DK155329B - 7-AMINOCEPHALOSPORINES USED AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC EFFECTIVE 7-ACYLAMINO-CEPHALOSPORINES - Google Patents
7-AMINOCEPHALOSPORINES USED AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC EFFECTIVE 7-ACYLAMINO-CEPHALOSPORINES Download PDFInfo
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- DK155329B DK155329B DK453687A DK453687A DK155329B DK 155329 B DK155329 B DK 155329B DK 453687 A DK453687 A DK 453687A DK 453687 A DK453687 A DK 453687A DK 155329 B DK155329 B DK 155329B
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- 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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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
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- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
iin
DK 155329 BDK 155329 B
Den foreliggende opfindelse angår hidtil ukendte 7-amino-cephalospo-riner til anvendelse som mellemprodukter ved fremstilling af terapeutisk virksomme 7~acylamino-cephalosporiner. De hidtil ukendte forbindelser har den almene formel IThe present invention relates to novel 7-amino-cephalosporins for use as intermediates in the preparation of therapeutically active 7-acylamino-cephalosporins. The novel compounds have the general formula I
R1 »S.R1 »S.
h2n—p—i 5 0 J—CH2-s-Y ih2n-p-i 5 J-CH 2 -s-Y i
COOHCOOH
hvor betegner hydrogen eller methoxy, og Y betegner en i det mindste ved ét af nitrogenatomerne med lavere alkyl, lavere alkenyl, med lavere alkoxy substitueret lavere alkyl, lavere alkoxy, amino, mono- eller di (lavere alkyl)amino substitueret og 10 eventuelt ved ét eller flere carbonatomer med lavere alkyl, halo gen eller oxo substitueret pyrimidonyl-, pyrazonyl-, pyridazonyl-eller triazonylgruppe, hvorhos "lavere" overalt refererer til grupper med højst 6 carbonatomer.where Y represents hydrogen or methoxy, and Y represents at least one of the lower alkyl, lower alkenyl nitrogen atoms, lower alkoxy substituted lower alkyl, lower alkoxy, amino, mono- or di (lower alkyl) amino substituted and optionally at one or more lower alkyl, halo gene or oxo substituted pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group atoms, wherein "lower" generally refers to groups having a maximum of 6 carbon atoms.
De ovennævnte 7-amino-cephalosporiner med formlen I er hidtil ukend-15 te mellemprodukter, der, efter beskyttelse af carboxygruppen i 4-stil-lingen, kan omdannes til terapeutisk virksomme 7-acylaminocephalospo-riner, nemlig ved acylering med en syre med den almene formel IIThe above-mentioned 7-amino-cephalosporins of formula I are novel intermediates which, after protecting the carboxy group in the 4-position, can be converted into therapeutically effective 7-acylaminocephalosporins, namely by acylation with an acid with the general formula II
Z-OH IIZ-OH II
hvor Z betegner en acylgruppe, der kan anvendes som substitu-20 ent i aminogruppen i 7-stillingen i en cephalosporin, eller med et reaktivt funktionelt derivat deraf, hvorefter beskyttelsesgruppen fraspaltes, og reaktionsproduktet om ønsket omdannes til et salt.wherein Z represents an acyl group which can be used as a substituent in the amino group at the 7-position of a cephalosporin, or with a reactive functional derivative thereof, after which the protecting group is cleaved and the reaction product is converted into a salt if desired.
Som syrer med formten II i den ovennævnte reaktion kan der anven des syrer med den almene formel ilaAs acids of the formula II in the above reaction, acids of the general formula
DK 155329 BDK 155329 B
2 R2-CH-COOH Ila 5 R3 hvor R2 betegner cyan, 4-pyridylthio, n-butyl, isobutyl, phenyl, hydroxyphenyl, cyclohexyl, 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyI eller 3-sydnonyl, R^ betegner hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy eller sulfo, 10 hvorhos en fra cyan forskellig gruppe R2 kan være substitueret med hydroxy, halogen, lavere alkyl eller lavere alkoxy, og såfremt R2 betegner en pyridylthiogruppe, er Rg hydrogen.2 R 2 -CH-COOH IIa R 3 wherein R 2 represents cyano, 4-pyridylthio, n-butyl, isobutyl, phenyl, hydroxyphenyl, cyclohexyl, 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl or Represents hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, wherein a group different from cyano may be substituted with hydroxy, halogen, lower alkyl or lower alkoxy, and if R2 represents a pyridylthio group, is Rg hydrogen.
Når der anvendes syrer med formlen Ila eller deres reaktive funktionelle derivater, fås som antibiotisk virksomme cephalosporinderivater 15 sådanne, der har den almene formel IIIWhen acids of formula IIa or their reactive functional derivatives are used, antibiotic-active cephalosporin derivatives 15 are obtained which have the general formula III
R, HR, H
—CH—CONH—r-1 *3 -Νγ^Η2-3-ϊ m—CH — CONH — r-1 * 3 -Νγ ^ Η2-3-ϊ m
C00HC00H
hvor Rj betegner hydrogen eller methoxy, og R2, R^ og Y har den ovenfor anførte betydning, og salte deraf.wherein R 1 represents hydrogen or methoxy and R 2, R 2 and Y are as defined above, and salts thereof.
20 I nærværende beskrivelse betegner udtrykket "halogen" chlor, fluor eller brom, hvorhos chlor foretrækkes. Udtrykket "en lavere alkyl-gruppe, lavere alkoxygruppe eller lavere alkenylgruppe" betegner en ligekædet eller forgrenet alkyl-, alkoxy- eller alkenylgruppe med op til 6 carbonatomer, fx methyl, ethyl, propyl, isopropyl, n-butyl, 25 isobutyl, pentyl og hexyl, vinyl, propenyl, butenyl, pentenyl og hexenyl, hvorhos alkylgrupperne med 4 carbonatomer, især n-butyl og isobutyl, er foretrukne.In this specification, the term "halogen" refers to chlorine, fluorine or bromine, which chlorine is preferred. The term "a lower alkyl group, lower alkoxy group or lower alkenyl group" means a straight or branched alkyl, alkoxy or alkenyl group having up to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl, vinyl, propenyl, butenyl, pentenyl and hexenyl, with the alkyl groups having 4 carbon atoms, especially n-butyl and isobutyl being preferred.
DK 155329 BDK 155329 B
33
Som eksempler på særlig foretrukne forbindelser med formlen II eller Ila kan nævnes sådanne, i hvilke 1^ er 2-thienyl, 2-furyl, 1-tetra-5 zolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyr-idylthio eller cyan, hvorhos, såfremt er 4-pyridylthio, er hydrogen.Examples of particularly preferred compounds of formula II or IIa are those in which 1 is 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl , 4-pyridylthio or cyano, wherein, if 4-pyridylthio, is hydrogen.
Som eksempler på sådanne forbindelser kan nævnes forbindelser, i hvilke Y er 10 en 2-oxopyridin-4-ylgruppe, en 2-oxopyrimidin-4-ylgruppe, fx en 1-amino-, 1-ethyl- eller 1-but-oxy-1,2-dihydro-2-oxopyrimidin-4-ylgruppe eller· en 1-butoxy-1,2-di-hyd ro-5-methyl-2-oxopyrimidin-4-ylgruppe, en 4-oxopyrimidin-2-ylgruppe, fx en 1-ethyl-1,4-dihydro-6-methyl-15 4-oxopyrimidin-2-ylgruppe eller en 1,4-dimethyl-1,6-dihydro-6-oxo-pyrimidin-2-ylgruppe, en 2,6-dioxopyrimidin-4-ylgruppe, en 2-oxopyrazin-3-ylgruppe, en 2,3,5-trioxopyrazinyl-6-ylgruppe, 20 en 3-oxopyridazin-6-ylgruppe, en 3-oxopyridazin“4-ylgruppe, en 5,6-dioxo-as-triazin-3-yIgruppe, fx en 4-ethyl-, 4-methyl-, 4-al-lyl-, 4-butyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl- eller 1,4-diethyl- 1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-ylgruppe eller en 1,2,5,6-25 tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-ylgruppe,Examples of such compounds are compounds in which Y is a 2-oxopyridin-4-yl group, a 2-oxopyrimidin-4-yl group, e.g., a 1-amino, 1-ethyl or 1-butoxy group. A 1,2-dihydro-2-oxopyrimidin-4-yl group or a 1-butoxy-1,2-dihydro-5-methyl-2-oxopyrimidin-4-yl group, a 4-oxopyrimidin-2-yl group, for example, a 1-ethyl-1,4-dihydro-6-methyl-4-oxopyrimidin-2-yl group or a 1,4-dimethyl-1,6-dihydro-6-oxo-pyrimidin-2-yl group, a 2 , 6-dioxopyrimidin-4-yl group, a 2-oxopyrazin-3-yl group, a 2,3,5-trioxopyrazinyl-6-yl group, a 3-oxopyridazin-6-yl group, a 3-oxopyridazin-4-yl group, a 5,6-dioxo-as-triazin-3-yl group, e.g., a 4-ethyl, 4-methyl, 4-allyl, 4-butyl, 4- (2-methoxyethyl) -1, 4-dimethyl or 1,4-diethyl 1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl group or a 1,2,5,6,6-tetrahydro-1-ethyl -5,6-dioxo-as-triazin-3-yl group,
, DK 155329 B, DK 155329 B
4 en 2-oxotriazin-4-yIgruppe eller en 2,4-dioxotriazin-6-ylgruppe.4 a 2-oxotriazin-4-yl group or a 2,4-dioxotriazin-6-yl group.
Som substituenter på et ringnitrogenatom kan endvidere nævnes lavere alkyl eller alkenyl, lavere alkoxy, amino, mono- eller di(lavere 5 alkyDamino, og som substituent på et ringcarbonatom kan nævnes lavere alkyl, halogen eller oxo, hvorhos en til et carbon- eller nitrogenatom bundet lavere alkylgrup-pe igen kan være substitueret med hydroxy eller lavere alkoxy.Further substituents on a ring nitrogen atom may be mentioned lower alkyl or alkenyl, lower alkoxy, amino, mono- or di (lower alkydamino) and as substituent on a ring carbon atom may be mentioned lower alkyl, halogen or oxo, wherein one to a carbon or nitrogen atom bonded lower alkyl group may again be substituted by hydroxy or lower alkoxy.
10 De ovenfor anførte lavere alkyl-, alkenyl- eller alkoxygrupper indeholder op til 6 carbonatomer. Eksempler på sådanne alkylgrupper er methyl og ethyl. Eksempler på sådanne alkenylgrupper er vinyl og allyl. Eksempler på sådanne alkoxygrupper er methoxy og ethoxy.The lower alkyl, alkenyl or alkoxy groups listed above contain up to 6 carbon atoms. Examples of such alkyl groups are methyl and ethyl. Examples of such alkenyl groups are vinyl and allyl. Examples of such alkoxy groups are methoxy and ethoxy.
Som særligt foretrukne forbindelser med formlen I kan nævnes: 15 7-amino-3-{ [(1,4,5,6-tetrahydro-4-ethy I -5,6-dioxo-as -triazin -3-yl)- thio] methyl >-3-cephem-4-carboxylsyre, 7-amino-3-{[(l<.4/5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)- thio]methyl}-3-cephem-4-carboxylsyre, 7-amino-3-{[ (1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) -20 th io] methyl} -3-cephem-4-carboxyl syre, 7-amino-3-{ [(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as~triazin-3-yl)-thio]methyl}-3-cephem-4-carboxylsyre, 7-amino-3-{[(1,4,5/6-tetrahydro-4- (2-methoxyethyI)-5,6-dioxo-as-tri-azin-3-yl)thio]methyl}-3-cephem-4-carboxyisyre,Particularly preferred compounds of formula I include: 7-amino-3- {[(1,4,5,6-tetrahydro-4-ethyl I -5,6-dioxo-as-triazin-3-yl) - thio] methyl> -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4 <5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) ) - thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazine-3- yl) -20 thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3- {[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-ash) triazin-3-yl) -thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4,5 / 6-tetrahydro-4- (2-methoxyethyl) -5,6 dioxo-as-tri-azine-3-yl) thio] methyl} -3-cephem-4-carboxylic acid,
DK 155329 BDK 155329 B
5 7-amino-3-{[(1,4,5,6-tetrahydro-l,4-dimethyl-5,6-dioxo-as-triazin- 3-yl)thio] methyl }-3-cephem-4-ca rboxylsyre, 7-amino-3-{[(1 ,4,5,6-tetrahydro-l ,4-diethyl-5,6-dioxo-as-triazin-3-yl)thio]methy!}-3-cephem-4-carboxylsyre, 5 7-amino-3-{[(1,2,5,6-tetrahydro-l-ethyl-5,6-dioxo-as-triazin-3-yl)- thio]methyl}-3-cephem-4-carboxylsyre, 7-amino-7-methoxy-3-{[(l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-tri-azin-3-yl)thio]methyl}-3-cephem-4-ca rboxylsyre, 7-amino-3-{[(l-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl}-3-10 cephem-4-carboxylsyre, 7-amino-3-{[(1-ethyl-l, 2-dihydro-2-oxo-4-py rimidinyl)thio] methyl >-3-cephem-4-ca rboxylsyre, 7-amino-3-{ [(Ί-butoxy-l,2-dihydro-2-oxo-4-pyrimidinyl)thio] methyl}- 3-cephem-4-carboxyisyre, 15 7-amino-3-{[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio] methyl }-3-cephem-4-ca rboxylsyre, 7-amino-3-{[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)thio]meth-yl}-3-cephem-4-ca rboxylsyre, 7-3πιίηο-3-{[(1-6ίΙιγΜ,4-^ϊΙ^Γθ-6-ιηβίΙιγΙ-4-οχο-4-^ππιι^ίηγΙ)ΐΐΉθ]-20 methyl}-3-cephem-4-carboxylsyre og 7-amino-3-{(l ,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thiomethyl}-3-cephem-4-ca rboxylsyre.7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -3-cephem-4 -carboxylic acid, 7-amino-3 - {[(1, 4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -3 -cephem-4-carboxylic acid, 7-amino-3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl} 3-Cephem-4-carboxylic acid, 7-amino-7-methoxy-3 - {[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-tri-azine-3- yl) thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3- Cephem-4-carboxylic acid, 7-amino-3 - {[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl> -3-cephem-4-carboxylic acid, 7 -amino-3- {[(Ί-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1 -butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thio] methyl} -3-cephem-4-carboxylic acid, 7-amino-3 - {[(1,4-dimethyl) -1,6-dihydro-6-oxo-2-pyrimidinyl) thio] methyl} -3-cephem-4-carboxylic acid, 7-3πιίηο-3 - {[(1-6ίΙιγΜ, 4- ^ ϊΙ ^ Γθ -6-ιηβίΙιγΙ-4-οχο-4- ^ ^ ππιι ίη γΙ) ΐΐΉθ] -20 methyl} -3-cephem-4-carboxylic acid and 7-amino-3 - {(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine-3) -yl) -thiomethyl} -3-cephem-4-carboxylic acid.
Forbindelser med formlen I kan foreligge som optisk rene isomere og som isomerblandinger.Compounds of formula I may exist as optically pure isomers and as isomer mixtures.
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66
Forbindelserne med formlen I og salte deraf kan fremstilles ved, at en forbindelse med den almene formel IVThe compounds of formula I and their salts can be prepared by a compound of general formula IV
R1 H SR1 H S
v-MT \ o-'*-W1v-MT \ o - '* - W1
T IVT IV
COOHCOOH
hvor har den ovenfor anførte betydning, betegner en fra-5 spaltelig enhed og carboxygruppen i 4Tstillingen er beskyttet ved saltdannelse med en uorganisk eller tertiær organisk base,where the meaning given above denotes a cleavable moiety and the carboxy group in the 4 position is protected by salt formation with an inorganic or tertiary organic base;
omsættes med en forbindelse med den almene formel Vis reacted with a compound of general formula V
H-S-V VH-S-V V
hvor Y har den ovenfor anførte betydning, 10 og beskyttelsesgruppen om ønsket fraspaltes.where Y has the meaning given above, and the protecting group is split off if desired.
Beskyttelsen af carboxygruppen i en forbindelse med formlen I eller IV kan foretages ved saltdannelse med en uorganisk eller tertiær organisk base såsom triethylamin.The protection of the carboxy group in a compound of formula I or IV may be effected by salt formation with an inorganic or tertiary organic base such as triethylamine.
Som fraspaltelig enhed i en forbindelse med formlen IV kan fx an-15 vendes halogener såsom chlor, brom eller iod, acyioxygrupper såsom lavere alkanoylgrupper, fx acetoxy, lavere alkyl- eller arylsulfonyl-oxygrupper såsom mesyloxy eller tosyloxy eller en azidogruppe.As the leaving group of a compound of formula IV, for example, halogens such as chlorine, bromine or iodine, acyoxy groups such as lower alkanoyl groups, for example acetoxy, lower alkyl or arylsulfonyl oxy groups such as mesyloxy or tosyloxy or an azido group may be used.
Omsætningen af en forbindelse med formlen IV og en forbindelse med formlen V kan foretages på i og for sig kendt måde, fx ved en tem-20 peratur mellem ca. 40 og 80°C, hensigtsmæssigt ved ca. 60°C, i vand eller en pufferopløsning med en pH-værdi på ca. 6-7, fortrinsvis 6,5, i løbet af et tidsrum på 3-8, fortrinsvis 6, timer.The reaction of a compound of formula IV and a compound of formula V can be carried out in a manner known per se, for example at a temperature between ca. 40 and 80 ° C, conveniently at approx. 60 ° C, in water or a buffer solution with a pH of approx. 6-7, preferably 6.5, over a period of 3-8, preferably 6, hours.
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Efter endt omsætning af en forbindelse med formlen IV og en forbindelse med formlen V fraspaltes beskyttelsesgruppen om ønsket. Carb-oxygruppen i en syre med formlen IV er beskyttet ved saltdannelse (fx med triethylamin); fraspaltningen af denne saltdannende beskyt-5 telsesgruppe kan foretages ved behandling med syre ved forholdsmæssig lav temperatur, fx ved ca. 0 - ca. 10°C. Som syre til dette formål kan anvendes fx saltsyre, svovlsyre, phosphorsyre eller citronsyre.Upon completion of reaction of a compound of formula IV and a compound of formula V, the protecting group is split off as desired. The carboxy group of an acid of formula IV is protected by salt formation (e.g. with triethylamine); the cleavage of this salt-forming protecting group can be effected by treatment with acid at a relatively low temperature, e.g. 0 - approx. 10 ° C. As acid for this purpose can be used, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.
Forbindelserne med formlen V er for nogles vedkommende hidtil 10 ukendte, for nogles vedkommende kendte. De hidtil ukendte forbindelser med formlen V kan fremstilles analogt med fremstillingen af kendte forbindelser.The compounds of formula V are unknown to some, and to some known. The novel compounds of formula V can be prepared analogously to the preparation of known compounds.
Således kan en 1-substitueret 2-oxo-4-mercaptopyridin fremstilles ud fra den tilsvarende substituerede 4-chlor-2-oxopyridin [Chem. Ber.Thus, a 1-substituted 2-oxo-4-mercaptopyridine can be prepared from the corresponding substituted 4-chloro-2-oxopyridine [Chem. Ber.
15 99, 255 (1966)] ved nucleofil udskiftning, fx med et a I kalimetal hydro gensulfid.15 99, 255 (1966)] by nucleophilic replacement, for example, with an alpha potassium hydrogen sulfide.
På samme måde kan en 1,3-disubstitueret 2,6-dioxo-1,2,3,6-tetrahy-dro-4-mercaptopyrimidin fremstilles ud fra den tilsvarende 4-chlor- 2.6- dioxo-1,2,3,6-tetrahydropyrimidin.Similarly, a 1,3-disubstituted 2,6-dioxo-1,2,3,6-tetrahydro-4-mercaptopyrimidine can be prepared from the corresponding 4-chloro-2,6-dioxo-1,2,3, 6-tetrahydropyrimidine.
20 5,6-Dioxo-3-mercapto-as-triazinerne kan fremstilles ud fra de tilsvarende substituerede thiosemicarbazider i analogi med syntesen af 1.4.5.6- tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazin, jfr. Dissertation af K.H. Ongania (Innsbruck 1972).The 5,6-Dioxo-3-mercapto-as-triazines can be prepared from the corresponding substituted thiosemicarbazides by analogy with the synthesis of 1,4.5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. , cf. Dissertation by K.H. Ongania (Innsbruck 1972).
En thiol med formlen V, som har en dobbeltbinding mellem det med 25 mercaptogruppen substituerede carbonatom og et nabostillet nitrogenatom, kan foreligge i form af den tautomere thioketon.A thiol of formula V having a double bond between the carbon atom substituted by the mercapto group and a neighboring nitrogen atom may be in the form of the tautomeric thioketone.
Forbindelserne med formlen II og de reaktive funktionelle derivater deraf er kendte eller analoge til kendte forbindelser og kan fremstilles på i og for sig kendt måde.The compounds of formula II and the reactive functional derivatives thereof are known or analogous to known compounds and can be prepared in a manner known per se.
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Forbindelserne med formlen III, saltene deraf og hydraterne af disse salte er antibiotisk, især bactericidt, virksomme. De har bredt virkningsspektrum mod grampositive og gramnegative mikroorganismer, især mod penicillinase-positive staphylococcer samt forskellige cephalo-5 sporinase-positive gramnegative bakterier, fx Escherichia coli-, Proteus-, Klebsiella-, Aerobacter- og Serratia-arter.The compounds of formula III, the salts thereof and the hydrates of these salts are antibiotically active, especially bactericidal. They have broad spectrum of action against Gram-positive and Gram-negative microorganisms, especially against penicillinase-positive staphylococci as well as various cephalo-5 sporinase-positive Gram-negative bacteria, e.g., Escherichia coli, Proteus, Klebsiella, Aerobacter and Serratia species.
Forbindelserne med formlen III samt de farmaceutisk tolerable salte og hydratiserede former deraf kan anvendes til behandling og profylakse af infektionssygdomme samt som desinfektionsmidler. Til voksne kan 10 anvendes en daglig dosis på ca. 1 - ca. 4 g. Der foretrækkes især parenteral administration af de omhandlede .forbindelser.The compounds of formula III, as well as the pharmaceutically tolerable salts and hydrated forms thereof, can be used for the treatment and prophylaxis of infectious diseases as well as disinfectants. For adults, a daily dose of approx. 1 - approx. Particular preference is given to parenteral administration of the subject compounds.
Den antimikrobielle aktivitet hos to af de ovennævnte forbindelser, nemlig natri umsaltet af (7R) -3- C [ (1,4,5,6-tetrahyd ro-4-ethyl-5,6-dioxo-as- 15 triazin-3-yI)thio]methyl)-7-[2-(5-oxo-l ,2,3-oxadiazolidin-3-yl)acet- amido]-3-cephem-4-carboxylsyre (forbindelse A i den nedenfor anførte tabel) og natriumsaltet af (7R)-3-([(l ,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)thio] methyl) -7- [2- (1 -H-tetrazol-1 -yl)acetamido]-3-ceph-20 em-4-carboxylsyre (forbindelse B i den nedenfor anførte tabel), fremgår af de nedenfor anførte CD^-værdier (mg/kg subcutant på mus):The antimicrobial activity of two of the above compounds, namely the sodium salt of (7R) -3-C [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-asrazine-3) (yl) thio] methyl) -7- [2- (5-oxo-1,2,3-oxadiazolidin-3-yl) acetamido] -3-cephem-4-carboxylic acid (Compound A in the table below) ) and the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2 - (1-H-tetrazol-1-yl) acetamido] -3-ceph-20-em-4-carboxylic acid (Compound B in the table below) is shown in the CD 2 values listed below (mg / kg subcutaneously in mouse):
Forbindelse Penicillinfølsomme Penicillinresistente Escherichia staphylococcer staphylococcer coli 25 _ A 0,25 5,5 0,38 B 0,60 ' 3,2 0,90Compound Penicillin Sensitive Penicillin Resistant Escherichia staphylococcer staphylococcer coli 25 A 0.25 5.5 0.38 B 0.60 3.2 3.2 0.90
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Den akutte toxicitet (LD^q) af disse stoffer ved intravenøs administration på mus andrager 2000-4000 mg/kg for stoffet A og 1000-2000 mg/kg for stoffet B.The acute toxicity (LD 2) of these substances by intravenous administration in mice is 2000-4000 mg / kg for drug A and 1000-2000 mg / kg for drug B.
Fremstilling af mellemprodukterne med formlen I ifølge opfindelsen be-5 lyses nærmere ved nedenstående eksempler 1-26, og omdannelsen deraf til antibiotisk virksomme forbindelser med formlen III belyses i eksempel 27-30: EKSEMPEL 1 2,72 g 7-amino-cephalosporansyre suspenderes sammen med 1,4,5,6-10 tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazin i 100 ml vand. Til denne suspension sættes 1,85 g natriumhydrogencarbonat, hvorved der dannes en opløsning med pH-værdi 6,4. Denne opløsning omrøres i 3 timer ved 60°C under nitrogenatmosfære. Opløsningen afkøles til 20°C og omrøres under tilsætning af 1 g aktivkul under nitrogenat-15 mosfære i yderligere 1 time. Efter filtrering indstilles filtratet på pH-værdi 3,8 ved tilsætning af 2N saltsyreopløsning, afkøles til 0°C og omrøres i 1 time, hvorved stoffet udkrystalliseres. Dette isoleres ved sugefiltrering, vaskes med en lille mængde isvand, acetone, ether og petroleumsether i den anførte rækkefølge og tørres i højvakuum 20 ved 50°C. Udbytte 2,3 g (60%) 7-amino-3-desacetoxy-3-[(1,4,5,6-te-trahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)thio]cephalosporansyre i form af et beigefarvet pulver med smeltepunkt 230-235°C (sønderdeling).Preparation of the intermediates of formula I according to the invention is further elucidated by Examples 1-26 below, and the conversion thereof into antibiotic-active compounds of formula III is illustrated in Examples 27-30: EXAMPLE 1 2.72 g of 7-amino-cephalosporanoic acid are suspended together with 1,4,5,6-10 tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine in 100 ml of water. To this suspension is added 1.85 g of sodium bicarbonate to form a solution of pH 6.4. This solution is stirred for 3 hours at 60 ° C under a nitrogen atmosphere. The solution is cooled to 20 ° C and stirred with the addition of 1 g of activated charcoal under nitrogen atmosphere for an additional 1 hour. After filtration, the filtrate is adjusted to pH 3.8 by the addition of 2N hydrochloric acid solution, cooled to 0 ° C and stirred for 1 hour to crystallize the substance. This is isolated by suction filtration, washed with a small amount of ice water, acetone, ether and petroleum ether in the order indicated and dried in high vacuum 20 at 50 ° C. Yield 2.3 g (60%) of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid in the form of a beige powder, m.p. 230-235 ° C (decomposition).
Den ved den ovenfor beskrevne fremgangsmåde anvendte 1,4,5,6-te-25 trahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles på følgende måde: 120 g 4-ethylthiosemicarbazid omsættes i nærværelse af 23 g natrium i 1 liter methanol i 4 timer med 116 g oxalsyredimethylester ved reaktionsblandingens kogepunkt. Triazinen isoleres fra reaktionsblandingen 30 i form af natriumsaltet og fås derefter ved syrning af en vandig opløsning, smeltepunkt 189-190°C.The 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the process described above can be prepared as follows: 120 g of 4-ethylthiosemicarbazide are reacted in the presence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 g of oxalic acid dimethyl ester at the boiling point of the reaction mixture. The triazine is isolated from the reaction mixture 30 in the form of the sodium salt and then obtained by acidification of an aqueous solution, mp 189-190 ° C.
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EKSEMPEL 2 10 5.1 g 7-amino-3-azido-3-desacetoxy-cephalosporansyre omrøres med 5,16 g 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazin og 4.2 g natnumhydrogencarbonat i 200 ml af en puffer med pH-værdi 5 7,0 i 6 timer ved 60°C under nitrogenatmosfære. Reaktionsopløsningen afkøles til 25°C og indstilles derefter på pH-værdi 3,5 ved tilsætning af 2N saltsyreopløsning. Den ønskede 7-amino-3-desacetoxy-3-[ (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio]cephalospo-ransyre udkrystalliseres og isoleres ved sugefiltrering (2,2 g). Ved 10 inddampning af moderluden fås yderligere 1,7 g. Totaludbytte 3,9 g (50%).EXAMPLE 2 5.1 g of 7-amino-3-azido-3-desacetoxy-cephalosporanoic acid is stirred with 5.16 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-ash. triazine and 4.2 g of sodium bicarbonate in 200 ml of a pH 5 buffer 7.0 for 6 hours at 60 ° C under a nitrogen atmosphere. The reaction solution is cooled to 25 ° C and then adjusted to pH 3.5 by the addition of 2N hydrochloric acid solution. The desired 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid is crystallized and isolated by suction filtration (2.2 g). Evaporation of the mother liquor yields an additional 1.7 g. Total yield 3.9 g (50%).
EKSEMPEL 3 I analogi med eksempel 1 eller 2 kan der fås: 7-Amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-15 triazin-3-yl)thio]cephalosporansyre i form af et beigefarvet pulver, smeltepunkt 240-245°C (sønderdeling).EXAMPLE 3 In analogy to Examples 1 or 2, there is obtained: 7-Amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine) 3-yl) thio] cephalosporanoic acid in the form of a beige powder, m.p. 240-245 ° C (dec.).
Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-dro-4-methyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles analogt med eksempel 1 ud fra 176 g 4-methylthiosemicarbazid og 198 g oxal-20 syredimethylester, smeltepunkt 218-220°C (sønderdeling).The 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 176 g of 4-methylthiosemicarbazide and 198 g of oxalic acid dimethyl ester, m.p. 218-220 ° C (dec.).
EKSEMPEL 4 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Ami no-3- [ (1,2,5,6-tetrahyd ro-2-methy I -5,6-dioxo-as-triazin-3-yl) -thio]-3-cephem-4-carboxy!syre i form af et beigefarvet pulver, smel-25 tepunkt 245-250°C (sønderdeling).EXAMPLE 4 In analogy to Examples 1 or 2, 7-Amino-3- [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazine-3) may also be obtained. -yl) -thio] -3-cephem-4-carboxylic acid in the form of a beige powder, m.p. 245-250 ° C (dec.).
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Det ved den ovennævnte fremgangsmåde anvendte 1,2,5,6-tetrahy-dro-5,6-dioxo-3-mercapto-2-methyl-as-triazin kan fremstilles analogt med eksempel 1 ud fra 31,5 g 2-methylthiosemicarbazid og 35,4 g oxalsyredimethylester, smeltepunkt 260°C.The 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine used in the above process can be prepared analogously to Example 1 from 31.5 g of 2-methylthiosemicarbazide and 35.4 g of oxalic acid dimethyl ester, m.p. 260 ° C.
5 EKSEMPEL 5 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(1 ,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl}-3-cephem-4-carboxylsyre.EXAMPLE 5 By analogy with Examples 1 or 2, 7-Amino-3 - {[(1, 4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazine-3) can also be obtained. yl) thio] methyl} -3-cephem-4-carboxylic acid.
Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-10 dro-4-allyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles analogt med eksempel 1 ud fra 26,2 g 4-allylthiosemicarbazid og 23,6 g oxalsyredimethylester, smeltepunkt 138-140°C.The 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 26.2 g of 4- allylthiosemicarbazide and 23.6 g of oxalic acid dimethyl ester, mp 138-140 ° C.
EKSEMPEL 6 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 15 7-Amino-3-{ [(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)- thio]methyl}-3-cephem-4-carboxylsyre.EXAMPLE 6 By analogy to Examples 1 or 2, 7-Amino-3- {[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazine-3) can also be obtained. yl) - thio] methyl} -3-cephem-4-carboxylic acid.
Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-dro-4-butyl-5,6-dioxo-as-triazin kan fremstilles analogt med eksempel 1 ud fra 14,7 g 4-butylthiosemicarbazid og 11,8 g oxalsyredimethyl-20 ester, smeltepunkt 180-181°C.The 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazine used in the above process can be prepared analogously to Example 1 from 14.7 g of 4-butylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester, m.p. 180-181 ° C.
EKSEMPEL 7 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 12 DK 1553298 7-Amino-3-{[n,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-tri- azin-3-yl)thio]methyI}-3-cephem-4-carboxylsyre.EXAMPLE 7 By analogy to Examples 1 or 2, 7-Amino-3 - {[n, 4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-asa] can also be obtained. (triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid.
5 Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-dro-4-(2-methoxyethyl)-5,6-dioxo-3-mercapto-as-triazin kan fremstilles analogt med eksempel 1 ud fra 14,9 g 4-(2-methoxyethyl)thiosemi-carbazid og 11,8 g oxalsyredimethylester, smeltepunkt 158-160°C.The 1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 14, 9 g of 4- (2-methoxyethyl) thiosemic carbazide and 11.8 g of oxalic acid dimethyl ester, mp 158-160 ° C.
EKSEMPEL 8 10 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(1,4,5,6-tetrahydro-1,4-dimethyI-5,6-dioxo-as-triazin- 3-yl)thio]methyl}-3-cephem-4-ca rboxylsyre.EXAMPLE 8 10 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazine) is also obtained. 3-yl) thio] methyl} -3-cephem-4-carboxylic acid.
Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-dro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles ana-15 logt med eksempel 1 ud fra 11,9 g 1,4-dimethylthio-semicarbazid og 11,8 g oxalsyredimethylester, smeltepunkt 231-233°C (sønderdeling).The 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 11, 9 g of 1,4-dimethylthio-semicarbazide and 11.8 g of oxalic acid dimethyl ester, mp 231-233 ° C (dec.).
EKSEMPEL 9 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-20 3-yl)thio]methyI}-3-cephem-4-carboxylsyre.EXAMPLE 9 By analogy with Examples 1 or 2, 7-Amino-3 - {[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazine-20) can also be obtained. 3-yl) thio] methyl} -3-cephem-4-carboxylic acid.
Det ved den ovennævnte fremgangsmåde anvendte 1,4,5,6-tetrahy-dro-l,4-diethyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles analogt med eksempel 1 ud fra 14,7 g 1,4-diethylcarbazid og 11,8 g oxalsyredimethylester, smeltepunkt 177-179°C.The 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto-as-triazine used in the above process can be prepared analogously to Example 1 from 14.7 g of 1 , 4-diethylcarbazide and 11.8 g of oxalic acid dimethyl ester, mp 177-179 ° C.
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EKSEMPEL 10 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 13 7-Amino-3-{[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio] methyl }-3-cephem-4-carboxylsyre.EXAMPLE 10 By analogy to Examples 1 or 2, 13 7-Amino-3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazine-3 yl) -thio] methyl} -3-cephem-4-carboxylic acid.
5 Den ved den ovenfor beskrevne fremgangsmåde anvendte 1,2,5,6-te-trahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazin kan fremstilles på følgende måde: 46,5 g 1-ethylthiosemicarbazid omsættes i 700 ml acetone ved 40°C med 48 g oxalsyremonomethylesterchlorid. Til 34,3 g af det vundne pro-10 dukt sættes 9,2 g natriummethylat i 300 ml methanol. Triazinen isoleres fra reaktionsblandingen i form af natriumsaltet og fås derefter ved syrning i en vandig opløsning, smeltepunkt 213-214°C (sønderdeling).The 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the process described above can be prepared as follows: 46.5 g of 1-ethylthiosemicarbazide react in 700 ml of acetone at 40 ° C with 48 g of oxalic acid monomethyl ester chloride. To 34.3 g of the product obtained is added 9.2 g of sodium methylate in 300 ml of methanol. The triazine is isolated from the reaction mixture in the form of the sodium salt and then obtained by acidification in an aqueous solution, mp 213-214 ° C (dec.).
EKSEMPEL 11 15 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl}- 3-cephem-4-carboxylsyre.EXAMPLE 11 In analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem can also be obtained. -4-carboxylic acid.
EKSEMPEL 12 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 20 7-Ami no-3-{ [(1~butoxy-1,2-dihyd ro-2-oxo-4-pyrimidinyl)thio] meth yl }-3-cephem-4-ca rboxylsyre.EXAMPLE 12 By analogy to Examples 1 or 2, 7-Amino-3- {[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} 3-cephem-4-ca rboxylic acid.
Det i den ovennævnte fremgangsmåde anvendte 1-butoxy-1,2-dihy-dro-4-mercapto-2-oxo-pyrimidin kan fremstilles ud fra 2 g 1-butoxy-uracil og 4 g phosphorpentasulfid, smeltepunkt 99-100°C.The 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 2 g of 1-butoxy-uracil and 4 g of phosphorus pentasulfide, mp 99-100 ° C.
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EKSEMPEL 13 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 14 7-Amino-3-{ [ (1 -butoxy-1,2-dihydro-5-methyf-2-oxo-4-pyrimidinyl) -thiolmethyl}-3-cephem-4-carboxylsyre.EXAMPLE 13 By analogy to Examples 1 or 2, there are also available: 14 7-Amino-3- {[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thiolmethyl} - 3-cephem-4-carboxylic acid.
5 Det i den ovennævnte fremgangsmåde anvendte 1-butoxy-1,2-dihy-dro-4-mercapto-5-methyl-2-oxo-pyrimidin kan fremstilles analogt med eksempel 12 ved omsætning af 25 g 1-butoxy-5-methyl-uracil og 50 g phosphorpentasulfid. 7-Butoxy-5-methyl-uracil kan fremstilles ved omsætning af 110 g butoxyurinstof med 184 g β,β-diethoxy-a-methyl-10 propionsyreester.The 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine used in the above process can be prepared analogously to Example 12 by reacting 25 g of 1-butoxy-5-methyl -uracil and 50 g of phosphorus pentasulfide. 7-Butoxy-5-methyl-uracil can be prepared by reacting 110 g of butoxyurea with 184 g of β, β-diethoxy-α-methyl-propionic acid ester.
EKSEMPEL 14 I analogi med eksempel 1 eller 2 kan der ligeledes fremstilles: 7-Amino-3-{[(1,4-dimethyl-l, 6-dihydro-6-oxo-2-pyrimidinyl)thio] methyl }-3-cephem-4-carboxyIsyre.EXAMPLE 14 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) thio] methyl} -3- cephem-4-carboxylic acid.
15 EKSEMPEL 15 I analogi med eksempel 1 eller 2 kan der ligeledes fremstilles: 7-Amino-3-{[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)thio]-methy I} -3 -cep h em -4- ca r boxy I sy re.EXAMPLE 15 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) thio] methyl can also be prepared. I} -3 -cep h em -4- ca r boxy In his re.
Det i den ovennævnte fremgangsmåde anvendte 1-ethyl-l,4-dihydro-20 2-mercapto-6-methyl-4-oxopyrimidin kan fremstilles på følgende måde: 18 g N-ethylthiourinstof opløses i 50 ml eddikesyre, koges under til-bagesvaling og tilsættes dråbevis 17,2 g diketen. Derefter koges der under tilbagesvaling i 20 minutter, hvorefter der inddampes til 50 ml.The 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine used in the above process can be prepared as follows: 18 g of N-ethylthiourea is dissolved in 50 ml of acetic acid, boiled under reflux and 17.2 g of the diket is added dropwise. Then, reflux for 20 minutes, then evaporate to 50 ml.
Under afkøling og omrøring tilsættes 50 ml vand. De gullige krystallerWhile cooling and stirring, add 50 ml of water. The yellow crystals
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15 udfældes. De isoleres ved s ugef titrering og omkrystalliseres af tetra-hydrofuran, smeltepunkt 190°C.15 precipitates. They are isolated by weekly titration and recrystallized from tetrahydrofuran, mp 190 ° C.
EKSEMPEL 16 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 5 7-Amino-3-{[0-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl}- 3- cephem-4-carboxylsyre.EXAMPLE 16 By analogy to Examples 1 or 2, there is also obtained: 5 7-Amino-3 - {[O-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -3-cephem 4-carboxylic acid.
EKSEMPEL 17 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyi}-10 3-cephem-4-carboxylsyre.EXAMPLE 17 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -10 3-cephem can also be obtained. -4-carboxylic acid.
Den i den ovennævnte fremgangsmåde anvendte 1-amino-1,2-dihydro- 4- mercapto-2-oxo-pyrimidin kan fremstilles ud fra 8,6 g 1-benzy3iden-amino-uracil [smeltepunkt 220-223°C; Lit.: Monatshefte fur Chemie 96, 1735 (1965)] og 12 g phosphorpentasulfid i pyridin efterfulgt af hy- 15 drolyse med saltsyre.The 1-amino-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 8.6 g of 1-benzylidene-amino-uracil [mp 220-223 ° C; Lit .: Monatshefte fur Chemie 96, 1735 (1965)] and 12 g of phosphorus pentasulfide in pyridine followed by hydrolysis with hydrochloric acid.
EKSEMPEL 18 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{ [(1,2-dihydro-l-methyl-2-oxo-4-pyrimidmyl)thio]meth-yl)-3-cephem-4-carboxylsyre.EXAMPLE 18 By analogy to Examples 1 or 2, 7-Amino-3- {[(1,2-dihydro-1-methyl-2-oxo-4-pyrimidmyl) thio] methyl) -3- cephem-4-carboxylic acid.
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EKSEMPEL 19 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 16 7-Amino-3-{[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl)thio]meth- yl}-3-cephem-4-carboxylsyre.EXAMPLE 19 In analogy to Examples 1 or 2, there is also obtained: 16 7-Amino-3 - {[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl) thio] methyl} -3 -cephem-4-carboxylic acid.
5 Den i den ovennævnte fremgangsmåde anvendte 1,2-dihydro-4-mercap-tomethoxy-2-oxo-pyrimidin kan fremstilles ud fra 6 g 1-methoxyuracil og 18 g phosphorpentasulfid, smeltepunkt 177°C.The 1,2-dihydro-4-mercaptomethoxy-2-oxo-pyrimidine used in the above process can be prepared from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulfide, mp 177 ° C.
EKSEMPEL 20 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 10 7-Amino-3-{ [(1-ethoxy-2,2-di hydro-2-oxo-4-py rimidiny I )thio] meth yl }-3-cephem-4-carboxylsyre.EXAMPLE 20 In analogy to Examples 1 or 2, 7-Amino-3- {[(1-ethoxy-2,2-di hydro-2-oxo-4-pyrimidinyl) thio] methyl} can also be obtained. -3-cephem-4-carboxylic acid.
Den i den ovennævnte fremgangsmåde anvendte 1-ethoxy-2,2-dihy-dro-4-mercapto-2-oxo-pyrimidin kan fremstilles ud fra 6,4 g 1-eth-oxyuracil og 18 g phosphorpentasulfid, smeltepunkt 119-120°C.The 1-ethoxy-2,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared from 6.4 g of 1-ethoxy-oxyuracil and 18 g of phosphorus pentasulfide, m.p. 119-120 °. C.
15 EKSEMPEL 21 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{[(l,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)thio]meth- yl}-3-cephem-4-carboxylsyre.EXAMPLE 21 By analogy to Examples 1 or 2, 7-Amino-3 - {[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl) thio] methyl} -3 can also be obtained. -cephem-4-carboxylic acid.
Den i den ovennævnte fremgangsmåde anvendte 1,6-dihydro-3-mercap-20 to-1-methyl-6-oxo-pyridazin kan fremstilles ud fra 2,88 g 3-chlor- 1,6-dihydro-1-methyl-6-oxo-pyridazin [smeltepunkt 91-92°C, Lit.: Monatshefte fiir Chemie 99, 33 (1968)] og 5,88 g natriumhydrogen-sulfid i ethanol ved 130°C og 5-7 atm, smeltepunkt 115°C.The 1,6-dihydro-3-mercap-20 to-1-methyl-6-oxo-pyridazine used in the above process can be prepared from 2.88 g of 3-chloro-1,6-dihydro-1-methyl 6-oxo-pyridazine [m.p. 91-92 ° C, Lit .: Monatshefir Chemie 99, 33 (1968)] and 5.88 g of sodium hydrogen sulfide in ethanol at 130 ° C and 5-7 atm, m.p. 115 ° C .
I analogi med eksempel 1 eller 2 kan der ligeledes fås: EKSEMPEL 22By analogy to Examples 1 or 2, one can also obtain: EXAMPLE 22
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17 7-Amino-3-{[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl)- thiomethyl}]-3-cephem-4-carboxy!syre.17 7-Amino-3 - {[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl) -thiomethyl}] - 3-cephem-4-carboxy !acid.
5 Det i den ovennævnte fremgangsmåde anvendte 1,2,3,6-tetrahydro- 2,6-dioxo-4-mercapto-1-methyl-s-triazin kan fremstilles på følgende måde:The 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine used in the above process can be prepared as follows:
Til en opløsning af 14,8 g natrium i 1000 ml methanol sættes 39,9 g 5-methyl-2-thio-biuret og 72 g diethylcarbonat, og der koges i 24 10 timer under tilbagesvaling. Reaktionsopløsningen inddampes i vakuum til et volumen på 200 ml. Det derved udkrystalliserede stof isoleres ved sugefiltrering, opløses derefter i 200 ml vand og syrnes med 2N saltsyre. Den udfældede forbindelse isoleres ved sugefiltrering og omkrystalliseres af 350 ml ethanol. Udbytte 11,2 g (23%) farveløst 15 stof, smeltepunkt 275°C.To a solution of 14.8 g of sodium in 1000 ml of methanol is added 39.9 g of 5-methyl-2-thio-biuret and 72 g of diethyl carbonate and reflux for 24 hours. The reaction solution is evaporated in vacuo to a volume of 200 ml. The crystallized substance thus obtained is isolated by suction filtration, then dissolved in 200 ml of water and acidified with 2N hydrochloric acid. The precipitated compound is isolated by suction filtration and recrystallized from 350 ml of ethanol. Yield 11.2 g (23%) of colorless substance, m.p. 275 ° C.
Den i den ovennævnte fremgangsmåde anvendte 5-methy!-2-thio-biuret kan fremstilles på følgende måde:The 5-methyl-2-thio-biuret used in the above process can be prepared as follows:
Til en opløsning af 76 g thiourinstof i 1000 ml dimethylformamid sættes 65,4 ml methylisocyanat, hvorefter der omrøres i 72 timer ved 50-20 55°C. Reaktionsopløsningen inddampes i vakuum, og remanensen omkrystalliseres af vand. Udbytte 79,4 g (60%) farveløst stof, smeltepunkt 209-210°C.To a solution of 76 g of thiourea in 1000 ml of dimethylformamide is added 65.4 ml of methyl isocyanate and then stirred for 72 hours at 50-20 55 ° C. The reaction solution is evaporated in vacuo and the residue is recrystallized from water. Yield 79.4 g (60%) of colorless substance, mp 209-210 ° C.
EKSEMPEL 23 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 25 7-Amino-3-{[(1-ethyl-5-chlor-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]-methyl)-3-cephem-4-carboxylsyre.EXAMPLE 23 In analogy to Examples 1 or 2, 7-Amino-3 - {[(1-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl can also be obtained. ) -3-cephem-4-carboxylic acid.
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Den i den ovennævnte fremgangsmåde anvendte 1-ethyl-5-chIor-1,2-dihydro-4-mercapto-2-oxo-pyrimidin kan fremstilles på følgende måde: 1,74 g l-ethyl-5-chlor-uraciI blandes først med 4,44 g phosphorpenta-sulfid og 0,1 ml vand, tilsættes derefter 30 ml pyridin og koges i 5 3,75 time under tilbagesvaling. Reaktionsblandingen indddampes i vakuum ved 40°C, og remanensen suspenderes i 30 ml vand og tilsættes 30 ml 2N saltsyre. Det krystallinske stof isoleres ved sugefiltrering, vaskes med vand og omkrystalliseres af ethanol. Udbytte 1,3 g (68%) gult stof, smeltepunkt 217-220°C.The 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used in the above process can be prepared as follows: 1.74 g of 1-ethyl-5-chloro-uracil is first mixed with 4.44 g of phosphorus pentasulfide and 0.1 ml of water, then 30 ml of pyridine is added and refluxed for 5.75 hours. The reaction mixture is evaporated in vacuo at 40 ° C and the residue is suspended in 30 ml of water and 30 ml of 2N hydrochloric acid is added. The crystalline substance is isolated by suction filtration, washed with water and recrystallized from ethanol. Yield 1.3 g (68%) of yellow substance, mp 217-220 ° C.
10 Det i den ovennævnte fremgangsmåde anvendte 1 -ethyl-5-chlor-uracil kan fremstilles på følgende måde:The 1-ethyl-5-chloro-uracil used in the above process can be prepared as follows:
Ind i en opløsning af 9,9 g 1-ethyl-uracil i 150 ml iseddike ledes chlor i så lang tid (ca. 1/2 time), at iodkalium-stivelsespapir reagerer positivt, og der ikke mere ved tyndtlagschromatografi kan påvises 15 1-ethyl-uracil. Reaktionsblandingen inddampes i vakuum ved 40°C, og den krystallinske remanens omkrystalliseres af 300 ml ethanol. Udbytte 10,0 g (81%) farveløse, fine nåle, smeltepunkt 244-247°C.Into a solution of 9.9 g of 1-ethyl-uracil in 150 ml of glacial acetic acid, chlorine is passed for so long (about 1/2 hour) that iodine potassium starch paper reacts positively and no longer can be detected by thin layer chromatography. ethyl-uracil. The reaction mixture is evaporated in vacuo at 40 ° C and the crystalline residue is recrystallized from ethanol (300 ml). Yield 10.0 g (81%) of colorless fine needles, mp 244-247 ° C.
Det i den ovennævnte fremgangsmåde anvendte 1-ethyl-uracil kan fremstilles på følgende måde: 1 2 3 4 5 6 7 8 9 10 11The 1-ethyl-uracil used in the above process can be prepared as follows: 1 2 3 4 5 6 7 8 9 10 11
Til en opløsning af 15,0 g natrium i 700 ml ethanol sættes 44 g N- 2 ethylurinstof og 105 g β,β-diethoxypropionsyre-ethylester. Derefter 3 holdes den gule reaktionsopløsning i 3 timer ved 25°C og koges der 4 efter i 15 timer under tilbagesvaling. Reaktionsopløsningen inddampes 5 i vakuum, den ovenstående remanens opløses i 300 ml vand, afkøles 6 til 0°C og syrnes med 100 ml koncentreret saltsyre, hvorved et kry 7 stallinsk mellemprodukt udfældes (43 g). Det sidstnævnte isoleres ved 8 sugefiltrering, vaskes med 100 ml isvand og opvarmes derefter til 9 80-100°C i 250 ml vand, indtil omdannelsen til det ønskede vandoplø 10 selige 1-ethyl-uracil er bragt til ende. Opløsningen inddampes i 11 vakuum ved 40°C, og den tilbageblivende remanens omkrystalliseres af ethanol-ether. Udbytte 14,0 g (20%) farveløst stof, smeltepunkt 150°C.To a solution of 15.0 g of sodium in 700 ml of ethanol is added 44 g of N-2 ethyl urea and 105 g of β, β-diethoxypropionic acid ethyl ester. Then, the yellow reaction solution is kept for 3 hours at 25 ° C and 4 is refluxed for 15 hours. The reaction solution is evaporated in vacuo, the above residue is dissolved in 300 ml of water, cooled 6 to 0 ° C and acidified with 100 ml of concentrated hydrochloric acid to precipitate a crude 7 stallin intermediate (43 g). The latter is isolated by 8 suction filtration, washed with 100 ml of ice water and then heated to 9 80-100 ° C in 250 ml of water until the conversion to the desired water-soluble 10-ethyl-uracil is completed. The solution is evaporated in 11 vacuum at 40 ° C and the residue is recrystallized from ethanol-ether. Yield 14.0 g (20%) of colorless substance, mp 150 ° C.
I analogi med eksempel 1 eller 2 kan der ligeledes fås: EKSEMPEL 24 19By analogy to Examples 1 or 2, one can also obtain: EXAMPLE 24 19
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7-Amino-3-{[(l-(dimethylamino)-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methy!}-3-cephem-4-ca rboxylsyre.7-Amino-3 - {[(1- (dimethylamino) -1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl} -3-cephem-4-carboxylic acid.
5 EKSEMPEL 25 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{ [(3-chlor-1,6-dihyd ro-1-methyl-6-oxo-4-pyridaziny I )thio]-methyl}-3-cephem-4-ca rboxylsyre.EXAMPLE 25 In analogy to Examples 1 or 2, 7-Amino-3- {[(3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl) thio] can also be obtained. -methyl} -3-cephem-4-carboxylic acid.
Det i den ovennævnte fremgangsmåde anvendte 3-chlor-1,6-dihydro-10 4-mercapto-1-methyl-6-oxo-pyridazin kan fremstilles på følgende måde:The 3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine used in the above process can be prepared as follows:
Til en opløsning af 17,9 g 3,4-dichlor-1,6-dihydro-1-methyI-6-oxo-pyridazin i 200 ml methanol sættes en opløsning af 14,8 g natriumhy-drogensulfid-monohydrat i 200 ml methanol. Reaktionsblandingen omrøres derefter i 1 1/2 time ved 25°C under nitrogenatmosfære.To a solution of 17.9 g of 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine in 200 ml of methanol is added a solution of 14.8 g of sodium hydrogen sulfide monohydrate in 200 ml of methanol. . The reaction mixture is then stirred for 1 1/2 hours at 25 ° C under nitrogen atmosphere.
15 Derpå frafiltreres noget uopløst stof, og filtratet inddampes i vakuum. Remanensen suspenderes i 150 ml vand, indstilles på sur reaktion med 1N saltsyre og ekstraheres tre gange med ethylacetat. De samlede ethylacetatekstrakter vaskes med vand, tørres over natriumsulfat og inddampes i vakuum. Den således vundne remanens omkrystalliseres af 20 ethanol. Udbytte 9 g gullige nåle, smeltepunkt 163°C.Then, some undissolved substance is filtered off and the filtrate is evaporated in vacuo. The residue is suspended in 150 ml of water, adjusted to acidic reaction with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue thus obtained is recrystallized from ethanol. Yield 9 g of yellow needles, mp 163 ° C.
Den i den ovennævnte fremgangsmåde anvendte 3,4-dichlor-1,6-dihy-dro-1-methyl-6-oxo-pyridazin kan fremstilles på følgende måde: 67,75 g 3,4-dichlor-6-hydroxy-pyridazin opløses i 205 ml 2N natrium-hydroxidopløsning, og der tildryppes 36 ml dimethylsulfat. Derefter 25 opvarmes reaktionsblandingen til 70°C i 1/2 time, hvorefter den afkøles og ekstraheres to gange med chloroform. De samlede chloro-formekstrakter vaskes med vand, tørres over natriumsulfat og ind-The 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine used in the above process can be prepared as follows: 67.75 g of 3,4-dichloro-6-hydroxy-pyridazine dissolve in 205 ml of 2N sodium hydroxide solution and add 36 ml of dimethyl sulfate. Then, the reaction mixture is heated to 70 ° C for 1/2 hour, then cooled and extracted twice with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and concentrated by evaporation.
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20 dampes i vakuum. Remanensen om krystal lise res af højtkogende petro-leumsether. Udbytte 54 g (73%), smeltepunkt 97°C.20 is evaporated in vacuo. The crystal lysis residue is made from high boiling petro-leum ether. Yield 54 g (73%), mp 97 ° C.
EKSEMPEL 26 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 5 7-Amino-3-{[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl)thio]meth-yl}-3-cephem-4-carboxylsyre.EXAMPLE 26 By analogy to Examples 1 or 2, there is also obtained: 5 7-Amino-3 - {[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl) thio] methyl} -3-cephem-4-carboxylic acid.
EKSEMPEL 27 I analogi med eksempel 1 eller 2 kan der ligeledes fås: 7-Amino-3-{ [(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl)thio]methyl}-3-10 cephem-4-carboxylsyre.EXAMPLE 27 By analogy to Examples 1 or 2, 7-Amino-3- {[(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl) thio] methyl} -3-10 cephem can also be obtained. -4-carboxylic acid.
Den i den ovennævnte fremgangsmåde anvendte 1-ethyl-1,2-dihydro- 3-mercapto-2-oxo-pyrazin kan fremstilles på følgende måde:The 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used in the above process can be prepared as follows:
Til .en opløsning af 22,2 g natriumhydrogensulfid-monohydrat i 1000 ml methanol sættes 23,7 g 1 -ethyl-3-chlor-1,2-dihydro-2-oxo-pyrazin, og 15 der omrøres i 3 timer ved 25°C. Derefter frafiltreres udfældet natri-umchlorid, og det gule filtrat inddampes i vakuum ved 40°C. Ind-dampningsremanensen omkrystalliseres af ethanol. Udbytte 8,0 g (34%) gult råstof. Til rensning suspenderes 5,0 g i 50 ml 0,5N saltsyre, hvorefter der syrnes kraftigt ved tilsætning af 10 ml 2N saltsyre, 20 blandingen omrøres i 10 minutter ved 25°C og opbevares derefter natten over i køleskab. De derved dannede orange-gule krystaller (3,65 g) isoleres ved sugefiltrering, vaskes med lidt isvand og tørres i vakuum ved 50°C. Smeltepunkt 204-206°C (sønderdeling).To a solution of 22.2 g of sodium hydrogen sulfide monohydrate in 1000 ml of methanol is added 23.7 g of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine and stirred for 3 hours at 25 ° C. The precipitated sodium chloride is then filtered off and the yellow filtrate is evaporated in vacuo at 40 ° C. The evaporation residue is recrystallized from ethanol. Yield 8.0 g (34%) of yellow crude. For purification, 5.0 g in 50 ml of 0.5N hydrochloric acid is suspended, then vigorously acidified by the addition of 10 ml of 2N hydrochloric acid, the mixture is stirred for 10 minutes at 25 ° C and then stored overnight in a refrigerator. The orange-yellow crystals thus formed (3.65 g) are isolated by suction filtration, washed with a little ice water and dried in vacuo at 50 ° C. Melting point 204-206 ° C (dec.).
EKSEMPEL 28EXAMPLE 28
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2121
Fremstilling af natriumsaltet af (7R)-3-{[(1,4,5,6-tetrahydro-4-ethyl- 5,6-dioxo-as-triazin-3-yl)thio]methyl}-7-[2-(1-H-tetrazol-1-yl)acet- amido]-3-cephem-4-carboxylsyre.Preparation of the sodium salt of (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -7- [2 - (1-H-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid.
5 1,28 g tetrazol-1-eddikesyre opløses i en blanding af 50 ml tetraby- drofuran og 5 ml dimethylformamid. Til denne opløsning sættes ved -20°C 1,18 ml N-methylmorpholin og 1,4 ml chlormyresyre-isobutyl-ester i den anførte rækkefølge, hvorefter der omrøres i 20 minutter ved en temperatur mellem -10 og -20°C. Derefter tilsættes en iskold 10 opløsning af det ud fra 3,85 g 7-amino-3-desacetoxy-3-[(1,4,5(,6-te-trahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)thio]cephalosporansyre og 1,4 ml triethylamin vundne salt i 50 ml vand. Reaktionsblandingen omrøres derpå i 30 minutter ved 0°C og i 1 time ved 20°C. Reaktionsblandingen inddampes i vakuum, og den vandige fase syrnes 15 med 5 ml 2N saltsyreopløsning, hvorved det ønskede stof udfældes i form af den rå syre. Denne syre isoleres ved sugefiltrering, vaskes med meget ethylacetat og opløses i dimethylformamid. Til denne opløsning sættes en 2N opløsning af natriumsaltet af 2-ethylcapronsyre i ethylacetat, og der fortyndes derefter med ethanol og ether, hvorved 20 det ønskede, rå natriumsalt (3,3 g) udfældes. Til rensning opløses det således vundne stof i 20 ml vand og tilsættes 60 ml ethanol, hvorved der udfældes en mørk harpiks, som kasseres. Filtratet inddampes i vakuum, og remanensen behandles med ethanol og ether, hvorved der fås 2,3 g (44,5%) rent stof i form af et lyst beigefarvet ? n 25 pulver med smeltepunkt 210°C (sønderdeling) og [a]^ = +23° (c = 0,824 i vand).Dissolve 1.28 g of tetrazole-1-acetic acid in a mixture of 50 ml of tetrahydrofuran and 5 ml of dimethylformamide. To this solution is added at -20 ° C 1.18 ml of N-methylmorpholine and 1.4 ml of chloroformic acid isobutyl ester in the order given, then stirred for 20 minutes at a temperature between -10 and -20 ° C. Then an ice-cold solution of it is added from 3.85 g of 7-amino-3-desacetoxy-3 - [(1,4,5 (, 6-tetrahydro-4-ethyl-5,6-dioxo-ash) -Triazin-3-yl) thio] cephalosporanoic acid and 1.4 ml of triethylamine obtained salt in 50 ml of water, then the reaction mixture is stirred for 30 minutes at 0 ° C and for 1 hour at 20 ° C. The reaction mixture is evaporated in vacuo The acid is isolated by suction filtration, washed with a lot of ethyl acetate and dissolved in dimethylformamide. ethyl acetate and then diluted with ethanol and ether to precipitate the desired crude sodium salt (3.3 g). To purify, the thus obtained substance is dissolved in 20 ml of water and 60 ml of ethanol are added to give a dark resin, The filtrate is evaporated in vacuo and the residue is treated with ethanol and ether to give 2.3 g (44.5%) of pure fabric in the form of a light beige color? n 25 powder with melting point 210 ° C (dec.) and [a] + = + 23 ° (c = 0.824 in water).
EKSEMPEL 29EXAMPLE 29
DK 155329 BDK 155329 B
2222
Fremstilling af natriumsaltet af (7R)-3-{[(1,4,5,6-tetrahydro-4-ethyl- 5,6-dioxo-as-triazin-3-yl)thio]methyl}-7-[(R)-2-hydroxyhexanamido]- 3-cephem-4-carboxylsyre.Preparation of the sodium salt of (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -7 - [( R) -2-hydroxyhexanamido] -3-cephem-4-carboxylic acid.
5 4,4 g 7-amino-3-desacetoxy-3-[(l,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- as-triazin-3-yl)thio]cephalosporansyre opløses ved 0°C under omrøring i en blanding af 44 ml vand og 44 ml acetone ved tilsætning af 2,5 g kaliumhydrogencarbonat. Derefter tildryppes ved 0°C under omrøring en opløsning af 3 g (R)-2-dichloracetoxy-n-capronsyrechlorid (koge- 10 punkt« c__u„ = 75-76°C) i 30 ml acetone, og der omrøres i 2 timer ved 0°C og i 1 time ved 20°C. Af den filtrerede opløsning afdestille-res acetonet under reduceret tryk ved 30°C. Den vandige opløsning tilsættes kaliumcarbonat og omrøres i 45 minutter ved en pH-værdi på 9,5, hvorefter den ekstraheres to gange med ethylacetat og indstilles 15 ved 0°C på en pH-værdi på 1,5-2,0 ved tilsætning af 3N svovlsyreopløsning. Der ekstraheres med ethylacetat under tilsætning af di-methylformamid. Ethylacetatopløsningen vaskes flere gange med 10%'s natriumchloridopløsning, tørres med magnesiumsulfat og inddampes under reduceret tryk ved 25°C. Remanensen opløses i 100 ml isoprop-20 anol og tilsættes 12 ml af en 2N opløsning af natriumsaltet af 2-ethyl-capronsyre i isopropanol. Det rå natriumsalt frasuges, udfældes af vand-isopropanol og tørres under reduceret tryk. Der fås et beige-farvet pulver med smeltepunkt fra 183°C (sønderdeling); [a]^ = +8,2° (c = 1,00 i vand). Udbytte 56%.4.4 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxoaz-triazin-3-yl) thio] cephalosporanoic acid is dissolved by 0 ° C with stirring in a mixture of 44 ml of water and 44 ml of acetone by the addition of 2.5 g of potassium hydrogen carbonate. Then, at 0 ° C, with stirring, a solution of 3 g of (R) -2-dichloroacetoxy-n-capric acid chloride (boiling point "c at 0 ° C and for 1 hour at 20 ° C. Of the filtered solution, the acetone is distilled off under reduced pressure at 30 ° C. The aqueous solution is added to potassium carbonate and stirred for 45 minutes at a pH of 9.5, then extracted twice with ethyl acetate and adjusted to 15 at 0 ° C at a pH of 1.5-2.0 by the addition of 3N sulfuric acid solution. Extract with ethyl acetate with the addition of dimethylformamide. The ethyl acetate solution is washed several times with 10% sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure at 25 ° C. The residue is dissolved in 100 ml of isoprop-20 anol and 12 ml of a 2N solution of the sodium salt of 2-ethyl-capric acid in isopropanol is added. The crude sodium salt is suctioned off, precipitated by water isopropanol and dried under reduced pressure. A beige colored powder is obtained having a melting point of 183 ° C (decomposition); [α] D = + 8.2 ° (c = 1.00 in water). Yield 56%.
25 EKSEMPEL 30EXAMPLE 30
Fremstilling af natriumsaltet af (7R)-3-{[(1,2,5,6-tetrahydro-2-meth-yl-5,6-dioxo-as-triazin-3-yI)thio] methyl )-7-[2-(lH-tetrazol-l-y |)acet-amido] -3-cephem-4-carboxylsyre.Preparation of the sodium salt of (7R) -3 - {[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2- (1H-tetrazole-ly) acetamido] -3-cephem-4-carboxylic acid.
Denne forbindelse fremstilles analogt med den i eksempel 28 beskrevne 30 fremgangsmåde ud fra 2,95 g tetrazol-1 -eddikesyre og 8,55 g 7-ami-no-3-[(1 ,2,5,6-tetrahydro-2-methy!-5,6-dioxo-as-triazin-3-y|)thio]ce-This compound is prepared analogously to the procedure described in Example 28 from 2.95 g of tetrazole-1-acetic acid and 8.55 g of 7-amino-3 - [(1,2,5,6-tetrahydro-2 methyl-5,6-dioxo-as-triazin-3-y |) thio] CE
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CH853774 | 1974-06-21 | ||
CH853774A CH609989A5 (en) | 1974-06-21 | 1974-06-21 | Process for the preparation of acyl derivatives |
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DK453687A DK155329C (en) | 1974-06-21 | 1987-08-28 | 7-AMINOCEPHALOSPORINES USED AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC EFFECTIVE 7-ACYLAMINO-CEPHALOSPORINES |
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GB1599232A (en) * | 1977-06-03 | 1981-09-30 | Hoffmann La Roche | 7-(2-oximinoacetamido)-cephalosporin derivatives |
JPS5419990A (en) * | 1977-07-14 | 1979-02-15 | Shionogi & Co Ltd | Dihydrotriazinylthioxacephalosporin |
MC1259A1 (en) * | 1978-05-30 | 1980-01-14 | Hoffmann La Roche | ACYL DERIVATIVES |
FR2474030A1 (en) * | 1980-01-17 | 1981-07-24 | Rhone Poulenc Ind | 2-Mercapto-1,2,4-triazine, 1,3,4-triazole or tetrazole derivs. - useful as intermediates for antibacterial cephalosporin(s) |
FR2494278A1 (en) * | 1980-11-20 | 1982-05-21 | Rhone Poulenc Ind | NEW DERIVATIVES OF CEPHALOSPORIN, THEIR PREPARATIONS AND THE MEDICINAL PRODUCTS CONTAINING THEM |
CN1531598A (en) * | 2001-04-19 | 2004-09-22 | ��ŷ�����¶����ǹɷ�����˾ | Enzymatic process for preparing cephalosporanic acid derivatives |
EP2250156B1 (en) * | 2008-03-05 | 2015-05-06 | Merck Patent GmbH | Pyrazinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes |
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