DK149283B - ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES Download PDFInfo
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- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
1Λ92831Λ9283
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af terapeutisk virksomme cephalosporin-derivater med den almene formel IThe present invention relates to an analogous process for the preparation of therapeutically effective cephalosporin derivatives of the general formula I
Η HΗ H
5 IIs5 IIs
CH3ON=rC- C0NH —r-NCH3ON = rC-COHH -r-N
ri r^nAs/ .ri r ^ nAs /.
10 COOH10 COOH
hvor X betegner en 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo--as-triazin-3-ylgruppe eller den tautomere 2,5-dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-gruppe, og R° be-15 tegner hydrogen eller en fraspaltelig gruppe,som kan være tert.butoxycarbonyl, trityl, trifluoracetyl eller chlor-, brom- eller iodacetyl, eller farmaceutisk tolerable salte eller hydrater af forbindelser med formlen I, hvor R° betegner hydrogen, eller hydrater af disse salte.wherein X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the tautomeric 2,5-dihydro-6-hydroxy-2-methyl group. 5-oxo-as-triazin-3-yl group, and R ° represents hydrogen or a leaving group which may be tert-butoxycarbonyl, trityl, trifluoroacetyl or chloro, bromo or iodoacetyl, or pharmaceutically tolerable salts or hydrates of compounds of formula I wherein R ° represents hydrogen, or hydrates of these salts.
2020
Eksempler på farmaceutisk tolerable salte af forbindelser med formlen I er alkalimetalsalte, f.eks. natrium- og kaliumsaltet; ammoniumsaltet; jordalkali-metalsalte, f.eks. calciumsaltet; salte med organis-25 ke baser, f.eks. salte med aminer såsom, salte med N-ethylpiperidin, procain, dibenzylamin, Ν,Ν'-dibenzyl-ethylethylendiamin, alkylaminer eller dialkylaminer samt salte med aminosyrer, f.eks. salte med arginin eller lysin. Saltene kan være monosalte eller disalte. Den anden salt-30 dannelse kan optræde i forbindelser med hydroxygruppen i 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-ylgruppen.Examples of pharmaceutically tolerable salts of compounds of formula I are alkali metal salts, e.g. the sodium and potassium salt; the ammonium salt; alkaline earth metal salts, e.g. calcium salt; salts with organic bases, e.g. salts with amines such as, salts with N-ethylpiperidine, procaine, dibenzylamine, Ν, Ν'-dibenzylethylethylenediamine, alkylamines or dialkylamines, and salts with amino acids, e.g. salts with arginine or lysine. The salts may be monosaltic or disaltic. The second salt formation can occur in compounds with the hydroxy group of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.
Forbindelserne med formlen I danner ligeledes additionssalte med organiske eller uorganiske syrer. Eksempler på 35 sådanne salte er hydrohalogenider, f.eks. hydrochlorider, hydrobromider og hydroiodider, samt andre mineralsyresalte såsom sulfater, nitrater og phosphater, alkyl- og mono-arylsulfonater såsom ethansulfonater, toluensulfonater og 2 149283 benzensulfonater samt andre organiske syresalte såsom acetater, tartrater, maleater, citrater, benzoater, sa-licylater og ascorbater.The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, e.g. hydrochlorides, hydrobromides and hydroiodides, as well as other mineral acid salts such as sulphates, nitrates and phosphates, alkyl and mono-aryl sulphonates such as ethane sulphonates, toluene sulphonates and benzene sulphonates and other organic acid salts such as acetates, tartrates, malates, citrates, benzoates, benzoates, .
5 Forbindelserne med formlen I (herunder deres salte) kan være hydratiserede. Hydratiseringen kan foretages under fremstillingsfremgangsmåden eller efterhånden på grund af hygroskopiske egenskaber i et i starten vandfrit produkt.The compounds of formula I (including their salts) may be hydrated. The hydration can be carried out during the manufacturing process or eventually due to hygroscopic properties of an initially anhydrous product.
1010
De omhandlede produkter kan foreligge i den syn-isomere form N — C—CONH_? 15 'JCS u * 0CH3 eller i den anti-isomere form 20 v CH,0The products in question may be in the syn-isomeric form N - C-CONH_? 15 'JCS u * OCH 3 or in the anti-isomeric form 20 v CH, O
25 J25 J
eller som blandinger af disse to former. Der foretrækkes den syn-isomere form eller blandinger, i hvilke den syn--isomere form dominerer.or as mixtures of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form predominates are preferred.
30 Foretrukne produkter er (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)--acetamido]-3-([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]-methyl)-8-oxo-5-thia-l-azabicyclo-35 [4.2.0]oct-2-en-2-carboxylsyre og salte deraf samt de tilsvarende hydrater.Preferred products are (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - ([(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo-[4.2.0] oct-2-en-2 -carboxylic acid and its salts as well as the corresponding hydrates.
Fremgangsmåden ifølge opfindelsen til fremstilling af de ovenfor anførte acylderivater I er ejendommelig ved, at man 3 149283The process of the invention for the preparation of the above-mentioned acyl derivatives I is characterized in that:
omsætter en forbindelse *ed den almene formel XII Η Htranslates a compound * ed into the general formula XII Η H
5 H2N—[—[ ^ J— * ch2— s— x 1115 H2N - [- [^ J— * ch2— s— x 111
COOHCOOH
10 hvor X har den ovenfor anførte betydning, og carboxy-Wherein X is as defined above and carboxy
gruppen og/eller aminogruppen kan foreligge i beskyttet form, med en syre med den almene formel IVthe group and / or the amino group may be in protected form, with an acid of the general formula IV
CHjONrsrC- COOHCHjONrsrC-COOH
Å RHN / hvor R betegner en fraspaltelig gruppe som defineret oven-20 for, eller med et reaktivt funktionelt derivat af denne syre, om nødvendigt fraspalter beskyttelsesgruppen R og/eller en eventuelt tilstedeværende carboxybeskyttelsesgruppe og om ønsket til fremstilling af salte eller hydrater af en forbindelse med formlen I, hvor R° betegner hydrogen, eller 25 af hydrater af disse salte omdanner en forbindelse med formlen I til et salt eller hydrat eller et hydrat af dette salt.Å RHN / where R represents a leaving group as defined above, or with a reactive functional derivative of this acid, if necessary, protecting group R and / or any carboxy protecting group present and if desired to prepare salts or hydrates of a compound of formula I wherein R ° represents hydrogen, or 25 of hydrates of these salts convert a compound of formula I into a salt or hydrate or hydrate of this salt.
Den i udgangsforbindelsen med formlen III tilstedeværende 3q carboxygruppe kan om ønsket være beskyttet, f.eks. ved forestring til en let spaltelig ester, f.eks. en silyl-ester såsom trimethylsilylesteren. Der kan også komme let hydrolyserbare estere på tale. Ved let hydrolyserbare estere forstås forbindelser, hvis carboxygruppe foreligger 35 i form af en let hydrolyserbar estergruppe. Eksempler på sådanne estere, der kan være af sædvanlig natur, er de lavere alkanoyloxyalkylestere, f.eks. acetoxymethyl-, pivaloyloxymethyl-, 1-acetoxyethyl- og 1-pivaloyloxyethyl- 149283 4 ester; de lavere alkoxycarbonyloxyalkylestere, f.eks. methoxycarbonyloxymethyl-, 1-ethoxycarbonyloxyethyl- og 1-isopropoxycarbonyloxyethylestere; lactonylestere, f.eks. phthalidyl- og thiophthalidylestere; de lavere alkoxyme-5 thylestere, f.eks. methoxymethylester; og de lavere alkan- oylaminomethylestere, f.eks. acetamidomethylester. Carb-oxygruppen kan også være beskyttet ved saltdannelse med en uorganisk eller tertiær organisk base såsom triethyl-amin. Aminogruppen i forbindelsen med formlen III kan 10 f.eks. være beskyttet med en silylbeskyttelsesgruppe så som trimethylsilyl. Mulige R-beskyttelsesgrupper i udgangs-forbindelserne med formlen IV er f.eks. ved sur hydrolyse fraspaltelige beskyttelsesgrupper, f.eks. tert.butoxycarbo-nyl eller trityl, eller ved basisk hydrolyse fraspalte-15 lige beskyttelsesgrupper, f.eks. trifluoracetyl. Foretrukne R-beskyttelsesgrupper er chlor-, brom- og iodacetyl, især chloracetyl. De sidste beskyttelsesgrupper kan fraspaltes ved behandling med thiourinstof.The 3q carboxy group present in the starting compound of formula III may, if desired, be protected, e.g. by esterification to a readily cleavable ester, e.g. a silyl ester such as the trimethylsilyl ester. Speech hydrolyzable esters may also be present. By easily hydrolyzable esters is meant compounds whose carboxy group is in the form of a readily hydrolyzable ester group. Examples of such esters which may be of a conventional nature are the lower alkanoyloxyalkyl esters, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester; the lower alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; lactonyl esters, e.g. phthalidyl and thiophthalidyl esters; the lower alkoxymethyl esters, e.g. methoxymethyl ester; and the lower alkanoylaminomethyl esters, e.g. acetamidomethylester. The carboxy group may also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. The amino group of the compound of formula III can e.g. be protected with a silyl protecting group such as trimethylsilyl. Possible R protecting groups in the starting compounds of formula IV are e.g. by acid hydrolysis, cleavable protecting groups, e.g. tert-butoxycarbonyl or trityl, or by basic hydrolysis leaving protective groups, e.g. trifluoroacetyl. Preferred R protecting groups are chloro, bromo and iodoacetyl, especially chloroacetyl. The last protecting groups can be split off by treatment with thiourea.
20 Som reaktive funktionelle derivater af syrer med formlen IV kan f.eks. nævnes halogenider, dvs. chlorider, bromider og fluorider; azider; anhydrider, især blandede anhydrider med stærke syrer; reaktive estere såsom N-hydroxysuccinimid-· ester; og amider såsom imidazolider.As reactive functional derivatives of acids of formula IV, e.g. are mentioned halides, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with strong acids; reactive esters such as N-hydroxysuccinimide ester; and amides such as imidazolides.
2525
Omsætningen mellem 7-aminoforbindelsen med formlen III og syren med formlen IV eller et reaktivt funktionelt derivat deraf kan udføres på i og for sig kendt måde.The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se.
Således kan f.eks. en fri syre med formlen IV kondenseres 2Q med en af de nævnte estere svarende til form len III ved hjælp af et carbodiimid, f.eks. dicyclohexyl-carbodiimid, i et inert opløsningsmiddel, f.eks. ethyl-acetat, acetonitril, dioxan, chloroform, methylenchlorid, benzen eller dimethylformamid, hvorefter estergruppen fraspaltes. I stedet for carbodiimider kan der som kondensationsmidler også anvendes oxazoliumsalte, f.eks. N-ethyl-5-phenyl-isoxazolium-3'-sulfonat.Thus, e.g. a free acid of formula IV is condensed 2Q with one of said esters corresponding to formula III by a carbodiimide, e.g. dicyclohexylcarbodiimide, in an inert solvent, e.g. ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and the ester group is decomposed. Instead of carbodiimides, oxazolium salts, e.g. N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
5 1492835 149283
Ved en anden udførelsesfonn omsættes et salt af en syre med formlen III, f.eks. et trialkylammoniumsalt, f.eks. triethylammoniumsaltet, med et reaktivt funktionelt derivat af en syre med formlen IV som ovenfor omtalt i et 5 inert opløsningsmiddel, f.eks. et af de ovenfor anførte.In another embodiment, a salt of an acid of formula III is reacted, e.g. a trialkylammonium salt, e.g. the triethylammonium salt, with a reactive functional derivative of an acid of formula IV as mentioned above in an inert solvent, e.g. one of the above.
Ved en yderligere udførelsesform omsættes et syrehalogenid, fortrinsvis chloridet, af en syre med formlen IV, med aminen med formlen III. Omsætningen foretages fortrinsvis 10 i nærværelse af et syrebindende middel, f.eks. i nærværelse af vandig base, fortrinsvis natriumhydroxidopløsning, eller i nærværelse af et alkalimetalcarbonat, f.eks. kalium-carbonat, eller i nærværelse af en lavere-alkyleret amin, f.eks. triethylamin. Som opløsningsmiddel anvendes for-15 trinsvis vand, eventuelt i blanding med et inert organisk opløsningsmiddel såsom tetrahydrofuran eller dioxan. Der kan også arbejdes i et aprot organisk opløsningsmiddel, f.eks. dimethylformamid, dimethylsulfoxid eller hexamethyl-phosphorsyretriamid. Ved anvendelse af silylerede udgangs-20 forbindelser med formlen III arbejdes der i vandfrit medium.In a further embodiment, an acid halide, preferably the chloride, of an acid of formula IV is reacted with the amine of formula III. The reaction is preferably carried out in the presence of an acid binding agent, e.g. in the presence of aqueous base, preferably sodium hydroxide solution, or in the presence of an alkali metal carbonate, e.g. potassium carbonate, or in the presence of a lower alkylated amine, e.g. triethylamine. Preferably water is used as solvent, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. An aprotic organic solvent, e.g. dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide. Using silylated starting compounds of formula III, it is worked in anhydrous medium.
Omsætningen mellem 7-aminoforbindelsen med formlen III og syren med formlen IV eller et reaktivt funktionelt 25 derivat deraf kan hensigtsmæssigt foretages ved tempera turer mellem ca. -40°C og stuetemperatur, f.eks. ved ca.The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can conveniently be carried out at temperatures between -40 ° C and room temperature, e.g. at about.
0 - 10°C.0 - 10 ° C.
Omsætning af forbindelserne med formlen III med carboxyl-30 syrerne med formlen IV eller et reaktivt funktionelt deReaction of the compounds of formula III with the carboxylic acids of formula IV or a reactive functional
rivat deraf fører til cephalosporinderivater roed den almene formel IIderivatives thereof leading to cephalosporin derivatives redden the general formula II
Η HΗ H
35 CH3ON=C—CONH--CH3ON = C-CONH--
//c^>nJ-CH2_s_-x II// c ^> nJ-CH2_s_-x II
ς/ iς / i
COOHCOOH
6 149283 hvor X har den ovenfor anførte betydning, og R betegner en fraspaltelig beskyttelsesgruppe. Disse forbindelser med formlen II kan omdannes til forbindelser med formlen I, hvor R° betegner hydrogen, ved fraspaltning af amino-5 beskyttelsesgruppen R. Ved sur hydrolyse fra spaltelige beskyttelsesgrupper fjernes fortrinsvis ved hjælp af en lavere alkancarboxylsyre, som eventuelt kan være halogeneret. Især anvendes myresyre eller trifluor-eddikesyre. Temperaturen er i reglen stuetemperatur, selv XO om der kan anvendes lidt højere eller lidt lavere tempe ratur, f.eks. i området mellem 0 og +40°C. Alkalisk fraspaltelige beskyttelsesgrupper hydrolyseres generelt med fortyndede vandige baser ved 0 - 30°C. Chloracetyl-, bromacetyl- og iodacetylbeskyttelsesgrupper kan fra-15 spaltes ved hjælp af thiourinstof i surt, neutralt eller alkalisk miljø ved ca. 0 - 30°C. Hydrogenolytisk fraspalt-ning (f.eks. fraspaltning af benzyl) er uegnet her, da oximfunktionen ved hydrogenolysen reduceres til en amino-gruppe.6 149283 where X has the meaning given above and R represents a leaving group protecting group. These compounds of formula II can be converted to compounds of formula I, wherein R hydrogen represents hydrogen, by cleavage of the amino-protecting group R. Preferably, acidic hydrolysis of cleavable protecting groups is removed by means of a lower alkane carboxylic acid, which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature, although XO can be used slightly higher or slightly lower temperature, e.g. in the range between 0 and + 40 ° C. Alkaline cleavable protecting groups are generally hydrolyzed with dilute aqueous bases at 0 - 30 ° C. Chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved by thiourea in an acidic, neutral or alkaline environment at approx. 0 - 30 ° C. Hydrogenolytic cleavage (e.g. benzyl cleavage) is unsuitable here as the oxime function of the hydrogenolysis is reduced to an amino group.
2020
Efter fraspaltning af aminobeskyttelsesgruppen R kan, om ønsket, en eventuelt i reaktionsproduktet tilstedeværende carboxy-beskyttelsesgruppe fraspaltes. Når beskyttelsesgruppen er en silylgruppe (silylester), kan denne gruppe fraspaltes 25 særlig let ved behandling af omsætningsproduktet med vand. Lavere alkanoyloxyalky1-, alkoxycarbonyloxyalkyl-, lactonyl-, alkoxymethyl- og alkanoylaminomethylestere fraspaltes fortrinsvis enzymatisk ved hjælp af en egnet esterase (ved ca. 20 - 40°C). Når carboxylgruppen er be-30 skyttet ved saltdannelse (f.eks. med triethylamin), kan fraspaltningen af denne saltdannende beskyttelsesgruppe foretages ved behandling med syre. Som syre kan der til dette formål f.eks. anvendes saltsyre, svovlsyre, phosphor-syre eller citronsyre.After cleavage of the amino protecting group R, if desired, a carboxy protecting group present in the reaction product may be cleaved off. When the protecting group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxymethyl and alkanoylaminomethyl esters are preferably enzymatically cleaved by a suitable esterase (at about 20 - 40 ° C). When the carboxyl group is protected by salt formation (e.g. with triethylamine), the cleavage of this salt-forming protecting group can be effected by treatment with acid. As an acid, for this purpose e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid are used.
Carboxybeskyttelsesgruppen kan fraspaltes på lignende 35 7 149283 måde som ovenfor beskrevet også før fraspaltningen af beskyttelsesgruppen R.The carboxy protecting group can be cleaved in a similar manner as described above even before the cleaving of the protecting group R.
Fremstillingen af saltene og hydraterne af forbindelser med 5 formlen I, hvor R° betegner hydrogen, eller hydraterne af disse salte kan foretages på i og for sig kendt måde, f.eks. ved omsætning af carboxylsyren med formlen I, hvor R° betegner hydrogen, med en ækvivalent mængde af den ønskede base, hensigtsmæssigt i et opløsningsmiddel såsom vand eller i 10 et organisk opløsningsmiddel såsom ethanol, methanol eller acetone. Ved anvendelse af et yderligere ækvivalent base foregår saltdannelse også på den eventuelt tilstedeværende tautomere enolform (2,5-dihydro-6-hydroxy-2-methy1-5-oxo--as-triazin-3-ylgruppe X), hvorved der dannes et disalt.The preparation of the salts and hydrates of compounds of formula I wherein R ° represents hydrogen or the hydrates of these salts can be made in a manner known per se, e.g. by reacting the carboxylic acid of formula I wherein R ° represents hydrogen, with an equivalent amount of the desired base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol or acetone. Using an additional equivalent base, salt formation also occurs on the possibly tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), thereby forming a disalt.
15 Temperaturen ved saltdannelsen er ikke kritisk. Den ligger almindeligvis ved stuetemperatur, men kan også ligge lidt derover eller derunder, f.eks. i området mellem 0 og +50°C.The temperature of the salt formation is not critical. It is usually at room temperature, but may also lie slightly above or below, e.g. in the range between 0 and + 50 ° C.
Fremstillingen af hydraterne foretages ofte automatisk under 20 fremstillingsprocessen eller på grund af et i starten vand frit produkts hygroskopiske egenskaber. Et hydrat kan fremstilles ud fra et helt eller delvis vandfrit produkt (carboxylsyre med formlen I eller ester, ether eller salt deraf) ved at udsætte det for en fugtig at-25 mosfære, f.eks. ved ca. 10 - 40°C.The hydrates are often made automatically during the manufacturing process or due to the hygroscopic properties of an initially water free product. A hydrate can be prepared from a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) by exposing it to a humid atmosphere, e.g. at about. 10 - 40 ° C.
De ovenfor anvendte 7-aminoforbindelser med formlen III kan fremstilles ud fra forbindelser med den almene formel VII 30The above 7-amino compounds of formula III may be prepared from compounds of general formula VII 30
Η HΗ H
: I s.: Ice.
h2n-^—y J—K^—cs^ VI1h2n - ^ - y J — K ^ —cs ^ VI1
35 I35 I
COOHCOOH
8 1492838 149283
hvor Y betegner en fraspaltelig enhed, og carboxygruppen kan foreligge i beskyttet form, ved omsætning med en thiol med den almene formel VIwherein Y represents a leaving group and the carboxy group may be in protected form by reaction with a thiol of general formula VI
5 HS - X VI5 HS - X VI
hvor X har den ovenfor anførte betydning, i nærværelse af vand.where X has the meaning given above, in the presence of water.
Som fraspaltelig enhed Y i en forbindelse med formlen VII 10 kan der f.eks. nævnes halogener, f.eks. chlor, brom eller iod, acyloxygrupper, f.eks. lavere alkanoyloxygrupper, såsom acetoxy, lavere alkyl- eller arylsulfonyloxygrupper såsom mesyloxy eller tosyloxy eller azido. Forbindelserne VII kan ved carboxygruppen være beskyttet på den for udgangsfor-15 bindeisen med formlen III beskrevne måde.As a leaving group Y in a compound of formula VII 10, e.g. are mentioned halogens, e.g. chlorine, bromine or iodine, acyloxy groups, e.g. lower alkanoyloxy groups such as acetoxy, lower alkyl or arylsulfonyloxy groups such as mesyloxy or tosyloxy or azido. Compounds VII may be protected by the carboxy group in the manner described for the starting compound of formula III.
Omsætningen af forbindelsen med formlen VII med thiolen med formlen VI kan foretages på i og for sig kendt måde, f.eks. ved en temperatur mellem ca. 40 og 80°C, hensigts-20 mæssigt ved ca. 60°C, i vand eller i en pufferopløsning med en pH-værdi på ca. 6-7, fortrinsvis 6,5.The reaction of the compound of formula VII with the thiol of formula VI can be carried out in a manner known per se, e.g. at a temperature between ca. 40 and 80 ° C, conveniently at approx. 60 ° C, in water or in a buffer solution with a pH of approx. 6-7, preferably 6.5.
En eventuelt vundet syn/anti-blanding af en forbindelse med formlen I kan opspaltes på sædvanlig måde i de til-25 svarende syn- og anti-former, f.eks. ved omkrystallisation eller ved chromatografiske metoder under anvendelse af et egnet opløsningsmiddel eller en egnet opløsningsmiddelblanding. 1 2 3 4 5 6An optionally obtained syn / anti-blend of a compound of formula I can be split in the usual manner into the corresponding syn and anti forms, e.g. by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture. 1 2 3 4 5 6
Forbindelserne med formlen I samt de tilsvarende salte eller hydraterne 2 af disse produkter er antibiotisk., især baktericidt virk 3 somme. De har et bredt virkningsspektrum mod gram-positive 4 og gram-negative mikroorganismer, herunder β-lactamase- 5 dannende Staphylococcer og forskellige β-lactamase-dannende 6 gram-negative bakterier, f.eks. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, Proteus- og Klebsiellaarter.The compounds of formula I as well as the corresponding salts or hydrates 2 of these products are antibiotic, especially bactericidal activity 3. They have a broad spectrum of action against gram-positive 4 and gram-negative microorganisms, including β-lactamase-forming Staphylococci and various β-lactamase-forming 6 gram-negative bacteria, e.g. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, Proteus and Klebsiell species.
9 1492839 149283
Forbindelserne ned formlen I samt de tilsvarende salte eller hydraterne af d.isse produkter kan anvendes til behandling ag profylakse af infektionssygdomme. Til voksne kan anvendes én daglig dosis på ca. 0,1 - ca. 2 g. Den parenterale admi-5 nistration af de omhandlede forbindelser er særlig foretrukket.The compounds of formula I as well as the corresponding salts or hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. For adults, one daily dose of approx. 0.1 - approx. The parenteral administration of the compounds of this invention is particularly preferred.
Til påvisning af den antimikrobielle aktivitet af de omhandlede produkter er følgende repræsentative forbindelser 10 afprøvet:To detect the antimicrobial activity of the products in question, the following representative compounds 10 have been tested:
Produkt A: (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z- -methoxyimino)acetamido]-3-([(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-15 -methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0.]oct- -2-en-2-carboxylsyre.Product A: (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z- methoxyimino) acetamido] -3 - ([(2,5-dihydro-6-hydroxy) -2-methyl-5-oxo-az-triazin-3-yl) thio] -15-methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0.] Oct--2-en-2 carboxylic acid.
Produkt B: (6R,7R)-7-(2-[2-(2-chloracetamido)-4- -thiazolyl]-2-(Z-methoxyimino)acetamido)-3-20 -([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as- -triazin-3-yl)thiolmethyl)-8-oxo-5-thia-l--azabicyclo[4.2.0]oct-2-en-2-carboxylsyre.Product B: (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4- -thiazolyl] -2- (Z-methoxyimino) acetamido) -3-20 - ([(2,5- dihydro-6-hydroxy-2-methyl-5-oxo-asa-triazin-3-yl) thiolmethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 carboxylic acid.
Aktivitet i vitro: Mindste hæmmende koncentration ( ,ug/ml) 25 10 149283 ___________A__B_In vitro activity: Minimum inhibitory concentration (, µg / ml) 25 10 149283 ___________A__B_
Haemophilus influenzae Stamme 1 0,08 1,2 5 Stamme 2 0,005 0,3Haemophilus influenzae Strain 1 0.08 1.2 5 Strain 2 0.005 0.3
Stamme 3' 0,005 0,16Strain 3 '0.005 0.16
Stamme 4 0,005 0,16Strain 4 0.005 0.16
Stamme 5 0,0025 0,08Strain 5 0.0025 0.08
Stamme 6 0,0025 0,16 10 __Stamme 7 0,0025 0,16Strain 6 0.0025 0.16 10 __Strain 7 0.0025 0.16
Klebsiella pneumoniae 1,2 10Klebsiella pneumoniae 1,2 10
Escherichia coli Stamme 1 . 0,02 0,16Escherichia coli Strain 1. 0.02 0.16
Stamme 2 0,6 5 15 Proteus mirabilis Stamme 1 ^0,01 0,08Strain 2 0.6 5 15 Proteus mirabilis Strain 1 ^ 0.01 0.08
Stamme 2 ^0,01 0,16Strain 2 ^ 0.01 0.01
Proteus vulgaris ^0,01 0,16Proteus vulgaris ^ 0.01 0.01
Proteus rettgeri ^0,01 0,16 20 Staphylococcus aureus Stamme ATCC 6538 2,5 2,5Proteus Straightening 0.01 0.01 16 Staphylococcus aureus Strain ATCC 6538 2.5 2.5
Penicillinresistent stamme 2,5 5Penicillin resistant strain 2.5 5
Pseudomonas aeruginosa Stamme 1 0,3 1,2Pseudomonas aeruginosa Strain 1 0.3 1.2
Stamme 2 10 ^80 25 Stamme 3 2,5 40Tribe 2 10 ^ 80 25 Tribe 3 2.5 40
Stamme 4 5 80Tribe 4 5 80
Stamme 5 5 80Tribe 5 5 80
Stamme 6 10 80Strain 6 10 80
Stamme 7 '5 80 30 " — — ' " -1- —- " "Strain 7 '5 80 30 "- -" "-1- —-" "
Serratia marcescens 0,08 2,5Serratia marcescens 0.08 2.5
Aktivitet in vivo.In vivo activity.
35 Grupper på hver 5 mus inficeres intraperitonealt med en vandig suspension af Escherichia coli. Tre gange, dvs. 1 time, 2 1/2 timer og 4 timer efter infektionen administreres forsøgsstoffet subcutant i fysiologisk kogesaltop- 149283 11 løsning. Antallet af overlevende dyr bestemmes den 4, dag.35 groups of every 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. Three times, ie At 1 hour, 2 1/2 hours and 4 hours after infection, the test substance is administered subcutaneously in physiological boiling salt solution. The number of surviving animals is determined on the 4th day.
Der administreres forskellige doseringer, og ved inter-polering bestemmes den dosis,, ved hvilken 50% af forsøgs-^ dyrene overlever (CD5q, mg/kg)Various dosages are administered and, when interpolated, the dose at which 50% of the test animals survive is determined (CD5q, mg / kg).
Forsøgsstof A BTest substance A B
CD50, mg/kg £ 0,005 0,16 10CD50, mg / kg £ 0.005 0.16 10
Toxicitet ....Toxicity ....
Forsøgsstof A BTest substance A B
ης LD,.n, mg/kg intra- 250 - 500 250 - 500 venøst subcu- >4000 2000 - 4000 tant pero- >5000 ^5000 ralt 20 I tysk fremlæggelsesskrift nr. 27 15 385 og 27 07 565 er der beskrevet cephalosporinderivater, der i lighed med de ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede cephalosporiner indeholder en 25 7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetami- do]-gruppe. De ifølge den foreliggende opfindelse fremstillede cephalosporiner adskiller sig imidlertid på karakteristisk måde fra de kendte forbindelser ved konfigurationen af substituenten i 3-stilling, og der er så-30 ledes tilvejebragt hidtil ukendte forbindelser med over raskende virkningsfordele. Således har en sammenligning med en strukturelt nærtliggende, sammenlignelig forbindelse fra den kendte teknik (den eneste forbindelse, som i 3-stilling, i lighed med de omhandlede 35 cephalosporiner, indeholder en 6-leddet N-heterocyclisk 12 149283 thiomethylgruppe, nemlig en (6-methyl-l-oxido-pyridazin--3-yl)thiomethylgruppe), vist, at en repræsentativ forbindelse blandt de ifølge opfindelsen fremstillede ce-g phalosporiner med formlen I, hvor X er en 1,2,5,6-tetra- hydro-2-methyl-5,6-dioxo-as-triazin-3-ylgruppe eller dennes tilsvarende tautomere form, en 2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-ylgruppe, har en massiv (over 50 gange kraftigere) virkningsoverlegen-hed i en profylaktisk in vivo test på mus imod de patogene mikroorganismer Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis og Proteus vulgaris.ης LD, .n, mg / kg intra-250 - 500 250 - 500 venous subcu-> 4000 2000 - 4000 aunt pero-> 5000 ^ 5000 altogether 20 German presentation no. 27 15 385 and 27 07 565 cephalosporin derivatives are described. which, like the cephalosporins prepared by the process of the present invention, contains a 7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] group. However, the cephalosporins prepared according to the present invention differ in a distinct manner from the known compounds in the configuration of the substituent in 3-position, and thus novel compounds with surprising effects have been provided. Thus, a comparison with a structurally close, comparable compound of the prior art (the only compound which, at the 3-position, similar to the subject cephalosporins, contains a 6-membered N-heterocyclic thiomethyl group, namely a ( -methyl-1-oxido-pyridazine-3-yl) thiomethyl group, shown to represent a representative compound of the ce-g phalosporins of formula I of the invention wherein X is a 1,2,5,6 hydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or its corresponding tautomeric form, a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3 -yl group, has a massive (over 50 times more potent) efficacy superior in a prophylactic in vivo test on mice against the pathogenic microorganisms Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris.
De omhandlede produkter kan anvendes som lægemidler, f.eks.The products in question can be used as pharmaceuticals, e.g.
^ i form af farmaceutiske præparater, som indeholder dem eller salte deraf i blanding med et til enteral eller parenteral applikation egnet farmaceutisk, organisk eller uorganisk inert bærestof.in the form of pharmaceutical compositions containing them or their salts in admixture with a pharmaceutically, organically or inorganically inert carrier suitable for enteral or parenteral application.
2q Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempler:2q The process according to the invention is further illustrated by the following examples:
Eksempel 1.Example 1.
25 Fremstilling af (6R,7R)-7-(2-[2-(2-chloracetamido)-4- -thiazolyl]-2-(Z-methoxyimino)acetamido)-3-([(2,5-dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl)-8--oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre. 1 2 3 4 5 6 22,24 g 2-(2-chloracetamido-thiazol-4-yl)-2-(Z-methoxy 2 imino) eddikesyre suspenderes i 240 ml methylenchlorid.Preparation of (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4- -thiazolyl] -2- (Z-methoxyimino) acetamido) -3 - ([(2,5-dihydro) -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8 - oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene 2-carboxylic acid. 22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- (Z-methoxy 2-imino) acetic acid are suspended in 240 ml of methylene chloride.
33
Til denne suspension sættes 13,39 ml triethylamin, hvor 4 ved der dannes en lysebrun opløsning. Denne opløsning af 5 køles til 0 - 5°C, tilsættes 16,72 g phosphorpentachlorid 6 og omrøres i 5 minutter ved 0 - 5°C og i 20 minutter uden afkøling. Den gule opløsning inddampes i vakuum ved 35°C. Inddampningsremanensen udrystes to gange med n-heptan, som fradekanteres. Den harpiksagtige remanens behandles med 13 149283 240 ml tetrahydrofuran, og det uopløste triethylamin-hydro-chlorid frafiltreres. Det gule filtrat indeholder syre-chloridet.To this suspension is added 13.39 ml of triethylamine, 4 of which forms a light brown solution. This solution of 5 is cooled to 0 - 5 ° C, 16.72 g of phosphorus pentachloride 6 is added and stirred for 5 minutes at 0 - 5 ° C and for 20 minutes without cooling. The yellow solution is evaporated in vacuo at 35 ° C. The evaporation residue is shaken twice with n-heptane which is decanted off. The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. The yellow filtrate contains the acid chloride.
5 22 g (7R)-7-amino-3-desacetoxy-3-[ (2,5-dihydro-6-hydroxy- - · -2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporansyre suspenderes i en blanding af 300 ml vand og 150 ml tetrahydrofuran. Til suspensionen dryppes under godt dække af nitrogengas 2N natriumhydroxidopløsning ved hjælp af ^0 en autotitrator, til der dannes en brunrød opløsning med pH-værdi 8. Denne afkøles til 0 - 5°C og tilsættes i løbet af 15 minutter dråbevis den ovenfor fremstillede opløsning af syrechloridet i tetrahydrofuran. Derefter omrøres der i 2 1/2 timer ved 25°C. pH-værdien i acyleringsblandingen ^ holdes konstant på 8 ved tilsætning af 2N natriumhydroxid opløsning. Den praktisk taget sorte opløsning befries for tetrahydrofuran i vakuum ved 40°C. Der tilsættes derefter 100 ml 2N svovlsyreopløsning. Det derved udfældede stof isoleres ved sugefiltrering, vaskes med vand og afsuges 20 grundigt. Det fugtige, brune filtreringsprodukt opløses i 1,5 liter acetone. Den mørke opløsning frafiltreres en ringe mængde mørkt uopløst materiale over "Hyflo" 'S/ tilsættes kul, omrøres i 30 minutter og filtreres igen over "Hyflo"®. Det orangerøde filtrat tørres over natrium-25 sulfat, inddampes i vakuum og afdampes med ethylacetat.22 g (7R) -7-amino-3-desacetoxy-3- [(2,5-dihydro-6-hydroxy- - 2-methyl-5-oxo-az-triazin-3-yl) thio] cephalosporanoic acid is suspended in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. To the suspension, drop under a good cover of nitrogen gas 2N sodium hydroxide solution by using an autotitrator until a tan solution of pH 8 is formed. of the acid chloride in tetrahydrofuran. Then stir for 2 1/2 hours at 25 ° C. The pH of the acylation mixture is kept constant at 8 by the addition of 2N sodium hydroxide solution. The practically black solution is frozen for tetrahydrofuran in vacuo at 40 ° C. 100 ml of 2N sulfuric acid solution is then added. The thus precipitated substance is isolated by suction filtration, washed with water and thoroughly aspirated. The moist brown filtration product is dissolved in 1.5 liters of acetone. The dark solution is filtered off a small amount of dark undissolved material over "Hyflo" S / charcoal, stirred for 30 minutes and filtered again over "Hyflo" ®. The orange-red filtrate is dried over sodium sulfate, evaporated in vacuo and evaporated with ethyl acetate.
Derved udfældes en sort harpiks, som frafiltreres og kasseres. Det 2-fasede, stadig vandholdige filtrat underkastes azeotrop destillation 3 gange med benzen i vakuum ved 40°C. Det derved udfældede stof isoleres ved sugefil-^ trering og tørres i vakuum ved 40°C. Stoffet udrøres 2 gange med hver gang 1 liter acetone, hvorved der som remanens fås en brun harpiks, som kasseres. De samlede orangefarvede acetoneekstrakter inddampes i vakuum til 150 ml ved 40°C, hvorhos en brun harpiks frafiltreres og kasse-35 res. Til filtratet sættes 1 liter ethylacetat, og der inddampes i vakuum ved 40°C. Det derved udfældede stof isoleres ved sugefiltrering, vaskes med ethylacetat og derefter med ether [(6R,7R)-7-(2-[2-(2-chloracetamido)- 14 149283 -4-thiazolyl]-2-(Z-methoxyimino)acetamido)-3-([(2,5-di-hydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl--8-oxo-5-thia-l-azabicycloί4.2.0]oct-2-en-2-carboxylsyre, fraktion I: en beigefarvet, amorf syre]. Denne fraktion I 5 kan anvendes direkte til fremstilling af det ønskede slut produkt.Thereby a black resin is precipitated which is filtered off and discarded. The 2-phase, still aqueous filtrate is subjected to azeotropic distillation 3 times with benzene in vacuo at 40 ° C. The precipitate thus obtained is isolated by suction filtration and dried in vacuo at 40 ° C. The substance is stirred twice with 1 liter of acetone each time, whereby as a residue a brown resin is obtained, which is discarded. The combined orange colored acetone extracts are evaporated in vacuo to 150 ml at 40 ° C, whereupon a brown resin is filtered off and discarded. To the filtrate is added 1 liter of ethyl acetate and evaporated in vacuo at 40 ° C. The precipitate thus obtained is isolated by suction filtration, washed with ethyl acetate and then with ether [(6R, 7R) -7- (2- [2- (2-chloroacetamido) - 14 149283 -4-thiazolyl] -2- (Z-methoxyimino ) acetamido) -3 - ([(2,5-di-hydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl - 8-oxo-5-thia- 1-azabicycloί4.2.0] oct-2-ene-2-carboxylic acid, fraction I: a beige colored, amorphous acid] This fraction I 5 can be used directly to prepare the desired final product.
Ethylacetatmoderluden inddampes kraftigt i vakuum ved 40°C og fortyndes med ether, og det udfældede stof isole-res ved sugefiltrering [(6R,7R>-7-(2-[2-(2-chloracetamido)--4-thiazolyl]-2-(Z-methoxyimino)acetamido)-3-([(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)-8-oxo--5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre, fraktion II: en lysbeige, amorf syre, tyndtlagschromatografisk ]_5 noget renere end fraktion I].The ethyl acetate mother liquor is vaporized vigorously in vacuo at 40 ° C and diluted with ether, and the precipitate is isolated by suction filtration [(6R, 7R> -7- (2- [2- (2-chloroacetamido) - 4-thiazolyl] - 2- (Z-methoxyimino) acetamido) -3 - ([(2,5-dihydro-6 - hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8-oxo - 5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, fraction II: a light beige, amorphous acid, thin layer chromatographic] _5 somewhat purer than fraction I].
Til fremstilling af dinatriumsaltet opløses 3,5 g syre (fraktion II) i en blanding af 20 ml acetone og 11 ml vand.To prepare the disodium salt, 3.5 g of acid (fraction II) is dissolved in a mixture of 20 ml of acetone and 11 ml of water.
Til denne opløsning sættes 7 ml af en 2N opløsning af 20 2-ethylcapronsyre-natriumsalt i ethylacetat, hvorved di natriumsaltet krystalliserer. Der tilsættes derefter portionsvis 25 ml acetone, og blandingen opbevares i dybfryser i 2 timer. Derefter isoleres krystallisatet ved sugefiltrering, vaskes med 25 ml af en iskold acetone-vand-blan-25 ding (80:20), rent acetone og lavtkogende petroleumsether i den anførte rækkefølge og tørres natten over i høj-vakuum ved 40°C. Der fås dinatriumsaltet af (6R,7R)-7--(2-[2-(2-chloracetamido)-4-thiazolyl]-2-(Z-methoxyimino)-acetamido)-3-([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-30 -triazin-3-yl)thio]-methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]— oct-2-en-2-carboxylsyre i form af lysegule krystaller.To this solution is added 7 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate, thereby crystallizing the sodium salt. Then 25 ml of acetone is added portionwise and the mixture is stored in the freezer for 2 hours. Then, the crystallate is isolated by suction filtration, washed with 25 ml of an ice-cold acetone-water mixture (80:20), pure acetone and low-boiling petroleum ether in the order given and dried overnight in high vacuum at 40 ° C. There is obtained the disodium salt of (6R, 7R) -7 - (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamido) -3 - ([(2.5- dihydro-6-hydroxy-2-methyl-5-oxo-as-30-triazin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] - oct-2 -an-2-carboxylic acid in the form of light yellow crystals.
= -142,7° (c = 1 .i vand), Kerneresonansspektrum og mikroanalysen svarer til den angivne struktur.= -142.7 ° (c = 1 in water), Nuclear resonance spectrum and microanalysis correspond to the structure indicated.
3535
Eksempel 2.Example 2.
Fremstilling af dinatriumsaltet af (6R,7R)-7-[2-(2--amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-([2,5- 15 149283 -dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thiol--methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-car-boxylsyre.Preparation of the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3- ([2,5- 149283-dihydro-6 -hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiol - methyl) -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-car -boxylsyre.
5 15/3 g (6R,7R)-7-(2-[2-(2-chloracetamido)-4-thia- zolyl]-2-(Z-methoxyimino)acetamido)-3-([2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)-8--oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre (fraktion I, se ovenfor) suspenderes sammen med 5 g 10 thiourinstof i 150 ml vand. Under god nitrogenbegasning og omrøring indstilles pH-værdien på 6,8 - 7,0 med mættet natriumhydrogencarbonatopløsning, hvorved der dannes en orangefarvet opløsning. Ved hjælp af autotitratbr holdes pH-værdien i reaktionsopløsningen konstant ved 6,8 i 6 15 timer under tilsætning af natriumhydrogencarbonatopløsning.15/3 g (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido) -3- ([2,5- dihydro-6 - hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8 - oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene 2-Carboxylic acid (Fraction I, see above) is suspended together with 5 g of 10 thiourea in 150 ml of water. Under good nitrogen gasification and stirring, the pH of 6.8 - 7.0 is adjusted with saturated sodium hydrogen carbonate solution to give an orange solution. Using autotitrate br, the pH of the reaction solution is kept constant at 6.8 for 6 hours while adding sodium hydrogen carbonate solution.
Derefter tilsættes yderligere 2,5 g thiourinstof, og opløsningen omrøres i yderligere 3 timer, medens pH-værdien holdes på 6,8 under tilsætning af mættet natrium-hydrogencarbonatopløsning. Derefter opbevares den røde 20 opløsning natten over i køleskab, hvorved den bliver mørkere. pH-værdien i denne opløsning indstilles på 2,0 - 2,5 ved tilsætning af 100%'s myresyre, hvorved stoffet udfælder. Dette isoleres ved sugefiltrering og vaskes med 100 ml 10%'s myresyreopløsning. Moderluden kasseres.Then an additional 2.5 g of thiourea is added and the solution is stirred for an additional 3 hours while maintaining the pH of 6.8 with the addition of saturated sodium hydrogen carbonate solution. Then the red 20 solution is stored in the refrigerator overnight, thereby darkening. The pH of this solution is adjusted to 2.0 - 2.5 by the addition of 100% formic acid, whereby the substance precipitates. This is isolated by suction filtration and washed with 100 ml of 10% formic acid solution. The mother liquor is discarded.
25 Det brunlige sugefiltreringsprodukt suspenderes i 200 ml vand, og pH-værdien indstilles på 7 med triethylamin, hvorved der dannes en brun opløsning. Denne opløsning røres med 2 g aktivkul i 30 minutter, kullet frafiltreres, og det stadig brune filtrat indstilles under kraftig om-30 røring på pH-værdi 3,5 med 100%'s myresyre. Det derved udfældede stof isoleres ved sugefiltrering, vaskes med 50 ml 10%'s myresyreopløsning og kasseres. Det mørkegule filtrat indstilles på pH-værdi 2-2,5 med 1001's myresyre, hvorved stoffet udfældes. Dette isoleres ved suge-35 filtrering, vaskes med isvand .og tørres. Den vundne cephalosporinsyre suspenderes med henblik på omdannelse til dinatriumsaltet i en blanding af 40 ml acetone og 40 ml vand og tilsættes 20 ml af en 2-N-opløsning afThe brownish suction filtration product is suspended in 200 ml of water and the pH is adjusted to 7 with triethylamine to give a brown solution. This solution is stirred with 2 g of activated charcoal for 30 minutes, the charcoal is filtered off and the still brown filtrate is adjusted with vigorous stirring to pH 3.5 with 100% formic acid. The thus precipitated substance is isolated by suction filtration, washed with 50 ml of 10% formic acid solution and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 1001 formic acid, whereby the substance precipitates. This is isolated by suction filtration, washed with ice water and dried. The cephalosporic acid obtained is suspended for conversion to the disodium salt in a mixture of 40 ml of acetone and 40 ml of water and 20 ml of a 2-N solution of
Claims (7)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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DK388984A DK149283C (en) | 1978-05-30 | 1984-08-10 | ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH588278A CH641468A5 (en) | 1978-05-30 | 1978-05-30 | CEPHEM DERIVATIVES. |
CH588278 | 1978-05-30 | ||
CH224879 | 1979-03-08 | ||
CH224879 | 1979-03-08 | ||
DK222679 | 1979-05-29 | ||
DK222679A DK149282C (en) | 1978-05-30 | 1979-05-29 | ANALOGY PROCEDURE FOR THE PREPARATION OF A CEPHEM DERIVATIVE |
DK388984 | 1984-08-10 | ||
DK388984A DK149283C (en) | 1978-05-30 | 1984-08-10 | ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES |
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DK388984D0 DK388984D0 (en) | 1984-08-10 |
DK388984A DK388984A (en) | 1984-08-10 |
DK149283B true DK149283B (en) | 1986-04-21 |
DK149283C DK149283C (en) | 1986-09-01 |
Family
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DK478983A DK150600C (en) | 1978-05-30 | 1983-10-17 | cephalosporin |
DK388984A DK149283C (en) | 1978-05-30 | 1984-08-10 | ANALOGY PROCEDURE FOR PREPARING CEPHALOSPORINE DERIVATIVES |
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DK478983A DK150600C (en) | 1978-05-30 | 1983-10-17 | cephalosporin |
Country Status (1)
Country | Link |
---|---|
DK (2) | DK150600C (en) |
-
1983
- 1983-10-17 DK DK478983A patent/DK150600C/en not_active IP Right Cessation
-
1984
- 1984-08-10 DK DK388984A patent/DK149283C/en active
Also Published As
Publication number | Publication date |
---|---|
DK149283C (en) | 1986-09-01 |
DK150600B (en) | 1987-04-06 |
DK478983A (en) | 1983-10-17 |
DK478983D0 (en) | 1983-10-17 |
DK388984D0 (en) | 1984-08-10 |
DK388984A (en) | 1984-08-10 |
DK150600C (en) | 1987-12-21 |
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