NO801402L - CEPHALOSPORINE INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES - Google Patents

CEPHALOSPORINE INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES

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Publication number
NO801402L
NO801402L NO80801402A NO801402A NO801402L NO 801402 L NO801402 L NO 801402L NO 80801402 A NO80801402 A NO 80801402A NO 801402 A NO801402 A NO 801402A NO 801402 L NO801402 L NO 801402L
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Norway
Prior art keywords
acid
alkyl
ester
cephalosporine
group
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NO80801402A
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Norwegian (no)
Inventor
Kamiya
Tanaka
Teraji
Hemmi
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Fujisawa Pharmaceutical Co
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Publication date
Priority claimed from JP48037205A external-priority patent/JPS5939439B2/en
Priority claimed from JP48073898A external-priority patent/JPS5852997B2/en
Priority claimed from JP13936473A external-priority patent/JPS5716118B2/ja
Priority claimed from JP741096A external-priority patent/JPS5734837B2/ja
Priority claimed from JP1308374A external-priority patent/JPS5732074B2/ja
Publication of NO801402L publication Critical patent/NO801402L/en
Application filed by Fujisawa Pharmaceutical Co filed Critical Fujisawa Pharmaceutical Co

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Description

Foreliggende oppfinnelse angår hittil ukjente cefalosporan7syrederivater som kan anvendes som utgangsmateriale for fremstilling av nye antibakterielt aktive cefalosporansyredérivater med den generelle formel I The present invention relates to hitherto unknown cephalosporanic acid derivatives which can be used as starting material for the production of new antibacterially active cephalosporanic acid derivatives with the general formula I

hvor where

R er acyl,R is acyl,

R 2 er en amino-lavere-alkyl-, lavere alkanoylamino-lavere-alkyl-, R 2 is an amino-lower-alkyl-, lower-alkanoylamino-lower-alkyl-,

lavere alkoksykarbonylamino-lavere-alkyl-, lavere alkan-sulfonylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkanoylamino-lavere-alkyl-, lavere alkylureido-lavere-alkyl-, guanidino-karbonylamino-lavere-alkyl- eller hydroksy-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, og lower alkoxycarbonylamino-lower-alkyl-, lower alkane-sulfonylamino-lower-alkyl-, lower alkoxycarbonylamino-lower-alkanoylamino-lower-alkyl-, lower alkylureido-lower-alkyl-, guanidino-carbonylamino-lower-alkyl or hydroxy-lower -alkyl-substituted thiadiazolyl or tetrazolyl group, and

M er et hydrogenatom eller et ugiftig, farmasøytisk godtagbart kation^. M is a hydrogen atom or a non-toxic, pharmaceutically acceptable cation.

Betegnelsen "acyl", som er angitt som betydningen av R , betyr særlig en lavere alkanoylgruppe som er substituert med en lavere alkyltiogruppe, en fenylgruppe eller en lavere alkyl-substituert oksadiazolyl-, tienyl- eller tetrazolylgruppe, The term "acyl", which is given as the meaning of R , means in particular a lower alkanoyl group substituted by a lower alkylthio group, a phenyl group or a lower alkyl-substituted oxadiazolyl, thienyl or tetrazolyl group,

idet alkyldelen av den lavere alkanoylgruppe kan være ytterligere substituert med en hydroksygruppe, en aminogruppe eller en lavere alkoksykarbonylaminogruppe, wherein the alkyl part of the lower alkanoyl group may be further substituted with a hydroxy group, an amino group or a lower alkoxycarbonylamino group,

"Amino-lavere-alkyl", som er en substituent i tiadiazolyl-eller .tetrazolylgruppen, er f;eks. aminometyl, 1-aminoetyl, 2-aminoetyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropy1, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobuty1, 5-amino-pentyl, 6-aminoheksyl, 2-aminoisopropyl og 3-aminoisobutyl. "Amino-lower-alkyl", which is a substituent in the thiadiazolyl or tetrazolyl group, is e.g. aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl1, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobuty1, 5-amino-pentyl, 6-aminohexyl, 2- aminoisopropyl and 3-aminoisobutyl.

Andre substituenter er f.eks. en alkoksykarbonyl-substituert aminoalkylgruppe, hvor alkoksykarbonylgruppen kan være metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl og tért.butoksykarbonyl, en alkansulfonylsubstituert aminoalkyl gruppe, hvor alkansulfonylgruppen kan være metansulfony1, etansulfonyl, propansulfony1, isopropansulfonyl, butansulfonyl, isobutansulfonyl, tert.butansulfonyl, pentansulfonyl og heksan-sulfonyl, en N-alkyl-karbamoylsubstituert aminoalkylgruppe, hvor N-alkylkarbamoylgruppen kan være N-metylkarbamoy1, N-etylkarbamoyl og N-propylkarbamoyl, og en 1-guanidino-karbonylsubstituert aminoalkylgruppe. Other substituents are e.g. an alkoxycarbonyl-substituted aminoalkyl group, where the alkoxycarbonyl group can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and tert.butoxycarbonyl, an alkanesulfonyl-substituted aminoalkyl group, where the alkanesulfonyl group can be methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, tert.butanesulfonyl , pentanesulfonyl and hexanesulfonyl, an N-alkyl-carbamoyl-substituted aminoalkyl group, where the N-alkylcarbamoyl group can be N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl, and a 1-guanidino-carbonyl-substituted aminoalkyl group.

"Hydroksy-lavere-alkyl", som er en annen substituent i tiadiazol- eller tetrazolylgruppen, er f.eks. hydroksymetyl, 1-hydroksyetyl, 2-hydroksyetyl, 1-hydroksypropyl, 2-hydroksypropyl, 3-hydroksypropyl, 1-hydroksybutyl, 2-hydroksybutyl, 3-hydroksybutyl, 4-hydroksybutyl, 5-hydroksypentyl, 6-hydroksy-heksyl, 2-hydroksyisopropyl og 3-hydroksyisobutyl. "Hydroxy-lower alkyl", which is another substituent in the thiadiazole or tetrazolyl group, is e.g. hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2- hydroxyisopropyl and 3-hydroxyisobutyl.

De nye forbindelser i henhold til oppfinnelsen har den generelle formel The new compounds according to the invention have the general formula

hvor R 2 og M har den ovenfor angitte betydning. where R 2 and M have the meaning indicated above.

De her omhandlede cefalosporansyredérivater med den generelle formel IV kan fremstilles ved at en 7-substituert cefalosporansyre med den generelle formel II The herein mentioned cephalosporanic acid derivatives with the general formula IV can be prepared by a 7-substituted cephalosporanic acid with the general formula II

hvor R^ betegner en alkanoylgruppe og M har den ovenfor angitte betydning, omsettes med en tiolforbindelse med den generelle formel III where R 1 denotes an alkanoyl group and M has the meaning given above, is reacted with a thiol compound of the general formula III

hvor R 2hår den ovenfor angitte betydning, eller et alkalimetallsalt derav. where R 2 has the meaning given above, or an alkali metal salt thereof.

Betegnelsen "alkanoyl", som er angitt i sammenheng med R 3 i formel II, angir f.eks. acetyl, propionyl, butyryl, pentanoyl! og heksanoyl. The term "alkanoyl", which is indicated in connection with R 3 in formula II, indicates e.g. acetyl, propionyl, butyryl, pentanoyl! and hexanoyl.

Alkalimetallsalter av tiolforbindelsen med den generelle formel III kan f.eks. være natrium- eller kaliumsalter. Alkali metal salts of the thiol compound with the general formula III can e.g. be sodium or potassium salts.

Omsetningen av en 7-substituert cefalosporansyre med den generelle formel II med en tiolforbindelse med den generelle formel III eller et alkalimetallsalt derav kan utføres i et opp-løsningsmiddel så som vann, aceton, kloroform, nitrobenzen, dimetylformamid, metanol, etanol, dimétylsulfoksyd eller et hvilket som helst organisk oppløsningsmiddel, som er inert overfor reaksjonen, fortrinnsvis i et sterkt polart oppløsningsmiddel. Det kan som oppløsningsmidler anvendes hydrofile oppløsnings-midler i blanding med vann. Omsetningen utføres fortrinnsvis i omtrentlig nøytralt medium. Når . forbindelsen med den generelle formel II eller tiolforbindelsen med den generelle formel III anvendes i fri form, utføres omsetningen fortrinnsvis i nærvær av en base så som et alkalimetallhydroksyd, alkalimetallkarbonåt, alkalimetallbikarbonat eller et trialkylamin. Reaksjonstemperaturen er ikke begrenset, og omsetningen utføres vanligvis ved romtemperatur eller under oppvarmning. Reaksjonsproduktet kan under anvendelse av konvensjonell fremgangsmåter isoleres fra reaksjonsblandingen. The reaction of a 7-substituted cephalosporanic acid of the general formula II with a thiol compound of the general formula III or an alkali metal salt thereof can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, dimethylformamide, methanol, ethanol, dimethylsulfoxide or a any organic solvent, which is inert to the reaction, preferably in a strongly polar solvent. Hydrophilic solvents mixed with water can be used as solvents. The reaction is preferably carried out in an approximately neutral medium. When . the compound of the general formula II or the thiol compound of the general formula III is used in free form, the reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate or a trialkylamine. The reaction temperature is not limited, and the reaction is usually carried out at room temperature or under heating. The reaction product can be isolated from the reaction mixture using conventional methods.

Når omsetningen utføres under anvendelse av en forbindelse med den generelle formel III, hvor R 2er en amino-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, kan de frie aminogrupper beskyttes under anvendelse av konvensjonelle beskyttelsesgrupper. I dette tilfelle kan amino-beskyttelsesgruppen om nødvendig fjernes fra reaksjonsproduktet. When the reaction is carried out using a compound of the general formula III, where R 2 is an amino-lower-alkyl-substituted thiadiazolyl or tetrazolyl group, the free amino groups can be protected using conventional protecting groups. In this case, if necessary, the amino protecting group can be removed from the reaction product.

Fjernelsen av aminobeskyttelsesgruppen kan utføres under anvendelse av en konvensjonell fremgangsmåte så som spaltning med syre og katalytisk reduksjon, og fremgangsmåten velges avhengig av arten åv beskyttelsesgruppen på aminogruppen. Spaltningen med syre er. en av de mest egnede fremgangsmåter og kan anvendes til fjernelse av substituenter så som benzyloksykarbonyl, substituert benzyloksykarbonyl, alkoksykarbonyl, substituert alkoksykarbonyl, aralkoksykarbony1, adamantyloksy-karbonyl, trityl, substituert fenyltio, substituert aralkyliden, substituert alkyliden og substituert cykloalkyliden.. Den til den ovenfor angitte omsetning anvendte syre velges avhengig av arten av aminobeskyttelsesgruppen, og egnede syrer er f.eks.I maursyre og trifluoreddiksyre, som lett avdampes under redusert trykk. Når spaltningen med syre utføres i et oppløsningsmiddel, kan det som oppløsningsmiddel anvendes et hydrofilt organisk oppløsningsmiddel, vann eller en blanding derav. Den kata-lytiske reduksjon kan anvendes til fjernelse av amino-beskyttelsesgrupper så som benzyloksykarbonyl, substituert benzyloksykarbonyl og 2-pyridyImetoksykarbony 1. En egnet katalysator er palladium, men det kan også anvendes andre katalysatorer,.som konvensjonelt anvendes til katalytisk reduksjon. The removal of the amino protecting group can be carried out using a conventional method such as cleavage with acid and catalytic reduction, and the method is selected depending on the nature of the protecting group on the amino group. The cleavage with acid is. one of the most suitable methods and can be used for the removal of substituents such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene and substituted cycloalkylidene.. The one to the one above indicated reaction, the acid used is chosen depending on the nature of the amino protecting group, and suitable acids are, for example, formic acid and trifluoroacetic acid, which are easily evaporated under reduced pressure. When the cleavage with acid is carried out in a solvent, a hydrophilic organic solvent, water or a mixture thereof can be used as solvent. The catalytic reduction can be used for the removal of amino-protecting groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl and 2-pyridyImethoxycarbonyl 1. A suitable catalyst is palladium, but other catalysts, which are conventionally used for catalytic reduction, can also be used.

Trifluoracetylgruppen kan fjernes ved behandling av reaksjonsproduktet med vann, og halogensubstituerte alkoksy-karbonylgrupper og 8-kinolyloksykarbonylgrupper kan fjernes ved behandling av reaksjonsproduktet med et tungmetall så som kobber og sink. Fjernelsen av aminobeskyttelsesgruppen kan utføres uten isolering og rensning av reaks jonsproduktet 'fra • reaksjonsmediet. The trifluoroacetyl group can be removed by treating the reaction product with water, and halogen-substituted alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups can be removed by treating the reaction product with a heavy metal such as copper and zinc. The removal of the amino protecting group can be carried out without isolating and purifying the reaction product from the reaction medium.

Forbindelsene med den generelle formel I kan fremstilles ved at en forbindelse med den generelle formel IV eller et derivat derav ved aminogruppen og/eller karboksylgruppen, omsettes med en organisk karboksylsyre med den generelle formel V The compounds with the general formula I can be prepared by reacting a compound with the general formula IV or a derivative thereof at the amino group and/or the carboxyl group with an organic carboxylic acid with the general formula V

hvor R''" har den ovenfor angitte betydning, eller et reaktivt derivat derav ved karboksylgruppen. where R''" has the above meaning, or a reactive derivative thereof at the carboxyl group.

Derivatet av forbindelsen med den generelle formel IV ved karboksylgruppen kan være et salt så som et magnesiumsalt, kalsium-salt eller trietylaminsalt, en ester så som en metylester, etyl-ester, propylester, butylester, pentylester, trimetylsilylester, 2-mesyletylester, 2-jodetylester, 2,2,2-trikloretylester, benzyl-ester, 4-metoksybenzylester, 4-nitrobenzylester, fenacylester, fenetylester, tritylester, difenylmetylester, bis (metoksyfenyl)-metylester, 3,4-dimetoksybenzylester, (1-cyklopropyl)etylester, etynylester eller 4-hydroksy-3,5-di-tert.butylbenzylester, et The derivative of the compound of general formula IV at the carboxyl group may be a salt such as a magnesium salt, calcium salt or triethylamine salt, an ester such as a methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, trimethylsilyl ester, 2-mesyl ethyl ester, 2- iodoethyl ester, 2,2,2-trichloroethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis (methoxyphenyl)-methyl ester, 3,4-dimethoxybenzyl ester, (1-cyclopropyl)ethyl ester, ethynyl ester or 4-hydroxy-3,5-di-tert.butyl benzyl ester, et

aktivert amid, et syrcanhydrid el.':i.r ct syrchalocjenid.activated amide, an acid anhydride or.':i.r ct acid chalocenide.

Derivatet av forbindelsen med den generelle formel IV ved aminogruppen kan være reaksjonsproduktet av en forbindelse med den generelle formel IV og en silylforbindelse så som bis (trimetyl- 'i silyl)acetamido. The derivative of the compound of the general formula IV at the amino group can be the reaction product of a compound of the general formula IV and a silyl compound such as bis(trimethyl-1 silyl)acetamido.

Det reaktive derivat av den organiske karboksylsyre med den generelle formel V ved karboksylgruppen kan være et syre-halogenid, et syrcanhydrid, et aktivert amid eller en aktivert ester. Som eksempler på egnede forbindelser kan angis ot syre-klorid, et syreazid, et blandet syreanhydrid med en syre så som en dialkylfosforsyre, fenylfosforsyre, difenylfosforsyre, dibenzyl-fosforsyre,. halogenert fosforsyre, dialkylfosforsyrling, svovel-syrling, tiosvovelsyre, svovelsyre, alkylkarbonsyre, alifatisk karboksylsyre (f.eks. pivalinsyre, pentansyre, isopentansyre, 2,-etylsmørsyre eller trikloreddiksyrc) eller aromatisk karboksylsyre (f;eks. benzocsyre), et symmetrisk syreanhydrid, et syreamid med imidazol, 4-substituert imidazol, dimetylpyrazol, triazol eller tetrazol eller en ester (f.eks. cyanometylester, metoksy-metylester, vinylester, propargylester, p-nitrofenylester, (2,4-di-nitrofenylester, triklorfenylester, pentaklorfenylester, metan-sulfonylfenylester, fenylazofenylester, fenyltioester, p-nitro-fenyltioester, p-kresyltioester, karboksymetyltioester, pyranyl-ester,. pyridylester, piperidylester, 8-kinoly ltioester eller en ester med N, N-dimety lhydroksylamin, 1-hyd rok sy- 2- (III) - pyr idon , N-hydroksysuccinimid eller N-hydroksyftalimid). Det egnede derivat kan eventuelt utvelges avhengig av arten av den anvendte organiske karboksylsyre med den generelle formel V. The reactive derivative of the organic carboxylic acid with the general formula V at the carboxyl group can be an acid halide, an acid anhydride, an activated amide or an activated ester. Examples of suitable compounds include acid chloride, an acid azide, a mixed acid anhydride with an acid such as a dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid. halogenated phosphoric acid, dialkylphosphoric acid, sulfuric acid, thiosulphuric acid, sulfuric acid, alkylcarboxylic acid, aliphatic carboxylic acid (eg pivalic acid, pentanoic acid, isopentanoic acid, 2,-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acid (eg benzoic acid), a symmetrical acid anhydride, an acid amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole or an ester (e.g. cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, (2,4-di-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenylester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranylester, pyridylester, piperidylester, 8-quinolylthioester or an ester with N,N-dimethylhydroxylamine, 1-hydroxy 2-(III)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide).The suitable derivative can optionally be selected depending on the nature of the organic carboxylic acid used with the general form or V.

Omsetningen utføres vanligvis i et oppløsningsmiddel såThe reaction is usually carried out in a solvent so

som aceton, dioksan, acetonitril, kloroform, metylenklorid, etylen-klorid, tetrahydrof uran, etylacetat, dirnetylformamid, pyridin . eller et hvilket som helst annet organisk oppløsningsmiddel, som er inert overfor omsetningen. Blant disse oppløsningsmidler kan hydrofile oppløsningsmidler anvendes i blanding med vann. such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dirnetylformamide, pyridine. or any other organic solvent, which is inert to the reaction. Among these solvents, hydrophilic solvents can be used in mixture with water.

Når den organiske karboksylsyre med den generelle formel V anvendes i form. av den frie syre eller et salt derav, utføres, omsetningen fortrinnsvis i nærvær av et kondensasjonsmiddel så' som N,N'-dicykloheksylkarbodiimid, N-cykloheksyl-N<1->morfolinoetyl-karbodiimid, N-cykloheksyl-N'-(4-dietylaminocykloheksyl)karbodiimid, N,N<1->dietyl-karbodiimid, N,N<1->diisopropylkarbodiimid, N-étyl-N'-(3-dimetylaminopropyl)karbodiimid,N,N'-karbonyldi-(2-metylimidazol) pentametylenketen-N-cykloheksylim.in, difenylketen-N-cyklo-heksylimin, alkoksyacetylen, 1-alkoksy-l-kloretylen, trialkyl- | fosfitt, etylpolyfosfat, isopropylpolyfosfat, fosforoksyklorid, fosfortriklorid, tionylklorid, oksalylklorid, trifen<y>lfos fin, 2-etyl-7-hydroksy-benzisoksazoliumsalt, 2-etyl-5-(m-sulfofeny1)-isoksazoliumhydroksy-intermolekylært salt og (klormetylen) - dimetylammoniumklorid. Saltet av den organiske karboksylsyre med den generelle formel V kan være et alkalimetallsalt, et jordalkalimetallsalt, et ammoniumsalt eller et salt med en organisk base så som trimetylamin eller dicykloheksylamin. When the organic carboxylic acid of the general formula V is used in the form of the free acid or a salt thereof, the reaction is preferably carried out in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N<1->morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4 -diethylaminocyclohexyl)carbodiimide, N,N<1->diethylcarbodiimide, N,N<1->diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,N,N'-carbonyldi-(2-methylimidazole) ) pentamethyleneketen-N-cyclohexylim.in, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-l-chloroethylene, trialkyl- | phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphen<y>lfosfine, 2-ethyl-7-hydroxy-benzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxy intermolecular salt and (chloromethylene ) - dimethylammonium chloride. The salt of the organic carboxylic acid of the general formula V may be an alkali metal salt, an alkaline earth metal salt, an ammonium salt or a salt with an organic base such as trimethylamine or dicyclohexylamine.

Omsetningen kan utføres i nærvær av en base så som et alkalimetallbikarbonat, et trialkylamin eller N,N-dialkyl-benzylamin eller pyridin. Når basen eller kondensasjonsmidlet er flytende, kan den også anvendes som oppløsningsmiddel. Reaksjonstemperaturen er.ikke begrenset, og omsetningen utføres vanligvis under avkjøling eller ved romtemperatur. The reaction can be carried out in the presence of a base such as an alkali metal bicarbonate, a trialkylamine or N,N-dialkylbenzylamine or pyridine. When the base or condensation agent is liquid, it can also be used as a solvent. The reaction temperature is not limited, and the reaction is usually carried out under cooling or at room temperature.

Forbindelsene med formel I oppviser en høy antibakteriell aktivitet og hemmer veksten av et antall mikroorganismer,' herunder grampositive og gramnegative bakterier. The compounds of formula I exhibit a high antibacterial activity and inhibit the growth of a number of microorganisms, including gram-positive and gram-negative bacteria.

Fremstilling av forbindelsene ifølge foreliggende oppfinnelse belyses nærmere ved de følgende eksempler: Production of the compounds according to the present invention is illustrated in more detail by the following examples:

Eksempel 1Example 1

1,36 g 7-aminocefalosporansyre, 1,04 g 5-acetamidometyl-1,3,4-tiadiazol-2-tiol og 885 mg natriumhydrogenkarbonat oppløses i 70 ml vann, og oppløsningen omrøres ved 60°C i 5 timer. Efter omsetningen innstilles reaksjonsblandingen på 1.36 g of 7-aminocephalosporanic acid, 1.04 g of 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol and 885 mg of sodium bicarbonate are dissolved in 70 ml of water, and the solution is stirred at 60°C for 5 hours. After the reaction, the reaction mixture is adjusted to

ehpH-verdi på 5, og reaksjonsblandingen får derefter stå natten over i et kjøleskap. De utfelte krystaller oppsamles ved filtrering, hvorved fåes 1,03 g 7-amino-3-(5-acetamido'metyl-1,3,4-tiadiazol-2-yl)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt 195-197°C (spaltning). ehpH value of 5, and the reaction mixture is then allowed to stand overnight in a refrigerator. The precipitated crystals are collected by filtration, whereby 1.03 g of 7-amino-3-(5-acetamido'methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid with a melting point of 195 -197°C (decomposition).

IR-spektrum: vJJJJjjg1:1795og1640cm"<1.>IR spectrum: vJJJJjjg1:1795 and 1640cm"<1.>

NMR-spektrum: 6 (D20 + DC1) (ppm): 2,12 (3H, s), 3,83 (2H, s), 4,30 (1H, d, J = 14 Hz) , 4,64 (lH, d, J = 14 Hz) , 4,79 (2H, s) , 5,22 (1H, d, J = 5 Hz), 5,37 (1H, d, J 4,5 Hz). NMR spectrum: 6 (D 2 O + DC 1 ) (ppm): 2.12 (3H, s), 3.83 (2H, s), 4.30 (1H, d, J = 14 Hz) , 4.64 ( 1H, d, J = 14 Hz) , 4.79 (2H, s) , 5.22 (1H, d, J = 5 Hz), 5.37 (1H, d, J 4.5 Hz).

Eksempel 2 i Example 2 i

I IN

1,24 g 5-tert.butoksykarbonylaminometyl-1,3,4-tiadiazol-2-tiol oppløses i 10 ml aceton. Oppløsningen settes til 40 ml av en vandig oppløsning inneholdende 0,84 g natriumhydrogenkarbonat. Den- blandede oppløsning oppvarmes på et vannbad ved 70-75°C. Til oppløsningen settes på en gang ved 55°C 1,35 g 7-aminocefalosporansyre. Blandingen omrøres ved 65-70°C i 2 timer og avkjøles derefter med is til 0-5°C. Reaksjonsblandingen innstilles på en pH-verdi på 5,0-5,2 med 10%ig saltsyre. Den utfelte lysegule bestanddel fraskilles ved filtrering, vaskes med vann og aceton og tørres derefter, hvorved fåes 1,28 g 7-an]ino-3-(5-tert .butoksykarbonylaminomety 1-1,3,4-tiadiazol-2-y1)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt over 2 20°C. 1.24 g of 5-tert.butoxycarbonylaminomethyl-1,3,4-thiadiazole-2-thiol are dissolved in 10 ml of acetone. The solution is added to 40 ml of an aqueous solution containing 0.84 g of sodium bicarbonate. The mixed solution is heated in a water bath at 70-75°C. 1.35 g of 7-aminocephalosporanic acid is added to the solution all at once at 55°C. The mixture is stirred at 65-70°C for 2 hours and then cooled with ice to 0-5°C. The reaction mixture is adjusted to a pH value of 5.0-5.2 with 10% hydrochloric acid. The precipitated pale yellow component is separated by filtration, washed with water and acetone and then dried, thereby obtaining 1.28 g of 7-an]ino-3-(5-tert.butoxycarbonylaminomethyl 1-1,3,4-thiadiazol-2-yl )thiomethyl-3-cephem-4-carboxylic acid with a melting point above 2 20°C.

IR-spektrum: vJJ^ks1' 1805'1700°91625 cm~ 1-IR spectrum: vJJ^ks1' 1805'1700°91625 cm~ 1-

NMR-spektrum: 6 (D20 + NaHC03) (ppm): 1,41 (9H, s), 3,39NMR spectrum: δ (D 2 O + NaHCO 3 ) (ppm): 1.41 (9H, s), 3.39

(1H, d, J = 17- Hz) , 3,79 (1H, d, J = 17 Hz) , 4,08 (1H, d., (1H, d, J = 17- Hz) , 3.79 (1H, d, J = 17 Hz) , 4.08 (1H, d.,

J J

J = 14 Hz), 4,55 (lH, d, J = 14 Hz), 4,60 (2H, s), 5,08 (1H, d, J = 4,5 Hz), 5,50 (1H, d, J = 4,5 Hz). J = 14 Hz), 4.55 (lH, d, J = 14 Hz), 4.60 (2H, s), 5.08 (1H, d, J = 4.5 Hz), 5.50 (1H , d, J = 4.5 Hz).

Eksempel 3Example 3

0,84 g natriumhydrogenkarbonat og 0,74 g 5-hydroksymety1-1,3,4-tiadiazol-2-tiol oppløses■i 40 ml vann, og oppløsningen oppvarmes på et vannbad. 0.84 g of sodium bicarbonate and 0.74 g of 5-hydroxymethyl-1,3,4-thiadiazole-2-thiol are dissolved in 40 ml of water, and the solution is heated on a water bath.

Til oppløsningen settes på én gang ved 45°C 1,36 g 7-aminocef alosporansyre. Blandingen omrøres ved 70-7.3°C i 1 time. Efter omsetningen avkjøles blandingen til 0-5°C, og innstilles på en pH-verdi- på 5,0 med 10%ig saltsyre. De utfelte krystaller oppsamles ved filtrering, hvorved fåes 1,20 g 7-amino-3-(5-hydroksymety1-1,3,4-tiadiazol-2-yl)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt 194-199°C (spaltning). 1.36 g of 7-aminocephalosporanic acid is added to the solution at once at 45°C. The mixture is stirred at 70-7.3°C for 1 hour. After the reaction, the mixture is cooled to 0-5°C, and adjusted to a pH value of 5.0 with 10% hydrochloric acid. The precipitated crystals are collected by filtration, whereby 1.20 g of 7-amino-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid with melting point 194-199 is obtained °C (decomposition).

IR-spektrum: v™^<1>: 3200, 1805'og 1625 cm"<1>IR spectrum: v™^<1>: 3200, 1805'and 1625 cm"<1>

NMR-spektrum: 6 (D20 + DC1) (ppm): 3,85 (2H, s). , 4,38 (1H, d, J = 14 Hz), 4,70 (1H, d, J = 14 Hz), 5,12 (2H, s), 5,20 (1H, d, J = 5 Hz), 5,38 (1H, d, J = 5 Hz). NMR spectrum: δ (D 2 O + DC 1 ) (ppm): 3.85 (2H, s). , 4.38 (1H, d, J = 14 Hz), 4.70 (1H, d, J = 14 Hz), 5.12 (2H, s), 5.20 (1H, d, J = 5 Hz ), 5.38 (1H, d, J = 5 Hz).

Claims (1)

Cefalosporin-mellomprodukt for fremstilling av terapeutisk aktive cefalosporinderivater med formelen Cephalosporin intermediate for the manufacture of therapeutically active cephalosporin derivatives with the formula hvor R"*" er acyl, R 2 er en amino-lavere-alkyl-, lavere ålkanoylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkyl-, lavere alkan- sulfonylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkanoylamino-lavere-alkyl-, lavere alkylureido-lavere-alkyl-, guanidino-k.arbonylamino-lavere-alkyl- eiler hydroksy-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, og M er et hydrogenatom eller et ugiftig, farmasøytisk godtagbart kation, karakterisert ved at det har den generelle formel. where R"*" is acyl, R 2 is an amino-lower-alkyl-, lower alkanoylamino-lower-alkyl-, lower alkoxycarbonylamino-lower-alkyl-, lower-alkane- sulfonylamino-lower-alkyl-, lower alkoxycarbonylamino-lower-alkanoylamino-lower-alkyl-, lower alkylureido-lower-alkyl-, guanidino-k.carbonylamino-lower-alkyl- yl hydroxy-lower-alkyl-substituted thiadiazolyl or tetrazolyl group, and M is a hydrogen atom or a non-toxic, pharmaceutically acceptable cation, characterized in that it has the general formula. hvor R 2 og M er som angitt ovenfor.where R 2 and M are as indicated above.
NO80801402A 1973-03-30 1980-05-12 CEPHALOSPORINE INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES NO801402L (en)

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JP48073898A JPS5852997B2 (en) 1973-06-29 1973-06-29 7- Chikane -3- Hydroxyalkylthikane Fusocanethiomethyl -3- Cefem -4- Carbonsanluino Seizouhou
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US4379924A (en) 1973-12-25 1983-04-12 Takeda Chemical Industries, Ltd. Cephalosporin derivatives
US4093723A (en) 1976-05-19 1978-06-06 Smithkline Corporation 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl) cephalosporins
BE845338A (en) * 1975-09-02 1977-02-21 NEW CEPHALOSPORINS, PROCESS FOR OBTAINING THEM AND PHARMACEUTICAL APPLICATION
US4171433A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Amino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporin intermediates for preparing 7-acylamino cephalosporins
US4171362A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins antibacterial compositions containing them and methods of treating bacterial infections with them
US4171368A (en) * 1975-10-30 1979-10-16 Smithkline Corporation 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them
IL50546A (en) * 1975-10-30 1980-07-31 Smithkline Corp 7-acyl-3-(1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions containing them
US4118491A (en) * 1976-03-11 1978-10-03 Smithkline Corporation 7-Acyl-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them
US4066762A (en) * 1976-07-12 1978-01-03 Smithkline Corporation Derivatives of 7-(2-substituted-2-hydroxyiminoacetamido)-3-(1-substituted tetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid
US4101656A (en) 1976-07-12 1978-07-18 Smithkline Corporation 7β-Acylamino-3-(alkanesulfonamidoalkyl substituted tetrazolylthiomethyl) cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them
US4083975A (en) 1976-09-24 1978-04-11 Smithkline Corporation 7-Acylamino-3-(3-sulfomethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids
US4064242A (en) * 1976-11-04 1977-12-20 Smithkline Corporation 7-Acylamino-3-[1-(2,3-dihydroxypropyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acids
US4117123A (en) * 1977-06-09 1978-09-26 Smithkline Corporation 7-Acylamino-3-[1-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids
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US3757014A (en) * 1971-05-07 1973-09-04 Bristol Myers Co Ts 1,3,4 - oxadiazol-2-yl)thiomethyl)-3-cephem-4-carboxylic acid and sal7-(d-(alpha-amino-alpha-pheyle-acetamido)) - 3-(s-(5-hydroxymethyl -
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