2-tri-chloroethyl, 2,2,2-trifluoroethyl , acetylmethyl, benzoylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p - methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl, 6-methoxynaphthyl-2-methyl, p-chlorophenyl or p-methoxyphenyl.
En foretrukken gruppe af forbindelser med formlen IV er sådanne, hvor A er en gruppe med én af underformierne a) - d): -CA1A2 - X - CO - A3 a)A preferred group of compounds of formula IV are those wherein A is a group having one of the subforms a) - d): -CA1A2 - X - CO - A3 a)
- |H - Z- | H - Z
0_\ b)0_ \ b)
OISLAND
4 5 - CHA A c) - A 6 d) 1 2 hvor A betegner et hydrogenatom eller en methylgruppe, A betegner et hydrogenatom eller en alkylgruppe med 1-4 carbonatomer, en phe-nylgruppe eller en benzylgruppe, A betegner en -alkylgruppe, en arylgruppe eller en aralkylgruppe med 7-11 carbonatomer, X betegner oxygen eller svovl, Z betegner en divalent organisk gruppe, A 4 betegner et hydrogenatom eller en inert arylgruppe, A5 betegner en inert arylgruppe, og A^ betegner en carbonhydridgruppe med 1-9 carbonatomer, som eventuelt er substitueret med halogenatomer eller med C^y-alkyl, C-^y-acyl eller C^-acyleret hydroxy.4 - CHA A c) - A 6 d) 1 2 where A represents a hydrogen atom or a methyl group, A represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, a phenyl group or a benzyl group, A represents an alkyl group, an aryl group or an aralkyl group having 7-11 carbon atoms, X represents oxygen or sulfur, Z represents a divalent organic group, A 4 represents a hydrogen atom or an inert aryl group, A5 represents an inert aryl group, and A carbon atoms optionally substituted with halogen atoms or with C 1-6 alkyl, C 1-6 acyl or C 1-6 acylated hydroxy.
I de ovenfor anførte underformler er A1 hensigtsmæssigt et hydrogen- 2 3 atom, A er et hydrogenatom eller en methylgruppe, A er en methyl-, tert.butyl eller phenylgruppe, X er oxygen, Z er -CH=CH-, 142702 5In the sub-formulas listed above, A1 is suitably a hydrogen atom, A is a hydrogen atom or a methyl group, A is a methyl, tert-butyl or phenyl group, X is oxygen, Z is -CH = CH-, 142702.
X! ~ XCX! ~ XC
OCH3 4 A er hydrogen, phenyl, tolyl, halogenphenyl eller methoxyphenyl, A8 er phenyl, tolyl, halogenphenyl eller methoxyphenyl, og A8 er en carbonhydridgruppe med 1-6 carbonatomer, som eventuelt er substitueret med chlor, brom, iod, trifluormethyl, C(CH3)3, methoxy, acetyl, benzoyl eller acetoxy.OCH 3 4 A is hydrogen, phenyl, tolyl, halophenyl or methoxyphenyl, A8 is phenyl, tolyl, halophenyl or methoxyphenyl, and A8 is a hydrocarbon group having 1-6 carbon atoms optionally substituted with chlorine, bromine, iodine, trifluoromethyl, C ( CH3) 3, methoxy, acetyl, benzoyl or acetoxy.
En særlig foretrukken gruppe af forbindelser med formlen IV er sådanne, hvor A er en gruppe med en af underfcrmlerne e) og f): A 7 I 9 - C - 0 - CO - A* e) i8 - CH - A12 i10- C = AU £> *7 g hvor A betegner et hydrogenatom eller en methylgruppe, A betegner g et hydrogenatom eller en methyl-, ethyl- eller phenylgruppe, A betegner en alkylgruppe med 1-6 carbonatomer eller en phenyl- eller benzylgruppe, A"^8 betegner -Cfc^Ct^-, -CH=CH-, X xc-xc ch3 och3 11 12 og A og A betegner oxygen eller svovl.A particularly preferred group of compounds of formula IV are those wherein A is a group having one of sub-formulas e) and f): A 7 - 9 - C - 0 - CO - A * e) i8 - CH - A12 i10-C = AU £> * 7 g where A represents a hydrogen atom or a methyl group, A represents g a hydrogen atom or a methyl, ethyl or phenyl group, A represents an alkyl group of 1-6 carbon atoms or a phenyl or benzyl group, A 8 represents -Cfc ^ Ct ^ -, -CH = CH-, X xc-xc ch3 and 3 11 12 and A and A denote oxygen or sulfur.
g I de ovenfor anførte underformler e) og f) er A særlig hensigts- q mæssigt et hydrogenatom, A er særlig hensigtsmæssigt en methyl-, 11 12 ethyl-, propyl-, butyl- eller phenylgruppe, A og A er særlig hensigtsmæssigt oxygenatomer, og A10 er særlig hensigtsmæssigt en gruppe 6 142702 X. v /OCH- eller OCH3 Særlig egnede hydrogenolyserbare estergrupper A er f.eks. benzyl-, naphthylmethyl-, benzhydryl- og tritylgrupper og deres inerte substituerede derivater såsom 4-brombenzyl-, 3,4-dimethoxybenzyl-, 6-methoxy-2-naphthylmethyl-, 4,4-dimethoxybenzhydryl og 2-nitro--benzylgrupper.g In the sub-formulas (e) and (f) above, A is particularly conveniently a hydrogen atom, A is suitably a methyl, 11 12 ethyl, propyl, butyl or phenyl group, A and A are particularly suitably oxygen atoms, and A10 is particularly convenient for a group of 6,670,702 X. v / OCH or OCH3 Particularly suitable hydrogenolysable ester groups A are e.g. benzyl, naphthylmethyl, benzhydryl and trityl groups and their inert substituted derivatives such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 6-methoxy-2-naphthylmethyl, 4,4-dimethoxybenzhydryl and 2-nitrobenzyl groups.
Af de ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser kan der fremstilles farmaceutiske præparater, som indeholder forbindelser med den almene formel I. Sådanne præparater kan også indeholde et farmaceutisk tolerabelt bærestof.From the compounds of the process of the present invention, pharmaceutical compositions containing compounds of the general formula I may be prepared. Such preparations may also contain a pharmaceutically tolerable carrier.
De pågældende præparater tildannes normalt til administration til mennesker eller andre pattedyr, f.eks. til sædvanlige behandlingsmåder af bakterielle sygdomme i urinvejene, åndedrætssystemet og blødt væv samt sygdomme såsom otitis media og mastitis.The compositions in question are usually administered for administration to humans or other mammals, e.g. for usual treatment methods of bacterial diseases of the urinary tract, respiratory system and soft tissue, as well as diseases such as otitis media and mastitis.
Velegnede præparatformer er f.eks. tabletter, kapsler, cremer, sirupper, suspensioner, opløsninger, rekonstituerbare pulvere og sterile former, som er egnede til injektion eller infusion. Sådanne præparater kan indeholde sædvanlige farmaceutisk tolerable stoffer såsom fortyndingsstoffer, bindemidler, farvestoffer, smagsstoffer, konserveringsstoffer, desintegranter og lignende stoffer i overensstemmelse med farmaceutisk praksis.Suitable formulations are e.g. tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion. Such compositions may contain usual pharmaceutically tolerable substances such as diluents, binders, dyes, flavors, preservatives, disintegrants and similar substances in accordance with pharmaceutical practice.
Forbindelsen med formlen I kan forekomme i præparatet som det eneste terapeutiske middel eller sammen med andre terapeutiske midler såsom penicillin- eller cephalosporinantibiotika.The compound of formula I may be present in the composition as the sole therapeutic agent or together with other therapeutic agents such as penicillin or cephalosporin antibiotics.
Den totale mængde antibakterielle midler, som forekommer i enhedsdosisform, vil normalt ligge mellem 50 og 1500 mg og vil sædvanligvis ligge mellem 100 og 1000 mg. Injicerbare eller infunderbare præparater kan imidlertid, om ønsket, indeholde større mængder, f.eks.The total amount of antibacterial agents present in unit dosage form will usually be between 50 and 1500 mg and will usually be between 100 and 1000 mg. However, injectable or infusible compositions may, if desired, contain greater amounts, e.g.
4 g eller mere aktivstof.4 g or more active substance.
7 1427027 142702
Normalt vil mellem 50 og 6000 mg af præparaterne blive administreret hver behandlingsdag, fortrinsvis mellem 500 og 3000 mg af præparaterne pr, dag. Til behandling af alvorlige systemiske infektioner eller infektioner, der skyldes særlig hårdnakkede organismer, kan der imidlertid anvendes større doser, i overensstemmelse med klinisk praksis.Usually between 50 and 6000 mg of the compositions will be administered each day of treatment, preferably between 500 and 3000 mg of the compositions per day. However, for the treatment of severe systemic infections or infections caused by particularly stubborn organisms, larger doses may be used, in accordance with clinical practice.
Ved et aspekt af fremgangsmåden ifølge den foreliggende opfindelse udføres isomeriseringsreaktionen ved, at en forbindelse med formlen VI bringes i kontakt med en overgangsmetalkatalysator i nærværelse af hydrogen.In one aspect of the process of the present invention, the isomerization reaction is carried out by contacting a compound of formula VI with a transition metal catalyst in the presence of hydrogen.
Hvis isomeriseringsreaktionen udføres på en ester af forbindelsen med formlen VI, vil slutproduktet ofte være en forbindelse med formlen I eller et salt heraf, hvis den i udgangsforbindelsen forekommende estergruppe er en hydrogenolyserbar estergruppe.If the isomerization reaction is carried out on an ester of the compound of formula VI, the final product will often be a compound of formula I or a salt thereof if the ester group present in the starting compound is a hydrogenolysable ester group.
En særlig velegnet metode til fremstilling af forbindelsen med formlen I eller et salt heraf består i at bringe forbindelser med den almene formel VIIA particularly suitable method for preparing the compound of formula I or a salt thereof is to bring compounds of general formula VII
HH
iin
' ^.0. CH-OH'^ .0. CH-OH
—[ \=/ J.-N\/ C) ' COOA' hvor COOA' er en hydrogenolyserbar estergruppe, i kontakt med en overgangsmetalkatalysator i nærværelse af hydrogen, hvorhos denne reaktion udføres i nærværelse af en base, når der skal fremstilles et salt af forbindelsen med formlen I.- [\ = / J.-N \ / C) 'COOA' wherein COOA 'is a hydrogen-soluble ester group, in contact with a transition metal catalyst in the presence of hydrogen, wherein this reaction is carried out in the presence of a base to produce a salt of the compound of formula I.
En særlig velegnet overgangsmetalkatalysator til udførelse af isomeriseringsreaktionen er palladium, f.eks. 10%'s palladium/kul.A particularly suitable transition metal catalyst for carrying out the isomerization reaction is palladium, e.g. 10% palladium / coal.
Ved udførelse af isomeriseringsreaktionen vil vægtforholdet mellem overgangsmetalkatalysatoren og forbindelsen med formlen VI eller VII hensigtsmæssigt være mindre end 1:3, f.eks. 1:2,5 - 1:3. (i nærværende 8 142702 beskrivelse omfatter udtrykket "vægten af overgangsmetalkatalysatoren" også vægten af et eventuelt tilstedeværende bærestof for overgangsmetalkatalysatoren). En særlig foretrukken variant af fremgangsmåden ifølge opfindelsen går ud på, at overgangskatalysatoren er palladium, og at vægtforholdet mellem katalysatoren og udgangsmaterialet er mindre end 1:3, da dette medfører reduceret tilbøjelighed til bireaktioner såsom reduktion af C^OH--gruppen til en CH-,-gruppe.In carrying out the isomerization reaction, the weight ratio of the transition metal catalyst to the compound of formula VI or VII will conveniently be less than 1: 3, e.g. 1: 2.5 - 1: 3. (in the present specification the term "the weight of the transition metal catalyst" also includes the weight of any carrier present for the transition metal catalyst). A particularly preferred variant of the process of the invention is that the transition catalyst is palladium and that the weight ratio of the catalyst to the starting material is less than 1: 3, as this results in reduced propensity for side reactions such as reduction of the C -,-group.
Hvis reaktionen udføres i nærværelse af 1 atmosfære hydrogentryk, vil reaktionen normalt være færdig på mindre end 10 timer. Særlig lange reaktionstider skal undgås, da de kan føre til en uacceptabel reduktionsgrad for den exocycliske dobbeltbinding i forbindelsen I.If the reaction is carried out in the presence of 1 atmosphere of hydrogen pressure, the reaction will usually be completed in less than 10 hours. Particularly long reaction times must be avoided as they may lead to an unacceptable reduction rate for the exocyclic double bond of compound I.
Reaktionen kan udføres ved en hvilken som helst ikke-ekstrem temperatur, f.eks. mellem -20 og +100°C, f.eks. mellem -5 og +40°C såsom mellem 0 og +20°C.The reaction can be carried out at any non-extreme temperature, e.g. between -20 and + 100 ° C, e.g. between -5 and + 40 ° C such as between 0 and + 20 ° C.
Reaktionen udføres normalt i et organisk opløsningsmiddel, som er inert under reaktionsbetingelserne. Egnede opløsningsmidler omfatter lavere alkanoler såsom ethanol, lavtkogende halogencarbonhydrider såsom chloroform og dichlormethan og ethere såsom tetrahydrofuran.The reaction is usually carried out in an organic solvent which is inert under the reaction conditions. Suitable solvents include lower alkanols such as ethanol, low boiling halohydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran.
Det er klart, at forbindelserne med formlerne VI og VII ikke altid omdannes fuldstændigt til de tilsvarende forbindelser med formlen I, og at der ofte fremkommer en ligevægtsblanding af forbindelserne VI og I eller VII og I. Sådanne blandinger kan derefter, om ønsket, adskilles på sædvanlig måde, f.eks. ved hjælp af chromatografi.It is to be understood that the compounds of formulas VI and VII are not always completely converted to the corresponding compounds of formula I, and that an equilibrium mixture of compounds VI and I or VII and I. often arises. usual way, e.g. by chromatography.
Den ultraviolette bestråling af udgangsmaterialerne udføres hensigtsmæssigt på benzylesteren af en forbindelse med formlen VI.The ultraviolet irradiation of the starting materials is conveniently carried out on the benzyl ester of a compound of formula VI.
Denne reaktion udføres normalt i et afgasset organisk opløsningsmiddel såsom benzen, carbontetrachlorid, acetonitril eller andre sædvanlige opløsningsmidler.This reaction is usually carried out in a degassed organic solvent such as benzene, carbon tetrachloride, acetonitrile or other conventional solvents.
Reaktionen udføres normalt i en inert atmosfære, f.eks. under argon eller nitrogen.The reaction is usually carried out in an inert atmosphere, e.g. under argon or nitrogen.
9 U27029 U2702
Reaktionen udføres normalt ved stuetemperatur af bekvemmelighedsgrunde, men der kan anvendes en hvilken som helst ikke-ekstrem temperatur, f.eks. mellem -20 og +80°C, selv om der foretrækkes moderate temperaturer, f.eks. mellem 0 og +30°C.The reaction is usually carried out at room temperature for convenience, but any non-extreme temperature, e.g. between -20 and + 80 ° C, although moderate temperatures are preferred, e.g. between 0 and + 30 ° C.
I overensstemmelse med sædvanlig praksis kan der, om ønsket, anvendes en "photosensitizer”. Således kan der anvendes midler såsom dibenzyl, iod, acetophenon eller benzophenon.In accordance with conventional practice, a photosensitizer may be used, if desired, so agents such as dibenzyl, iodine, acetophenone or benzophenone may be used.
Der kan anvendes et bredt eller snævert ultraviolet spektrum til at fremkalde den photolytiske isomerisering af forbindelsen med formlen VI. Det har vist sig, at "Hanovia" ® lavtryks- og mellemtrykskviksølvlamper giver tilfredsstillende resultater. Ved brug af sådanne lamper kan der anvendes en vandkølingskappe af siliciumdioxid eller glas ("Pyrex"®).A wide or narrow ultraviolet spectrum can be used to induce the photolytic isomerization of the compound of formula VI. "Hanovia" ® low-pressure and medium-pressure mercury lamps have been found to give satisfactory results. When using such lamps, a silicon or glass water cooling sheath ("Pyrex" ®) can be used.
Når en forbindelse med formlen VI bestråles med ultraviolet lys, kan forbindelsen med formlen I dannes i blanding med udgangsmaterialet eller sammen med et antal andre produkter. Denne blanding kan adskilles på sædvanlig måde, f.eks. ved chromatografi. Det har vist sig, at adskillelse af forbindelsen med formlen I ofte hensigtsmæssigt kan udføres ved søjlechromatografi, f.eks. ved søjlechromatogra-fi på silicagel med en ethylacetat/cyclohexan-blanding.When a compound of formula VI is irradiated with ultraviolet light, the compound of formula I can be formed in admixture with the starting material or together with a number of other products. This mixture can be separated in the usual manner, e.g. by chromatography. It has been found that separation of the compound of formula I can often be conveniently carried out by column chromatography, e.g. by column chromatography on silica gel with an ethyl acetate / cyclohexane mixture.
Den carboxylsyreafledte funktion i 2-stillingen i forbindelsen med formlen I kan omdannes til en anden carboxylsyreafledt funktion på sædvanlig måde, som er velkendt for fagmanden.The carboxylic acid-derived function at the 2-position of the compound of formula I can be converted to another carboxylic acid-derived function in the usual manner well known to those skilled in the art.
Når der f.eks. er en fri carboxylsyregruppe i 2-stillingen, kan denne omdannes til en estergruppe ved omsætning med en alkohol AOH, hvor A har den i forbindelse med formlen IV anførte betydning, i nærværelse af et kondensationsfremmende middel, f.eks. dicyclohexyl-carbodiimid, eller ved omsætning med en diazoforbindelse, f.eks. diazomethan, eller den kan omdannes til et salt ved behandling med en base, f.eks. natrium- eller kaliumhydrogencarbonat.For example, when is a free carboxylic acid group at the 2-position, it can be converted to an ester group by reaction with an alcohol AOH, where A has the meaning given in formula IV, in the presence of a condensation promoting agent, e.g. dicyclohexylcarbodiimide, or by reaction with a diazo compound, e.g. diazomethane or it can be converted to a salt by treatment with a base, e.g. sodium or potassium hydrogen carbonate.
Et salt af en forbindelse med formlen I kan omdannes til en ester ved en sædvanlig nucleofil substitutionsreaktion ved omsætning med en forbindelse AQ, hvor A har den i forbindelse med formlen IV anførte definition, og Q er en god fraspaltelig gruppe, f.eks. Cl,A salt of a compound of formula I may be converted to an ester by a conventional nucleophilic substitution reaction by reaction with a compound AQ wherein A has the definition of formula IV and Q is a good leaving group, e.g. Cl,
Br, I, 0S02CH3 eller 0S02CgH4CH3.Br, I, OSO2CH3 or OSO2CgH4CH3.
142702142702
Fremgangsmåden ifølge opfindelsen illustreres ved nedenstående eksempler:The process according to the invention is illustrated by the following examples:
Eksempel 1.Example 1.
H HH H
I TI T
l/\ ,CS20H ,_|/\ f y=j i [ v=, dil / \, CS20H, _ | / \ f y = j i [v =, di
J— "Ύ O Ύ 'CH2°HJ— "Ύ O Ύ 'CH2 ° H
I * I * C00CHoC0CcHt- ' 2 65 COOCH2COC6H5 (1) (2)I * I * C00CHoC0CcHt- '2 65 COOCH2COC6H5 (1) (2)
En fortyndet opløsning af 100 mg phenacylclavulanat (1) i 100 ml tørt ben zen blev bestrålet i en kvartsbeholder under anvendelse af en 450 watts "Hanovia"®mellemtrykskviksølvlampe (fra Engelhard Hanovia Lamps,A diluted solution of 100 mg phenacylclavulanate (1) in 100 ml dry benzene was irradiated in a quartz vessel using a 450 watt "Hanovia" ® medium pressure mercury lamp (from Engelhard Hanovia Lamps,
Bath Road, Slough, Buckinghamshire, England) under nitrogenatmosfære i 3 timer. Opløsningsmidlet blev fjernet ved inddampning i vakuum, og tyndtlagschromatografi af remanensen viste to komponenter, som blev adskilt ved chromatografi på silicagel med ethylacetat/cyclo-hexan (1:1) som eluant. Den mere polære komponent blev undersøgt spektroskopisk og viste sig at være identisk med udgangsmaterialet.Bath Road, Slough, Buckinghamshire, England) under nitrogen atmosphere for 3 hours. The solvent was removed by evaporation in vacuo and thin layer chromatography of the residue showed two components which were separated by silica gel chromatography with ethyl acetate / cyclohexane (1: 1) as eluant. The more polar component was investigated spectroscopically and found to be identical to the starting material.
Den mindre polære komponent blev undersøgt ved hjælp af hplc (høj“ tryksvæskechromatografi) og viste sig at være en blanding af to forbindelser, som blev adskilt ved hjælp af præparativ hplc. Den anden eluerede komponent blev vundet i form af en farveløs olie i et udbytte på 151 af det teoretiske og blev ved spektroskopisk undersøgelse tillagt den som (2) viste struktur.The minor polar component was investigated by hplc (high pressure liquid chromatography) and found to be a mixture of two compounds which were separated by preparative hplc. The second eluted component was obtained in the form of a colorless oil in a yield of 151 by the theoretical and was added by spectroscopic examination to the structure shown as (2).
IR-spektrum (film): 3480, 1790, 1750 og 1690 cm-1.IR spectrum (film): 3480, 1790, 1750 and 1690 cm -1.
NMR-spektrum (CDCLj): 3,02 (IH, dd, J 17Hz, J' 1Hz, 6β-Η); 3,52 (IH, dd, J 17Hz, J* 3Hz, 6a-H); 4,27 (2H, d, J 9Hz, CH2OH); 5,43 (IH, s, CHC02R); 5,48 (IH, m, CHCH2OH); 5,52 (2H, s, CH2C0Ph); 5,73 (IH, dd, J 3Hz, J' 1Hz, 5-H) og 7,7 (5H, m, aromatisk -H).NMR Spectrum (CDCL3): 3.02 (1H, dd, J 17Hz, J '1Hz, 6β-Η); 3.52 (1H, dd, J 17Hz, J * 3Hz, 6a-H); 4.27 (2H, d, J 9Hz, CH 2 OH); 5.43 (1H, s, CHCO 2 R); 5.48 (1H, m, CHCH 2 OH); 5.52 (2H, s, CH 2 COPh); 5.73 (1H, dd, J 3Hz, J '1Hz, 5-H) and 7.7 (5H, m, aromatic -H).
Eksempel 2.Example 2.
11 14270211 142702
! f ,_V°\ /CHjOH _yO! f, _V ° \ / CHjOH _yO
f i y=\ + »if i y = \ + »i
0>-J,Y 0J-*Y CH2OH0> -J, Y 0J- * Y CH 2 OH
• ! COOCH2C6H5 COOCH2CgH5 (3) (4)•! COOCH2C6H5 COOCH2CgH5 (3) (4)
En opløsning af 300 mg benzylclavulanat (3) i 300 ml tørt benzen blev bestrålet under nitrogenatmosfære i en kvartsbeholder under anvendelse af en "Hanovia"® Photochemical "Reading Reactor", hvorved der fås benzylisoclavulanat (4) i form af en farveløs olie og i et udbytte på 40% efter søjlechromatografi med ethylacetat/cyclohexan (1:2) som eluant. Lampeenheden (fra Engelhard Hanovia Lamps, Bath Road, Slough, Buckinghamshire, England) indeholder to lavtryksultraviolette lamper på hver 45 watt med et energimaksimum ved 254 nm.A solution of 300 mg of benzylclavulanate (3) in 300 ml of dry benzene was irradiated under nitrogen atmosphere in a quartz vessel using a "Hanovia" Photochemical "Reading Reactor" to give benzyl isoclavulanate (4) as a colorless oil and a 40% yield after column chromatography with ethyl acetate / cyclohexane (1: 2) as eluant. The lamp unit (from Engelhard Hanovia Lamps, Bath Road, Slough, Buckinghamshire, England) contains two low-pressure ultraviolet lamps of 45 watts each with an energy maximum at 254 nm.
IR-spektrum (CH2C12): 3550, 1795, 1740 og 1685 cm NMR-spektrum (CDC13): 1,85 (IH, s, CH2OH); 2,98 (IH, dd, J 17Hz, J' 1Hz, 6β-Η); 3,45 (IH, dd, J 17Hz, J' 2,5Hz, 6a-H); 4,05 (2H, d, J 7Hz, CH20H) ; 5,18 (2H, s, Ci^C^) 5,32 (IH, s, CHCC>2CH2C6H5) ; 5,35 (IH, m, forstyrret af signal ved 5,32, CHCHjOH); 5,63 (IH, dd, J 2,5Hz, J' 1Hz, 5-H); 7,36 (5H, s, aromatisk -H). Massespektrum af dette produkt viste en molekylær ion ved m/e 289.0949 (ci5Hy5N05 har en teoretisk værdi på 289.0950).IR spectrum (CH 2 Cl 2): 3550, 1795, 1740 and 1685 cm NMR spectrum (CDCl 3): 1.85 (1H, s, CH 2 OH); 2.98 (1H, dd, J 17Hz, J '1Hz, 6β-Η); 3.45 (1H, dd, J 17Hz, J '2.5Hz, 6a-H); 4.05 (2H, d, J 7Hz, CH 2 OH); 5.18 (2H, s, Ci 2 C 2) 5.32 (1H, s, CHCC> 2CH 2 C 6 H 5); 5.35 (1H, m, perturbed by signal at 5.32, CHCH₂OH); 5.63 (1H, dd, J 2.5Hz, J '1Hz, 5-H); 7.36 (5H, s, aromatic -H). Mass spectrum of this product showed a molecular ion at m / e 289.0949 (ci5Hy5N05 has a theoretical value of 289.0950).
12 14270212 142702
Eksempel 3.Example 3
HH
, Η H, Η H
,_,CH OH l a i Λ ' CH OH !, _, CH OH l a i Λ 'CH OH!
COOCH„CfiHR ' ICOOCH "CfiHR" I
COOCH2C6H4Br COOCH2C6H4Br (3) (5) (6) 94 mg benzylclavulanat (3) i 8 ml ethanol blev hydrogeneret over 30 mg 10%'s palladium/kul og 28 mg natriumhydrogencarbonat i 60 minutter. Katalysatoren blev frafiltreret og vasket med vand, hvorefter ethanolet og de samlede filtrater blev inddampet. Remanensen blev opløst i 2,5 ml tørt dimethylformamid indeholdende 245 mg m-bromben-zylbromid, og opløsningen blev hensat ved stuetemperatur i 2 timer. Opløsningen blev fraktioneret på silicagel under anvendelse af først ethylacetat-hexan i forholdet 1:1 og derefter ethylacetat. Fraktionerne 16 - 19 blev inddampet, hvorved der blev vundet 11 mg p-brombenzylisoclavulanat (5) i form af tynde stænger med smeltepunkt 134 - 134,5°C (af methylenchlorid-carbontetrachlorid). Fraktionerne 21 - 24 blev inddampet, hvorved der blev vundet 52 mg p-brombenzyl-clavulanat (6) i form af nåle med smeltepunkt 103 - 104°C (af methyl enchlorid-carbontetrachlorid).COOCH2C6H4Br COOCH2C6H4Br (3) (5) (6) 94 mg of benzyl clavulanate (3) in 8 ml of ethanol was hydrogenated over 30 mg of 10% palladium / carbon and 28 mg of sodium bicarbonate for 60 minutes. The catalyst was filtered off and washed with water, then the ethanol and the combined filtrates were evaporated. The residue was dissolved in 2.5 ml of dry dimethylformamide containing 245 mg of m-bromobenzyl bromide and the solution was allowed to stand at room temperature for 2 hours. The solution was fractionated on silica gel using first 1: 1 ethyl acetate-hexane and then ethyl acetate. Fractions 16 - 19 were evaporated to give 11 mg of p-bromobenzylisoclavulanate (5) in the form of thin bars of mp 134 - 134.5 ° C (of methylene chloride-carbon tetrachloride). Fractions 21-24 were evaporated to give 52 mg of p-bromobenzyl clavulanate (6) in the form of needles, mp 103 - 104 ° C (of methylene chloride-carbon tetrachloride).
Strukturerne af og den absolutte stereokemi for de to produkter (5) og (6) blev fastslået ved røntgenanalyse.The structures and absolute stereochemistry of the two products (5) and (6) were determined by X-ray analysis.
Eksempel 4.Example 4
13 142702 H f rh_ -* rfh J—NX/ V, nH S ch2oh γ' f CH~OH O ' 213 142702 H f rh_ - * rfh J — NX / V, nH S ch2oh γ 'f CH ~ OH O' 2
0,2 I0.2 I
i ' h00CHoC,H, ' - + 2 6 5 COO Na (4) (7)in 'H00CHoC, H,' - + 2 6 5 COO Na (4) (7)
En blanding af 60 mg benzylisoclavulanat (4), 17,6 mg natriumhy-drogencarbonat og 20 mg 10%'s palladium/kul i ethanol blev hydrogeneret ved 20°C og 1 atmosfæres tryk i 105 minutter, hvorefter tyndtlagschromatografi (ethylacetat-cyclohexan i forholdet 1:1) viste, at reaktionen var fuldstændig. Katalysatoren blev frafiltreret og vasket med vand, og filtratet og de samlede vaskevæsker blev inddampet. Remanensen blev behandlet to gange med ethanol og inddampet, behandlet med acetone og inddampet og tritureret med acetone/ether, hvorved der blev opnået 30 mg natrium-isoclavulanat (7) i form af et off-white pulver.A mixture of 60 mg of benzyl isoclavulanate (4), 17.6 mg of sodium hydrogen carbonate and 20 mg of 10% palladium / carbon in ethanol was hydrogenated at 20 ° C and 1 atmosphere pressure for 105 minutes, followed by thin layer chromatography (ethyl acetate-cyclohexane the 1: 1 ratio showed that the reaction was complete. The catalyst was filtered off and washed with water and the filtrate and the combined washings were evaporated. The residue was treated twice with ethanol and evaporated, treated with acetone and evaporated and triturated with acetone / ether to give 30 mg of sodium isoclavulanate (7) as an off-white powder.
NMR-spektrum (D20): 3,10 (IH, d, J 17,5Hz, δβ-CH); 3,64 (IH, dd, J 17,5Hz, J' 3,0Hz) ; 4,18 (2H, d, J 7,5Hz, CH2<0H) ; 5,22 (2H, m, =CH-CH2OH, 3-CH); 5,86 (IH, d, J 3,0Hz, 5-CH).NMR Spectrum (D 2 O): 3.10 (1H, d, J 17.5Hz, δβ-CH); 3.64 (1H, dd, J 17.5Hz, J '3.0Hz); 4.18 (2H, d, J 7.5Hz, CH 2 <OH); 5.22 (2H, m, = CH-CH 2 OH, 3-CH); 5.86 (1H, d, J 3.0Hz, 5-CH).
De minimale inhiberingskoncentrationer (MIC) i ^ug/ml af natriumiso-clavulanat, ampicillin og kombinationer af natriumisoclavulanat med ampicillin mod visse f5-lactamase-producerende organismer er anført i tabel I. Resultaterne blev opnået ved mikrotiterteknikken med et inokulum, der var opnået ved dyrkning natten over, hvorefter der i testen blev anvendt en fortynding af dyrkningsvæsken i forholdet 1:500.The minimum inhibitory concentrations (MIC) in µg / ml of sodium isoclavulanate, ampicillin and combinations of sodium isoclavulanate with ampicillin against certain β-lactamase-producing organisms are given in Table I. The results were obtained by the microtiter technique with an inoculum obtained by overnight cultivation and then a 1: 500 dilution of the culture fluid was used.
14 142702 O +1 tn β •h G s β β H m o •η β oi o M > h m μ td14 142702 O + 1 tn β • h G s β β H m o • η β oi o M> h m μ td
Ml id HMl id H
Id S o μ tu --—____ 115 .Id S o µ tu --—____ 115.
μ ^ ® -3µ ^ ® -3
? M? M
.5 +> +> J + G td ^ c c S C id.5 +> +> J + G td ^ c c S C id
-ri ri i—I-ri ri i — I
7^ O Η £ β O' Λ ^ H \ > ro oj m pq TtO> Id "· g1 o β h o yj u cn *h \ u 0) Λ o g g so ω -η tu rtj nj Η Η cn η ο -;-- -μ μ ι ο m 6 η ns 37 ^ O Η £ β O 'Λ ^ H \> ro oj m pq TtO> Id "· g1 o β ho yj u cn * h \ u 0) Λ ogg so ω -η tu rtj nj Η Η cn η ο - ; - -µ μ ι ο m 6 η ns 3
Qi Η g td μ +> β h + +> td ι—i td c ^ <U G C td +J Η Ή r-1 td tn 1-1 ^ _ C ΰ μ Η £ > ω β tu a) -H\td t-~ m η h tn otnH ' S« H Η β O o oj > <U ft \ O ^ h td tj> Ό g tn η o G «! m h HU ·Η (U OH Λ Λ tn η μ------- td -η ω ο ι Εη ε tn ft gQi Η g td µ +> β h ++ + td ι — i td c ^ <UGC td + J Η Ή r-1 td tn 1-1 ^ _ C ΰ µ Η £> ω β tu a) -H \ td t- ~ m η h tn otnH 'S «H Η β O o oj> <U ft \ O ^ h td tj> Ό g tn η o G«! m h HU · Η (U OH Λ Λ tn η μ ------- td -η ω ο ι Εη ε tn ft g
Gtn GGtn G
Η β -Η Μ ft Μ -Ρ 4J + -μ idΗ β -Η Μ ft Μ -Ρ 4J + -µ id
βω <d Cβω <d C
C β G G <d <D -HH ΟΊ o 14-1 μ Η Η β *· * td β η ε > H mC β G G <d <D -HH ΟΊ o 14-1 μ Η Η β * · * td β η ε> H m
β Η \ β Hβ Η \ β H
H O O' HH O O 'H
ε ω η β o \ β ft \ ο tn ο ε ω β ο <1 Η Η \ Ο__ε ω η β o \ β ft \ ο tn ο ε ω β ο <1 Η Η \ Ο__
UU
Η Ο GΗ Ο G
Η ·Η μ >ι -) _ _ 1) ^ Η Ο Ο Η ft Η ° Ο -β β Ο mm Μ -μ ·Η 8) ω ft > Β I Ό__^_____ α ο η ε S Η ω η β Η Ο Ο 0 Γ" u ω ft Ο ω β tu υ β Η ω g ο ft η tu ω høg -η >ι ω η ø G ,β β ω ίβ β ft (U X! Ο tn β μ tu μ μ +J β Η 0) ο C0 β ft βΗ · Η μ> ι -) _ _ 1) ^ Η Ο Ο Η ft Η ° Ο -β β Ο mm Μ -μ · Η 8) ω ft> Β I Ό __ ^ _____ α ο η ε S Η ω η β Η Ο Ο 0 Γ "u ω ft Ο ω β tu υ β Η ω g ο ft η tu ω high -η> ι ω η ø G, β β ω ίβ β ft (UX! Ο tn β μ tu μ μ + J β Η 0) ο C0 β ft β
Claims (1)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB54788/74A GB1534508A (en) | 1974-12-18 | 1974-12-18 | Isoclavulanic acid derivatives |
GB5478874 | 1974-12-18 | ||
GB1521175 | 1975-04-14 | ||
GB1521175 | 1975-04-14 |
Publications (3)
Publication Number | Publication Date |
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DK574875A DK574875A (en) | 1976-06-19 |
DK142702B true DK142702B (en) | 1980-12-22 |
DK142702C DK142702C (en) | 1981-08-10 |
Family
ID=26251138
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Application Number | Title | Priority Date | Filing Date |
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DK574875AA DK142702B (en) | 1974-12-18 | 1975-12-17 | Process for the preparation of isoclavulanic acid derivatives. |
Country Status (11)
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JP (1) | JPS51138693A (en) |
AU (1) | AU500572B2 (en) |
CA (1) | CA1064039A (en) |
CH (1) | CH619230A5 (en) |
DE (1) | DE2555626A1 (en) |
DK (1) | DK142702B (en) |
FR (1) | FR2294701A1 (en) |
IE (1) | IE42370B1 (en) |
IL (1) | IL48607A (en) |
NL (1) | NL7514545A (en) |
SE (1) | SE428564B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7711640A (en) * | 1976-10-25 | 1978-04-27 | Glaxo Lab Ltd | PROCESS FOR THE PREPARATION OF NEW CLAVAM DERIVATIVES. |
GB1587612A (en) * | 1976-10-30 | 1981-04-08 | Beecham Group Ltd | Isoclavulanic acid derivatives |
-
1975
- 1975-12-04 IE IE2645/75A patent/IE42370B1/en unknown
- 1975-12-05 IL IL48607A patent/IL48607A/en unknown
- 1975-12-10 DE DE19752555626 patent/DE2555626A1/en not_active Withdrawn
- 1975-12-11 SE SE7514029A patent/SE428564B/en unknown
- 1975-12-12 AU AU87521/75A patent/AU500572B2/en not_active Expired
- 1975-12-12 NL NL7514545A patent/NL7514545A/en not_active Application Discontinuation
- 1975-12-15 FR FR7538284A patent/FR2294701A1/en active Granted
- 1975-12-17 CH CH1634675A patent/CH619230A5/en not_active IP Right Cessation
- 1975-12-17 DK DK574875AA patent/DK142702B/en unknown
- 1975-12-17 CA CA241,930A patent/CA1064039A/en not_active Expired
- 1975-12-18 JP JP50152683A patent/JPS51138693A/en active Pending
Also Published As
Publication number | Publication date |
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IE42370L (en) | 1976-06-18 |
CH619230A5 (en) | 1980-09-15 |
AU500572B2 (en) | 1979-05-24 |
CA1064039A (en) | 1979-10-09 |
IL48607A0 (en) | 1976-02-29 |
SE428564B (en) | 1983-07-11 |
AU8752175A (en) | 1977-06-16 |
IL48607A (en) | 1979-07-25 |
DE2555626A1 (en) | 1976-07-01 |
DK574875A (en) | 1976-06-19 |
IE42370B1 (en) | 1980-07-30 |
FR2294701A1 (en) | 1976-07-16 |
FR2294701B1 (en) | 1982-07-23 |
NL7514545A (en) | 1976-06-22 |
SE7514029L (en) | 1976-06-21 |
DK142702C (en) | 1981-08-10 |
JPS51138693A (en) | 1976-11-30 |
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