NO791996L - PROCEDURE FOR THE PREPARATION OF ANTIBACTERIAL ACTIVE IMINOTIOAZOLYL-UREIDO-CEPHALOSPORINES - Google Patents

PROCEDURE FOR THE PREPARATION OF ANTIBACTERIAL ACTIVE IMINOTIOAZOLYL-UREIDO-CEPHALOSPORINES

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Publication number
NO791996L
NO791996L NO791996A NO791996A NO791996L NO 791996 L NO791996 L NO 791996L NO 791996 A NO791996 A NO 791996A NO 791996 A NO791996 A NO 791996A NO 791996 L NO791996 L NO 791996L
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Norway
Prior art keywords
amino
methyl
imino
dihydro
oct
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NO791996A
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Norwegian (no)
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Hermann Breuer
Uwe D Treuner
Theodor Denzel
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Squibb & Sons Inc
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Publication of NO791996L publication Critical patent/NO791996L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

"Analogifremgangsraåte for fremstilling av antibakterielt aktive iminotiazolyl- ureido- cefalosporiner " "Analog process for the production of antibacterially active iminothiazolyl-ureido-cephalosporins"

Denne oppfinnelse angår fremstilling av nye cefalosporiner med formelen: This invention relates to the production of new cephalosporins with the formula:

(I) (IN)

innbefattet dens amino-tautomere form, hvor including its amino tautomeric form, where

R er hydrogen, natrium, kalium, t-butyl, benzyl, p-metoksybenzyl, p-nitrobenzyl, difenylmetyl, 2,2,2-trikloretyl, trimetylsilyl, -CH -O-lavere alkyl,-CH-0-CO-lavere alkyl eller R is hydrogen, sodium, potassium, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, trimethylsilyl, -CH -O-lower alkyl, -CH-0-CO-lower alkyl or

er i a-konfigurasjon og er hydrogen eller metoksy; R2 er hydrogen, -C0-CH2C1, -CO-CH2Br, -CO-CF3, -CO-0-CH2CCl3, -COH eller -R^ er hydrogen eller lavere alkyl; is in α-configuration and is hydrogen or methoxy; R 2 is hydrogen, -C0-CH 2 Cl , -CO-CH 2 Br, -CO-CF 3 , -CO-O-CH 2 CCl 3 , -COH or -R 3 is hydrogen or lower alkyl;

X er hydrogen, -0-CO-lavere alkyl, -0-CO-NH , X is hydrogen, -0-CO-lower alkyl, -0-CO-NH,

R^er hydrogen eller lavere alkyl; R5 er hydrogen, lavere alkyl, -(CrO -CO-OR,, R 1 is hydrogen or lower alkyl; R5 is hydrogen, lower alkyl, -(CrO -CO-OR,,

eller -(CH2)<->N-(lavere alkyl)2; or -(CH2)<->N-(lower alkyl)2;

Rg er hydrogen, natrium eller kalium, ogRg is hydrogen, sodium or potassium, and

n er et helt tall fra 1 til 4 .n is an integer from 1 to 4.

Symbolet C it i formel I og i de følgende formler representerer et asymmetrisk karbonatom. The symbol C it in formula I and in the following formulas represents an asymmetric carbon atom.

Når X er pyridinium eller karbamoyl-substituert pyridinium, kan forbindelsene strukturelt representeres med formelen: When X is pyridinium or carbamoyl-substituted pyridinium, the compounds can be structurally represented by the formula:

(Ia) (Ia)

hvor Z er hydrogen eller karbamoyl. where Z is hydrogen or carbamoyl.

De lavere alkylgrupper som omtales her, omfatterThe lower alkyl groups referred to herein include

lineære eller forgrenede hydrokarbongrupper inneholdende 1 til 4 karbonatomer, f.eks. metyl, etyl, i-propyl, t-butyl, osv. linear or branched hydrocarbon groups containing 1 to 4 carbon atoms, e.g. methyl, ethyl, i-propyl, t-butyl, etc.

Cefalosporiner som har en ureido-substituert acyl-sidekjede og forskjellige grupper i 3-stilling, er beskrevet i US-patenter 3.673.183, 3.708.479, 3.833.568, 3.860.591, Cephalosporins having a ureido-substituted acyl side chain and various groups in the 3-position are described in US Patents 3,673,183, 3,708,479, 3,833,568, 3,860,591,

3.996.217, 3.996.218 og 4.024.135, og i belgisk patent 833.640. 3,996,217, 3,996,218 and 4,024,135, and in Belgian patent 833,640.

Forskjellige 7a-metoksy-cefalosporiner med en ureido-substituert acyl-sidekjede og forskjellige grupper i 3-stilling er beskrevet i US-patenter 3.978.051, 3.989.693, 3.989.697, 4.000.134 og 4.061.852. Various 7α-methoxy cephalosporins with a ureido-substituted acyl side chain and various groups in the 3-position are described in US Patents 3,978,051, 3,989,693, 3,989,697, 4,000,134 and 4,061,852.

I US-patent 4.098.888 beskrives cefalosporiner som harUS patent 4,098,888 describes cephalosporins which have

en iminotiazolyl-acetamido-acyl-sidekjede med en amino-, hydroksy-eller iminogruppe på a-karbonatomet i acyl-sidekjeden. an iminothiazolyl-acetamido-acyl side chain with an amino, hydroxy or imino group on the α-carbon atom of the acyl side chain.

Cefalosporiner med en iminotiazolyl- eller substituert iminotiazolyl-acetamido-acyl-sidekjede og forskjellige grupper i 3-stilling er beskrevet i tysk off.skrift 2.461.478. Desmetoksy-cefalosporiner med en alkoksyimino- eller hydroksyimino- substituert iminotiazoly 1-acetamido-acy 1-sidekjede og forskjellige grupper i 3-stilling er beskrevet i belgiske patenter 850.662, 852.860, 852.427, 853.545 og 856.045. Cephalosporins with an iminothiazolyl or substituted iminothiazolyl-acetamido-acyl side chain and various groups in the 3-position are described in German official publication 2,461,478. Desmethoxy-cephalosporins with an alkoxyimino- or hydroxyimino-substituted iminothiazoly 1-acetamido-acy 1 side chain and various groups in the 3-position are described in Belgian patents 850,662, 852,860, 852,427, 853,545 and 856,045.

Forbindelsene med formel I og de nedenfor beskrevne mellomprodukter som omfatter 2-iminotiazolyl-gruppen som en del av sin struktur., er selvsagt tautomere og kan også representeres strukturelt som en 2-amino-gruppe. Således kan f.eks. forbindelsene med formel I representeres som The compounds of formula I and the intermediates described below which comprise the 2-iminothiazolyl group as part of their structure are of course tautomers and can also be represented structurally as a 2-amino group. Thus, e.g. the compounds of formula I are represented as

(II) (II)

Mellomproduktene og sluttproduktene er her angitt The intermediate products and final products are indicated here

og omtalt som 2-iminotiazoler, selv om begge former fremstilles ifølge oppfinnelsen. and referred to as 2-iminothiazoles, although both forms are produced according to the invention.

Forbindelsene med formel I kan i henhold til oppfinnelsen fremstilles ved flere metoder. Forbindelsene med formel I hvor X er hydrogen, -0-CO-lavere alkyl, -O-CO-NP^, According to the invention, the compounds of formula I can be prepared by several methods. The compounds of formula I where X is hydrogen, -O-CO-lower alkyl, -O-CO-NP^,

, kan f.eks. fremstilles ved , can e.g. produced by

ved acylering av en 73-amino-7a-metoksy- eller desmetoksy-cefalosporansyreester med formelen by acylation of a 73-amino-7α-methoxy- or desmethoxy-cephalosporanic acid ester with the formula

(III) (III)

hvor er t-butyl, benzyl, p-metoksybenzyl, p-nitrobenzy1, difenylmetyl, trimetylsilyl, lavere alkoksymetyl eller 2,2,2-trikloretyl, særlig difenylmetyl, med et aktivert derivat med where is t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzy1, diphenylmethyl, trimethylsilyl, lower alkoxymethyl or 2,2,2-trichloroethyl, especially diphenylmethyl, with an activated derivative with

formelen the formula

(IV) (IV)

hvor R„ er som ovenfor angitt, og B er en beskyttende gruppe så som i eller where R„ is as indicated above, and B is a protecting group such as in or

for å danne et mellomprodukt med formelen to form an intermediate with the formula

(V) (V)

Egnede aktiverte derivater av forbindelsen med formel IV er syrekloridet eller -bromidet, et anhydrid eller blandet anhydrid eller en aktivert ester dannet ved kjente metoder. Suitable activated derivatives of the compound of formula IV are the acid chloride or bromide, an anhydride or mixed anhydride or an activated ester formed by known methods.

Alternativt kan acyleringen foretas direkte med syren med formel IV ved anvendelse av koblingsmidler så som karbodiimider. Denne direkte acylering foretrekkes særlig når R«er hydrogen. Alternatively, the acylation can be carried out directly with the acid of formula IV using coupling agents such as carbodiimides. This direct acylation is particularly preferred when R is hydrogen.

Mellomproduktet med formel V behandles derefter med tri fluoreddiksyre og anisol for å gi a-amino-cefalosporinet med formelen The intermediate of formula V is then treated with trifluoroacetic acid and anisole to give the α-amino-cephalosporin of the formula

(VI) (WE)

Behandling av trifluoreddiksyresaltet med formel VI med kalium- eller natriumcyanat gir forbindelsene med formel I hvor R2er som ovenfor angitt. Treatment of the trifluoroacetic acid salt of formula VI with potassium or sodium cyanate gives the compounds of formula I where R 2 is as indicated above.

Alternativt kan en 2,3-dihydro-a-beskyttet amino-4-tiazoleddiksyre med formel IV behandles med trifluoreddiksyre og anisol for å danne en forbindelse med formelen Alternatively, a 2,3-dihydro-α-protected amino-4-thiazoleacetic acid of formula IV may be treated with trifluoroacetic acid and anisole to form a compound of the formula

(VII) (VIII)

som behandles med kaliumcyanat for å danne en forbindelse med formelen (VIII) . • which is treated with potassium cyanate to form a compound of formula (VIII). •

a-ureido-mellomproduktet med formel VIII omdannes derefter til en aktivert form så som et blandet anhydrid eller en aktivert ester. Acylering av esteren med formel III med den aktiverte forbindelse med formel VIII fører til dannelse av forbindelser med formelen The α-ureido intermediate of formula VIII is then converted to an activated form such as a mixed anhydride or an activated ester. Acylation of the ester of formula III with the activated compound of formula VIII leads to the formation of compounds of the formula

(IX) (IX)

Estergruppen R_, kan derefter fjernes i henhold til kjente metoder for å danne forbindelser med formel I. The ester group R_ can then be removed according to known methods to form compounds of formula I.

kan syren med formel VIII can the acid of formula VIII

også behandles med tionylklorid for å danne et aktivert mellomprodukt som kan representeres ved formelen: is also treated with thionyl chloride to form an activated intermediate which can be represented by the formula:

(X) (X)

Acylering av esteren med formel III med den aktiverte forbindelse med formel X fører til forbindelsene med formel I hvor Acylation of the ester of formula III with the activated compound of formula X leads to the compounds of formula I wherein

Forbindelsen med formel IV hvor R2er hydrogen, fremstilles ved at en 2,3-dihydro-2-imino-a-amino-4-tiazol-eddiksyre omsettes med en amino-beskyttende gruppe så som (p-metoksyfenyl)-metoksy-karbonylazid. Forbindelsene med formel IV hvor R2er forskjellig fra hydrogen, fremstilles ved at en forbindelse hvor R2er hydrogen, omsettes med den imino-beskyttende gruppe som beskrevet i belgiske patenter 850.662, 852.860, 852.427, 853.545 og 856.045 og tysk off.skrift 2.461.478 som er nevnt ovenfor. The compound of formula IV where R 2 is hydrogen is prepared by reacting a 2,3-dihydro-2-imino-α-amino-4-thiazole-acetic acid with an amino-protecting group such as (p-methoxyphenyl)-methoxy-carbonyl azide. The compounds of formula IV where R2 is different from hydrogen are prepared by reacting a compound where R2 is hydrogen with the imino-protecting group as described in Belgian patents 850,662, 852,860, 852,427, 853,545 and 856,045 and German official publication 2,461,478 which is mentioned above.

Forbindelsene med formel I hvor R2 er forskjellig fra hydrogen, kan behandles i henhold til kjente metoder for å fjerne den imino-beskyttende gruppe og danne forbindelsene hvor R2er hydrogen. Forbindelsen med formel I hvor R2er -C0-CH2C1 og R er en estergruppe så som difenylmetyl, behandles f.eks. først, med tiourinstoff for å fjerne -CO-CH2Cl-gruppen og behandles derefter med trifluoreddiksyre og anisol for å fjerne difenyl-mety1-estergruppen. The compounds of formula I where R 2 is different from hydrogen can be treated according to known methods to remove the imino-protecting group and form the compounds where R 2 is hydrogen. The compound of formula I where R2 is -C0-CH2C1 and R is an ester group such as diphenylmethyl, is treated e.g. first, with thiourea to remove the -CO-CH2Cl group and then treated with trifluoroacetic acid and anisole to remove the diphenyl methyl ester group.

Forbindelsene med formel Ia kan fremstilles ved omsetning av en forbindelse med formel I hvor R er hydrogen og X er -O-CO-CH^eller -0-C0-NH2med pyridin eller karbamoy1-substituert pyridin i et polart oppløsningsmiddel så som vann, og i nærvær av én katalysator så som et alkalimetalltiocyanat i henhold til fremgangsmåtene beskrevet i US-patent 3.792.047 og tysk off.skrift 2.234.280. The compounds of formula Ia can be prepared by reacting a compound of formula I where R is hydrogen and X is -O-CO-CH^ or -O-C0-NH2 with pyridine or carbamoyl-substituted pyridine in a polar solvent such as water, and in the presence of one catalyst such as an alkali metal thiocyanate according to the methods described in US Patent 3,792,047 and German Off.skrift 2,234,280.

Forbindelsene med formel I hvor X er heterotioThe compounds of formula I where X is heterothio

(dvs. (ie

kan også fremstilles can also be produced

ved at en forbindelse med formel I hvor R er hydrogen og X er -0-C0-CH3eller -0-C0-NH2, omsettes med et merkaptan med formelen in that a compound of formula I where R is hydrogen and X is -0-C0-CH3 or -0-C0-NH2 is reacted with a mercaptan of the formula

(XI) (XI)

eller et alkalimetall- (fortrinnsvis natrium-) merkaptansalt or an alkali metal (preferably sodium) mercaptan salt

■med formelen■with the formula

(XII) (XII)

hetero-S-alkalimetall.hetero-S-alkali metal.

Slike metoder for innføring av en heterotiogruppe i 3-stilling er beskrevet i forskjellige US-patenter så som Such methods for introducing a heterothio group in the 3-position are described in various US patents such as

3.855.213 og 4.066.762. 3,855,213 and 4,066,762.

Forbindelsene med formel I hvor R er natrium ellerThe compounds of formula I where R is sodium or

kalium, fremstilles ved at den tilsvarende frie syre med formel Ipotassium, is produced by the corresponding free acid with formula I

(R er hydrogen) omsettes med det passende saltdannende ion.(R is hydrogen) is reacted with the appropriate salt-forming ion.

Forbindelsen med formel I hvor R er. ■ The compound of formula I wherein R is ■

lavere alkyl, lower alkyl,

kan erholdes ved at den tilsvarende frie syre med formel I behandles med 1 eller 2 mol av en forbindelse med formelen: can be obtained by treating the corresponding free acid of formula I with 1 or 2 mol of a compound of the formula:

(XIII) (XIII)

hvor halo er klor eller brom, i et inert oppløsningsmiddel så som dimetylformamid, ved eller under omgivelsestemperatur. wherein halo is chlorine or bromine, in an inert solvent such as dimethylformamide, at or below ambient temperature.

Forbindelsene med formel I hvor R erThe compounds of formula I where R is

, kan likeledes fremstilles ved at den frie syre med , can likewise be produced by adding the free acid with

formel I omsettes med en forbindelse med formelen formula I is reacted with a compound of the formula

(XIV) (xiv)

som beskrevet i US-patent 3.860.579. as described in US Patent 3,860,579.

Symbolet C i de foregående formler betyr etThe symbol C in the preceding formulas means a

asymmetrisk karbonatom.asymmetric carbon atom.

Ved valg av de passende utgangsmaterialer er det muligBy choosing the appropriate starting materials it is possible

å oppnå forbindelsene med formel I som en blanding av optisk aktive isomerer eller isolert som en enkelt isomer. Når sluttproduktet oppnås i ;D,.L-form, kan også de rene D- og L-diastereoisomerer erholdes<1>ved preparativ høyeffektiv væskekromatografi (HPLC). De forskjellige isomerer og deres blandinger kan fremstilles ifølge oppfinnelsen. to obtain the compounds of formula I as a mixture of optically active isomers or isolated as a single isomer. When the final product is obtained in ;D,.L form, the pure D- and L-diastereoisomers can also be obtained<1>by preparative high-performance liquid chromatography (HPLC). The various isomers and their mixtures can be prepared according to the invention.

Foretrukne forbindelser med formel I er de hvor R er hydrogen, natrium eller kalium; R^er hydrogen; R2er hydrogen eller -C0-CH2C1, særlig hydrogen; X er hydrogen , -0-CO-CH.., Preferred compounds of formula I are those where R is hydrogen, sodium or potassium; R 1 is hydrogen; R2 is hydrogen or -C0-CH2C1, especially hydrogen; X is hydrogen, -0-CO-CH..,

er hydrogen, is hydrogen,

og Rg er hydrogen, natrium eller kalium. and Rg is hydrogen, sodium or potassium.

Spesielt foretrukne forbindelser med formel I er de Particularly preferred compounds of formula I are those

hvor X er -0-C0-CH3 eller where X is -O-C0-CH3 or

Foretrukket som mellomprodukter er forbindelsene med formel I hvor R er t-butyl, benzyl, difenylmetyl eller 2,2,2-trikloretyl; og R2er -C0-CH2C1, -C0-CH2Br, -C0-CF3, -CO-0-CH2CCl3, -COH eller Forbindelsene med formel I hvor R er hydrogen, natrium, kalium, -CH2-0-lavere alkyl, avere alkyl eller og R2 er hydrogen, -C0-CH2C1, -CO-CH2Br, -CO-CF3, Preferred as intermediates are the compounds of formula I where R is t-butyl, benzyl, diphenylmethyl or 2,2,2-trichloroethyl; and R2 is -C0-CH2C1, -C0-CH2Br, -C0-CF3, -CO-0-CH2CCl3, -COH or The compounds of formula I where R is hydrogen, sodium, potassium, -CH2-0-lower alkyl, avere alkyl or and R2 is hydrogen, -C0-CH2C1, -CO-CH2Br, -CO-CF3,

eller -COH er nyttige som antibakterielle midler som or -COH are useful as antibacterial agents which

er aktive mot forskjellige gram-positive og gram-negative organismer så som Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella aerogenes, Proteus rettgeri, Proteus vulgarius, Proteus mirabilis, Serratia marcescens, Salmonella typhomurium, Shigella sonnei, Citrobacter freundii etc. De foretrukne og spesielt foretrukne sluttprodukter er særlig aktive mot gram-negative organismer så som Proteus, Escherichia coli, Klebsiella og Salmonella. are active against various gram-positive and gram-negative organisms such as Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella aerogenes, Proteus rettgeri, Proteus vulgarius, Proteus mirabilis, Serratia marcescens, Salmonella typhomurium, Shigella sonnei, Citrobacter freundii etc. The preferred and especially preferred end products are particularly active against gram-negative organisms such as Proteus, Escherichia coli, Klebsiella and Salmonella.

De aktive sluttprodukter kan anvendes som antibakterielle midler for bekjempelse av infeksjoner som skyldes slike organismer som de ovenfor angitte, og generelt kan de anvendes på samme måte som cefalotin og andre cefalosporiner. En forbindelse med formel I eller et fysiologisk godtagbart salt eller en ester derav kan f.eks. anvendes i forskjellige dyrearter i en mengde på ca. 1 til 100 mg/kg daglig, parenteralt, i en enkel eller to til fire oppdelte doser for å behp.ndle infeksjoner som skyldes bakterier, f.eks. 5,0 mg/kg i mus. The active end products can be used as antibacterial agents for combating infections caused by such organisms as those indicated above, and in general they can be used in the same way as cephalothin and other cephalosporins. A compound of formula I or a physiologically acceptable salt or an ester thereof can e.g. used in different animal species in an amount of approx. 1 to 100 mg/kg daily, parenterally, in a single or two to four divided doses to treat infections caused by bacteria, e.g. 5.0 mg/kg in mice.

Opptil ca. 600 mg av en syreforbindelse med formel IUp to approx. 600 mg of an acid compound of formula I

eller et fysiologisk godtagbart salt eller en ester derav kan innarbeides i en injiserbar form i et sterilt, vandig bæremiddel fremstilt i henhold til vanlig farmasøytisk praksis. or a physiologically acceptable salt or ester thereof may be incorporated in an injectable form in a sterile aqueous vehicle prepared according to ordinary pharmaceutical practice.

Illustrerende fremgangsmåtedetaljer er vist i eksempleneIllustrative process details are shown in the examples

for de forskjellige omsetninger. Alle temperaturer er i °C.for the different turnovers. All temperatures are in °C.

Eksempel 1 Example 1

7g-[[ D, L-[( aminokarbonyl) amino]-( 2-[( kloracetyl) imino]- 2, 3- dihydro-4- tiazolyl) acetyl] amino]- 3-[[( l- metyl- lH- tetrazol- 5- yl) tio]- metyl]-8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- ?- en- 2- karboksylsyre-natriumsalt 7g-[[ D, L-[( aminocarbonyl) amino]-( 2-[( chloroacetyl) imino]- 2, 3- dihydro-4- thiazolyl) acetyl] amino]- 3-[[( l- methyl- lH - tetrazol- 5- yl) thio]- methyl]-8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- ?- en- 2- carboxylic acid sodium salt

a) D, L- 2 , 3- dihydro- 2- imino- g- [ [ [,( 4- metoksyfeny 1) metoksy ] - karbonyl] amino]- 4- tiazoleddiksyre a) D, L- 2 , 3- dihydro- 2- imino-g- [ [ [,( 4- methoxypheny 1) methoxy ] - carbonyl] amino]- 4- thiazoleacetic acid

0,1 mol^ D,L-2,3-dihydro-2-imino-a-amino-4-tiazol-0.1 mol^ D,L-2,3-dihydro-2-imino-α-amino-4-thiazole-

eddiksyre oppløses i 150 ml vann og bringes i oppløsning ved tilsetning av 0,3 ml trietylamin. En oppløsning av 22,7 g (p-metoksyfenyl)metoksykarbonylazid i 150 ml dioksan tilsettes Acetic acid is dissolved in 150 ml of water and dissolved by adding 0.3 ml of triethylamine. A solution of 22.7 g of (p-methoxyphenyl)methoxycarbonyl azide in 150 ml of dioxane is added

under kraftig omrøring. Den uklare blanding blir klar efter 30 minutter. Denne blanding omrørés derefter i 1 time ved romtemperatur, og dioksanet avdestilleres. Den vandige base ekstraheres med eter, avkjøles til 0° og surgjøres til pH 3,5 ved tilsetning av 2N saltsyre. Det ønskede produkt utkrystal-liserer og filtreres under sugning for å gi 27 g D,L-2,3-dihydro-2-imino-a-[[[(4-metoksyfeny1)metoksy]karbonyl]amino]-4-tiazol-eddiksyre, sm.p. 141-142° (spaltn.) under vigorous stirring. The cloudy mixture becomes clear after 30 minutes. This mixture is then stirred for 1 hour at room temperature, and the dioxane is distilled off. The aqueous base is extracted with ether, cooled to 0° and acidified to pH 3.5 by adding 2N hydrochloric acid. The desired product crystallizes and is filtered with suction to give 27 g of D,L-2,3-dihydro-2-imino-α-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-4-thiazole- acetic acid, m.p. 141-142° (split.)

b) D, L- 2-[( kloracetyl) imino]- 2, 3- dihydro- a— [[[( 4- metoksyfenyl) metoksy] karbonyl] amino]- 4- tiazoleddiksyre b) D, L- 2-[( chloroacetyl) imino]- 2, 3- dihydro- a— [[[( 4- methoxyphenyl) methoxy] carbonyl] amino]- 4- thiazoleacetic acid

34 g (0,1 mol) av produktet fra del (a) oppløses i34 g (0.1 mol) of the product from part (a) is dissolved in

300 ml dimetylacetamid og 13,6 g (0,12 mol) kloracetylklorid tilsettes dråpevis under isavkjøling. Blandingen omrøres i 1 time ved romtemperatur, avkjøles og ekstraheres derefter flere ganger med etylacetat. De samlede etylacetat-ekstrakter vaskes med vann, tørres med magnesiumsulfat, behandles med aktivt kull og konsentreres i vakuum. Residuet krystalliserer og utgnies med eter og filtreres under sugning for å gi 25,9 g D,L-2-[(kloracetyl) imino]-2,3-dihydro-a-[[[(4-metoksyfeny1)metoksy]karbonyl]-amino]-4-tiazoleddiksyre, sm.p. 157-158°C (spaltn.) 300 ml of dimethylacetamide and 13.6 g (0.12 mol) of chloroacetyl chloride are added dropwise under ice cooling. The mixture is stirred for 1 hour at room temperature, cooled and then extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried with magnesium sulphate, treated with activated charcoal and concentrated in vacuo. The residue crystallizes and is triturated with ether and filtered with suction to give 25.9 g of D,L-2-[(chloroacetyl)imino]-2,3-dihydro-α-[[[(4-methoxyphenyl)methoxy]carbonyl] -amino]-4-thiazoleacetic acid, m.p. 157-158°C (dec.)

c) 7 3~[[ D, L-[[[( 4- metoksyfeny1) metoksy] karbonyl] amino]-( 2-[( kloracetyl) imino]- 2, 3- dihydro- 4- tiazolyl) acetyl]-amino]- 3-[[( l- metyl- lH- tetrazol- 5- yl) tio] metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre-difenyImetylester c) 7 3~[[ D, L-[[[( 4- methoxyphenyl) methoxy] carbonyl] amino]-( 2-[( chloroacetyl) imino]- 2, 3- dihydro- 4- thiazolyl) acetyl]-amino ]- 3-[[( l- methyl- lH- tetrazol- 5- yl) thio] methyl]- 8- oxo-5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylic acid diphenyl methyl ester

1,6 g (0,00386 mol) av produktet fra del (b) oppløses i1.6 g (0.00386 mol) of the product from part (b) is dissolved in

30 ml vannfri tetrahydrofuran og blandes med en oppløsning av30 ml anhydrous tetrahydrofuran and mixed with a solution of

1,89 g (0,0032 mol) 73~amino-3-[[ (l-metyl-lH-tetrazol-5-yl)tio]-metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester i 20 ml metylenklorid. Blandingen avkjøles til 0-5°, og en oppløsning av 0,72 g (0,0035 mol) dicykloheksy1-karbodiimid i 5 ml tetrahydrofuran tilsettes. Blandingen om-røres i 90 minutter ved 0-5° og 90 minutter ved romtemperatur. 1.89 g (0.0032 mol) 73-amino-3-[[ (1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid diphenyl methyl ester in 20 ml of methylene chloride. The mixture is cooled to 0-5°, and a solution of 0.72 g (0.0035 mol) of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran is added. The mixture is stirred for 90 minutes at 0-5° and 90 minutes at room temperature.

Det utfelte dicykloheksylurinstoff frafiltreres, og filtratet inndampes til tørrhet i vakuum. Residuet settes til en blanding av tetrahydrofuran og etylacetat og vaskes med natriumbikarbonat-oppløsning. Efter vasking med vann, tørring med magnesiumsulfat, The precipitated dicyclohexylurea is filtered off, and the filtrate is evaporated to dryness in vacuo. The residue is added to a mixture of tetrahydrofuran and ethyl acetate and washed with sodium bicarbonate solution. After washing with water, drying with magnesium sulfate,

■ behandling med aktivt kull og filtrering, konsentreres blandingen. Det faste residuum utgnies med eter og filtreres under sugning ■ treatment with activated carbon and filtration, the mixture is concentrated. The solid residue is triturated with ether and filtered with suction

for å gi 2,7 g 73-[ [D, L- [[[ (4-metoksy feny 1) me toksy ] karbonyl ] - amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)acetyl]-amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-1-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester, sm.p. 165-167° (spaltn.). to give 2.7 g of 73-[ [D, L- [[[ (4-methoxy phenyl 1) methoxy ] carbonyl ] -amino]-(2-[(chloroacetyl)imino]-2,3-dihydro- 4-thiazolyl)acetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid diphenyl methyl ester, m.p. 165-167° (dec.).

d) 73~[[ D, L-( g- amino- 2-[( kloracetyl) imino]- 2, 3- dihydro- 4-tiazolyl) acetyl] amino]- 3- [ [( l- metyl- lH- tetrazol- 5- yl)-tio] metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en-2- karboksylsyre- trifluoreddiksyresalt d) 73~[[ D, L-( g- amino- 2-[( chloroacetyl) imino]- 2, 3- dihydro- 4-thiazolyl) acetyl] amino]- 3- [ [( l- methyl- lH- tetrazol- 5- yl)-thio] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene-2- carboxylic acid- trifluoroacetic acid salt

2,6 g av difenylmetylesterproduktet fra del (c) suspenderes i 10 ml anisol, og 20 ml tri fluoreddiksyre tilsettes dråpevis. Den klare oppløsning holdes ved 0-5° i 10 minutter, 2.6 g of the diphenyl methyl ester product from part (c) is suspended in 10 ml of anisole, and 20 ml of trifluoroacetic acid is added dropwise. The clear solution is kept at 0-5° for 10 minutes,

og trifluoreddiksyren avdestilleres i vakuum. Residuet behandles med eter og filtreres under sugning for å gi 2,1 g 70-[[D,L-(a-amino-2-[(kloracetyl)imino]-2,3-dihydro-4-tiazoly1)acetyl]-amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-1-azabicyk.lo [4.2.0] okt-2-en-2-karboksylsyre-trif luoreddiksyre-salt, sm.p. 144-145° (spaltn.). e) 73-[ D, L-[( aminokarbonyl) amino]- 2-[( kloracetyl) imino]-2, 3- dihydro- 4- tiazolyl) acetyl] amino]- 3-[[( 1- metyl- lH-t etrazol- 5- yl) tio] metyl- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2Tkarboksylsyre- natriumsalt 2 g av trifluoreddiksyresalt-produktet fra del (d) settes til en oppløsning av 0,48 g kaliumcyanat i 15 ml vann. Blandingen omrøres i 3 timer ved romtemperatur. Den noe uklare oppløsning filtreres, og surgjøres til pH 2,5 under isavkjøling. Det and the trifluoroacetic acid is distilled off in a vacuum. The residue is treated with ether and filtered with suction to give 2.1 g of 70-[[D,L-(α-amino-2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl)acetyl]- amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyk.lo [4.2.0] oct-2-en-2 -carboxylic acid-trifluoroacetic acid salt, m.p. 144-145° (dec.). e) 73-[ D, L-[( aminocarbonyl) amino]- 2-[( chloroacetyl) imino]-2, 3- dihydro- 4- thiazolyl) acetyl] amino]- 3-[[( 1- methyl- lH -t etrazol- 5- yl) thio] methyl- 8- oxo- 5- thia- l- azabicyclo-[ 4. 2. 0] oct- 2- ene- 2T carboxylic acid sodium salt 2 g of the trifluoroacetic acid salt product from part (d ) is added to a solution of 0.48 g of potassium cyanate in 15 ml of water. The mixture is stirred for 3 hours at room temperature. The somewhat cloudy solution is filtered and acidified to pH 2.5 under ice cooling. The

resulterende bunnfall filtreres under sugning og tørres for åresulting precipitate is filtered under suction and dried to

gi 1,2 g 73-[[D,L-[(aminokarbonyl)amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)acetyl]amino]-3-[[(1-mety1-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre, sm.p. 230-231° (spaltn.). give 1.2 g of 73-[[D,L-[(aminocarbonyl)amino]-(2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl)acetyl]amino]-3-[[( 1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 230-231° (dec.).

0,8 g av den ovenstående frie syre oppløses i en0.8 g of the above free acid is dissolved in a

blanding av metanol og acetonitril (50:50). Noe mer enn en molar ekvivalent andel av natriumetylheksanoat tilsettes. Blandingen omrøres ved romtemperatur i 20 minutter, og eter tilsettes inntil utfelning er fullført for å gi 0,6 g 73_[[D,L-[(aminokarbonyl)-amino] -.(2- [ (kloracetyl) imino] -2 , 3-dihydro-4-tiazolyl) acetyl] - amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-1-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt, mixture of methanol and acetonitrile (50:50). Slightly more than a molar equivalent proportion of sodium ethyl hexanoate is added. The mixture is stirred at room temperature for 20 minutes, and ether is added until precipitation is complete to give 0.6 g of 73_[[D,L-[(aminocarbonyl)-amino] -.(2- [ (chloroacetyl) imino] -2 , 3-dihydro-4-thiazolyl)acetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt,

sm.p. 243-245° (spaltn.).sm.p. 243-245° (dec.).

Eksempel 2 '. Example 2 '.

73~[[ D, L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazoly1)-acetyl] amino]- 3-[[( 1- metyl- lH- tetrazol- 5- y1) tio] metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- kårboksylsyre- natriumsalt 73~[[ D, L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazoly1)-acetyl] amino]- 3-[[( 1- methyl- 1H- tetrazole- 5 - y1) thio] methyl]- 8- oxo-5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt

a) 73-[[ D/ L-[( aminokarbonyl) amino]-( 2-[( kloracetyl) imino]-2, 3- dihydro- 4- tiazolyl) acetyl] amino]- 3-[[( 1- metyl- lH-tetrazol- 5- yl) tio] metyl]- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- difenyImetylester 2 g av syren fra eksempel 1 (e) oppløses i en blanding a) 73-[[ D/ L-[( aminocarbonyl) amino]-( 2-[( chloroacetyl) imino]-2, 3- dihydro- 4- thiazolyl) acetyl] amino]- 3-[[( 1- methyl - 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 2 g of the acid from example 1 (e) is dissolved in a mixture

av acetonitril og metanol (1:1). Til denne oppløsning settesof acetonitrile and methanol (1:1). To this solution is added

4 ml av en oppløsning av 0,5 mol difenyldiazometan i 200 ml dioksan. Denne blanding omrøres natten over ved romtemperatur, 4 ml of a solution of 0.5 mol of diphenyldiazomethane in 200 ml of dioxane. This mixture is stirred overnight at room temperature,

og det resulterende bunnfall filtreres under sugning for å gi 1,36 g 73-[[D,L-[(aminokarbonyl)amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)-acetyl]amino]-3-[[(1-metyl-lH-tetrazol-5-y1)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester, sm.p. 170-173° (spaltn.). and the resulting precipitate is filtered with suction to give 1.36 g of 73-[[D,L-[(aminocarbonyl)amino]-(2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl)- acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-y1)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2 -carboxylic acid diphenyl methyl ester, m.p. 170-173° (dec.).

Ytterligere difenylmetylesterprodukt kan erholdes vedAdditional diphenyl methyl ester product can be obtained by

først å tilsette en liten mengde p-toluensulfonsyre til filtratet. Efter at den røde farve av difenyldiazometan forsvinner, konsentreres blandingen, og residuet utgnies med vann og eter for å gi ytterligere 1 g difenylmetylesterprodukt. first adding a small amount of p-toluenesulfonic acid to the filtrate. After the red color of diphenyldiazomethane disappears, the mixture is concentrated, and the residue is triturated with water and ether to give an additional 1 g of diphenylmethyl ester product.

b) 73-[[ D, L- [ ( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- tiazolyl) acetyl] amino]- 3-[[( 1- metyl- lH- tetrazol- 5- yl)-tio] metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en-2- karboksylsyre- difenyImetylester 1 g av difenylmetylesterproduktet fra del (a) og 0,2 g tiourinstoff tilbakeløpsbehandles i 50 ml av en blanding av kloroform, metanol og dioksan (2:1:1). Efter tilbakeløps-behandling i 3 timer konsentreres den resulterende, klare opp-løsning, og vann settes til residuet for å gi 0,9 g uren 73-[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazoly1)-acetyl]amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester, sm.p. 140-170° (spaltn.). b) 73-[[ D, L- [ ( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- thiazolyl) acetyl] amino]- 3-[[( 1- methyl- 1H- tetrazole- 5- yl)-thio] methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene-2- carboxylic acid diphenyl methyl ester 1 g of the diphenyl methyl ester product from part (a) and 0 .2 g of thiourea is refluxed in 50 ml of a mixture of chloroform, methanol and dioxane (2:1:1). After refluxing for 3 hours, the resulting clear solution is concentrated and water is added to the residue to give 0.9 g of impure 73-[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro -2-imino-4-thiazolyl)-acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid diphenyl methyl ester, m.p. 140-170° (split.).

c) 73~[[ D, L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- tiazolyl) acetyl] amino] - 3- [ [ ( l- metyl- lH- tetrazol- 5- y 1) - c) 73~[[ D, L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- thiazolyl) acetyl] amino] - 3- [ [ ( l- methyl- lH- tetrazol- 5- y 1) -

tio] metyl ] - 8- okso'- 5- tia- l- azabicyklo [ 4 . 2 . 0] okt- 2- en-2- karboksylsyre- natriumsalt thio] methyl ] - 8- oxo'- 5- thia- l- azabicyclo [ 4 . 2. 0] oct-2-ene-2-carboxylic acid sodium salt

Ert blanding av 3,44 ml tri fluoreddiksyre og 1,77 ml anisol settes til 0,45 g av di fenylmetylesterproduktet fra del (b) . Efter konsentrering opptas residuet i eter og behandles for å gi 0,4 g 73-[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(1-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre. A mixture of 3.44 ml of trifluoroacetic acid and 1.77 ml of anisole is added to 0.45 g of the diphenylmethyl ester product from part (b). After concentration, the residue is taken up in ether and treated to give 0.4 g of 73-[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

0,4 g av det frie syreprodukt suspenderes derefter i0.4 g of the free acid product is then suspended in

vann og bringes i oppløsning ved tilsetning av natriumbikarbonat-oppløsning. Oppløsningen frysetørres for å gi 73~[[D,L-[(aminokarbonyl) amino]-2-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]-amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-1-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt som et hvitt pulver. Dette natriumsaltprodukt smelter med spaltning ved under 225°. water and dissolved by adding sodium bicarbonate solution. The solution is lyophilized to give 73~[[D,L-[(aminocarbonyl)amino]-2-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]-amino]-3-[[(l -methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt as a white powder. This sodium salt product melts with decomposition at below 225°.

Eksempel 3 Example 3

7( 3- [ [ D- [ ( aminokarbonyl) amino] - ( 2 , 3- dihydro- 2- imino- 4- tiazolyl) - acetyl] amino]- 3-[[( l- metyl- lH- tetrazol- 5- y1) tio] metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriumsalt og 7| 3- [ [ L- [ ( aminokarbonyl) amino] - ( 2 , 3- dihydro- 2- imino- 4- tiazoly 1) - acetyl] amino]- 3-[[( 1- mety1- lH- tetrazol- 5- yl) tio] metyl]- 8- okso-5- tia- l- azabicyklo [ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriumsalt 7( 3- [ [ D- [ ( aminocarbonyl) amino] - ( 2 , 3- dihydro- 2- imino- 4- thiazolyl) - acetyl] amino]- 3- [[( l- methyl- lH- tetrazole- 5 - y1) thio] methyl]- 8- oxo-5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt and 7| 3- [ [ L- [ ( aminocarbonyl) amino] - ( 2 , 3- dihydro- 2- imino-4- thiazoly 1)- acetyl] amino]- 3-[[( 1- methyl1- 1H- tetrazol- 5- yl) thio] methyl]- 8- oxo -5- thia- l- azabicyclo [ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt

D,L-produktet erholdt i eksempel 2 separeres i D- og L-isomerene ved hjelp av preparativ høyeffektiv væskekromatografi (HPLC) under anvendelse av en 7 ym revers fase C-8 kolonne (25 mm ID x 250 mm). Det anvendte elueringsmiddel er en blanding av metanol og 0,01M fosfatbuffer (1:9) ved en strømnings- The D,L product obtained in Example 2 is separated into the D and L isomers by preparative high performance liquid chromatography (HPLC) using a 7 µm reverse phase C-8 column (25 mm ID x 250 mm). The eluent used is a mixture of methanol and 0.01 M phosphate buffer (1:9) at a flow

hastighet på 20 ml/min. Adskillelsen foretas ved romtemperatur,rate of 20 ml/min. The separation is carried out at room temperature,

og elueringsmidlet overvåkes ved 254 nm (UV). L-isomeren adskilles først, fulgt av D-isomeren. De separerte isomerer. behandles derefter ved HPLC på en 25-40 ym RP-18 kolonne (16 mm ID x 250 mm) under anvendelse av en blanding av metanol og vann (1:99) som oppløsningsmiddel. and the eluent is monitored at 254 nm (UV). The L-isomer separates first, followed by the D-isomer. They separated isomers. then processed by HPLC on a 25-40 um RP-18 column (16 mm ID x 250 mm) using a mixture of methanol and water (1:99) as the solvent.

Denne fremgangsmåte fører til 70-[[D-[[[(aminokarbonyl) - amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(1-mety1-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt; • This procedure leads to 70-[[D-[[[(aminocarbonyl)-amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]-3-[[(1-methyl-1H -tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt; •

NMR (D20) 6 3,52 (ABq; J = 18 Hz, 2H), 4,0 (s, 3H), 4,15 (ABq,NMR (D 2 O) δ 3.52 (ABq; J = 18 Hz, 2H), 4.0 (s, 3H), 4.15 (ABq,

J = 14 Hz, 2H), 5,03 (d, J = 5Hz, 1H), 5,25 (s, 1H), 5,65 J = 14 Hz, 2H), 5.03 (d, J = 5Hz, 1H), 5.25 (s, 1H), 5.65

(d, J = 5Hz, 1H) og 6,67 (s, 1H) ; (d, J = 5Hz, 1H) and 6.67 (s, 1H);

IR (KBr) 1760 cm"<1>; IR (KBr) 1760 cm"<1>;

UV mak. s 258 nm, e = 12,230;.UV max. s 258 nm, e = 12.230;.

[ct]<24>-27,3° (c = 4,4 mg/ml; H20) ' og [ct]<24>-27.3° (c = 4.4 mg/ml; H 2 O) ' and

73~[[L-[[[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino]-3-[[(1-metyl-lH-tetrazol-5-y1)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt; 73~[[L-[[[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5 -y1)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt;

NMR (D20).6 3,60 (ABq, J = 18 Hz, 2H), 4,03 (s, 3H), 4,18 (ABq,NMR (D 2 O).6 3.60 (ABq, J = 18 Hz, 2H), 4.03 (s, 3H), 4.18 (ABq,

J = 14 Hz, 2H), 5,10 (d, J = 5 Hz, 1H), 5,26 (s, 1H), 5,58 J = 14 Hz, 2H), 5.10 (d, J = 5 Hz, 1H), 5.26 (s, 1H), 5.58

(d, J = 5 Hz, 1H) og 6,68 (s, 1H); (d, J = 5 Hz, 1H) and 6.68 (s, 1H);

IR (KBr) 1760 cm"<1>; IR (KBr) 1760 cm"<1>;

UV mak. s 256 nm, e = 12,4 70; UV max. s 256 nm, e = 12.4 70;

[a]2<4>+ 43,8° (c = 4,2 mg/ml; H20). [α]2<4>+ 43.8° (c = 4.2 mg/ml; H 2 O).

Eksempel 4 Example 4

73-[[ D, L-[( aminokarbonyl) amino]- 2-[( kloracetyl) imino]- 2, 3- dihydro-4- tiazolyl), acetyl] amino]- 3-[( acetyloksy) metyl]- 8- okso- 5- tia- l-azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriumsalt 73-[[ D, L-[( aminocarbonyl) amino]- 2-[( chloroacetyl) imino]- 2, 3- dihydro-4- thiazolyl), acetyl] amino]- 3-[( acetyloxy) methyl]- 8 - oxo- 5- thia- l-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid sodium salt

a) 73-[[ D, L-[[[( 4- metoksyfenyl) metoksy] karbonyl] amino]-( 2-[( kloracetyl) imino]- 2, 3- dihydro- 4- tiazolyl) acetyl]-amino]- 3-[( acetyloksy) metyl]- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- difenylmetylester En oppløsning av 0,033 mol dicykloheksylkarbodiimid i tetrahydrofuran settes dråpevis ved 0-5° til en oppløsning av a) 73-[[ D, L-[[[( 4- methoxyphenyl) methoxy] carbonyl] amino]-( 2-[( chloroacetyl) imino]- 2, 3- dihydro- 4- thiazolyl) acetyl]-amino] - 3-[( acetyloxy) methyl]- 8- oxo- 5- thi- l- azabicyclo-[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid diphenyl methyl ester A solution of 0.033 mol of dicyclohexylcarbodiimide in tetrahydrofuran is added dropwise at 0-5° to a solution of

0,036 mol D,L-2-[(kloracetyl)imino]-2,3-dihydro-a-[[[(4-metoksyfenyl) metoksy]karbonyl]amino]-4-tiazoleddiksyre fra eksempel 1(b) og 0,03 mol 73-aminocefalosporansyre-difenyImetylester i tetrahydrofuran. Blandingen omrøres i 30 minutter ved 0-5° og 0.036 mol of D,L-2-[(chloroacetyl)imino]-2,3-dihydro-α-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-4-thiazoleacetic acid from example 1(b) and 0, 03 mol 73-aminocephalosporanic acid diphenyl methyl ester in tetrahydrofuran. The mixture is stirred for 30 minutes at 0-5° and

jj

1 time ved romtemperatur, ;filtreres derefter, og filtratet konsentreres. Residuet opptas i etylacetat, vaskes med natrium-bikarbonat og med vann, tørres med magnesiumsulfat og konsentreres igjen. Residuet utgnies med eter, og man får 73"[[D,L-[[[(4-metoksyfenyl)metoksy]karbonyl]amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5- tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester som et fast residuum. b) 7 3- [ [ D, L- ( 2- amino- 2- [ ( kloracetyl) imino]- 2 , 3- dihydro-^ 4-tiazolyl) acetyl] amino]- 3-[( acetyloksy)- metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre-trifluoreddjksyresalt 2 g av difenylmetylesterproduktet fra del (a) settes til en blanding av 30 ml trifluoreddiksyre og 6 ml anisol ved 0°. Blandingen omrøres i 10 minutter., og trif luoreddiksy ren avdampes derefter i vakuum. Residuet behandles med eter, og det resulterende bunnfall filtreres under sugning for å gi 73"[[D,L-(2-amino-2-[(kloracetyl)imino]-2,3-dihydrb-4-tiazolyl)acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-trifluoreddiksyresalt. 1 hour at room temperature, then filtered and the filtrate concentrated. The residue is taken up in ethyl acetate, washed with sodium bicarbonate and with water, dried with magnesium sulfate and concentrated again. The residue is triturated with ether, and one obtains 73"[[D,L-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-(2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl )acetyl]amino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenyl methyl ester as a solid residue. b) 7 3- [ [ D, L- ( 2- amino- 2- [ ( chloroacetyl) imino]- 2 , 3- dihydro-^ 4-thiazolyl) acetyl] amino]- 3-[( acetyloxy)- methyl]- 8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-trifluoroacetic acid salt 2 g of the diphenylmethyl ester product from part (a) is added to a mixture of 30 ml of trifluoroacetic acid and 6 ml of anisole at 0 °. The mixture is stirred for 10 min., and the trifluoroacetic acid is then evaporated in vacuo. The residue is treated with ether, and the resulting precipitate is filtered with suction to give 73"[[D,L-(2-amino-2-[( chloroacetyl)imino]-2,3-dihydrob-4-thiazolyl)acetyl]amino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid trifluoroacetic acid salt.

c) 73-[[ D, L-[( aminokarbonyl) amino]~( 2 —[( kloracetyl) imino]~ 2, 3- dihydro- 4— tiazolyl) acetyl] amino]- 3-[( acetyloksy)-m etyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2-karboksylsyre- natriumsalt c) 73-[[ D, L-[( aminocarbonyl) amino]~( 2 —[( chloroacetyl) imino]~ 2, 3- dihydro- 4— thiazolyl) acetyl] amino]- 3-[( acetyloxy)-m ethyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2-carboxylic acid sodium salt

0,1 mol av trifluoreddiksyresaltet fra del (b)0.1 mol of the trifluoroacetic acid salt from part (b)

suspenderes i 40 ml vann. 0,02 mol kaliumcyanat tilsettes, og blandingen omrøres i 3 timer ved romtemperatur inntil den synes å være noe melkeaktig uklar. Denne blanding filtreres, og suspended in 40 ml of water. 0.02 mol of potassium cyanate is added, and the mixture is stirred for 3 hours at room temperature until it appears to be somewhat milky cloudy. This mixture is filtered, and

filtratet reguleres til en pH på 1,5 med 2N saltsyre. Det resulterende bunnfall filtreres under sugning for å gi 73~[[D,L-[(aminokarbonyl) amino] — (2 —[(kloracety1)imino]—2,3—dihydro — 4 — tiazolyl)acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre. the filtrate is adjusted to a pH of 1.5 with 2N hydrochloric acid. The resulting precipitate is filtered with suction to give 73~[[D,L-[(aminocarbonyl)amino] — (2 —[(chloroacety1)imino]—2,3—dihydro — 4 — thiazolyl)acetyl]amino]-3 -[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Den ovenfor erholdte frie syre behandles méd natriumetylheksanoat ved fremgangsmåten ifølge eksempel 1(e) for å danne det tilsvarende natriumsalt. The free acid obtained above is treated with sodium ethyl hexanoate by the method according to example 1(e) to form the corresponding sodium salt.

Eksempel 5 Example 5

73~[[ D/ L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazoly1)-acetyl] amino]- 3-[( acetyloksy) mety1]- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriumsalt 73~[[ D/ L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazoly1)-acetyl] amino]- 3-[( acetyloxy) methyl1]- 8- oxo- 5 - thia- l- azabicyclo-[ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt

73-[[D,L-[(aminokarbonyl)amino]-2-[(kloracetyl)imino]-2 , 3-dihydro-4-tiazoly 1) acetyl] amino] -3-.[ (acetyloksy) metyl] -8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyren fra eksempel 4 behandles ved fremgangsmåten ifølge eksempel 2 for å danne 73-[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl) acetyl] amino] -3 - [ (acetyloksy) metyl] -8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt. 73-[[D,L-[(aminocarbonyl)amino]-2-[(chloroacetyl)imino]-2 , 3-dihydro-4-thiazoly 1) acetyl] amino] -3-.[ (acetyloxy) methyl] - The 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid of Example 4 is treated by the method of Example 2 to form 73-[[D,L-[(aminocarbonyl)amino ]-(2,3-dihydro-2-imino-4-thiazolyl) acetyl] amino] -3 - [ (acetyloxy) methyl] -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 -ene-2-carboxylic acid sodium salt.

Eksempler 6- 24Examples 6-24

Ved å følge fremgangsmåten ifølge eksempler 1 og 4,By following the procedure according to examples 1 and 4,

men ved å anvende 2-(substituert imino)-2,3-dihydro-a-(beskyttet amino)-4-tiazoleddiksyren vist som struktur I og 76-amino-cefalosporansyreesteren vist som struktur II, får man mellomproduktet vist som struktur III. Fjernelse av den a-amino-beskyttende gruppe og behandling med kaliumcyanat gir produktet vist som struktur IV. Fjernelse av den imino-beskyttende gruppe ved fremgangsmåten ifølge eksempler.2 og 5 gir produktet vist som struktur V. but by using the 2-(substituted imino)-2,3-dihydro-α-(protected amino)-4-thiazolediacid shown as structure I and the 76-amino-cephalosporanic acid ester shown as structure II, the intermediate shown as structure III is obtained. Removal of the α-amino protecting group and treatment with potassium cyanate gives the product shown as structure IV. Removal of the imino-protecting group by the method of Examples 2 and 5 gives the product shown as structure V.

Cefalosporinsyreproduktene ifølge eksempler 6-24, vist som struktur IV og V, kan behandles for å danne det tilsvarende natrium- eller kaliumsalt. Når det gjelder forbindelsene ifølge eksemplene 9, 10, 21 og 22, får man dinatrium- eller dikaliumsaltet. Syreproduktene. ifølge eksemplene 6-24 vist som struktur IV og V, kan også behandles for å innføre en forskjellig estergruppe, så som forbindelsene hvor R er The cephalosporin acid products of Examples 6-24, shown as structures IV and V, can be treated to form the corresponding sodium or potassium salt. In the case of the compounds according to examples 9, 10, 21 and 22, the disodium or dipotassium salt is obtained. The acid products. according to examples 6-24 shown as structures IV and V, can also be treated to introduce a different ester group, such as the compounds where R is

Forbindelsene ifølge eksemplene 6-24 kan erholdes i The compounds according to examples 6-24 can be obtained in

D-, L- eller D,L-isomer form.D-, L- or D,L-isomeric form.

Eksempel 2 5 '• Example 2 5 '•

73-[[ D, L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino]- 3-[( acetyloksy) metyl]- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2- kårboksylsyre- natriumsalt 73-[[ D, L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazolyl)-acetyl] amino]- 3-[( acetyloxy) methyl]- 8- oxo- 5 - thia- l- azabicyclo-[ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt

Forbindelsene ifølge eksempel 5 kan også fremstillesThe compounds according to example 5 can also be prepared

i henhold til den følgende fremgangsmåte:according to the following procedure:

a) 7g-[[ D, L-[[[( 4- metoksyfenyl) metoksy] karbonyl] amino]- ( 2, 3- dihydro- 2- imino- 4- tiazolyl) ace tyl] amino]- 3-[( acetyloksy) metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0]-okt- 2- en- 2- karboksylsyre- difenyImetylester 4,38 g (0,01 mol) 70-amino-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester, dvs. 7-ACA-difenylmetylester, oppløses i en blanding av a) 7g-[[ D, L-[[[( 4- methoxyphenyl) methoxy] carbonyl] amino]- ( 2, 3- dihydro- 2- imino- 4- thiazolyl) acetyl] amino]- 3-[( acetyloxy) methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0]-oct - 2- en- 2- carboxylic acid- diphenyl methyl ester 4.38 g (0.01 mol) 70-amino-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct -2-ene-2-carboxylic acid diphenyl methyl ester, i.e. 7-ACA diphenyl methyl ester, is dissolved in a mixture of

10 ml dimetylformamid og 50 ml tetrahydrofuran. En oppløsning10 ml of dimethylformamide and 50 ml of tetrahydrofuran. A solution

av 3,71 g (0,011 mol) D,L-2,3-dihydro-2-imino-a-[[[(4-metoksyfenyl) metoksy] karbonyl ] amino ] -4-tiazoleddiksyre , fra eksempel 1(a), of 3.71 g (0.011 mol) D,L-2,3-dihydro-2-imino-α-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-4-thiazoleacetic acid, from Example 1(a) ,

i 30 ml dimetylformamid tilsettes, og den resulterende blanding fortynnes med 200 ml tetrahydrofuran. En oppløsning av 2,47 g in 30 ml of dimethylformamide is added, and the resulting mixture is diluted with 200 ml of tetrahydrofuran. A solution of 2.47 g

-dicykloheksylkarbodiimid i 20 ml tetrahydrofuran tilsettes dråpevis ved 0-5°. Reaksjonsblandingen omrøres i 90 minutter ved 0-5° og derefter ved romtemperatur. Efter 3 timer filtreres blandingen, og filtratet konsentreres i vakuum. Residuet opptas i etylacetat, filtreres,, vaskes med hatriumbikarbonat og vann, tørres med magnesiumsulfat og konsentreres i vakuum. Eter settes -dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise at 0-5°. The reaction mixture is stirred for 90 minutes at 0-5° and then at room temperature. After 3 hours, the mixture is filtered, and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, filtered, washed with sodium bicarbonate and water, dried with magnesium sulfate and concentrated in vacuo. Ether is set

til residuet som derefter filtreres under sugning for å gi 6,3 g 7(3-[[D,L-[[[ (4-metoksyfenyl) me toksy ] karbonyl ] amino] - (2 , 3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difenylmetylester, sm.p. 125-128°.-b) 73~[[ D/ L-( g- amino)-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino]- 3-[( acetyloksy) metyl]- 8- bkso- 5- tia- l-azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- tri fluoreddiksyresalt ( 1:2) to the residue which is then filtered under suction to give 6.3 g of 7(3-[[D,L-[[[ (4-methoxyphenyl)methoxy]carbonyl]amino]-(2,3-dihydro-2-imino -4-thiazolyl)acetyl]amino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester, m.p. . 125-128°.-b) 73~[[ D/ L-( g- amino)-( 2, 3- dihydro- 2- imino-4- thiazolyl)-acetyl] amino]- 3-[( acetyloxy) methyl]- 8- bxo- 5- thia- l-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid- trifluoroacetic acid salt ( 1:2)

6 g difenylmetylesterprodukt fra del (a) behandles med6 g of diphenyl methyl ester product from part (a) is treated with

en blanding av 25 ml anisol og 60 ml trifluoreddiksyre for å gi 6,9 g urent 73-[[D,L-(g<->amino)-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino] —3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre-trifluoreddiksyresalt (1:2), a mixture of 25 ml of anisole and 60 ml of trifluoroacetic acid to give 6.9 g of impure 73-[[D,L-(g<->amino)-(2,3-dihydro-2-imino-4-thiazolyl)- acetyl]amino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetic acid salt (1:2),

sm.p. 108-110° (spaltn.)'. ■ sm.p. 108-110° (dec.)'. ■

c) 73~[[ D/ L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- tiazolyl) acetyl] amino]- 3-[( acetyloksy) metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- kårboksylsyre-natriumsalt c) 73~[[ D/ L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- thiazolyl) acetyl] amino]- 3-[( acetyloxy) methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylic acid sodium salt

6 g urent tri fluoreddiksyresalt fra del (b) settes til6 g of impure trifluoroacetic acid salt from part (b) are added

en oppløsning av 1,8 g natriumcyanat i 50 ml vann. Blandingen omrøres i 3 timer.ved romtemperatur, og en liten mengde uopp-løselig materiale (0,3 g) fjernes ved filtrering. Oppløsningen kromatograferes derefter med ionebytterharpiksen "Amberlite XAD-2" og elueres først med vann og derefter med en 80:20 blanding av vann og metanol. Fraksjonen som inneholder det ønskede produkt, frysetørres for å gi 3,65 g 73~ [ [D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(acetyloksy)-metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt; sm.p. 157-160° (spaltn.). a solution of 1.8 g of sodium cyanate in 50 ml of water. The mixture is stirred for 3 hours at room temperature, and a small amount of insoluble material (0.3 g) is removed by filtration. The solution is then chromatographed with the ion exchange resin "Amberlite XAD-2" and eluted first with water and then with an 80:20 mixture of water and methanol. The fraction containing the desired product is freeze-dried to give 3.65 g of 73~ [ [D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]- 3-[[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt; sm.p. 157-160° (dec.).

Eksempel 26 Example 26

73~[[ D-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino]- 3-[( acetyloksy) metyl]- 8- okso- 5- tia- l- azabicyklo-[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriums alt og 73- [[ L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazolyl) acetyl] amino]-3-[( acetyloksy) metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en-2- kårboksylsyre- natriumsalt 73~[[ D-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazolyl)-acetyl] amino]- 3-[( acetyloxy) methyl]- 8- oxo- 5- thia - l- azabicyclo-[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid sodium salt and 73- [[ L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4 - thiazolyl) acetyl] amino]-3-[(acetyloxy) methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en-2- carboxylic acid sodium salt

D,L-produktet erholdt i eksempel 25 separeres i D- og L'-is orne rene ved hjelp av preparativ høyeffektiv væskekromatograf i (HPLC) under anvendelse av en 7 ym revers fase C-8 kolonne (25 mm ID x 250 mm). Det anvendte elueringsmiddel er en blanding av metanol og 0,01M fosfatbuffer (8:92) ved en strømnings-hastighet på 20 ml/min. Separeringen foretas ved romtemperatur, og elueringsmidlet overvåkes ved 254 nm (UV). L-isomeren' utskilles først, fulgt kv D-isomeren. De separerte isomerer behandles derefter ved HPLC på en 25-40 ym RP-18 kolonne The D,L product obtained in Example 25 is separated into pure D and L' ices by preparative high performance liquid chromatography (HPLC) using a 7 µm reverse phase C-8 column (25 mm ID x 250 mm) . The eluent used is a mixture of methanol and 0.01 M phosphate buffer (8:92) at a flow rate of 20 ml/min. The separation is carried out at room temperature, and the eluent is monitored at 254 nm (UV). The L-isomer' is secreted first, followed by the D-isomer. The separated isomers are then processed by HPLC on a 25-40 µm RP-18 column

(16 mm ID x 250 mm) under anvendelse av en blanding av metanol(16 mm ID x 250 mm) using a mixture of methanol

og vann (1:99) som oppløsningsmiddel.and water (1:99) as solvent.

Denne fremgangsmåte gir 73_[[D-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazoly1)acetyl]amino]-3-[(acetyloksy)-metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt; This procedure gives 73_[[D-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]-3-[(acetyloxy)-methyl]-8-oxo-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt;

NMR (DMS0-d6) 6 2,0 (s), 3,3 (bred s), 4,86 (ABq; J = 12,5 Hz), 4,88 (d, J = 5Hz), 5,25 (d, J = 8,5 Hz), 5,5 (dd, ^ = 9Hz, NMR (DMS0-d6) 6 2.0 (s), 3.3 (broad s), 4.86 (ABq; J = 12.5 Hz), 4.88 (d, J = 5Hz), 5.25 (d, J = 8.5 Hz), 5.5 (dd, ^ = 9Hz,

J2= 5Hz), 5,7 (bred s), 6,38 (s) , 6,41 (d, J = 8,5 Hz), 6,88 (s), 8,54 (d, J = 9Hz); J2= 5Hz), 5.7 (wide s), 6.38 (s) , 6.41 (d, J = 8.5 Hz), 6.88 (s), 8.54 (d, J = 9Hz );

IR (KBr) 1760 cm"<1>; UVmaks260 nm'e = 10/319; IR (KBr) 1760 cm"<1>; UVmax260 nm'e = 10/319;

[a]2<5>+ 30,9 (c =3,3 mg/ml, H20) og [a]2<5>+ 30.9 (c =3.3 mg/ml, H20) and

70-[[L-[(aminokarbonyl)amino]-[2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt; 70-[[L-[(aminocarbonyl)amino]-[2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino-3-[(acetyloxy)methyl]-8-oxo-5-thia- 1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid sodium salt;

NMR (DMS0-d6) 6 2,0 (s), 3,3 (bred s), 4,88 (ABq, J =12,5 Hz), 4,94 (d, J = 5Hz), 5,29 (d, J = 8,5 Hz), 5,4 (dd, ^ = 8,5 Hz, NMR (DMS0-d6) 6 2.0 (s), 3.3 (broad s), 4.88 (ABq, J =12.5 Hz), 4.94 (d, J = 5Hz), 5.29 (d, J = 8.5 Hz), 5.4 (dd, ^ = 8.5 Hz,

J2= 5Hz), 5,7 (bred s) , 6,35 (s), 6,45 (d, J = 8,5 Hz), 6,89 (s) , 8,64 (d, J = 8,5 Hz) ; J2= 5Hz), 5.7 (wide s) , 6.35 (s), 6.45 (d, J = 8.5 Hz), 6.89 (s) , 8.64 (d, J = 8 .5 Hz) ;

IR (KBr) 1760 cm"<1>; IR (KBr) 1760 cm"<1>;

UV mak. s 258 nm, e = 10,291; [a]<25>+ 81,8 (c = 3,3 mg/ml, H20). UV max. s 258 nm, e = 10.291; [α]<25>+ 81.8 (c = 3.3 mg/ml, H 2 O).

Eksempel 2 7 Example 2 7

73-[[ D, L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazoly1)-acetyl] amino]- 3-[[( 1- metyl- lH- tetrazol- 5- y1) tio] metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- natriumsalt 73-[[ D, L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazoly1)-acetyl] amino]- 3-[[( 1- methyl- 1H- tetrazole- 5 - y1) thio] methyl]- 8- oxo-5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid sodium salt

Forbindelsen ifølge eksempel 2 kan også fremstillesThe compound according to example 2 can also be prepared

i henhold til følgende fremgangsmåte. according to the following procedure.

a) 73~[[ D, L-[[[( 4- metoksyfenyl) metoksy] karbonyl] amino]-( 2, 3- dihydro- 2- imino- 4- tiazoly1) acetyl] amino]- 3-[[( l- metyl- lH- tetrazol- 5- yl) tio] metyl]- 8- okso- 5- tia- 1-azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre- difeny1-m etylester a) 73~[[ D, L-[[[( 4- methoxyphenyl) methoxy] carbonyl] amino]-( 2, 3- dihydro- 2- imino- 4- thiazoly1) acetyl] amino]- 3-[[( l- methyl- lH- tetrazol- 5- yl) thio] methyl]- 8- oxo- 5- thia- 1-azabicyclo[ 4. 2. 0] oct- 2- ene- 2- carboxylic acid- dipheny1-m ethyl ester

73-amino-3-[[(1-metyl-lH-tetrazol-5-y1)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-difeny1-metylester omsettes med D , L-2 , 3-dihydro-2-imino-cc- [[[ (4-metoksyfenyl)metoksy]karbonyl]amino]-4-tiazol-eddiksyre ved fremgangsmåten 4 ifølge eksempel 25 (a) for å gi 73-[[D,L-[[[(4-metoksyfenyl)-métoksy]karbonyl]amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]-amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-1-azabicyklo[4.2.0]-okt-2-en-2-karboksylsyre-difenylmetylester. b) 7 3-[[ D/ L-( g- amino)-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino]- 3-[[( 1- metyl- lH- tetrazol- 5- y1) tio]-. 73-amino-3-[[(1-methyl-1H-tetrazol-5-y1)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2- Carboxylic acid-diphenyl-1-methyl ester is reacted with D , L-2 , 3-dihydro-2-imino-cc-[[[ (4-methoxyphenyl)methoxy]carbonyl]amino]-4-thiazole-acetic acid in method 4 according to example 25 ( a) to give 73-[[D,L-[[[(4-methoxyphenyl)-methoxy]carbonyl]amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]-amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid diphenyl methyl ester . b) 7 3-[[ D/ L-( g-amino)-( 2, 3- dihydro- 2- imino-4- thiazolyl)-acetyl] amino]- 3-[[( 1- methyl- 1H- tetrazole - 5- y1) tio]-.

metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2-karboksylsyre- trifluoreddiksyre- salt methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- ene- 2-carboxylic acid- trifluoroacetic acid- salt

DifenyImetylesteren fra del (a) behandles med en blanding av trifluoreddiksyre og anisol ved fremgangsmåten ifølge eksempel 25 (b) for å gi 73_[[D,L-(a-amino)-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(l-metyl-lH-tetrazol-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-trifluoreddiksyresalt. The diphenylmethyl ester from part (a) is treated with a mixture of trifluoroacetic acid and anisole by the procedure of Example 25 (b) to give 73_[[D,L-(α-amino)-(2,3-dihydro-2-imino-4 -thiazolyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazole-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetic acid salt.

c) 7 3-[[ D/ L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4-tiazolyl) acetyl] amino]- 3-[[( 1- mety1- 1H- tetrazol- 5- y1) tio]-metyl]- 8- okso- 5- tia- l- azabicyklo[ 4. 2. 0] okt- 2- en- 2-k årboksylsyre- natriumsalt c) 7 3-[[ D/ L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino-4-thiazolyl) acetyl] amino]- 3-[[( 1- methyl1- 1H- tetrazole - 5- y1) thio]-methyl]- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2-carboxylic acid sodium salt

Trifluoreddiksyresaltet fra del (b) behandles med natriumcyanat for å gi 73~[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]-metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre. The trifluoroacetic acid salt from part (b) is treated with sodium cyanate to give 73~[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]-3-[ [(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Denne syre behandles derefter med natriumetylheksanoatThis acid is then treated with sodium ethyl hexanoate

som angitt i eksempel l(e) for å gi det tilsvarende natriumsalt. as indicated in Example 1(e) to give the corresponding sodium salt.

Eksempler 28- 39Examples 28-39

Ved å følge fremgangsmåten ifølge eksempel 25, men under By following the procedure according to example 25, but below

. anvendelse av 2,3-dihydro-2-imino-a-beskyttet amino-4-tiazol- eddiksyren vist som struktur I og 73-amino-cefalosporansyre-esteren vist som struktur II, får man mellomproduktet vist som struktur III. Den a-amino-beskyttende gruppe, og den ester-beskyttende gruppe fjernes derefter, og mellomproduktet omsettes med natriumcyanat og. behandles for å danne natriumsaltet vist som struktur IV. . use of 2,3-dihydro-2-imino-α-protected amino-4-thiazole- the acetic acid shown as structure I and the 73-amino-cephalosporanic acid ester shown as structure II, one obtains the intermediate shown as structure III. The α-amino protecting group and the ester protecting group are then removed, and the intermediate is reacted with sodium cyanate and. is processed to form the sodium salt shown as structure IV.

Forbindelsene fremstilt i eksemplene 28-39 kan erholdes The compounds prepared in Examples 28-39 can be obtained

i D-, L- eller D,L-isomer form.in D-, L- or D,L-isomer form.

Eksempel 40 Example 40

73-[[ D/ L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino- 3-[[ 4- ( aminokarbonyl) pyridino] metyl]- 8- okso- 5- tia-1- azabicyklo[ 4. 2. 0] okt- 2- en- 2- karboksylsyre 73-[[ D/ L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- thiazolyl)-acetyl] amino- 3-[[ 4- ( aminocarbonyl) pyridino] methyl]- 8 - oxo- 5- thia-1- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylic acid

En blanding av 0,005 mol av natriumsaltproduktet fra eksempel 25, 0,0075 mol 4-pyridinkarboksamid, 12 g kalium- A mixture of 0.005 mol of the sodium salt product from Example 25, 0.0075 mol of 4-pyridinecarboxamide, 12 g of potassium

tiocyanat og 7,5'ml vann oppvarmes ved 50° i 24 timer. Den resulterende oppløsning føres gjennom en kromatografikolonne fyllt med 150 g ionebytterharpiks "Amberlite XAD-2". Kolonnen vaskes med ca. 3 liter vann, og tittelforbindelsen elueres med en blanding av vann og metanol (8:2). Metanolen avdampes fra eluatet, og den vandige '. op■ pløsning lyofiliseres. Det amorfe , residuum utgnies med eter ,og filtreres under sugning for å gi 73-[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino]-3-[[4-(aminokarbonyl)pyridino]metyl]-8-okso-5-tia-1-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre. thiocyanate and 7.5 ml of water are heated at 50° for 24 hours. The resulting solution is passed through a chromatography column filled with 150 g of ion exchange resin "Amberlite XAD-2". The column is washed with approx. 3 liters of water, and the title compound is eluted with a mixture of water and methanol (8:2). The methanol is evaporated from the eluate, and the aqueous '. op■ solution is lyophilized. The amorphous residue is triturated with ether and filtered with suction to give 73-[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino] -3-[[4-(aminocarbonyl)pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

På tilsvarende måte ved å anvende natriumsaltproduktetIn a similar way by using the sodium salt product

fra eksempel 4 ved den ovenfor beskrevne fremgangsmåten,from example 4 by the method described above,

får man 73-[[D,L-[(aminokarbonyl)amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)acetyl]amino]-3-[[4-(aminokarbonyl)-pyridino]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre. 73-[[D,L-[(aminocarbonyl)amino]-(2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl)acetyl]amino]-3-[[4-(aminocarbonyl )-pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

♦ ♦

Eksempler 41- 57Examples 41-57

Ved å følge fremgangsmåten ifølge eksempel 40, men under anvendelse av cefalosporansyre-natriumsaltet vist som struktur I og pyridin-forbindelsen vist som struktur II, får man produktet vist som struktur III. By following the procedure according to example 40, but using the cephalosporanic acid sodium salt shown as structure I and the pyridine compound shown as structure II, the product shown as structure III is obtained.

Sluttproduktene oppnådd i eksemplene 41-57 erholdes i The final products obtained in Examples 41-57 are obtained in

D-, L- eller D,L-isomer form avhengig av den isomere form av cefalosporinet med struktur I. D-, L- or D,L-isomeric form depending on the isomeric form of the cephalosporin with structure I.

Eksempel 5 8 Example 5 8

73-[[ D, L-[( aminokarbonyl) amino]-( 2, 3- dihydro- 2- imino- 4- tiazolyl)-acetyl] amino]- 3-[[( 2- metyl- l, 3, 4- tiadiazol- 5- yl) tio] metyl]- 8- okso-5- tia- l- azabicyklo[ 4. 2. 0] okt- 3- en- 2- karboksylsyre- natriumsalt 73-[[ D, L-[( aminocarbonyl) amino]-( 2, 3- dihydro- 2- imino-4- thiazolyl)-acetyl] amino]- 3-[[( 2- methyl- l, 3, 4 - thiadiazol-5- yl) thio] methyl]- 8- oxo-5- thia- l- azabicyclo[ 4. 2. 0] oct- 3- ene- 2- carboxylic acid sodium salt

0,002 mol av natriumsaltproduktet fra eksempel 25 bringes i oppløsning i 100 ml av en fosfatbuffer ved en pH på 6,4. Derefter tilsettes 0,0024 mol 5-metyl-l,3,4-tiadiazoly1-2-tiol. Oppløsningen oppvarmes ved 60° i 6 timer. Efter avkjøling reguleres pH til 7,0, og oppløsningen kromatograferes på ionebytterharpiksen "Amberlite XAD-2". Den fraksjon som inneholder det ønskede produkt, frysetørres for å gi 73-[[D,L-[(aminokarbonyl) amino]-(2,3-dihydro-2-imino-4-tiazolyl)acetyl]amino]-3-[[(2-metyl-l,3,4-tiadiazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt. 0.002 mol of the sodium salt product from Example 25 is dissolved in 100 ml of a phosphate buffer at a pH of 6.4. Then 0.0024 mol of 5-methyl-1,3,4-thiadiazol1-2-thiol is added. The solution is heated at 60° for 6 hours. After cooling, the pH is adjusted to 7.0, and the solution is chromatographed on the ion exchange resin "Amberlite XAD-2". The fraction containing the desired product is lyophilized to give 73-[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)acetyl]amino]-3-[ [(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt .

På tilsvarende måte, ved å anvende natriumsaltproduktet fra eksempel 4 ved den ovenfor beskrevne fremgangsmåte, får In a similar way, by using the sodium salt product from example 4 by the method described above, you get

man 73-[[D,L-[(aminokarbonyl)amino]-(2-[(kloracetyl)imino]-2,3-dihydro-4-tiazolyl)acetyl]amino]-3-[[(2-metyl-l,3,4-tiadiazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre-natriumsalt. man 73-[[D,L-[(aminocarbonyl)amino]-(2-[(chloroacetyl)imino]-2,3-dihydro-4-thiazolyl)acetyl]amino]-3-[[(2-methyl- 1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt.

Eksempler 59- 69Examples 59-69

Ved å følge fremgangsmåten ifølge eksempel 58, menBy following the procedure of Example 58, however

under anvendelse av cefalosporansyre-natriumsaltet vist som struktur I og tiolen vist som struktur II, får man produktet vist som struktur III. using the cephalosporanic acid sodium salt shown as structure I and the thiol shown as structure II, the product shown as structure III is obtained.

Sluttproduktene fremstilt i eksemplene 59-69 erholdes i D-, L- eller D,L-isomer form, avhengig av den isomere form av cefalosporinet vist som struktur I. The final products prepared in Examples 59-69 are obtained in D-, L- or D,L-isomer form, depending on the isomeric form of the cephalosporin shown as structure I.

Claims (8)

1. Analogifremgangsmåte for fremstilling av en antibakteriell forbindelse med formelen(I) 1. Analogous process for the preparation of an antibacterial compound of the formula (I) innbefattet dens amino-tautomere form, hvor Rer hydrogen, natrium, kalium, t-butyl, benzyl, p-metoksybenzyl, p-nitrobenzyl, difenylmetyl, 2,2,2-triklorety1, trimetylsilyl,-CH2 -0-lavere alkyl, including its amino tautomeric form, where Rer hydrogen, sodium, potassium, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethy1, trimethylsilyl,-CH2 -0-lower alkyl, alkyl eller alkyl or R^ er i a-konfigurasjon og er hydrogen eller metoksy; R2 er hydrogen, -C0-CH2 C1, -CO-CH2 Br, -CO-CF3 , -CO-0-CH2 CCl3 , -COH eller R 1 is in α-configuration and is hydrogen or methoxy; R2 is hydrogen, -C0-CH2 C1, -CO-CH2 Br, -CO-CF3 , -CO-0-CH2 CCl3 , -COH or R3 er hydrogen eller lavere alkyl; X er hydrogen, -0-CO-lavere alkyl, -0-CO-NH2 , R 3 is hydrogen or lower alkyl; X is hydrogen, -0-CO-lower alkyl, -0-CO-NH2, er hydrogen eller lavere a" R,- er hydrogen, lavere alkyl, is hydrogen or lower a" R,- is hydrogen, lower alkyl, - (CH2) -N-(lavere alkyl)2 ; Rg er hydrogen, natrium eller kalium; og. n er et helt tall fra 1 til 4, karakterisert ved at et a-amino-cefalosporin med formelen - (CH 2 ) -N-(lower alkyl) 2 ; Rg is hydrogen, sodium or potassium; and. n is an integer from 1 to 4, characterized in that an α-amino-cephalosporin with the formula omsettes med kalium- eller natriumcyanat.reacted with potassium or sodium cyanate. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at man fremstiller 70-[[D,L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre2. Process as stated in claim 1, characterized in that 70-[[D,L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino]- 3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 3. Fremgangsmåte som.angitt i krav 1, karakterisert ' ved at man fremstiller 70-[[D-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino]-3-[(acetyloksy)metyl]-8-okso^ 5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre.3. Process as set forth in claim 1, characterized by preparing 70-[[D-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino]- 3-[(acetyloxy)methyl]-8-oxo, 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid. 4. Fremgangsmåte som angitt i krav 1, karakterisert ved at man fremstiller 73-[[L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]amino]-3-[(acetyloksy)metyl]-8-okso-5-tia-l-azabicyklo-[4.2.0]okt-2-en-2-karboksylsyre.4. Process as stated in claim 1, characterized in that 73-[[L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]amino]-3- [(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid. 5. Fremgangsmåte som angitt i krav 1, karakterisert ved at man fremstiller 73-[[D,L-[(aminokarbonyl)amino-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]-amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre.5. Process as stated in claim 1, characterized in that one prepares 73-[[D,L-[(aminocarbonyl)amino-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]-amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 6. Fremgangsmåte som angitt i krav 1, karakterisert ved at man fremstiller 73-[[D-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazoly1)-acetyl]amino]-3-[[(l-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo[4.2.0]okt-2-en-2-karboksylsyre.6. Process as stated in claim 1, characterized in that 73-[[D-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazol1)-acetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 7. Fremgangsmåte som angitt i krav 1, karakterisert ved at man fremstiller 70-[[L-[(aminokarbonyl)amino]-(2,3-dihydro-2-imino-4-tiazolyl)-acetyl]-amino]-3-[[(1-metyl-lH-tetrazol-5-yl)tio]metyl]-8-okso-5-tia-l-azabicyklo [4.2.0]okt-2-en-2-karboksylsyre.7. Process as stated in claim 1, characterized in that 70-[[L-[(aminocarbonyl)amino]-(2,3-dihydro-2-imino-4-thiazolyl)-acetyl]-amino]-3 is prepared -[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid. 8. Fremgangsmåte som angitt i et av kravene 2 til 7, karakterisert ved at man fremstiller natriumsaltet av forbindelsen.8. Method as stated in one of claims 2 to 7, characterized in that the sodium salt of the compound is produced.
NO791996A 1978-06-16 1979-06-15 PROCEDURE FOR THE PREPARATION OF ANTIBACTERIAL ACTIVE IMINOTIOAZOLYL-UREIDO-CEPHALOSPORINES NO791996L (en)

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