DK147683B - METHOD OF ANALOGY FOR THE PREPARATION OF CEPHALOSPORINE COMPOUNDS OR TOXIC SALTS, BIOLOGICAL ACCEPTABLE ESTERS, 1-OXYDS OR SOLVATES THEREOF - Google Patents
METHOD OF ANALOGY FOR THE PREPARATION OF CEPHALOSPORINE COMPOUNDS OR TOXIC SALTS, BIOLOGICAL ACCEPTABLE ESTERS, 1-OXYDS OR SOLVATES THEREOF Download PDFInfo
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- DK147683B DK147683B DK443274AA DK443274A DK147683B DK 147683 B DK147683 B DK 147683B DK 443274A A DK443274A A DK 443274AA DK 443274 A DK443274 A DK 443274A DK 147683 B DK147683 B DK 147683B
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- 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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Description
147683147683
Den foreliggende opfindelse angår en analogifremgangs- måde til fremstilling af cephalosporinforbindelser, nærmere betegnet visse 7-(2-oxyiminoætere) der har syn-konfiguration eller helt dominerende (mindst 90%) syn-konfiguration og den i krav l's indledning viste almene formel I, hvor R^ og R har de sammesteds angivne betydninger, eller ugiftige salte, biologisk acceptable estere, 1-oxyder eller solvater deraf. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte.The present invention relates to an analogous process for the preparation of cephalosporin compounds, in particular to certain 7- (2-oxyiminoethers) having vision configuration or wholly dominant (at least 90%) vision configuration and the general formula I of claim 1, wherein R 1 and R have the same meanings stated, or non-toxic salts, biologically acceptable esters, 1-oxides or solvates thereof. The process according to the invention is characterized by the characterizing part of claim 1.
Cephalosporinforbindelserne i nærværende beskrivelse er navngivet ud fra stoffet cepham i overensstemmelse med J. Am.Chem. Soc. 1962, 84, 3400, og navnet cephem refererer til den grundlæggende cephamstruktur med én dobbeltbinding.The cephalosporin compounds of this specification are named from the substance cepham in accordance with J. Am.Chem. Soc. 1962, 84, 3400, and the name cephem refers to the basic cepham structure with one double bond.
Der kendes mange cephalosporinforbindelser med en eller anden grad af antibakteriel aktivitet, og disse forbindelser har 3 Δ -umættethed og er som regel substitueret i 3-stillingen med en metylgruppe eller substitueret metylgruppe og i 73-stillingen med en acylamidogruppe. Der er nu almindelig enighed om at de antibiotiske egenskaber hos en given ceph-3-em-4~karboxylsyre overvejende kontrolleres af arten af både 7S-acylamidogruppen deri og substitu-enten i 3-stillingen; der er foretaget omfattende undersøgelser for at finde kombinationer af sådanne grupper der vil give antibiotika med specielle egenskaber.Many cephalosporin compounds with some degree of antibacterial activity are known and these compounds have 3 Δ unsaturation and are usually substituted at the 3 position with a methyl group or substituted methyl group and at the 73 position with an acylamido group. It is now generally agreed that the antibiotic properties of a given ceph-3-em-4-carboxylic acid are predominantly controlled by the nature of both the 7S-acylamido group therein and the substituent at the 3-position; Comprehensive studies have been conducted to find combinations of such groups that will provide antibiotics with special properties.
Cephalosporinantibiotika bruges udstrakt til behandling af sygdomme hos mennesker og dyr bevirket af patogene bakterier, fx til behandling af sygdomme bevirket af bakterier som er resistente mod andre antibiotika såsom penicillinforbindelser, samt til behandling af penicillinfølsomme patienter. Til mange anvendelser er det ønskeligt at bruge et cephalosporinantibiotikum som udviser aktivitet både mod grampositive og gramnegative mikroorganismer, og et væsentligt undersøgelsesarbejde er rettet mod udvikling af forbedrede bredspektrede cephalosporinantibiotika.Cephalosporin antibiotics are extensively used to treat human and animal diseases caused by pathogenic bacteria, for example, to treat diseases caused by bacteria that are resistant to other antibiotics such as penicillin compounds, and to treat penicillin-sensitive patients. For many applications, it is desirable to use a cephalosporin antibiotic that exhibits activity both against Gram-positive and Gram-negative microorganisms, and a major research effort is directed towards the development of improved broad-spectrum cephalosporin antibiotics.
Den praktiske nytte af et betydeligt antal kendte kommercielle og eksperimentelle cephalosporinantibiotika er begrænset af deres forholdsvis høje følsomhed for 3-laktamaser, der dannes af mange bakterier. En ønskelig egenskab hos et bredspektret cephalosporinantibiotikum er derfor at det udviser væsentlig mod- 147683 2 standsdygtighed mod β-laktamaser, herunder sådanne frembragt af gramnegative bakterier.The practical utility of a considerable number of known commercial and experimental cephalosporin antibiotics is limited by their relatively high sensitivity to 3-lactamases formed by many bacteria. Therefore, a desirable property of a broad-spectrum cephalosporin antibiotic is that it exhibits substantial resistance to β-lactamases, including those produced by gram-negative bacteria.
En yderligere vanskelighed hos mange cephalosporinr antibiotika til terapeutisk anvendelse er at de kan undergå nedbrydning in vivo. Således har det vist sig at et betydeligt antal kendte cephalosporinantibiotika har den ulempe at de deaktiveres efter indgiften, ofte hurtigt, af enzymer som fx esteraser der er til stede i legemet.A further difficulty of many cephalosporin antibiotics for therapeutic use is that they can undergo degradation in vivo. Thus, it has been found that a significant number of known cephalosporin antibiotics have the disadvantage of being deactivated upon administration, often rapidly, of enzymes such as esterases present in the body.
Blandt kendte, beslægtede cephalosporinforbindelser skal særlig nævnes tre grupper, kendt fra DK patentansøgningerne nr. 2373/73, 381/72 og 382/72.Among known related cephalosporin compounds, in particular, there are three groups known from DK patent applications Nos. 2373/73, 381/72 and 382/72.
De fra DK ans. 2373/72 kendte forbindelser har den almene formel R.C.CO.NH-- l I ] "-OR* /-Those from DK ans. 2373/72 known compounds have the general formula R.C.CO.NH-- 1 I] "-OR * / -
Lh hvor R betegner fenyl, naftyl, tienyl, furyl, benzotienyl, benzo-furyl, pyridyl eller N-metylpyrrolyl, Ra betegner en C^_4 alkyl-, C2_5 alkenyl-, propinyl-, propargyl-, C3_g cykloalkyl-, fenyl-, fenyl-C1_4-alkyl, trifenylmetyl-, furylmetyl- eller pyridylmetyl-gruppe eller en hvilken som helst af disse grupper substitueret med én substituent i form af hydroxy, metoxy, ætoxy, brom, nitro, amino, karboxy eller benzoyloxy, X betegner metyl, vinyl eller gruppen -CH2Y hvor Y kan have en lang række betydninger, idet forbindelserne foreligger som syn-isomerer.Wherein R represents phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, pyridyl or N-methylpyrrolyl, Ra represents a C 1-4 alkyl, C 2-8 alkenyl, propinyl, propargyl, C 3-6 cycloalkyl, phenyl, phenyl-C 1-4 alkyl, triphenylmethyl, furylmethyl or pyridylmethyl group or any of these groups substituted with one substituent in the form of hydroxy, methoxy, ethoxy, bromo, nitro, amino, carboxy or benzoyloxy, X represents methyl, vinyl or the group -CH 2 Y where Y can have a wide range of meanings, the compounds being syn-isomers.
De fra DK ans. 381/72 kendte forbindelser har den almene formelThose from DK ans. 381/72 known compounds have the general formula
Ry.^.CONH---Ry. ^. CONH ---
N JT „XN JT "X
N. w Å N · 1 R XN. w Å N · 1 R X
^0Rb /0Rb /
COOHCOOH
hvor Ry betegner fenyl, halogensubstitueret fenyl, naftyl, pyridyl, tienyl eller furyl, R et hydrogenatom, en eventuelt halogeneret alkanoylgruppe med indtil 7 kulstofatomer, en alkoxykarbonylgruppe 3 147633 med indtil 7 kulstofatomer, en benzoyl- eller nitrobenzoylgruppe eller en alkylkarbamoyl- eller halogenalkylkarbamoylgruppe med 1-7 kulstofatomer i alkyIdelen og Rx en metyl- eller vinylgruppe eller en gruppe -CH~Y hvor Y kan have en lang række forskelligewherein R 1 represents phenyl, halogen substituted phenyl, naphthyl, pyridyl, thienyl or furyl, R a hydrogen atom, optionally halogenated alkanoyl group of up to 7 carbon atoms, an alkoxycarbonyl group of up to 7 carbon atoms, a benzoyl or nitrobenzoyl group or an alkylcarbamoyl group or an alkylcarbamoyl group 1-7 carbon atoms in the alkyl moiety and Rx a methyl or vinyl group or a group -CH ~ Y where Y can have a wide variety of
^ X^ X
betydninger, men dog ikke således at R kan være en karbamoyloxy-metylgruppe; også disse forbindelser foreligger som syn-isomerer eller overvejende syn-isomerer. De fra DK ans. 382/72 kendte forbindelser er de til forbindelserne med formel IX svarende anti-isomerer.meanings, but not so that R may be a carbamoyloxy methyl group; also these compounds are available as syn isomers or predominantly syn isomers. Those from DK ans. 382/72 are the anti-isomers corresponding to the compounds of formula IX.
Som resultat a£ langvarige undersøgelser over talrige cephalosporinforbindelser er det nu lykkedes at finde frem til en gruppe cephalosporinantibiotika med en særlig kombination af 7β-acylamidogruppe og substituent i 3-stillingen, som giver forbindelsen god bredspektret aktivitet koblet med de ovennævnte ønskværdige egenskaber med hensyn til høj stabilitet over for β-lak-tamase og god stabilitet in vivo. Disse forbindelser er ejendommelige ved at 7P-acylamidogruppen er en 2-aryl-2-(forætret oxyimi-no)-acetamidogruppe som i det væsentlige er i syn-konfiguration (som det defineres senere i nærværende beskrivelse) og at 3-sub-stituenten er en karbamoyloxymetylgruppe. Forbindelserne har som nævnt den i krav l's indledning viste formel I, og betyd-1 2 nmgerne af R og R er defineret sammesteds.As a result of prolonged studies on numerous cephalosporin compounds, we have now succeeded in finding a group of cephalosporin antibiotics with a particular combination of 7β-acylamido group and substituent at the 3-position, which gives the compound good broad-spectrum activity coupled with the above desirable properties with respect to the above. high stability to β-lactamase and good in vivo stability. These compounds are characterized in that the 7β-acylamido group is a 2-aryl-2- (etherified oxyimino) -acetamido group which is substantially in syn configuration (as defined later in this specification) and that the 3-substituent is a carbamoyloxymethyl group. As mentioned, the compounds have the formula I shown in the preamble of claim 1, and the meanings of R and R are defined together.
Forbindelserne skal altså have den isomere syn-form 2 (cis-form) med hensyn til konfigurationen af gruppen OR i forhold til karboxamidogruppen. I nærværende beskrivelse angives syn-konfigurationen strukturelt som følger: R1.C.CONH- ftThus, the compounds must have the isomeric syn form 2 (cis form) with respect to the configuration of the group OR relative to the carboxamido group. In this specification, the vision configuration is structurally specified as follows: R1.C.CONH- ft
NN
"^OR2"^ OR2
Syn-formen tilskrives disse forbindelser på basis af et arbejde af Ahmad og Spenser som er rapporteret i Can. J. Chem. 1961, 39, 1340.The syn form is attributed to these compounds on the basis of a work by Ahmad and Spenser reported in Can. J. Chem. 1961, 39, 1340.
Benævnelsen ugiftig om derivaterne af de omhandlede forbindelser sigter til sådanne derivater som er fysiologisk acceptable ved de doser i hvilke de indgives. Sådanne derivater er altså salte, biologisk acceptable estere, 1-oxyder eller solvater (navnlig hydrater) af de omhandlede forbindelser.The term non-toxic about the derivatives of the compounds of the invention is intended for such derivatives which are physiologically acceptable at the doses in which they are administered. Thus, such derivatives are salts, biologically acceptable esters, 1-oxides or solvates (especially hydrates) of the compounds of the invention.
147683 4147683 4
Den biologiske virkning af en række af de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er på forskellige måder sammenlignet med kendte forbindelser, både sådanne der kendes fra de foran nævnte tre danske patentansøgninger og andre.The biological effect of a number of the compounds prepared by the process according to the invention is in various ways compared to known compounds, both those known from the aforementioned three Danish patent applications and others.
For det første henvises til tabel A, der viser virkningen in vitro af hovedparten af de i omstående eksempler angivne forbindelser mod nogle repræsentative testorganismer, målt ved agar rørfortyndingsteknikken. Tabellen angiver MIC (mindst inhiberende koncentration) i yg/ml, idet testorganismerne anvendtes i en koncentra-tion på 10 pr. ml. Til sammenligning indeholder tabel A resultater af afprøvning af de vigtigste cephalosporinantibiotika til indgift ved injektion (cephalotin, cephaloridin og cefazolin, 87/1, 87/4 og 541/296, et vigtigt eksempel på en kendt forbindelse med en karbamoyloxymetylgruppe i stilling 3(87/359), to sammenligningsforbindelser med formel IX, dvs. kendt fra DK ans. 2373/72 (586/1 og 640/1) af hvilke den sidstnævnte er den nærmeste analog fra nævnte ansøgning til den mest foretrukne blandt de foreliggende forbindelser med formel I, nemlig cefuroxim (640/359) og endelig anti-isomeren (750/359) svarende til cefuroxim.First, reference is made to Table A, showing the in vitro effect of the majority of the compounds listed in the examples below against some representative test organisms measured by the agar tube dilution technique. The table indicates MIC (least inhibitory concentration) in µg / ml, using the test organisms at a concentration of 10 per ml. ml. In comparison, Table A contains results of testing the main cephalosporin antibiotics for injection (cephalotine, cephaloridine and cefazoline, 87/1, 87/4 and 541/296, an important example of a known compound with a carbamoyloxymethyl group at position 3 (87 / 359), two comparative compounds of formula IX, i.e. known from DK No. 2373/72 (586/1 and 640/1) of which the latter is the closest analogue of said application to the most preferred among the present compounds of formula I, namely cefuroxime (640/359) and finally the anti-isomer (750/359) similar to cefuroxime.
Kodebetegnelserne for de afprøvede forbindelser fremgår af følgende oversigt:The code names for the tested compounds are shown in the following table:
Kode Forbindelse Bemærkning 87/1 (6R,7R)-3-acetoxymety1-7-(tien- cephalotin 2-ylacetamido)ceph-3-em-4-karb-oxylsyre 87/4 (6R,7R)-3-pyridiniummety1-7-(tien- cephaloridin 2-ylacetamido)ceph-3-em-4-karboxy-lat 541/296 (6R,7R)-3-(5-metyl-l,3,4-tiadiazol- cefazolin 2-yltiometyl)-7-(tetrazol-l-yl-acetamido)ceph-3-em-4-karboxylsyre 87/359 (6R,7R)-3-karbamoyloxymetyl-7- (tien-2-ylacetamido)ceph-3-em-4-karboxylsyre 147683 5Code Compound Note 87/1 (6R, 7R) -3-acetoxymethyl-7- (thiencephalotin 2-ylacetamido) ceph-3-em-4-carboxylic acid 87/4 (6R, 7R) -3-pyridinium methyl 7- (Thien-cephaloridin 2-ylacetamido) ceph-3-em-4-carboxylate 541/296 (6R, 7R) -3- (5-methyl-1,3,4-thiadiazole-cefazolin 2-ylthiomethyl) -7- (tetrazol-1-yl-acetamido) ceph-3-em-4-carboxylic acid 87/359 (6R, 7R) -3-carbamoyloxymethyl-7- (thien-2-ylacetamido) ceph-3-em-4 -carboxylic acid
Kode Forbindelse_ Bemærkning 640/359 (6R,7R)-3-karbamoyloxymetyl-7- cefuroxim - eks. 1-3 [2-(fur-2-yl)-2-metoxyimino-acet- og 5-10 amido]ceph-3-em-4-karboxylsyre (syn-isomer) 554/359 (6R,7R)-3-karbamoyloxymetyl-7- eks. 15 (2-metoxyimino-2-fenyl-acetamidoi-ceph-3-em-4-karboxylsyre (syn-iso-mer) 576/359 (6R,7R)-3-karbamoyloxymetyl-7-[2- eks. 4 metoxyimino-2-(tien-2-y1)acetamido]-ceph-3-em-4-karboxylsyre (syn-iso-mer) 617/359 (6R,7R)-3-karbamoyloxymetyl-7-(2- eks. 18 ætoxyimino-2-fenyl-acetamido)ceph- 3-em-4-karboxylsyre (syn-isomer) 678/359 (6R,7R)-3-karbamoyloxymetyl-7-(2- eks. 16 fenoxyimino-2-fenyl-acetamido)ceph- 3-em-4-karboxylsyre (syn-isorner) 695/359 (6R,7R)-3-karbamoyloxymetyl-7-[2- eks. 14 (fur-2-yl)-2-fenoxyimino-acetamido]τ ceph-3-em-4-karboxylsyre (syn-iso-mer) 586/359 (6R,7R)-3-karbamoyloxymetyl-7-[2- eks. 19 t-butoxyimino-2-(tien-2-yl)-acetamido] -ceph-3-em-4-karboxylsyre (syn-isomer) ________ 750/359 (6R,7R)-3-karbamoyloxymetyl-7-[2- anti-analogen til cefur’i (fur-2-yl)-2-metoxyiminoacetamido]- oxim (640/359) ceph-3-em-4-karboxylsyre (anti-iso-mer) 640/1 (6R,7R)-3-acetoxymetyl-7-[2-(fur- eks. 35 i 2- yl)-2-metoxyimino-acetamido]ceph- DK ans.2373/72 3- em-4-karboxylsyre (syn-isomer) 586/1 (6R,7R)-3-acetoxymetyl-7-[2-t-bu- eks. 14 i toxyimino-2-(tien-2-yl)'acetamido]- DK ans.2373/72 ceph-3-em-4-karboxylsyre (syn-iso-_mer)______Code Compound_ Note 640/359 (6R, 7R) -3-carbamoyloxymethyl-7-cefuroxime - Exs 1-3 [2- (fur-2-yl) -2-methoxyimino-acetate and 5-10 amido] ceph 3-em-4-carboxylic acid (syn isomer) 554/359 (6R, 7R) -3-carbamoyloxymethyl-7- Example (2-methoxyimino-2-phenyl-acetamido-ceph-3-em-4-carboxylic acid (syn-isomer) 576/359 (6R, 7R) -3-carbamoyloxymethyl-7- [2- Example 4 methoxyimino-2- (thien-2-yl) acetamido] -ceph-3-em-4 carboxylic acid (syn-isomer) 617/359 (6R, 7R) -3-carbamoyloxymethyl-7- (2- ex. 18-ethoxyimino-2-phenyl-acetamido) ceph-3-em-4-carboxylic acid (syn-isomer) ) 678/359 (6R, 7R) -3-carbamoyloxymethyl-7- (2- Ex. 16 phenoxyimino-2-phenyl-acetamido) ceph-3-em-4-carboxylic acid (synisorner) 695/359 (6R, 7R) -3-carbamoyloxymethyl-7- [2- Example 14 (fur-2-yl) -2-phenoxyimino-acetamido] τ ceph-3-em-4-carboxylic acid (syn-isomer) 586/359 ( 6R, 7R) -3-carbamoyloxymethyl-7- [2- Example 19 t-butoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer) ________ 750 / 359 (6R, 7R) -3-carbamoyloxymethyl-7- [2- anti-analog to cefuri (fur-2-yl) -2 -methoxyiminoacetamido] oxime (640/359) ceph-3-em-4-carboxylic acid (anti-isomer) 640/1 (6R, 7R) -3-acetoxymethyl-7- [2- (fur. 35) in 2- yl) -2-methoxyimino-acetamido] ceph-DK ans.2373 / 72 3- em-4-carboxylic acid (syn isomer) 586/1 (6R, 7R) -3-acetoxymethyl-7- [2- t-bux 14 in toxyimino-2- (thien-2-yl) acetamido] - DK ans.2373 / 72 ceph-3-em-4-carboxylic acid (syn-isomer) ______
Testorganismerne i tabel A er udvalgt under hensyn til den brede spredning af følsomheden for cephalosporinantibiotika. Således er Staphylococcus aureus 663E meget følsom for alle mikrobiologisk aktive cephalosporiner, mens stammerne 1414E og 853E er penicillinase-producerende og generelt mere resistente og stamme 1613E er methicillinresistent og ikke meget følsom for cephalospo- 147683 6 riner. Escherichia coli-stammerne 573E, 851E og 1507E er repræsentative for de stammer der normalt er følsomme for cephalosporiner, mens stamme 1193E har den overførbare res is tens faktor som formidler en klasse III type β-laktamase (M.H. Richmond og R.B.The test organisms in Table A are selected taking into account the wide spread of cephalosporin antibiotic sensitivity. Thus, Staphylococcus aureus 663E is highly sensitive to all microbiologically active cephalosporins, while strains 1414E and 853E are penicillinase producing and generally more resistant and strain 1613E is methicillin resistant and not very sensitive to cephalosporins. Escherichia coli strains 573E, 851E, and 1507E are representative of those strains normally sensitive to cephalosporins, whereas strain 1193E has the transmissible factor of transmission which mediates a class III type of β-lactamase (M.H. Richmond and R.B.
Sykes, 1973/ Advances in Microbial Physiology/ 31). Salmonella typhimurium 804E, Proteus mirabilis 431E og Haemophilus influenzae 1184E er følsomme stammer der er repræsentative for de respektive arter. Enterobacter cloacae 1321E og Klebsiella aerogenes 1522E er β-laktamase ikke-producerende mutanter af normalt resistente/ enzymproducerende stammer. Serratia marcescens 1324E, Providence sp. 1497E og Haemophilus influenzae 1788E er ampicillinresistente, β-laktamase-producerende bakterier. Alle nye cephalosporiner må normalt have virkning mod de normale følsomme organismer; desto større virkning de har mod de vanskeligere β-laktamase-producerende bakterier, desto større er deres potentielle terapeutiske værdi.Sykes, 1973 / Advances in Microbial Physiology / 31). Salmonella typhimurium 804E, Proteus mirabilis 431E and Haemophilus influenzae 1184E are sensitive strains representative of the respective species. Enterobacter cloacae 1321E and Klebsiella aerogenes 1522E are β-lactamase non-producing mutants of normally resistant / enzyme-producing strains. Serratia marcescens 1324E, Providence sp. 1497E and Haemophilus influenzae 1788E are ampicillin-resistant, β-lactamase-producing bacteria. All new cephalosporins must normally have an effect on the normal sensitive organisms; the greater the effect they have on the more difficult β-lactamase-producing bacteria, the greater their potential therapeutic value.
Af tabel A kan udledes: a) De fleste af forbindelserne med formel I og sammenligningsforbindelserne er aktive mod de tre normale stammer af Staphylococ-cus aureus, men mindre mod den methicillinresistente 1631E. Anti-forbindelsen 750/359 virker generelt dårligt mod stafylokokker.From Table A it can be deduced: a) Most of the compounds of formula I and the comparative compounds are active against the three normal strains of Staphylococcus aureus, but less against the methicillin resistant 1631E. Anti-compound 750/359 generally works poorly against staphylococci.
b) Alle forbindelserne undtagen anti-forbindelsen har god virkning mod de stammer af Escherichia coli, der ikke danner β-laktamase. De kommercielle sammenligningsforbindelser og 87/359 udviser stor aktivitetsforskel over for Escherichia coli 1193E og 1507, der henholdsvis har og mangler R-faktoren, mens forbindelserne med formel I og IX har ens aktivitet over for disse to stammer, hvilket tyder på at de er resistente mod ΤΕΜ-β-laktamasen, c) De kommercielle sammenligningsforbindelser og 87/359 har ringe eller ingen virkning mod Serratia, de anvendte β-laktamase-producerende gramnegative stammer af Providence sp. og især Serratia marcescens, mens forbindelserne I og IX har god virkning mod disse, hvilket bekræfter deres β-laktamase-stabilitet. Også over for de to teststammer af Haemophilus influenzae er forbindelserne I og IX aktive i modsætning til de kommercielle cephalosporiner og 87/359.b) All the compounds except the anti-compound have good effect against the strains of Escherichia coli which do not form β-lactamase. Commercial Comparative Compounds and 87/359 exhibit high activity difference to Escherichia coli 1193E and 1507, respectively, having and lacking the R factor, while the compounds of Formulas I and IX have similar activity to these two strains, suggesting that they are resistant against the ΤΕΜ-β-lactamase, c) The commercial comparison compounds and 87/359 have little or no effect against Serratia, the β-lactamase-producing gram-negative strains used by Providence sp. and, in particular, Serratia marcescens, while compounds I and IX have good activity against them, confirming their β-lactamase stability. Also against the two test strains of Haemophilus influenzae, compounds I and IX are active in contrast to the commercial cephalosporins and 87/359.
d) 1-Oxyderne står generelt ikke på højde med de øvrige forbindelser med formel I, men er værdifulde i sammenligning med kendte forbindelser mod Proteus mirabilis, Providence sp. og Haemophilus.d) The 1-oxides are generally not at par with the other compounds of formula I, but are valuable in comparison with known compounds against Proteus mirabilis, Providence sp. and Haemophilus.
7 147 683 I resumé har altså alle de afprøvede forbindelser undtagen anti-forbindelsen god virkning mod de testorganismer der ikke danner β-laktamase, men kun forbindelserne I og IX mod dem der gør det.Thus, in summary, all the tested compounds except the anti-compound have good effect against the test organisms that do not form β-lactamase, but only compounds I and IX against those that do.
I tabel B er vist yderligere resultater af afprøvning in vi-tro af de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser (formel I) og de kommercielle sammenligningsforbindelser samt 87/359.Table B shows further results of in vitro testing of the compounds of the invention (formula I) and the commercial comparison compounds as well as 87/359.
Om tabel B kan siges: a) Stammerne af Staphylococcus aureus var penicillinfølsomme og valgt med henblik på at afsløre forbindelser med dårlig virkning. Alle de afprøvede forbindelser var højaktive.It can be said about Table B: a) The strains of Staphylococcus aureus were penicillin sensitive and selected to reveal compounds with poor efficacy. All the compounds tested were highly active.
b) De β-laktamase-producerende stammer af Klebsiella var resistente mod 87/359 og de kommercielle cephalosporiner. Cefuroxim havde god aktivitet, bedre end de andre forbindelser med formel I.b) The β-lactamase producing strains of Klebsiella were resistant to 87/359 and the commercial cephalosporins. Cefuroxime had good activity, better than the other compounds of formula I.
c) Forbindelserne med formel I havde generelt bedre virkning mod Proteus (alle β-laktamase-producerende) end sammenligningsforbindelserne.c) The compounds of formula I generally had a better effect against Proteus (all β-lactamase producing) than the comparison compounds.
d) Cefuroxim var den mest virksomme forbindelse mod de β-laktamase-producerende stammer af Escherichia coli, selv om forskellene ikke er særlig store ved de anvendte organismekoncentrationer på 5 10 pr. ml. Forhøjes bakteriekoncentrationen til det 100-dobbelte, stiger MIC for de kommercielle cephalosporiner og 87/359 stærkt, men er i hovedsagen upåvirket for forbindelserne I.d) Cefuroxime was the most effective compound against the β-lactamase-producing strains of Escherichia coli, although the differences are not very large at the organism concentrations of 5 10 ml. If the bacterial concentration is increased to 100-fold, the MIC of the commercial cephalosporins and 87/359 increases significantly, but is essentially unaffected for the compounds I.
e) Testorganismerne af Salmonella og Shigella er β-laktamase-resistente på grund af de R-faktorer de bærer. Der opstår samme situation med Salmonella-stammen som med de ovenfor diskuterede stammer af E. coli; Shigella-stammerne er mere følsomme for forbindel- 5 serne I end sammenligningsforbindelserne, selv ved dosis 10 organismer pr. ml.e) The test organisms of Salmonella and Shigella are β-lactamase resistant due to the R factors they carry. The same situation occurs with the Salmonella strain as with the strains of E. coli discussed above; The Shigella strains are more sensitive to the compounds I than the comparison compounds, even at the dose of 10 organisms per ml. ml.
f) Citrobacter og Enterobacter stammerne har tendens til at være meget resistente mod sammenligningsforbindelserne, mens forbindelserne I har god virkning mod disse organismer.f) The Citrobacter and Enterobacter strains tend to be very resistant to the comparator compounds, while the compounds I have good activity against these organisms.
g) 1-Oxyderne er især virksomme i forhold til sammenligningsforbindelserne mod arter af Proteus og Enterobacter.g) The 1-oxides are particularly effective in relation to the comparative compounds against species of Proteus and Enterobacter.
Sammenfattende viser tabellerne A og B at de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med formel I og særlig cefuroxim (640/359) har langt bredere aktivitetsområde end sammenligningsforbindelserne, hvilket især er en følge af deres meget høje β-laktamase-stabilitet.In summary, Tables A and B show that the compounds of formula I and in particular cefuroxime (640/359) prepared by the process of the invention have far wider range of activity than the comparison compounds, which is mainly due to their very high β-lactamase stability.
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Tabel B, MIC, μg/mlTable B, MIC, µg / ml
Forb. med formel IConn. of formula I
Kendte forbindelser____Known Compounds____
Organisme Nr. 87/1 87/4 541/ 87/ 640/ 554/ __________ 296 359 _ 359 359_ S. aureus ' 3972 <0,1 <0,1 <0,1 <0,1 0,2 <0,1 748 <0,1 <0,1 <0,1 <0,1 <0,1 <0»1 864 <0,1 <0,1 <0,1 <0,1 <0,1 <0/1 K. Aerogenes 2972 125 62 31 62 8 31 " 47876 125 62 31 31 8 16 " 47877 250 250 62 62 8 16Organism no. 87/1 87/4 541/87/640/554 / __________ 296 359 _ 359 359_ S. aureus' 3972 <0.1 <0.1 <0.1 <0.1 <0.2 0.2 <0.1 748 < 0.1 <0.1 <0.1 <0.1 <0.1 <0 »1 864 <0.1 <0.1 <0.1 <0.1 <0.1 <0/1 K. Aerogenes 2972 125 62 31 62 8 31 "47876 125 62 31 31 8 16" 47877 250 250 62 62 8 16
Klebsiella sp. 1260E 250 62 62 250 4 8 P. Vulgaris Poole >250 250 62 >250 16 16 " 45343 31 62 16 62 4 4 " 45780 >250 250 62 >250 31 31 P. Morganii 1376E >250 250 62 >250 16 16 P. ftiirabilis 1315E 16 31 4 8 4 8 P. rettgeri 1484E 4 2 <0,1 16 <0,1 0,2 " 1353E 31 8 4 125 <0,1 0,2 E. coli J53 16 16 4 8 2 4 R825 " SM239 884124 " SM209 31 31 4 82 4Klebsiella sp. 1260E 250 62 62 250 4 8 P. Vulgaris Poole> 250 250 62> 250 16 16 "45343 31 62 16 62 4 4" 45780> 250 250 62> 250 31 31 P. Morganii 1376E> 250 250 62> 250 16 16 P ftiirabilis 1315E 16 31 4 8 4 8 P. Straightener 1484E 4 2 <0.1 16 <0.1 0.2 "1353E 31 8 4 125 <0.1 0.2 E. coli J53 16 16 4 8 2 4 R825 "SM239 884124" SM209 31 31 4 82 4
Salmonella sp. 1347E 2 2 0,5 2 4 8Salmonella sp. 1347E 2 2 0.5 2 4 8
Shigella flexneri 209A 250 125 31 >250 4 4Shigella flexneri 209A 250 125 31> 250 4 4
Shigella dysenteriae 1667E 250 62 250 250 31 31Shigella dysenteriae 1667E 250 62 250 250 31 31
Citrobacter freundii 159 250 125 125 250 2 8 " " 1506E 125 125 125. >250 8 8 " " 367 >250 250 >250 >250 62 31Citrobacter freundii 159 250 125 125 250 2 8 "" 1506E 125 125 125.> 250 8 8 "" 367> 250 250> 250> 250 62 31
Enterobacter hafniae 1333E >250 >250 125 >250 4 2 " 6372 62 62 62 31 8 16Enterobacter hafniae 1333E> 250> 250 125> 250 4 2 "6372 62 62 62 31 8 16
Enterobacter cloacae 1686E 16 16 2 62 8 31 " " 1015E 250 250 250 >250 8 16 " 1683E >250 >250 250 >250 8 31 147683 11Enterobacter cloacae 1686E 16 16 2 62 8 31 "" 1015E 250 250 250> 250 8 16 "1683E> 250> 250 250> 250 8 31 147683 11
Tabel B fortsat, MIC, μg/ml__Table B continued, MIC, µg / ml__
Forbindelser med formel ICompounds of Formula I
ls~ oxyd oxyd af af 640/ 640/ls ~ oxide oxide of 640/640 /
Organisme Nr. 576/ 617/ 678/ 695/ 586/ 359 359 ___359 359 359 359 359___ S. aureus 3972 <0,1 <0,1 <0,1 <0,1 0,5 4 4 " 748 <0,1 <0,1 <0,1 <0,1 <0,1 2 2 " 864 <0,1 <0,1 <0,1 <0,1 0,2 2 1 K. Aerogenes 2972 31 62 62 62 31 125 62 " 47876 31 31 62 62 125 125 31Organism no. 576/617/678/695/586/359 359 ___359 359 359 359 359___ S. aureus 3972 <0.1 <0.1 <0.1 <0.1 0.5 4 4 "748 <0.1 <0 , 1 <0.1 <0.1 <0.1 2 2 "864 <0.1 <0.1 <0.1 <0.1 0.2 2 1 K. Aerogenes 2972 31 62 62 62 31 125 62 "47876 31 31 62 62 125 125 31
" 47877 31 62 62 62 62 ND ND„47877 31 62 62 62 62 ND ND
Klebsiella sp. 1260E 8 8 8 8 8 16 62 P. Vulgaris Poole 31 16 16 16 62 4 250 " 45343 16 16 16 31 62 62 16 " 45780 125 62 16 62 125 >250 >250 vo P. Morganii 1376E 31 16 31 16 16 4 250 P. rttirabilis 1315E 16 16 31 4 16 4 31 P. rettgeri 1484E 0,5 0,5 1 1 1 <0,1 <0/1 " 1353E 0,5 1 2 2 2 0,2 0,2 E. coli J53 8 8 16 8 16 16 16 R825 " SM239 8 16 16 8 16 2 16 " SM209 8 4 8 4 4 4 31Klebsiella sp. 1260E 8 8 8 8 8 16 62 P. Vulgaris Poole 31 16 16 16 62 4 250 "45343 16 16 16 31 62 62 16" 45780 125 62 16 62 125> 250> 250 vo P. Morganii 1376E 31 16 31 16 16 4 250 P. rttirabilis 1315E 16 16 31 4 16 4 31 P. Straightening 1484E 0.5 0.5 1 1 1 <0.1 <0/1 "1353E 0.5 1 2 2 2 0.2 0.2 E. coli J53 8 8 16 8 16 16 16 R825 "SM239 8 16 16 8 16 2 16" SM209 8 4 8 4 4 4 31
Salmonella sp. 1347E 8 8 8 8 8 4 16Salmonella sp. 1347E 8 8 8 8 8 4 16
Shigella flexneri 209A 8 8 8 4 4 16 8Shigella flexneri 209A 8 8 8 4 4 16 8
Shigella dysenteriae 1667E 31 31 16 16 16 31 62Shigella dysenteriae 1667E 31 31 16 16 16 31 62
Citrobacter freundii 159 8 8 16 8 8 62 125 " " 1506E 16 8 16 8 8 31 62 " " 367 62 16 31 31 31 >250 250Citrobacter freundii 159 8 8 16 8 8 62 125 "" 1506E 16 8 16 8 8 31 62 "" 367 62 16 31 31 31> 250 250
Enterobacter hafniae 1333E 4 4 8 8 8 >250 125 " " 6372 16 1 8 8 8 16 31Enterobacter hafniae 1333E 4 4 8 8 8> 250 125 "" 6372 16 1 8 8 8 16 31
Enterobacter cloacae 1686E31 31 31 31 31 8 16 " " 1015E 16 8 16 16 16 16 62 " " 1683E 31 16 31 16 16 31 62 147683 12Enterobacter cloacae 1686E31 31 31 31 31 8 16 "" 1015E 16 8 16 16 16 16 62 "" 1683E 31 16 31 16 16 31 62 147683 12
Et område hvor cefuroxim (640/359) synes særlig lovende er dets aktivitet mod stammer af Haemophilus influenzae, og tabel C viser en detaljeret oversigt over virkningen af cefuroxim mod stammer af denne mikroorganisme i sammenligning med kommercielle β-lak-tam- antibiotika. Da ampicillin har god virkning mod stammer af H. influenzae brugtes en kommerciel prøve af dette antibiotikum i stedet for cephaloridin. Det ses af tabel C at cefuroxim stedse er mere aktivt en sammenligningsforbindelserne.One area where cefuroxime (640/359) seems particularly promising is its activity against strains of Haemophilus influenzae, and Table C shows a detailed overview of the action of cefuroxime against strains of this microorganism in comparison with commercial β-lacquer antibiotics. Since ampicillin has a good effect against strains of H. influenzae, a commercial sample of this antibiotic was used instead of cephaloridine. It is seen from Table C that cefuroxime is always more active than the comparison compounds.
Tabel CTable C
----—---——- H. influenzae __MIC, ua/ml __ stamme 640/359 . AMP 87/1 541/296 1184 E 2 0,5 4 16 LH 141 0,5 0,25 0,25 8 LH 147 0,5 0,25 1 8 LH 150 0,5 0,25 2 8 LH 151 0,5 0,25 2 8 SM 137 0,5 0,25 2 8 LH 143 0,5 <0,125 0,25 8 LH 144 0,5 <0,125 0,5 8 LH 145 0,5 <0,125 0,5 8 LH 146 0,5 <0,125 2 8 LH 148 0,5 <0,125 0,5 8 LH 152 0,5 <0,125 1 8----—---——- H. influenzae __MIC, ua / ml __ strain 640/359. AMP 87/1 541/296 1184 E 2 0.5 4 16 LH 141 0.5 0.25 0.25 8 LH 147 0.5 0.25 1 8 LH 150 0.5 0.25 2 8 LH 151 0 , 5 0.25 2 8 SM 137 0.5 0.25 2 8 LH 143 0.5 <0.125 0.25 8 LH 144 0.5 <0.125 0.5 8 LH 145 0.5 <0.125 0.5 8 LH 146 0.5 <0.125 2 8 LH 148 0.5 <0.125 0.5 8 LH 152 0.5 <0.125 1 8
248 6X 2 250 31 ND248 6X 2 250 31 ND
4347X 2 250 31 ND4347X 2 250 31 ND
12214X 1 250 31 ND12214X 1 250 31 ND
12256* 2 250 31 ND12256 * 2 250 31 ND
23141X 2 250 31 ND23141X 2 250 31 ND
23142X 0,5 250 16 ND23142X 0.5 250 16 ND
23143X 2 250 31 ND23143X 2 250 31 ND
23144 0,5 62 31 ND23144 0.5 62 31 ND
23145X 2 >250 31 ND23145X 2> 250 31 ND
23366X 2 250 16 ND23366X 2 250 16 ND
23367X 0,5 250 16 ND23367X 0.5 250 16 ND
23368X 0,5 250 62 ND23368X 0.5 250 62 ND
23369X 0,5 250 31 ND23369X 0.5 250 31 ND
ChistyX 0,5 250 31 NDChistyX 0.5 250 31 ND
| Birkert Q'5__250__31_i ^ 147683 13 x β-laktamase-dannere AMP = ampicillin ND - ikke bestemt| Birkert Q'5__250__31_i ^ 147683 13 x β-Lactamase Formers AMP = ampicillin ND - not determined
Cefazolin blev ikke afprøvet mod disse β-laktamase-dannende stammer fordi det havde dårlig virkning mod de følsomme stammer og er følsom over for den β-laktamase, som de ampicillinresistente stammer af H. influenzae danner.Cefazoline was not tested against these β-lactamase-forming strains because it had a poor effect on the sensitive strains and is sensitive to the β-lactamase that the ampicillin-resistant strains of H. influenzae form.
Et yderligere vigtigt område for cefuroxim er blevet afprøvet mod stammer af Neisseria. Tabel D giver en oversigt over et antal repræsentative stammer og giver også resultater for de tre kommercielle sammenligningsforbindelser. Det ses tydeligt at cefuroxim stedse har høj aktivitet mod stammer af Neisseria, generelt på langt højere niveau end sammenligningsforbindelserne.A further important site for cefuroxime has been tested against strains of Neisseria. Table D provides an overview of a number of representative strains and also provides results for the three commercial comparison compounds. It is clearly seen that cefuroxime always has high activity against strains of Neisseria, generally at a much higher level than the comparison compounds.
Tabel DTable D
Art Stamme _MIC, yg/ml _ 640/359 87/1 87/4 [541/296Art strain _MIC, yg / ml _ 640/359 87/1 87/4 [541/296
Neisseria meningitidis 891E 0,02 0,2 3,1 0,3Neisseria meningitidis 891E 0.02 0.2 3.1 0.3
Neisseria catarrhalis 668E 0,2 0,1 0,8 0,1Neisseria catarrhalis 668E 0.2 0.1 0.8 0.1
Neisseria gonorrhoeae 35 0,01 0,16 2,5 1,25 * 157 0,005 0,31 2,5 „ 0,6Neisseria gonorrhoeae 35 0.01 0.16 2.5 1.25 * 157 0.005 0.31 2.5 "0.6
" 27 0,005 0,31 ND ND„27 0.005 0.31 ND ND
" 33 0,02 ND 2,5 0,6 " 28 0,02 ND 2,5 0,3 " 13 0,02 ND 2,5 0,6 " 48 0,02 ND 0,62 0,08 " 1130 0,08 ND 2,5 1,25 " 110 0,01 0,62 0,62 1,25 " 163 0,01 0,62 0,62 1,25 " 19 0,08 ND 2,5 1,25 " 125 0,04 ND 2,5 1,25 " 40 0,04 ND 2,5 1,25 " 15 0,02 0,5 2,5 0,6 1 0,001 0,5 0,8 0,1 " 2 0,002 0,5 0,8 0,1 »__3__0,002 0,5__<Μ___0,05 j 147683 14"33 0.02 ND 2.5 0.6" 28 0.02 ND 2.5 0.3 "13 0.02 ND 2.5 0.6" 48 0.02 ND 0.62 0.08 "1130 0.08 ND 2.5 1.25 "110 0.01 0.62 0.62 1.25" 163 0.01 0.62 0.62 1.25 "19 0.08 ND 2.5 1.25 "125 0.04 ND 2.5 1.25" 40 0.04 ND 2.5 1.25 "15 0.02 0.5 2.5 0.6 1 0.001 0.5 0.8 0.1" 2 0.002 0.5 0.8 0.1 »__3__0.002 0.5 __ <Μ ___ 0.05 j
Tabel E og P viser virkning på MIC hos cefuroxim og kommercielle sammenligningsforbindelser af at forøge graden af infektio- 5 7 nen med testorganismen fra 10 til 10 organismer/ml. Det ses heraf at MIC for cefuroxim i de fleste tilfælde kun ændres lidet ved anvendelse af en 100 gange så stor mængde mikroorganismer ved bestemmelsen, mens sammenligningsforbindelserne generelt har tydeligt lavere aktivitet mod disse høje podekoncentrationer.Tables E and P show effect on MIC of cefuroxime and commercial comparison compounds of increasing the rate of infection with the test organism from 10 to 10 organisms / ml. It can be seen from this that in most cases the MIC for cefuroxime is only slightly altered using a 100 times the amount of microorganisms in the assay, whereas the comparator compounds generally have significantly lower activity against these high seed concentrations.
Sammenligningsforbindelserne med formel IX, altså repræsenterende DK-PA 2373/72, indgår ikke i tabel B-F fordi disse forbindelser generelt vil udvise en noget lignende aktivitet in vitro som de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser I, idet de har lignende stabilitet mod β-laktamase (en funktion af arten af 7 β-acylamidogruppen).The comparative compounds of formula IX, i.e. representing DK-PA 2373/72, are not included in Table BF because these compounds will generally exhibit somewhat similar activity in vitro to the compounds I prepared by the process of the invention, having similar stability to β-lactamase. (a function of the nature of the 7 β-acylamido group).
De foreliggende forbindelser har imidlertid en væsentlig fordel frem for forbindelserne med formel IX, nemlig den fordelagtige egenskab at have god stabilitet in vivo, navnlig mod esteraser. Dette er særdeles fordelagtigt fordi et antal kendte cephalosporinfor-bindelser har den ulempe at de undergår nedbrydning in vivo og derved deaktiveres inden de kan udvise deres fulde antibiotiske effekt. Tabel G viser graden af stabilitet af tre repræsentative forbindelser blandt de foreliggende med formel I samt af de to sammenligningsforbindelser med formel X over for et rotteleverhomogenisat, en praktisk kilde til animalsk esterase. Det ses umiddelbart af tabellen at de tre forbindelser med formel I er stabile i nærværelse af en sådan esterase, mens sammenligningsforbindelserne nedbrydes i betydelig grad, indtil ca. 50% på 4 timer.However, the present compounds have a significant advantage over the compounds of formula IX, namely the advantageous property of having good in vivo stability, especially against esterases. This is particularly advantageous because a number of known cephalosporin compounds have the disadvantage of undergoing degradation in vivo and thereby deactivated before they can exhibit their full antibiotic effect. Table G shows the degree of stability of three representative compounds of the present Formula I and of the two Comparative Compounds of Formula X against a rat liver homogenate, a practical source of animal esterase. It is immediately apparent from the table that the three compounds of formula I are stable in the presence of such an esterase, whereas the comparative compounds are degraded to a considerable extent until ca. 50% in 4 hours.
Forsøget udførtes ved at testforbindelsen i en koncentration på 100 yg/ml inkuberedes ved 37°C i nærværelse af 2% rotteleverhomogenisat. Kontrolprøver inkuberedes i nærværelse af fysiologisk saltopløsning. Prøver udtoges fra test- og kontrolmaterialet efter 0, 1, 2 og 4 timer og bestemtes for antibiotisk aktivitet. Resultaterne er angivet som den procentdel af forbindelsen, der er tilbage efter det angivne tidsrum, beregnet på basis af kontrol = 100%.The test was performed by incubating the test compound at a concentration of 100 µg / ml at 37 ° C in the presence of 2% rat liver homogenate. Control samples were incubated in the presence of physiological saline. Samples were taken from the test and control material after 0, 1, 2 and 4 hours and determined for antibiotic activity. The results are given as the percentage of the compound remaining after the specified time, calculated on the basis of control = 100%.
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Tabel GTable G
Stabilitet over for rotteleverhomogenisat.Stability to rat liver homogenate.
Forb.__% tilbage efter_ ____0_t__l_t__2_t__4 t 586/1 96 65 60 45 640/1 92 59 54 47 640/359 100 100 100 100 695/359 100 100 100 100 554/359__100__3£0__100__100For example, _% left after_ ____0_t__l_t__2_t__4 t 586/1 96 65 60 45 640/1 92 59 54 47 640/359 100 100 100 100 695/359 100 100 100 100 554 / 359__100__3 £ 0__100__100
Forbindelserne med formel X, dvs. dem der kendes fra DK-PA 381/72 afviger i to væsentlige henseende fra de foreliggende. For det første er de hydroxyoximer eller acyloxyoximer, dvs. estere, mens den foreliggende opfindelse angår oximætere. For det andet har de foreliggende forbindelser en karbamoyloxymetylgruppe i stilling 3, mens en sådan gruppe ikke er vist i den ældre ansøgning.The compounds of formula X, i. those known from DK-PA 381/72 differ in two essential respects from the present. First, they are hydroxyoxymers or acyloxyoxymers, i.e. esters, while the present invention relates to oximeters. Second, the present compounds have a carbamoyloxymethyl group at position 3, while such group is not shown in the older application.
Som bekendt er de kemiske egenskaber af ætere og estere ganske forskellige fra de kemiske egenskaber af estere og alkoholer i mange henseender, og det er derfor ikke nærliggende at antage at man kan slutte fra egenskaber hos estere til egenskaber hos ætere, i det foreliggende tilfælde så meget desto mindre som altså 3-stillingen er anderledes besat.As is well known, the chemical properties of ethers and esters are quite different from the chemical properties of esters and alcohols in many respects and it is therefore not obvious to assume that one can add from the properties of esters to those of ethers, in the present case so much the less the 3-position is otherwise occupied.
Det viser sig da også at der eksisterer biologiske forskelle mellem de kendte estere og de foreliggende ætere. De sidstnævnte er mere stabile mod esterase end de kendte forbindelser, og de har nedsat serumbinding.It also turns out that there are biological differences between the known esters and the present ethers. The latter are more stable to esterase than the known compounds and have decreased serum binding.
Tabel H viser stabiliteten mod rotteleverhomogenisat, bestemt på samme måde som beskrevet i forbindelse med tabel G. Det ses som foran at de foreliggende forbindelser ikke angribes af esterasen, mens de kendte forbindelser gør.Table H shows the stability to rat liver homogenate, determined in the same manner as described in Table G. It is seen as before that the present compounds are not attacked by the esterase while the known compounds do.
Tabel I viser bindingen af forbindelserne til serum. De foreliggende forbindelser bindes i langt lavere grad til serum end de kendte med formel X. En forbindelses praktiske nytte som antibiotikum afhænger ikke alene af dens antibiotiske aktivitet,· men også af dens modstandsdygtighed mod bl.a. esteraser og laktamaser, og af at den er til rådighed i organismen, en rådighed der nedsættes når den bindes hårdt til serum. Det ses derfor at de foreliggende forbindelser med formel I er fordelagtige frem for de kendte med formel XTable I shows the binding of the compounds to serum. The present compounds bind to a much lower degree to serum than those known in formula X. The practical utility of a compound as an antibiotic depends not only on its antibiotic activity, but also on its resistance to, among other things. esterases and lactamases, and of being available in the organism, an availability that is diminished when it is tightly bound to serum. Therefore, it is seen that the present compounds of formula I are advantageous over those of formula X
17 147683 i denne henseende.17 147683 in this regard.
De fra DK-PA 382/72 kendte anti-forbindelser står de fore-liggende forbindelser fjernere end de allerede diskuterede. De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser I har væsentlig højere antibiotisk aktivitet end de kendte anti-forbindelser som det fremgår af tabel J. I denne er de anførte anti-for-bindelser fra ans. 382/72 dem der strukturelt står de foreliggende forbindelser nærmest. Det skal bemærkes at de i tabel J anførte resultater ikke stammer fra parallelt udførte forsøg, men er kompileret fra forskellige forsøgsrækker. De viser dog tydeligt at de kendte anti-forbindelser har væsentlig ringere virkning, især mod gramnegative bakterier, end de foreliggende.The anti-compounds known from DK-PA 382/72 make the present compounds more distant than those already discussed. The compounds I prepared by the process of the invention have substantially higher antibiotic activity than the known anti-compounds as shown in Table J. In this, the listed anti-compounds from ans. 382/72 those which are structurally closest to the present compounds. It should be noted that the results given in Table J do not derive from parallel experiments, but are compiled from different series of experiments. However, they clearly show that the known anti-compounds have a significantly poorer effect, especially against gram-negative bacteria, than the present ones.
Tabel HTable H
RA-C-CONH__RA-C CONH__
I-o-*B J—« i rCI-o- * B J— «i rC
COOHCOOH
RA RB R^ % forbindelse tilbage efter _0_1_2_4 t O -H -CH2OCOCH3 kendt 80 70 60 50 ^ -C0CH3 -CH2OCOCH3 kendt 80 75 60 50 ^ -CH3 -CH2OCONH2 ny 100 100 100 100 “CH3 -CH2OCONH2 ny 100 100 100 100 ^ -ch2oconh2 ny 100 100 100 100 147683 18RA RB R ^% compound remaining after _0_1_2_4 t O -H -CH2OCOCH3 known 80 70 60 50 ^ -COCH3 -CH2OCOCH3 known 80 75 60 50 ^ -CH3 -CH2OCONH2 new 100 100 100 100 “CH3 -CH2OCONH2 new 100 100 100 100 ^ -ch2oconh2 new 100 100 100 100 147683 18
Tabel ITable I
ABCABC
R R R % serumbinding -H -CH2OCOCH3 kendt 90 -COC2H5 -CH2OCOCH3 kendt 80 "H -CH2OCOCH3 kendt 98 -COCH3 -CH2OCOCH3 kendt 95 -H -CH2OCOCH3 kendt 92 ^ Υ -CH3 -CH2OCONH2 ny 49 O -C2H5 -CH2OCONH2 ny 38 O* "0 -CH2CONH2 51 ^~y~ -CH3 -CH2OCONH2 ny 30 19 147683 DK-ans. 382/72 ^ -pRRR% serum binding -H -CH2OCOCH3 known 90 -COC2H5 -CH2OCOCH3 known 80 "H -CH2OCOCH3 known 98 -COCH3 -CH2OCOCH3 known 95 -H -CH2OCOCH3 known 92 ^ Υ -CH3 -CH2OCONH2 new 49 O -C2H5 -CH2OCONH2 new 38 "0 -CH2CONH2 51 ^ ~ y ~ -CH3 -CH2OCONH2 new 30 19 147683 DK-ans. 382/72 ^ -p
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20 ^_ 147683207 147683
Foreliggende opfindelseThe present invention
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Salte som kan dannes ud fra forbindelser med den almene formel I omfatter uorganiske basesalte såsom alkalimetalsalte, fx natriumsalte og kaliumsalte, jordalkalimetalsalte som fx kalciumsalte og organiske basesalte, fx prokain, fenylætylbenzylamin, dibenzylætylendiamin, ætanolamin, diætanolamin, triætanolamin eller N-metylglukosamin. Saltene kan også være resinater dannet med fx en polystyrenharpiks eller tværbundet polystyren-divinyl-benzen-kopolymerharpiks indeholdende aminogrupper eller kvaternæ-re aminogrupper.Salts that can be formed from compounds of general formula I include inorganic base salts such as alkali metal salts, e.g., sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and organic base salts, e.g. The salts may also be resinates formed with, for example, a polystyrene resin or cross-linked polystyrene-divinyl-benzene copolymer resin containing amino groups or quaternary amino groups.
Når R* i den almene formel I er en furylgruppe kan det være en fur-2-ylgruppe eller fur-3-ylgruppe og når det er en tie-nylgruppe kan det være en tien-2-ylgruppe eller tien-3-ylgruppe.When R * in general formula I is a furyl group, it can be a fur-2-yl group or fur-3-yl group and when it is a thienyl group it can be a thien-2-yl group or thien-3-yl group.
Fortrinsvis er gruppen R1 en fur-2-ylgruppe.Preferably, the group R1 is a fur-2-yl group.
22
Som nævnt er gruppen R i formel I en alkylgruppe med 1- 4 kulstofatomer, fx metyl, ætyl eller t-butyl; en cykloalkyl-gruppe med 3-7 kulstofatomer som fx en cyklopentylgruppe; eller en fenylgruppe.As mentioned, the group R of formula I is an alkyl group of 1-4 carbon atoms, for example methyl, ethyl or t-butyl; a cycloalkyl group having 3-7 carbon atoms such as a cyclopentyl group; or a phenyl group.
De omhandlede forbindelsers egenskaber gør dem nyttige til behandling af forskellige sygdomme som bevirkes af patogene bakterier hos mennesker og dyr. En særlig vigtig forbindelse er, som det ses af tabel A og B, cefuroxim (640/359) eller syn-isomeren af (6R,7R)-3-karbamoyloxymetyl-7-[2-(fur-2-yl)- 2- metoxyiminoacetamido]-ceph-3-em-4-karboxylsyre med formlenThe properties of the compounds of the invention make them useful for the treatment of various diseases caused by pathogenic bacteria in humans and animals. A particularly important compound is, as seen in Tables A and B, cefuroxime (640/359) or the syn isomer of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2 - methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid of the formula
Η HΗ H
O-"'00”--IIO - " '00" - II
V J-1 J—CHpO.CO.NHpV J-1 J — CHpO.CO.NHp
Ndch3 crNdch3 cr
COOHCOOH
og som hensigtsmæssigt antager form af et alkalimetalsalt, navnlig natriumsaltet. Forbindelsen er modstandsdygtig mod indvirkning af pattedyr-esteraser og er derfor stabil i menneskers og dyrs legemer, hvilket fremgår af høje grader af genvinding af uomdannet forbindelse i urinen. Desuden giver forbindelsen høje koncentrationer i serum efter parenteral indgift, både hos mennesker og dyr, og den udviser lav serum- 147683 22 binding. Ifølge opfindelsen fremstilles derfor særlig hensigtsmæssigt denne forbindelse, eventuelt i form af et ugiftigt salt, biologisk acceptabel ester, 1-oxyd eller solvat deraf.and suitably taking the form of an alkali metal salt, especially the sodium salt. The compound is resistant to the action of mammalian esterases and is therefore stable in human and animal bodies, as evidenced by high degrees of recovery of unchanged compound in the urine. In addition, the compound provides high serum concentrations after parenteral administration, both in humans and animals, and exhibits low serum binding. According to the invention, therefore, it is particularly convenient to prepare this compound, optionally in the form of a non-toxic salt, biologically acceptable ester, 1-oxide or solvate thereof.
Anvendelse af let opløselige basesalte (fx alkalimetalsalte såsom natriumsaltet) af forbindelsen er fordelagtig ved terapeutiske anvendelser på grund af deres hurtige fordeling i legemet efter indgift ved injektion. Ifølge opfindelsen udvindes derfor særlig hensigtsmæssigt Na-saltet af ce-furoxim.Use of easily soluble base salts (e.g., alkali metal salts such as the sodium salt) of the compound is advantageous in therapeutic applications because of their rapid distribution in the body after administration by injection. According to the invention, therefore, the Na salt of ce furoxim is particularly conveniently recovered.
Det har vist sig at natriumsaltet af cefuroxim forekommer i et antal forskellige krystallinske former, herunder solvater, hvis fremstilling alle omfattes af den foreliggende opfindelse.It has been found that the sodium salt of cefuroxime occurs in a number of different crystalline forms, including solvates, the preparation of which are all encompassed by the present invention.
Natriumsaltet fremstilles mest hensigtsmæssigt ved at man bringer en opløsning af forbindelsen II i et polært organisk opløsningsmiddel, fx dimetylacetamid, en blanding af sådanne opløsningsmidler, fx dimetylacetamid/acetone eller dimetylformamid/ metylalkoholdenatureret ætanol, eller et vandigt polært organisk opløsningsmiddel, fx vandig acetone, i kontakt med et lille molært overskud af natrium-2-ætylhexanoat opløst i et passende organisk opløsningsmiddel (fx en alkanol såsom ætanol, en keton såsom acetone eller en kloreret kulbrinte såsom metylenklorid, en ester såsom ætylacetat eller en æter såsom dioxan), hensigtsmæssigt ved stuetemperatur, hvorefter man opsamler det udfældede salt, eventuelt efter afkøling af opløsningen fx til 4°C.The sodium salt is most conveniently prepared by bringing a solution of compound II into a polar organic solvent, e.g., dimethylacetamide, a mixture of such solvents, e.g., dimethylacetamide / acetone or dimethylformamide / methylalcohol-denatured ethanol, or an aqueous polar organic solvent, contact with a small molar excess of sodium 2-ethyl hexanoate dissolved in a suitable organic solvent (e.g., an alkanol such as ethanol, a ketone such as acetone or a chlorinated hydrocarbon such as methylene chloride, an ester such as ethyl acetate or an ether such as dioxane), conveniently at room temperature , after which the precipitated salt is collected, possibly after cooling the solution, for example to 4 ° C.
Hvor der anvendes i det væsentlige vandfri opløsningsmidler ved denne proces vindes der Form I syn-isomer af natrium-(6R, 7R) -3-karbamoyloxymetyl-7-/2- (fur-2-yl) -2-metoxyiminoacetami-do7-ceph-3-em-4-karboxylat, og dette materiale indeholder ca. 1,5% vand. Hvis opløsningsmiddelsystemet indeholder mere end ca. 2% vand vindes der imidlertid salt af Form II, der normalt indeholder ca. 2% vand. Hvis opløsningsmiddelsystemet indeholder mere end ca. 60% dioxan vindes der normalt salt af Form III, og dette materiale omfatter et dioxansolvat indeholdende ca. 1 mol dioxan, selv om der eventuelt kan dannes salt af Form II hvis der bruges et vandvådt opløsningsmiddelsystem ved forhøjet temperatur (fx 60-80°C). Krystallisation af amorf frysetørret natrium-(6R,7R)-3-karbamoyl- 147683 23 oxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karb-oxylat (syn-isomer) ud fra passende tørre, vandholdige eller di-oxanrige opløsningsmiddelsystemer på tilsvarende måde giver salt af henholdsvis Form I, Form II eller Form III.Where substantially anhydrous solvents are used in this process, Form I syn isomers of sodium (6R, 7R) -3-carbamoyloxymethyl-7- / 2- (fur-2-yl) -2-methoxyiminoacetamido-7 ceph-3-em-4-carboxylate, and this material contains approx. 1.5% water. If the solvent system contains more than approx. However, 2% water is obtained from Form II salt, which usually contains approx. 2% water. If the solvent system contains more than approx. 60% dioxane is usually obtained from Form III salt, and this material comprises a dioxane solvate containing ca. 1 mole of dioxane, although it is possible that salt of Form II may be formed if a water-wet solvent system is used at elevated temperature (e.g. 60-80 ° C). Crystallization of amorphous freeze-dried sodium (6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carb oxylate (syn -isomer) from suitably dry, aqueous or dioxane-rich solvent systems similarly yields salt of Form I, Form II or Form III, respectively.
Hvis man udsætter saltet af Form I for vanddamp (fx ved en relativ fugtighed på 75%), bevirker det at saltet absorberer yderligere vand og undergår en ændring af krystalform der i almindelighed fører til et salt af Form IV. Det resulterende materiale indeholder ca. 4% vand (dvs. ca. 1 mol) og antages at være et hy-dtat. Denne ændring er reversibel så at saltet af Form IV kan omdannes til salt af Form I fx ved tørring i vakuum over et tørremiddel såsom fosforpentoxyd. Salt af Form II absorberer ikke yderligere vand når det udsættes for vanddamp, men kan omdannes til salt af Form I ved opvarmning (fx i ca. fem minutter) af en suspension af materiale af Form II i næsten kogende metanol.Exposing the salt of Form I to water vapor (e.g., at a relative humidity of 75%) causes the salt to absorb additional water and undergoes a change in crystal shape which generally leads to a salt of Form IV. The resulting material contains approx. 4% water (i.e., about 1 mole) and is believed to be a hydrate. This change is reversible so that the salt of Form IV can be converted to salt of Form I for example by drying in a vacuum over a desiccant such as phosphorus pentoxide. Salt of Form II does not absorb additional water when exposed to steam, but can be converted to salt of Form I by heating (e.g., for about five minutes) a suspension of Form II material in near-boiling methanol.
Salt af Form III vundet ved omsætning af forbindelsen II og natrium-2-ætylhexanoat i dioxanrige opløsningsmiddelsystemer som beskrevet ovenfor udfældes normalt som en gel, der kan tørres i vakuum og give et fast stof med meget lav rumvægt og med liden eller ingen krystallinitet. Det krystallinske salt af Form III kan imidlertid vindes ved at man behandler en vandig opløsning af natriumsaltet med et væsentligt overskud (fx ca. 3 rumfang) af dioxan, eventuelt sammen med en ringe mængde ætanol, idet man opsamler de resulterende hvide nåleformede krystaller, hensigtsmæssigt efter afkøling til en nedsat temperatur (fx 4°C) og vasker produktet med dioxan og derpå tørrer krystallerne, fx i vakuum ved 20°C.Form III salt obtained by reacting compound II and sodium 2-ethylhexanoate in dioxane-rich solvent systems as described above is usually precipitated as a gel which can be dried in vacuo to give a very low bulk weight solid with little or no crystallinity. However, the crystalline salt of Form III can be obtained by treating an aqueous solution of the sodium salt with a substantial excess (e.g., about 3 volumes) of dioxane, optionally with a small amount of ethanol, appropriately collecting the resulting white needle-shaped crystals. after cooling to a reduced temperature (e.g., 4 ° C) and washing the product with dioxane and then drying the crystals, e.g., in vacuo at 20 ° C.
Saltet af Form III er hygroskopisk og mister ved at blive udsat for vanddamp (fx ved en relativ fugtighed på 75%) alt tilstedeværende dioxan og danner materialer af Form IV der derefter kan tørres (fx over fosforpentoxyd) og give salt af Form I. Hvis krystallinsk materiale af Form III behandles på denne måde synes produktets krystalopførsel af blive opretholdt under omdannelsesfølgen. Salt af Form III kan også omdannestil salt af Form I ved at man opvarmer en suspension af materiale af Form III i næsten kogende metanol; denne omdannelse fører til tab af krystallinitet hvis der bruges krystallinsk materiale af Form III.The salt of Form III is hygroscopic and loses by exposure to water vapor (e.g. at a relative humidity of 75%) all dioxane present and forms materials of Form IV which can then be dried (e.g. over phosphorus pentoxide) to give salt of Form I. crystalline material of Form III is treated in this way, the crystal behavior of the product appears to be maintained during the conversion process. Salt of Form III can also convert salt of Form I by heating a suspension of Form III material in near-boiling methanol; this conversion leads to loss of crystallinity if crystalline material of Form III is used.
147683 2424
De fire former af syn-isomeren af natrium-(6R,7K)-3-karbamoyloxymety1-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7~ceph-3-em-4-karboxy1at som er beskrevet foran er karakteriseret ved følgende røntgen-pulvermønstre (d-afstande og intensiteter) og IR spektroskopiske data: Røntgen-pulver-mønstreThe four forms of the syn-isomer of sodium (6R, 7K) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylate described above is characterized by the following X-ray powder patterns (d distances and intensities) and IR spectroscopic data: X-ray powder patterns
Kamera - Debye-Scherrer, radius 114,6 mm Bestråling - kobber K^ = 1,5418 k Intensitetér (I) ved visuel sammenligning med en kalibreret standardCamera - Debye-Scherrer, radius 114.6 mm Radiation - copper K ^ = 1.5418 k Intensity (I) for visual comparison with a calibrated standard
Form IForm I
dl d I d Idl d I d I
8,33 80 3,82 24 2,40 10 7.44 4 3,62 28 2,35 10 6.85 45 3,47 28 2,26 4 6,38 5 3,32 10 2,20 3 5.86 4 3,19 10 2,11 8 (bred) 5.36 4 3,05 4 2,04 3 4,82 100 2,93 14 (bred) 1,94 4 4,56 35 2,72 8 )dårligt 1,89 5 4.36 6 2,69 10 )opløst 1,82 6 (bred) 4,19 40 2,57 9 1,77 2 3,95 26 2,47 68.33 80 3.82 24 2.40 10 7.44 4 3.62 28 2.35 10 6.85 45 3.47 28 2.26 4 6.38 5 3.32 10 2.20 3 5.86 4 3.19 10 2.11 8 (wide) 5.36 4 3.05 4 2.04 3 4.82 100 2.93 14 (wide) 1.94 4 4.56 35 2.72 8) poor 1.89 5 4.36 6 2, 69 10) dissolved 1.82 6 (wide) 4.19 40 2.57 9 1.77 2 3.95 26 2.47 6
Form IIForm II
dl 4 1 d Idl 4 1 d I
8,78 60 4,20 10 2,77 6 7,81 9 3,76 20 (bred) 2,32 3 (bred) 6,65 25 3,49 . 14 2,19 2 4,68 100 (bred) 3,07 6 (bred) 2,08 2 4.45 10 2,91 8 147683 258.78 60 4.20 10 2.77 6 7.81 9 3.76 20 (wide) 2.32 3 (wide) 6.65 25 3.49. 14 2.19 2 4.68 100 (wide) 3.07 6 (wide) 2.08 2 4.45 10 2.91 8 147683 25
Form IIIForm III
dl dl d Idl dl d I
14,98 60 5,57 20 3,47 5 12,95 40 4,98 40 3,32 10 10,16 20 4,73 60 3,26 30 8,23 45 4,29 20 3,13 17 (bred) 7,52 5 4,16 100 2,43 10 6,61 65 3,81 25 (bred) 2,15 15 6,08 3 3,60 2014.98 60 5.57 20 3.47 5 12.95 40 4.98 40 3.32 10 10.16 20 4.73 60 3.26 30 8.23 45 4.29 20 3.13 17 (wide ) 7.52 5 4.16 100 2.43 10 6.61 65 3.81 25 (wide) 2.15 15 6.08 3 3.60 20
Form IVForm IV
dl d I d Idl d I d I
8,85 70 4,65 100 2,93 4 7,80 6 4,30 25 2,76 12 7,15 25 4,01 25 2,62 1 6,01 20 3,75 35 2,41 2 5,06 18 3,10 1 2,30 3 IR-Spektre8.85 70 4.65 100 2.93 4 7.80 6 4.30 25 2.76 12 7.15 25 4.01 25 2.62 1 6.01 20 3.75 35 2.41 2 5, 06 18 3.10 1 2.30 3 IR Spectra
Spektrometer - Perkin-Elmer 521, område 4000-650 cm ^Spectrometer - Perkin-Elmer 521, range 4000-650 cm 2
Spektre opnoteret for nujolopslæmninger, idet bånd der kan tilskrives nujolen udgår.Spectra listed for nujol slurries, as bands attributable to nujol are deleted.
Form IForm I
3520 w 1620 s 1328 s 1112 m 882 s 3460 m x 1590 s 1284 m 1076 m 878 sh 3370 m 1556 m 1262 m 1054 sh 838 w 3265 s 1534 s 1248 m x 1042 s 814 w 1770 sh 1480 m 1170 m 1004 m 790 w 1752 s 1410 s 1152 m 978 m 778 w 1706 s 1400 s 1134 w 918 w 754 m 1660 s 1338 s 26 1676833520 w 1620 s 1328 s 1112 m 882 s 3460 mx 1590 s 1284 m 1076 m 878 sh 3370 m 1556 m 1262 m 1054 sh 838 w 3265 s 1534 s 1248 mx 1042 s 814 w 1770 sh 1480 m 1170 m 1004 m 790 w 1752 s 1410 s 1152 m 978 m 778 w 1706 s 1400 s 1134 w 918 w 754 m 1660 s 1338 s 26 167683
Form IIForm II
3526 m 1642 sh 1284 m 1080 m 882 m 3492 w 1624 s 1268 m 1058 m 878 w x 3364 m 1544 s 1240 m x 1045 m 840 w 3250 m 1478 m 1172 m 1005 m 818 w 1758 s 1412 s 1152 m 980 m 792 w 1695 s 1398 s 1142 m 954 w 752 m 1665 s 1332 s 1112 m 920 w3526 m 1642 sh 1284 m 1080 m 882 m 3492 w 1624 s 1268 m 1058 m 878 wx 3364 m 1544 s 1240 mx 1045 m 840 w 3250 m 1478 m 1172 m 1005 m 818 w 1758 s 1412 s 1152 m 980 m 792 w 1695 s 1398 s 1142 m 954 w 752 m 1665 s 1332 s 1112 m 920 w
Form IIIForm III
3465 m 1632 m 1285 m 1078 m 878 s 3415 m 1618 s 1260 m x 1058 s 836 w 3345 m 1552 m 1230 m 1048 s 820 w 3275 m 1532 s 1225 m 1014 m 800 w 3200 m 1482 m 1196 w 985 m 790 w 1780 s 1412 s 1180 m 938 w 768 m 1702 s 1395 s 1155 m 888 m 748 m 1660 s 1326 s x 1124 s3465 m 1632 m 1285 m 1078 m 878 s 3415 m 1618 s 1260 mx 1058 s 836 w 3345 m 1552 m 1230 m 1048 s 820 w 3275 m 1532 s 1225 m 1014 m 800 w 3200 m 1482 m 1196 w 985 m 790 w 1780 s 1412 s 1180 m 938 w 768 m 1702 s 1395 s 1155 m 888 m 748 m 1660 s 1326 sx 1124 s
Form IVForm IV
3585 w 1620 s 1330 s 1078 m 882 m 3520 w 1594 s 1285 m 1058 m 878 w 3370 m 1555 m 1264 m 1042 m 838 w x 3260 s 1540 m 1240 m 1008 m 818 w 1758 s 1478 m 1172 w 980 m 788 w 1712 s 1410 s 1152 m 956 w 752 m 1664 s 1400 s 1114 w 920 w3585 w 1620 s 1330 s 1078 m 882 m 3520 w 1594 s 1285 m 1058 m 878 w 3370 m 1555 m 1264 m 1042 m 838 wx 3260 s 1540 m 1240 m 1008 m 818 w 1758 s 1478 m 1172 w 980 m 788 w 1712 s 1410 s 1152 m 956 w 752 m 1664 s 1400 s 1114 w 920 w
Forkortelsesforklaring: s = stærk, sh = skulder, m = middel, w = svag.Short explanation: s = strong, sh = shoulder, m = medium, w = weak.
x betyder bånd der er karakteristisk for hver af krystalformerne .x means bands characteristic of each of the crystal forms.
Særlig værdifuldt er saltet af form II af cefuroxim, og ifølge opfindelsen går man derfor hensigtsmæssigt frem som angivet i krav 4.Particularly valuable is the salt of Form II of cefuroxime, and according to the invention, it is therefore convenient to proceed as set forth in claim 4.
I tilfælde hvor der ønskes uopløselige salte af forbindelsen I til en given anvendelse, fx til brug i depotpræparater, kan sådanne salte dannes på konventionel måde, fx med passende organiske aminer.In cases where insoluble salts of compound I are desired for a given application, for example, for use in depot preparations, such salts may be formed in a conventional manner, for example, with appropriate organic amines.
147683 27 Når man benytter den i krav 1 anførte fremgangsmåde a), kan R11 i forbindelsen med formel III fx være resten af en esterdannende alifatisk eller aralifatisk alkohol eller en esterdannende fenol, silanol eller stannanol, eller en symmetrisk eller blandet anhydridgruppe afledet af en passen-= 12 de syre. Nar R er en N-beskyttende gruppe, kan den fx være en acylgruppe, navnlig en lavere alkanoylgruppe såsom acetyl, en halogensubstitueret lavere alkanoylgruppe såsom mono-, di- eller trikloracetyl, eller en klorsulfonylgruppe. Et syreadditionssalt af forbindelsen III kan fx være dannet med en mineralsk syre såsom saltsyre, brombrintesyre, svovlsyre, salpetersyre eller fosforsyre eller en organisk syre såsom metansulfonsyre eller toluen-p-sulfonsyre.For example, when using the process (a) of claim 1, R 11 in the compound of formula III may be the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol, or a symmetrical or mixed anhydride group derived from a suitable - = 12 the acid. When R is an N-protecting group, it may be, for example, an acyl group, in particular a lower alkanoyl group such as acetyl, a halogen substituted lower alkanoyl group such as mono-, di- or trichloroacetyl, or a chlorosulfonyl group. For example, an acid addition salt of compound III may be formed with a mineral acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric or an organic acid such as methanesulfonic or toluene-p-sulfonic acid.
Ugiftige salte af forbindelser med den almene formel I kan dannes på en hvilken som helst hensigtsmæssig måde, fx ved i og for sig velkendte metoder. Således kan man fx danne basesalte ved at omsætte cephalosporinsyren med natrium- eller kalium- 2-ætylhexanoat. Biologisk acceptable esterderivater kan dannes ved hjælp af konventionelle forestringsmidler. 1-Oxyder kan dannes ved behandling af det tilsvarende cephalosporinsulfid med et passende oxydationsmiddel, fx med en persyre såsom metaperjodsyre, pereddikesyre, monoperftalsyre eller n-klorperbenzoesyre eller med t-butylhypoklorit hensigtsmæssigt i nærværelse af en svag base såsom pyridin.Non-toxic salts of compounds of general formula I can be formed in any convenient manner, for example, by methods well known in the art. Thus, for example, base salts can be formed by reacting the cephalosporic acid with sodium or potassium 2-ethylhexanoate. Biologically acceptable ester derivatives can be formed by conventional esterification agents. 1-Oxides can be formed by treating the corresponding cephalosporin sulfide with a suitable oxidizing agent, for example, with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or n-chloroperbenzoic acid or with t-butyl hypochlorite suitably in the presence of a weak base such as pyridine.
Forbindelser med den almene formel I kan hensigtsmæssigt fremstilles ved at man kondenserer en forbindelse med formel III med et acyleringsmiddel i form af et syrehalogenid, navnlig et syreklorid eller et syrebromid svarende til syren IV. En sådan acy-lering kan udføres ved en temperatur mellem -50 og +50°C, fortrinsvis ved en temperatur mellem -20 og +30°C. Acyleringen kan udføres i vandige eller ikke-vandige medier.Compounds of general formula I may conveniently be prepared by condensing a compound of formula III with an acylating agent in the form of an acid halide, in particular an acid chloride or an acid bromide corresponding to the acid IV. Such acylation can be carried out at a temperature between -50 and + 50 ° C, preferably at a temperature between -20 and + 30 ° C. The acylation can be carried out in aqueous or non-aqueous media.
Acylering med et syrehalogenid kan udføres i nærværelse af et syrebindende middel (fx en tertiær amin som triætylamin eller dimetylanilin, en uorganisk base såsom kalciumkarbonat eller natriumkarbonat eller et oxiran, fortrinsvis et lavere-1,2-alkylenoxyd såsom ætylenoxyd eller propylenoxyd) som tjener til at binde hydro-genhalogenid der frigøres ved acyleringsreaktionen.Acylation with an acid halide can be carried out in the presence of an acid-binding agent (e.g., a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium carbonate or an oxirane, preferably a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide). to bind hydrogen halide released by the acylation reaction.
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Den fri syreform af forbindelsen med den almene formel IV kan selv bruges som acyleringsmiddel. Sådanne acyleringer gennemføres hensigtsmæssigt i nærværelse af fx et karbodiimid såsom N,Ν'-diætyl-, dipropyl- eller diisopropylkarbodiimid, NjN'-dicyklo-hexylkarbodiimid eller N-ætyl-Ν'-γ-dimetylaminopropylkarbodiimid; en karbonylforbindelse såsom karbonyldiimidazol; eller et isoxazo-liniumsalt såsom N-ætyl-5-fenylisoxazolinium-3'-sulfonat eller N-t-butyl-metylisoxazoliniumperklorat. Kondensationsreaktionen genne-føres hensigtsmæssigt i et vandfrit reaktionsmedium, fx metylenklorid, dimetylformamid eller acetonitril.The free acid form of the compound of general formula IV can itself be used as an acylating agent. Such acylations are conveniently carried out in the presence of, for example, a carbodiimide such as N, Ν'-diethyl, dipropyl or diisopropylcarbodiimide, N a carbonyl compound such as carbonyl diimidazole; or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium 3'-sulfonate or N-t-butyl methylisoxazolinium perchlorate. The condensation reaction is suitably re-introduced in an anhydrous reaction medium, for example methylene chloride, dimethylformamide or acetonitrile.
Acyleringen kan også udføres med andre amiddannende derivater af den fri syre IV, fx et symmetrisk anhydrid eller et blandet anhydrid, fx med pivalinsyre eller dannet med et halogen-formiat såsom et lavere alkylhalogenformiat. De blandede eller symmetriske anhydrider kan udvikles in situ. Således kan man fx frembringe et blandet anhydrid ved at bruge N-ætoxykarbonyl-2-ætoxy-1,2-dihydrokinolin. Blandede anhydrider kan også dannes med fosforsyrer (fx fosforsyre eller fosforsyrling), svovlsyre eller alifatiske eller aromatiske sulfonsyrer som fx p-toluensul-fonsyre.The acylation can also be carried out with other amide-forming derivatives of the free acid IV, for example, a symmetrical anhydride or a mixed anhydride, for example with pivalic acid or formed with a haloformate such as a lower alkyl haloformate. The mixed or symmetrical anhydrides can be developed in situ. Thus, for example, a mixed anhydride can be prepared using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed with phosphoric acids (e.g., phosphoric acid or phosphoric acid), sulfuric acid, or aliphatic or aromatic sulfonic acids such as p-toluenesulfonic acid.
147683 29 Når der bruges et udgangsmateriale med den almene formel V indbefatter egnede karbamoyleringsmidler isocyanater 13 13 med den almene formel R .NCO (VIII), hvor R er en labil substituentgruppe; sådanne karbamoyleringsmidler tjener til i 3-stillingen at danne en N-beskyttet karbamoyloxymetylgrup- 13 13 pe med formlen -CH2O.CO.NHR hvor R har den ovenfor angivne betydning, hvilken gruppe derefter kan omdannes til den ønskede usubstituerede 3-karbamoyloxymetylgruppe ved efter- 13 følgende fraspaltning af gruppen R , fx ved hydrolyse. Labile grupper R13 der let kan fraspaltes ved en sådan efterfølgende behandling er bl.a. klorsulfonyl og bromsulfonyl; aral-kylgrupper såsom benzyl, p-metoxybenzyl og difenylmetyl; t-butyl; halogenerede lavere alkanoylgrupper såsom dikloracetyl og triklor-acetyl; og halogenerede lavere alkoxykarbonylgrupper såsom 2,2,2-triklorætoxykarbonyl. Grupper R af denne type, med undtagelse af aralkylgrupper såsom difenylmetyl, kan i almindelighed fraspaltes ved syrekatalyseret eller basekatalyseret hydrolyse, fx ved hjælp af natriumbikarbonat. Halogenerede grupper såsom klorsulfonyl, kloracetyl og 2,2,2-triklorætoxy-karbonyl kan også fraspaltes reduktivt, mens sådanne grupper som kloracetyl også kan fraspaltes ved behandling med tioamider såsom tiourinstof. Aralkylgrupper såsom difenylmetyl fraspaltes hensigtsmæssigt ved behandling med syre, fx en stærk organisk syre såsom tri fluoreddikesyre.When a starting material of the general formula V is used, suitable carbamoylating agents include isocyanates 13 13 of the general formula R .NCO (VIII), wherein R is a labile substituent group; such carbamoylating agents serve to form at the 3-position an N-protected carbamoyloxymethyl group of the formula -CH2O.CO.NHR where R has the meaning given above, which group can then be converted to the desired unsubstituted 3-carbamoyloxymethyl group by the following: 13 following the cleavage of the group R, for example by hydrolysis. Labile groups R13 that can be readily cleaved by such subsequent treatment are i.a. chlorosulfonyl and bromosulfonyl; aralkyl groups such as benzyl, p-methoxybenzyl and diphenylmethyl; t-butyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halogenated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Groups R of this type, with the exception of aralkyl groups such as diphenylmethyl, can generally be cleaved by acid-catalyzed or base-catalyzed hydrolysis, for example by means of sodium bicarbonate. Halogenated groups such as chlorosulfonyl, chloroacetyl and 2,2,2-trichloroethoxycarbonyl can also be reductively cleaved, while such groups as chloroacetyl can also be cleaved by treatment with thioamides such as thiourea. Aralkyl groups such as diphenylmethyl are conveniently cleaved by treatment with acid, for example a strong organic acid such as trifluoroacetic acid.
Karbamoyleringsmidlet med den almene formel VIII bruges hensigtsmæssigt i overskud, fx mindst 1,1 mol i forhold til forbindelsen med den almene formel V. Karbamoyleringen kan understøttes ved tilstedeværelse af base, fx en tertiær organisk base såsom en tri-(lavere alkyl)-amin, fx triætylamin, eller ved at man bruger syren V i form af et alkalimetalsalt, fx natriumsaltet, selv om en sådan understøttelse eventuelt ikke er nødvendig i tilfælde af mere aktive isocyanater, fx forbindelser med den almene formel VIIIThe carbamoylating agent of general formula VIII is conveniently used in excess, e.g., at least 1.1 mole relative to the compound of general formula V. The carbamoylation may be supported by the presence of base, e.g., a tertiary organic base such as a tri- (lower alkyl) amine , e.g., triethylamine, or using the acid V in the form of an alkali metal salt, e.g., the sodium salt, although such support may not be necessary in the case of more active isocyanates, e.g., compounds of general formula VIII
50 147683 hvor R er en stærkt elektrcntilbagetrækkende gruppe såsem klor-sulfonyl eller trikloracetyl. Karbamoyleringer som involverer re- 13 aktion af en fri syre V med overskud af isocyanat VIII, hvor R er en sådan gruppe som klorsulfonyl eller trikloracetyl,er således af særlig praktisk fordel på grund af reaktionsbetingelsernes enkelhed, idet der ikke er noget behov for midlertidig blokering og påfølgende afblokering af karboxygruppen i 4-stillingen i ce- 13 phalosporinet og eftersom den elektrontilbagetrækkende gruppe R i det resulterende N-beskyttende 3-karbamoyloxymetylcephalospo-rinprodukt let fjernes ved fx hydrolyse med vandigt natriumbikarbonat.Wherein R is a highly electron withdrawing group such as chlorosulfonyl or trichloroacetyl. Thus, carbamoylations involving the reaction of a free acid V with excess of isocyanate VIII, wherein R is such a group as chlorosulfonyl or trichloroacetyl, are of particular practical advantage due to the simplicity of the reaction conditions, as there is no need for temporary blocking. and subsequent unblocking of the carboxy group at the 4-position of the cephalosporin and since the electron withdrawing group R of the resulting N-protective 3-carbamoyloxymethylcephalosporin product is readily removed by, for example, hydrolysis with aqueous sodium bicarbonate.
Det skal bemærkes at det kan være hensigtsmæssigt at 13 bevare eller endog indføre en N-substituerende gruppe R under omdannelser af som mellemprodukter frembragte 3-karbamoyloxymetyl-forbindelser for til et minimum at nedbringe uønskede bireaktioner som involverer karbamoyloxymetylgruppen.It should be noted that it may be appropriate to maintain or even introduce an N-substituting group R during conversions of intermediates produced 3-carbamoyloxymethyl compounds to minimize undesired side reactions involving the carbamoyloxymethyl group.
Et andet praktisk anvendeligt karbamoyleringsmiddel er cyansyre, der hensigtsmæssigt kan dannes in situ ud fra fx et alkalimetal cyanat såsom natriumcyanat, idet reaktionen lettes ved tilstedeværelse af en syre, fx en stærk organisk syre såsom tri- fluoreddikesyre. Cyansyre svarer i effekt til forbindelsen med 13 . den almene formel VIII hvor E betegner hydrogen og bevirker derfor omdannelse af forbindelser med den almene formel VIII direkte til deres 3-karbamoyloxymetylanaloger.Another practically useful carbamoylating agent is cyanoic acid, which can conveniently be formed in situ from, for example, an alkali metal cyanate such as sodium cyanate, the reaction being facilitated by the presence of an acid, for example a strong organic acid such as trifluoroacetic acid. Cyanic acid corresponds in effect to the compound of 13. the general formula VIII wherein E represents hydrogen and therefore causes the conversion of compounds of the general formula VIII directly to their 3-carbamoyloxymethyl analogues.
3-Hydroxymetyl-udgangsmateriale til anvendelse ved denne udførelsesform for fremgangsmåden ifølge opfindelsen kan fremstilles fx ved de metoder der er beskrevet i britisk patentskrift nr. 1.121.308 og belgisk patentskrift nr. 783.449.3-Hydroxymethyl starting material for use in this embodiment of the process of the invention can be prepared, for example, by the methods described in British Patent No. 1,121,308 and Belgian Patent No. 783,449.
En hvilken som helst blokerende gruppe som er substitu-ent på 4-karboxygruppen i forbindelser med de almene formler III, V eller VI.er hensigtsmæssigt en gruppe som let kan fraspaltes på et senere trin af en reaktionsfølge og er med fordel en gruppe indeholdende 1-20 kulstofatomer. Egnede blokerede karboxylgrupper er velkendte på dette område af kemien, og en liste af repræsentative grupper indgår i ovennævnte belgiske patentskrift nr. 783.449. Eksempler på foretrukne blokerede karboxylgrupper er aryl-lavere-alkoxykarbonylgrupper såsom p-metoxybenzyloxykarbonyl, p-nitro- 147683 31 benzyloxykarbonyl og difenylmetoxykarbonyl; lavere alkoxykarbonyl-grupper såsom t-butoxykarbonyl; og lavere halogenalkoxykarbonyl-grupper såsom 2,2,2-triklorætoxykarbonyl. Den karboxylblokerende gruppe kan senere fjernes på en hvilken som helst af de hensigtsmæssige metoder der er beskrevet i literaturen; således er fx syrekatalyseret eller basekatalyseret hydrolyse anvendelig i mange tilfælde såvel som enzymatisk katalyserede hydrolyser.Any blocking group which is substituted on the 4-carboxy group in compounds of general formulas III, V or VI is suitably a group which can be readily decomposed at a later stage of a reaction sequence and is advantageously a group containing 1 -20 carbon atoms. Suitable blocked carboxyl groups are well known in the art of chemistry, and a list of representative groups is included in the aforementioned Belgian Patent Specification No. 783,449. Examples of preferred blocked carboxyl groups are aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group may later be removed by any of the appropriate methods described in the literature; thus, for example, acid-catalyzed or base-catalyzed hydrolysis is useful in many cases as well as enzymatically catalyzed hydrolyses.
Hvor der ved slutningen af en given præparationsfølge vindes en sulfoxydanalog til en forbindelse med den almene formel I, kan omdannelse til det tilsvarende sulfid fx gennemføres ved reduktion af det tilsvarende acyloxysulfoniumsalt eller alkyloxy-sulfoniumsalt fremstillet in situ fx ved omsætning med acetylklorid i tilfælde af et acetoxysulfoniumsalt, idet reduktionen udføres fx ved hjælp af natriumditionit eller ved hjælp af jodid-ioner (fx som en opløsning af kaliumjodid i et vandbiandbart opløsningsmiddel såsom eddikesyre, tetrahydrofuran, dioxan, dime-tylformamid eller dimetylacetamid). Reaktionen kan gennemføres ved en temperatur mellem -20 og +50°c.Where at the end of a given preparation sequence a sulfoxide analogue is obtained for a compound of general formula I, conversion to the corresponding sulfide can be carried out, for example, by reduction of the corresponding acyloxy sulfonium salt or alkyloxy sulfonium salt prepared in situ, for example by reaction with acetyl chloride in the case of a acetoxysulfonium salt, the reduction being carried out, for example, by sodium dithionite or by iodide ions (e.g. as a solution of potassium iodide in a water miscible solvent such as acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide). The reaction can be carried out at a temperature between -20 and + 50 ° c.
Når reaktionsproduktet er en ceph-2-em-4-karboxylsyre-ester kan den ønskede ceph-3-em-forbindelse vindes ved behandling af førstnævnte forbindelse med en base.When the reaction product is a ceph-2-em-4-carboxylic acid ester, the desired ceph-3-em compound can be obtained by treating the former with a base.
De antibiotisk virksomme forbindelser der frembringes ved fremgangsmåden ifølge opfindelsen kan oparbejdes til indgift på en hvilken som helst hensigtsmæssig måde i analogi med andre antibiotika.The antibiotic-active compounds produced by the method of the invention can be reprocessed for administration in any convenient manner by analogy with other antibiotics.
Til veterinærmedicinsk anvendelse kan præparaterne fx oparbejdes som intramammærpræparater i enten langtidsvirkende eller hurtigt afgivende grundlag.For veterinary use, the compositions may, for example, be worked up as intramammary preparations on either a long-acting or rapidly delivering basis.
Generelt kan præparaterne indeholde fra 0,1% af de aktive stof og opefter, fx 0,1-99% og fortrinsvis 10-60% af det aktive materiale i afhængighed af indgiftmetoden. Hvis præparatet har form af dosisenheder indeholder hver enhed fortrinsvis 50-1500 mg af det aktive stof. Den dosis der bruges til behandling af voksne mennesker vil fortrinsvis være i området 500-4000 mg om dagen i afhængighed af indgiftvejen og indgifthyppigheden.Generally, the compositions may contain from 0.1% of the active substance upwards, for example 0.1-99% and preferably 10-60% of the active material, depending on the method of administration. If the preparation is in dosage units, each unit preferably contains 50-1500 mg of the active substance. The dose used to treat adult humans will preferably be in the range of 500-4000 mg per day, depending on the route of administration and the frequency of administration.
De omhandlede forbindelser kan indgives i kombination med andre dermed forenelige lægemidler såsom antibiotika, fx penicilliner, tetracykliner eller andre cephalosporiner.The present compounds may be administered in combination with other compatible drugs such as antibiotics, for example, penicillins, tetracyclines or other cephalosporins.
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Nedenstående hidtil ukendte forbindelser er værdifulde som mellemprodukter ved fremstilling af antibiotisk virksomme forbindelser med den almene formel I: difenylmetyl-(6R,7R)-7-amino-3-trikloracetylkarbamoyl-oxymetylceph-3-em-4-karboxylat og toluen-p-sulfonsyresaltet deraf; difenylmetyl-(6R, 7R)-7-amino-3-karbamoyloxymetylceph-3-em-4-karboxylat-toluen-p-sulfonsyresalt; t-butyl-(6R,7 R)-7-/2-(£ur-2-yl)-2-metoxyimi noacetamidoj- 3-hydroxymetylceph-3-em-4-karboxylat (syn-isomer); (6R,7R)-7-amino-3-kloracetylkarbamoyloxymetylceph-3-em-4-karboxylsyre; og (6R,7R)-7-amino-3-trikloracetylkarbamoyloxymetylceph- 3-em-4-karboxylsyre.The following compounds are valuable as intermediates in the preparation of antibiotic-active compounds of general formula I: diphenylmethyl- (6R, 7R) -7-amino-3-trichloroacetylcarbamoyl-oxymethylceph-3-em-4-carboxylate and toluene-β the sulfonic acid salt thereof; diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt; t-butyl (6R, 7R) -7- [2- ([uro-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylceph-3-em-4-carboxylate (syn isomer); (6R, 7R) -7-amino-3-kloracetylkarbamoyloxymetylceph-3-em-4-carboxylic acid; and (6R, 7R) -7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid.
Nogle eksempler tjener til nærmere belysning af fremgangsmåden ifølge opfindelsen. I eksemplerne er smeltepunkter bestemt på en Kofler-blok.Some examples serve to elucidate the method of the invention. In the examples, melting points are determined on a Kofler block.
A) Fremstilling af udgangsmaterialerA) Preparation of starting materials
Udgangsmateriale 1 a) Difenylmetyl-(6R,7R)-7-(tien-2-ylacetamido)-3-tri-kloracetylkarbamoyloxymetylceph-3-em-4-karboxylat 13,2 g (70 mmol) trikloracetylisocyanat sattes til en under omrøring værende suspension af 26,0 g (50 mmol) difenylmetyl- (6R,7R)-3-hydroxymetyl-7-(tien-2-ylacetamido)-ceph-3-em-4-karboxylat i 600 ml acetone ved 20°C. Det faste stof opløste sig snart og efter at blandingen havde været omrørt ved 20°C i en time afkøledes den i en time og det resulterende faste stof frafiltre-redes og vaskedes med æter, hvorved der fremkom 33,1 g (93/0 af den i overskriften angivne forbindelse med smeltepunkt 183-184°C. o^1 = +24° (c = 0,95 i DMSO). λ infl. (ætanol) 235 nm (i = 14.500) og λ infl. (ætanol) 256 nm (é « 8.820).Starting material 1 a) Diphenylmethyl (6R, 7R) -7- (thien-2-ylacetamido) -3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate 13.2 g (70 mmol) of trichloroacetyl isocyanate was added under stirring. suspension of 26.0 g (50 mmol) of diphenylmethyl (6R, 7R) -3-hydroxymethyl-7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate in 600 ml of acetone at 20 ° C. The solid dissolved soon and after stirring at 20 ° C for one hour it was cooled for one hour and the resulting solid was filtered off and washed with ether to give 33.1 g (93/0 of the title compound having a melting point of 183-184 ° C. o ^ 1 = + 24 ° (c = 0.95 in DMSO) λ infl (ethanol) 235 nm (i = 14,500) and λ infl (ethanol) 256 nm (δ 8.820).
'IR-, NMR- og mikroanalytiske data bekræftede strukturen som værende den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed the structure as being the title compound.
147683 33 b) Difenylmetyl-(6R,7R)-7-amino-3-trikloracetylkarbamo-yloxymetylceph-3-em-4-karboxylat-toluen-p-sulfonsyre-salt 31 ral (0,384 mol) vandfrit pyridin sattes til en opløsning af 20 g (96 mmol) fosforpentaklorid i 300 ml tør diklormetan ved 3°C. Suspensionen omrørtes i ti minutter ved 3°C hvorefter der tilsattes 22,5 g (32 mmol) difenylmetyl-(6R,7R)-7-(tien-2-ylacet-amido)-3-trikloracetylkarbamoyloxymetylceph-3-em-4-karboxylat; reaktionsblandingen omrørtes ved ca. 2°C i en time. Den mørke opløsning udhældtes langsomt i en kold (0°C) vandfri blanding af 80 ml metanol og 200 ml diklormetan idet' temperaturen holdtes under 5°C. Man tillod derefter opløsningens temperatur at stige til 23°C og efter omrøring af opløsningen ved denne temperatur i en time tilsattes der 200 ml vand. Det organiske lag fraskiltes og vaskedes med 2N svovlsyre, vand, natriumbikarbonatopløsning og vand, tørredes over magniumsulfat og inddampedes i vakuum. Den resulterende olie opløstes i ætylacetat og der tilsattes en opløsning af 6,0 g (31,5 mmol) toluen-p-sulfonsyremonohydrat i ætylacetat. De forenede opløsning (ca. 350 ml ) udhældtes i ca. 1 liter diætylæter og det resulterende faste stof frafiltreredes og tørredes i vakuum, hvorved der fremkom 17,2 g (72%) af den i overskriften angivne forbindelse med smeltepunkt 150-153°C; a^1 = +7,5° (c = 0,82 i DMSO). λ max (ætanol 263 nm (£ = 7600) og K infl. (ætanol) 267 nm (.t = 7350).B) Diphenylmethyl- (6R, 7R) -7-amino-3-trichloroacetylcarbamoyl-oxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt 31al (0.384 mol) anhydrous pyridine was added to a solution of 20 g (96 mmol) of phosphorus pentachloride in 300 ml of dry dichloromethane at 3 ° C. The suspension was stirred for 10 minutes at 3 ° C and then added 22.5 g (32 mmol) of diphenylmethyl- (6R, 7R) -7- (thien-2-ylacetamido) -3-trichloroacetylcarbamoyloxymethylceph-3-em-4- carboxylate; the reaction mixture was stirred at ca. 2 ° C for one hour. The dark solution was slowly poured into a cold (0 ° C) anhydrous mixture of 80 ml of methanol and 200 ml of dichloromethane keeping the temperature below 5 ° C. The temperature of the solution was then allowed to rise to 23 ° C and after stirring the solution at this temperature for one hour 200 ml of water was added. The organic layer was separated and washed with 2N sulfuric acid, water, sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. The resulting oil was dissolved in ethyl acetate and a solution of 6.0 g (31.5 mmol) of toluene-p-sulfonic acid monohydrate in ethyl acetate was added. The combined solution (about 350 ml) was poured into ca. One liter of diethyl ether and the resulting solid were filtered off and dried in vacuo to give 17.2 g (72%) of the title compound, mp 150-153 ° C; α1 = + 7.5 ° (c = 0.82 in DMSO). λ max (ethanol 263 nm (£ = 7600) and K infl (ethanol) 267 nm (.t = 7350).
IR-, NMR- og mikroanalytiske data bekræftede at produktets struktur var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure of the product was the title compound.
Inddampning af filtratet og triturering af remanensen med ætanol gav 3,2 g (14,2%) uomdannet udgangsmateriale.Evaporation of the filtrate and trituration of the residue with ethanol gave 3.2 g (14.2%) of crude starting material.
c) Difenylmetyl-(6R,7R)-7-amino-3-karbamoyloxymetylceph- 3-em-4-karboxylat-toluen-p-sulfonsyresalt 17,2 g (22,7 mmol) af toluen-p-sulfonsyresaltet af dife-nylmetyl-(6R,7k)-7-amino-3-trikloracetylkarbamoyloxymetylceph-3-em-4-karboxylat opløstes i en blanding af 900 ml vandfri metanol og 45 ml acetylklorid og henstod ved 20°C i fem timer. Fjernelse af opløsningsmidlet under nedsat tryk gav en olie som opløstes i 147683 34 diklormetan. Denne opløsning rystedes med vandig natriumbikarbo-natopløsning og vaskedes derefter med vand. Der tilsattes 4*3 g (22,7 mmol) toluen-p-sulfonsyremonohydrat og opløsningsmidlet af-dampedes i vakuum. Remanensen opløstes i ca. 150 ml varm isopropa-nol og opløsningen udhældtes i ca. 600 ml diisopropylaeter. Det udfældede faste stof frafiltreredes og tørredes i vakuum, hvorved der fremkom 8,9 g (64%) af den i overskriften angivne forbindelse med smeltepunkt 110-112°C; = -14° ( c = 1,0 i CHCl^). Amax (ætanol) 259 nm (é = 6120) og λ infl. (ætanol) 227 nm (é = 15-800).c) Diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt 17.2 g (22.7 mmol) of the toluene-p-sulfonic acid salt of the Nylmethyl (6R, 7k) -7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate was dissolved in a mixture of 900 ml of anhydrous methanol and 45 ml of acetyl chloride and left at 20 ° C for five hours. Removal of the solvent under reduced pressure gave an oil which was dissolved in dichloromethane. This solution was shaken with aqueous sodium bicarbonate solution and then washed with water. 4 * 3 g (22.7 mmol) of toluene-p-sulfonic acid monohydrate was added and the solvent was evaporated in vacuo. The residue was dissolved in ca. 150 ml of warm isopropanol and the solution was poured into ca. 600 ml of diisopropyl ether. The precipitated solid was filtered off and dried in vacuo to give 8.9 g (64%) of the title compound, mp 110-112 ° C; = -14 ° (c = 1.0 in CHCl3). Amax (ethanol) 259 nm (é = 6120) and λ infl. (ethanol) 227 nm (e = 15-800).
IR-, NMR- og mikroanalytiske data bekræftede at produktets struktur var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure of the product was the title compound.
Udgangsmateriale 2Starting material 2
Difenylmetyl-(6R, 7 R) -7-amino-3-kar bamoyl oxymetylceph- 3-em-4-karboxylat-toluen-p-sulfonsyresaltDiphenylmethyl (6R, 7R) -7-amino-3-carbamoyl oxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt
En under omrøring værende suspension af 156 g (0,75 mol) fosforpentaklorid i 1,5 liter tør diklormetan afkøledes i et isbad og behandledes med 60,5 ml (0,75 mol) pyridin med en sådan hastighed at blandingens temperatur holdt sig på ca. 20-25°C. Blandingen omrørtes og afkøledes til 8°C og der tilsattes portionsvis i løbet af ti minutter 354,5 g (o,5 mol) difenylmetyl-(6R,7R)-7-(tien-2-yl)-acetamido-3-trikloracetylkarbamoyloxymetyl-ceph-3-em-4-karboxylat. Blandingen omrørtes ved ca. 8°C i l 3/4 time og sattes derefter i løbet af ti minutter til en under omrøring værende blanding af 225 ml (2,5 mol) butan-1,3-diol og 500 ml diklormetan, i forvejen afkølet til -20°C så at blandingens temperatur holdtes i området mellem -15 og -20°C. Kølebadet fjernedes og blandingen omrørtes ved ca--10°C i tyve minutter. Der til sattes 1 liter vand og den tofasede blanding omrørtes i 30 minutter. Den vandige fase ekstraheredes med 2 x 500 ml diklormetan og de organiske faser vaskedes efter hinanden med 1 liter 2N saltsyre, hvorefter de forenedes og inddampedes til en brun gummi. Gummien opløstes i 3,6 liter metanol og denne opløsning omrørtes og behandledes med 1,2 liter mættet vandig natriumhydrogenkarbonatopløsning over en periode på ti minutter. Blandingen omrørtes ved ca. 20°C i l/2 time og en ringe mængde brunt fast stof fjernedes ved fil 147683 35 trering. Det gule filtrat koncentreredes i vakuum (badtemperatur ikke over 40°C) til ca. 1,5 liter og der tilsattes 15 liter vand. Den resulterende suspension afkøledes i køleskab i en time og det gule faste stof frafiltreredes, vaskedes godt med vand, sugedes så tørt som muligt og tørredes i vakuum ved 40°C i 24 timer. Det derved vundne fedtede faste stof, efterfulgt af 81 g (0,425 mol) toluen-p-sulfonsyremonohydrat sattes til 2 liter omrørt kloroform. Efter nogle minutter begyndte toluen-p-sulfonsyresaltet at udkrystallisere. Omrøringen fortsattes i yderligere 30 minutter hvorefter vandet fjernedes azeotropt i vakuum med kontinuerlig erstatning af kloroformen for at opretholde et rumfang på 2 liter. Suspensionen køledes i køleskab natten over og produktet frafiltrere-des, opslæmningsvaskedes med 2 x 250 ml kloroform, filtreredes påny, vaskedes ved fortrængning med 250 ml kloroform og tørredes i vakuum ved 40°C for at give den i overskriften angivne forbindelse som et smudsighvidt krystallinsk fast stof i en mængde på 237»8 g (74,1%). kmax (ætanol) 262 nm (f = 7250). NMR-spektret (Me2S0-d6) angav tilstedeværelse af 0,25 mol kloroform.A stirred suspension of 156 g (0.75 mole) of phosphorus pentachloride in 1.5 liters of dry dichloromethane was cooled in an ice bath and treated with 60.5 ml (0.75 mole) of pyridine at such a rate that the temperature of the mixture remained at ca. 20-25 ° C. The mixture was stirred and cooled to 8 ° C and 354.5 g (0.5 mol) of diphenylmethyl- (6R, 7R) -7- (thien-2-yl) -acetamido-3-trichloroacetylcarbamoyloxymethyl was added portionwise over ten minutes. ceph-3-em-4-carboxylate. The mixture was stirred at ca. 8 ° C for 3/4 hour and then added over ten minutes to a stirred mixture of 225 ml (2.5 moles) of butane-1,3-diol and 500 ml of dichloromethane, pre-cooled to -20 ° C so that the temperature of the mixture is kept in the range between -15 and -20 ° C. The cooling bath was removed and the mixture was stirred at about - 10 ° C for twenty minutes. 1 liter of water was added and the biphasic mixture was stirred for 30 minutes. The aqueous phase was extracted with 2 x 500 ml of dichloromethane and the organic phases were washed successively with 1 liter of 2N hydrochloric acid, then combined and evaporated to a brown gum. The gum was dissolved in 3.6 liters of methanol and this solution was stirred and treated with 1.2 liters of saturated aqueous sodium hydrogen carbonate solution over a period of ten minutes. The mixture was stirred at ca. 20 ° C for 1/2 hour and a small amount of brown solid was removed by file. The yellow filtrate was concentrated in vacuo (bath temperature not above 40 ° C) to ca. 1.5 liters and 15 liters of water were added. The resulting suspension was cooled in the refrigerator for one hour and the yellow solid was filtered off, washed well with water, sucked as dry as possible and dried in vacuo at 40 ° C for 24 hours. The fatty solid thus obtained, followed by 81 g (0.425 mole) of toluene-p-sulfonic acid monohydrate, was added to 2 liters of stirred chloroform. After a few minutes, the toluene-β-sulfonic acid salt began to crystallize. Stirring was continued for another 30 minutes after which the water was azeotropically removed in vacuo with continuous replacement of the chloroform to maintain a volume of 2 liters. The suspension was refrigerated overnight and the product filtered off, slurry washed with 2 x 250 ml of chloroform, filtered again, washed by evaporation with 250 ml of chloroform and dried in vacuo at 40 ° C to give the title compound as a pale white crystalline solid in an amount of 237 »8 g (74.1%). kmax (ethanol) 262 nm (f = 7250). The NMR spectrum (Me 2 SO-d 6) indicated the presence of 0.25 mole of chloroform.
Udgangsmateriale 3 (6R,7R)-7-Amino-3-karbamoyloxymetylceph-3-em-4-karboxyl- syre.Starting material 3 (6R, 7R) -7-Amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid.
300,0 g (0,44 mol) difenylmetyl-(6R,7R)-7-amino-3-karba-moyloxymetylceph-3-em-4-karboxylat-toluen-p-suifonsyresalt, solva-teret med ca. 0,6 mol kloroform, sattes portionsvis i løbet af 30 minutter til en under omrøring værende blanding af 300 ml trifluor-eddikesyre og 300 ml anisol, der befandt sig i et vandbad ved 20°C. Blandingens temperatur steg fra 23°C til 28°C i løbet af de første 20 minutter, men gik ned til 26°C ved tilsætningens slutning. Den gyldengule opløsning omrørtes i en time og temperaturen faldt til 21°C, hvorefter den sattes til en under omrøring værende blanding af 1,5 liter ætylacetat og 1,5 liter vand, anbragt i et isbad. Den under omrøring værende blandings pH-værdi reguleredes til 3,8 i løbet af ti minutter ved hjælp af ammoniakvand (massefylde 0,880), og temperaturen steg til 38°C. Suspensionen omrørtes og afkøledes 147683 36 til 10°C i løbet af 1 l/4 time, hvorefter den filtreredes. Det flødefarvede faste stof vaskedes med 750 ml vand og 4 x 200 ml ætylacetat og tørredes i vakuum, hvorved der fremkom 115,6 g (96,2%) af den i overskriften angivne forbindelse. -Vmax (pH 6 fosfat) 265 nm (£ = 7750). Renheden bedømtes ved højtryksvæskekromatografi (HPLC) til 99,7%.300.0 g (0.44 mole) of diphenylmethyl (6R, 7R) -7-amino-3-carbamoylloxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt, solvated with ca. 0.6 mole of chloroform was added portionwise over 30 minutes to a stirring mixture of 300 ml of trifluoroacetic acid and 300 ml of anisole which was in a water bath at 20 ° C. The temperature of the mixture increased from 23 ° C to 28 ° C during the first 20 minutes but decreased to 26 ° C at the end of the addition. The golden yellow solution was stirred for one hour and the temperature dropped to 21 ° C, then added to a stirring mixture of 1.5 liters of ethyl acetate and 1.5 liters of water, placed in an ice bath. The pH of the stirred mixture was adjusted to 3.8 over ten minutes using ammonia water (density 0.880) and the temperature rose to 38 ° C. The suspension was stirred and cooled to 10 ° C over 1/4 hour, then filtered. The cream colored solid was washed with 750 ml of water and 4 x 200 ml of ethyl acetate and dried in vacuo to give 115.6 g (96.2%) of the title compound. -Vmax (pH 6 phosphate) 265 nm (λ = 7750). The purity was evaluated by 99.7% by high pressure liquid chromatography (HPLC).
Mikroanalytiske data bekræftede at strukturen var den i overskriften angivne forbindelses.Microanalytical data confirmed that the structure was the title compound.
Udgangsmateriale 4 a) (6R,7 R)-7-(R-5-Benzoylamino-5-karboxypentanamido) -3 -hydroxymetylceph-3-em-4-karboxylsyreStarting material 4 a) (6R, 7R) -7- (R-5-Benzoylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid
En under omrøring værende opløsning af 62,00 g (ca. 100 mmol) ca. 67% rent (6R,7R)-7-(R-5-amino-5-karboxypentanamido)-3-hydroxymetylceph-3-em-4-karboxylsyremonokaliumsalt i 300 ml vand afkøledes til +5°C og behandledes med en opløsning af 17,4 ml (150 mmol) benzoylklorid i 200 ml acetone i løbet af 25 minutter. Reaktionsblandingens pH-værdi holdtes på 8,2-8,5 ved kontrolleret tilsætning af 30%s v/r vandigt trikaliumortofosfat. Blandingen omrørtes i yderligere ti minutter og dækkedes derefter med 140 ml ætylacetat, og pH nedsattes til 5,6 med ortofosforsyre. Lagene adskiltes og den vandige del vaskedes med mere ætylacetat (2 x 400 ml). Den vandige del fortyndedes med 2 liter vand, dækkedes med 2 liter ætylacetat og den omrørte blandings pH førtes til 2,0 med ortofosforsyre. Lagene adskiltes og det vandige lag ekstraheredes med yderligere 3 x 1500 ml ætylacetat. De forenede ekstrakter vaskedes med 800 ml mættet saltlage, tørredes og koncentreredes i vakuum til et rumfang på 300-400 ml. Den resulterende opslæmning omrørtes med 2 liter æter i 20 minutter og filtreredes derefter.A stirred solution of 62.00 g (about 100 mmol) of ca. 67% pure (6R, 7R) -7- (R-5-amino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid mono-potassium salt in 300 ml of water was cooled to + 5 ° C and treated with a solution of 17.4 ml (150 mmol) of benzoyl chloride in 200 ml of acetone over 25 minutes. The pH of the reaction mixture was maintained at 8.2-8.5 by controlled addition of 30% w / v aqueous tricalcium orthophosphate. The mixture was stirred for a further ten minutes and then covered with 140 ml of ethyl acetate, and the pH was reduced to 5.6 with orthophosphoric acid. The layers were separated and the aqueous portion was washed with more ethyl acetate (2 x 400 ml). The aqueous portion was diluted with 2 liters of water, covered with 2 liters of ethyl acetate and the pH of the stirred mixture was brought to 2.0 with orthophosphoric acid. The layers were separated and the aqueous layer was extracted with an additional 3 x 1500 ml of ethyl acetate. The combined extracts were washed with 800 ml of saturated brine, dried and concentrated in vacuo to a volume of 300-400 ml. The resulting slurry was stirred with 2 liters of ether for 20 minutes and then filtered.
Det opsamlede faste^våskedes med 2 x 250 ml æter og tørredes i vakuum (l mm Hg), hvorved der fremkom 54,95 g (88,6%) af den i overskriften angivne forbindelse som et hvidt fast stof, aD = +74° (c = 1,00 i dioxan); Amax (pH 6 puffer) 231 nm (E^ = 275), 266 nm (inflektion, E^cm = 145)· NMR-Spektret (Me2S0-dg) viste tilstedeværelse af ca. 20% laktonurenhed og ætylacetat (ca. 0,4 mol).The collected solid was washed with ether (2 x 250 ml) and dried in vacuo (1 mm Hg) to give 54.95 g (88.6%) of the title compound as a white solid, aD = +74 ° (c = 1.00 in dioxane); Amax (pH 6 buffer) 231 nm (E ^ = 275), 266 nm (inflection, E ^ cm = 145) · The NMR spectrum (Me₂SO-dg) showed the presence of ca. 20% lactone impurity and ethyl acetate (about 0.4 mole).
1476 δ3 37 b) (6R,7R)-7-(R-5-Benzoylamino-5-karboxypentanamido)-3-kloracetylkarbamoyloxymetylceph-3-em-4-karboxylsyre-mononatriumsalt 25,46 g af produktet fra (a) behandledes med 9,00 g (75 mmol) kloracetylisocyanat i 92 ml tør acetone. Den resulterende opløsning omrørtes i 25 minutter ved ca. 20°C, afkøledes derefter til ca. 5°C i løbet af fem minutter og behandledes med en opløsning af 8,47 g (51 mmol) natrium-2-ætylhexanoat i 51 ml acetone. Den krystallinske suspension omrørtes ved ca. 5°C i fem minutter og det faste stof opsamledes ved filtrering, vaskedes med 80 ml acetone og 250 ml æter og tørredes derpå i vakuum (1 mm Hg) til frembringelse af 27,23 g (107%) af den i overskriften angivne forbindelse; α^° = +72,0° ( c = 1,00 i 3%s vandigt NaHCO,); kmax (pH 6 puffer) 227 nm (E^e = 249), 261 nm (inflektion, E.^ = 105).B76 (6R, 7R) -7- (R-5-Benzoylamino-5-carboxypentanamido) -3-chloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid monosodium salt 25.46 g of the product of (a) was treated with 9.00 g (75 mmol) of chloroacetyl isocyanate in 92 ml of dry acetone. The resulting solution was stirred for 25 minutes at ca. 20 ° C, then cooled to ca. 5 ° C over five minutes and treated with a solution of 8.47 g (51 mmol) of sodium 2-ethyl hexanoate in 51 ml of acetone. The crystalline suspension was stirred at ca. 5 ° C for five minutes and the solid was collected by filtration, washed with 80 ml of acetone and 250 ml of ether and then dried in vacuo (1 mm Hg) to give 27.23 g (107%) of the title compound ; = + 72.0 ° (c = 1.00 in 3% aqueous NaHCO 3); kmax (pH 6 buffer) 227 nm (E ^ e = 249), 261 nm (inflection, E ^ = 105).
Det kernemagnetiske resonansspektrum (MegSO-dg) viste tilstedeværelse af ca. 35% laktonurenhed og ca. 1,0 mol kloracetamid.The nuclear magnetic resonance spectrum (MegSO-dg) showed the presence of ca. 35% lactone impurity and approx. 1.0 mole of chloroacetamide.
147683 38 c) (6R,7R)-7-.Amino-3-kloracetylkarbamoyloxymetylceph- 3-em-4-karboxylsyreC) (6R, 7R) -7-Amino-3-chloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid
En suspension a£ 24,77 g af produktet fra (b) i 320 ml tørt metylenklorid under nitrogen afkøledes til ca. 10°C med omrøring. Der tilsattes 17,60 ml (218,0 mmol) pyridin og derpå 16,80 ml (139,2 mmol) diklordimetylsilan, og den lysebrune suspension omrørtes ved ca. 20°C i tyve minutter og afkøledes så til -17°C. Der tilsattes 10,84 g (52,0 mmol) fosforpentaklorid og blandingen omrørtes ved en temperatur mellem -17 og -23°C i to timer. Der tilsattes 6,48 ml (80,4 mmol) pyridin og blandingen sattes til metanol (104 ml + 20 ml vaskevæsker, forud afkølet til -35°C) med en sådan hastighed at temperaturen af den under omrøring værende opløsning ikke oversteg -10°C. Den under omrøring værende opløsning fik lov til at stige til en temperatur på +2°C i løbet af 25 minutter og der tilsattes så 88 ml vand, hvorpå blandingens pH-værdi førtes fra 0,6 til 3,8 med ammoniakvand (massefylde 0,880). Den resulterende tofasede blanding indeholdende et udfældet fast stof afkøledes i en time og filtreredes derefter. Det faste stof vaskedes successivt med 100 ml 50%s vandig metanol, 80 ml metanol og 40 ml metylenklorid og tørredes derefter i vakuum (l mm Hg) til frembringelse af 6,86 g (27,7%) af den i overskriften angivne forbindelse som et flødefarvet pulver, = +48° (c = 1,04 i MeoS0); Xmax (pH 6 puffer) 237,5 nm (E^ = 149), 261,5 nm (Ej^ =145).A suspension of 24.77 g of the product of (b) in 320 ml of dry methylene chloride under nitrogen was cooled to ca. 10 ° C with stirring. 17.60 ml (218.0 mmol) of pyridine was added then 16.80 ml (139.2 mmol) of dichlorodimethylsilane and the light brown suspension was stirred at ca. 20 ° C for twenty minutes and then cooled to -17 ° C. Phosphorus pentachloride (10.84 g (52.0 mmol)) was added and the mixture was stirred at a temperature between -17 and -23 ° C for two hours. 6.48 ml (80.4 mmol) of pyridine were added and the mixture was added to methanol (104 ml + 20 ml wash liquids, pre-cooled to -35 ° C) at a rate such that the temperature of the stirred solution did not exceed -10 ° C. The stirred solution was allowed to rise to a temperature of + 2 ° C over 25 minutes and then 88 ml of water was added and the pH of the mixture was adjusted from 0.6 to 3.8 with ammonia water (density 0.880 ). The resulting biphasic mixture containing a precipitated solid was cooled for one hour and then filtered. The solid was washed successively with 100 ml of 50% aqueous methanol, 80 ml of methanol and 40 ml of methylene chloride and then dried in vacuo (1 mm Hg) to give 6.86 g (27.7%) of the title compound. as a cream powder, = + 48 ° (c = 1.04 in MeoSO); Λ max (pH 6 buffer) 237.5 nm (E + = 149), 261.5 nm (EI = = 145).
b) Eksemplerb) Examples
Eksempel 1 a) Di£enylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-</2-(£ur- 2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat (syn-isomer) 147683 39Example 1 a) Diylenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2- (iodo-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate (syn isomer) ) 147683 39
Metode IMethod I
Råt difenylmetyl- (6R, 7R)-7-amino-3-karbamoyloxymetyl-ceph-3-em-4-karboxylat-toluen-p-sulfonsyresalt, vundet ud fra den tilsvarende 3-trikloracetylkarbamoyloxymetylforbindelse (25,0 g, 0,33 mol) opløstes i en blanding af ætylacetat og vandig natrium-bikarbonatopløsning. Det organiske lag fraskiltes, vaskedes med vand, tørredes over magniumsulfat og inddampedes på en roterende evaporator til frembringelse af 11,5 g (0,262 mol, 77%) difenylmetyl- (6R,7R)-7-amino-3-karbamoyloxymetylceph-3-em-4-karboxylat som et skum.Crude diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethyl-ceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt, obtained from the corresponding 3-trichloroacetylcarbamoyloxymethyl compound (25.0 g, 0.33 mol) was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated on a rotary evaporator to give 11.5 g (0.262 mol, 77%) of diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3- em-4-carboxylate as a foam.
Der sattes 5,32 g (0,312 mol) af syn-isomeren af 2-(fur- 2-yl)-2-metoxyiminoeddikesyre i 100 ml tør diklormetan til en opløsning af denne amin i 50 ml diklormetan, afkøledes til 3°C, efterfulgt ti minutter senere af en opløsning af 6,5 g (0,312 mol) DL-dicyklohexylkarbodiimid i 30 ml diklormetan. Reaktionsblandingen omrørtes i isbad i 45 minutter i løbet af hvilken periode der udkrystalliseredes fast stof (antagelig Ν,Ν'-dicyklohexylurinstof). Dette faste stof frafiltreredes og kasseredes og filtratet vaskedes med vandig natriumbikarbonatopløsning og vand, tørredes over magniumsulfat og inddampedes til tørhed. Remanensen tritureredes med ætanol og gav 10,6 g af et råt produkt som rensedes ved kro-matografering på 1 kg silikagel. Eluering med 10% acetone i diklormetan fjernede ikke-polære urenheder og fraktioner elueret med 20% acetone i diklormetan gav 4,8 g (31%) af den i overskriften angivne forbindelse med smeltepunkt 199-202°C; ot^1 = +14° (c = 1,0 i DMSO); Xmax (ætanol) 277 nm (£ = 18.600) og \infl. (ætanol) 270 nm (é = 17.900).5.32 g (0.312 mol) of the syn isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid in 100 ml of dry dichloromethane were added to a solution of this amine in 50 ml of dichloromethane, cooled to 3 ° C. followed ten minutes later by a solution of 6.5 g (0.312 mole) of DL-dicyclohexylcarbodiimide in 30 ml of dichloromethane. The reaction mixture was stirred in an ice bath for 45 minutes during which time the solid was crystallized (presumably Ν, Ν'-dicyclohexylurea). This solid was filtered off and discarded, and the filtrate was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. The residue was triturated with ethanol to give 10.6 g of a crude product which was purified by chromatography on 1 kg of silica gel. Elution with 10% acetone in dichloromethane removed nonpolar impurities and fractions eluted with 20% acetone in dichloromethane gave 4.8 g (31%) of the title compound, mp 199-202 ° C; = + 14 ° (c = 1.0 in DMSO); Xmax (ethanol) 277 nm (£ = 18,600) and \ infl. (ethanol) 270 nm (e = 17,900).
IR, NMR og mikroanalytiske data bekræftede strukturen som værende den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed the structure as being the title compound.
Metode IIMethod II
1,86 g (18,4 mmol) triætylamin sattes til en opløsning i 35 ml diklormetan af 3,1 g (18,4 mmol) af syn-isomeren af 2-(fur- 2-yl)-2-metoxyiminoeddikesyre. Efter afkøling af denne opløsning i et isbad i fem minutter tilsattes der 1,57 ml (18,4 mmol) oxalyl- 147683 40 klorid og en dråbe N,N-dimetylformamid. Efter 1/2 time fjernedes opløsningsmidler under nedsat tryk og den faste remanens tørredes i en time i vakuum. Der tilsattes 150 ml vandfri æter for at opløse det syreklorid som var blevet dannet, og det uopløselige tri-ætylaminhydroklorid (2,5 g) frafiltreredes. Æteren inddampedes på en roterende evaporator og den olieagtige remanens genopløstes i dikiormetan.1.86 g (18.4 mmol) of triethylamine was added to a solution in 35 ml of dichloromethane of 3.1 g (18.4 mmol) of the syn isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid. After cooling this solution in an ice bath for five minutes, 1.57 ml (18.4 mmol) of oxalyl chloride and a drop of N, N-dimethylformamide were added. After 1/2 hour, solvents were removed under reduced pressure and the solid residue dried for one hour in vacuo. 150 ml of anhydrous ether was added to dissolve the acid chloride that had been formed and the insoluble triethylamine hydrochloride (2.5 g) was filtered off. The ether was evaporated on a rotary evaporator and the oily residue redissolved in dichloromethane.
3,9 g (14,7 mmol) difenylmetyl-(6R,7K)-7-amino-3-karba-moyloxymetylceph-3-em-4-karboxylat-toluen-p-sulfonsyresalt opløstes i vandfri dikiormetan. Denne opløsning rystedes med vandig natriumbikarbonatopløsning, vaskedes med vand og tørredes over magniumsulfat. Til denne opløsning af den fri amin sattes diklor-metanopløsningen af syn-isomeren af 2-(fur-2-yl)-2-metoxyiminoace-tylklorid og 5 ml propylenoxyd. Efter ti minutter frafiltreredes 1,1 g krystallinsk fast stof som senere identificeredes som dife-nylmetyl-(6R, 7R)-7-amino-3-karbamoyloxymetylceph-3-em-4-karboxy-lat-hydroklorid. Filtratet vaskedes med 2N svovlsyre, vand, vandig natriumbikarbonatopløsning og vand og tørredes over magniumsulfat og inddampedes til tørhed for at give 2,5 g (30,5%) af den i overskriften angivne forbindelse, hvis fysiske egenskaber var som hos det produkt der vandtes ved den foran beskrevne metode I.3.9 g (14.7 mmol) of diphenylmethyl (6R, 7K) -7-amino-3-carbamoylloxymethylceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt was dissolved in anhydrous dichloromethane. This solution was shaken with aqueous sodium bicarbonate solution, washed with water and dried over magnesium sulfate. To this solution of the free amine was added the dichloromethane solution of the syn isomer of 2- (fur-2-yl) -2-methoxyiminoacetyl chloride and 5 ml of propylene oxide. After ten minutes, 1.1 g of crystalline solid was filtered off, which was later identified as diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate hydrochloride. The filtrate was washed with 2N sulfuric acid, water, aqueous sodium bicarbonate solution and water and dried over magnesium sulfate and evaporated to dryness to give 2.5 g (30.5%) of the title compound, the physical properties of which were as in the product obtained. by the method described above.
b) Natrium-(6K,7R)-3-karbamoyloxymetyl-7-/2-(fur-2-yl)- 2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat (syn-isomer) 20 ml trilfuoreddikesyre sattes langsomt til en blanding af 5 ml anisol og 4,7 g (8 mmol) af syn-isomeren af difenylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7- ceph-3-em-4-karboxylat som var blevet afkølet i isbad. Kolben rystedes lejlighedsvis i løbet af de næste ti minutter for at sikre at der indtrådte fuldstændig opløsning af faststoffet. Den fjernedes derefter fra isbadet og overskydende trifluoreddikesyre fjernedes på en roterende evaporator. Triturering af remanensen med 5 ml ætylacetat gav 3,3 g (94%) af syn-isomeren af (6R,7R)-3-karbamoyl-oxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-kar-boxylsyre som et fast stof som frafiltreredes og vaskedes med di--ætylæter.b) Sodium (6K, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate (syn isomer) 20 ml of trifluoroacetic acid was added slowly to a mixture of 5 ml of anisole and 4.7 g (8 mmol) of the syn isomer of diphenylmethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] ceph-3-em-4-carboxylate which had been cooled in an ice bath. The flask was occasionally shaken over the next ten minutes to ensure complete dissolution of the solid. It was then removed from the ice bath and excess trifluoroacetic acid removed on a rotary evaporator. Trituration of the residue with 5 ml of ethyl acetate gave 3.3 g (94%) of the syn isomer of (6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido ceph-3-em-4-carboxylic acid as a solid which was filtered off and washed with diethyl ether.
147683 41147683 41
Den fri syre opløstes i acetone og der tilsattes et lille overskud af natrium-2-ætylhexanoat i acetone (8,0 ml af en molær opløsning). Efter at reaktionsblandingen var blevet omrørt ved 0°C i to timer frafiltreredes 2,3 g (73%) af det i overskriften angivne salt. Dette forenedes med en anden portion på 0,8 g af det i overskriften angivne salt og der rensedes ved vask af en vandig opløsning (250 ml) med 2 x 100 ml og 1 x 50 ml æter.The free acid was dissolved in acetone and a small excess of sodium 2-ethyl hexanoate in acetone (8.0 ml of a molar solution) was added. After the reaction mixture was stirred at 0 ° C for two hours, 2.3 g (73%) of the title salt was filtered off. This was combined with a second portion of 0.8 g of the title salt and purified by washing an aqueous solution (250 ml) with 2 x 100 ml and 1 x 50 ml ether.
Den vandige opløsning frysetørredes, hvorved der fremkom 2,66 g af syn-isomeren af natrium-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur- 2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat. = +73,5° (c = 1,06 i Me2S0), Amax (pH 6 puffer) 274 nm (£ = 16.500). max (nujol) 3450, 3330, 3250 (NH,NH2 og HgO), 1752 (azetidin-2-on) og 1652 og 1600 cm-1 ( karboxylat); ^(MegSO-d^ 0,24 (d, J 8 Hz, CONH), 2,12 (d, J 2 Hz, furyl C5-H), 3,25 og 3,30 (m, furyl C3-H og C4-H), 3,44 (bred s, C0NH2), 4,34 (dd, J 5 og 8 Hz, C?-H), 4,92 (d, J 5 Hz, C6-H), 5,15 (q, J 13 Hz, C-j-CHg), 6,07 (s, N0CH„) og 6,58 (q, J 18 Hz, C2-H2). ~ “The aqueous solution was freeze-dried to give 2.66 g of the syn isomer of sodium (6R, 7R) -3-carbamoyloxymethyl-7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3 em-4-carboxylate. = + 73.5 ° (c = 1.06 in Me 2 SO), Amax (pH 6 buffer) 274 nm (£ = 16,500). max (nujol) 3450, 3330, 3250 (NH, NH2 and HgO), 1752 (azetidin-2-one) and 1652 and 1600 cm-1 (carboxylate); (MegSO-d 2) 0.24 (d, J 8 Hz, CONH), 2.12 (d, J 2 Hz, furyl C 5 -H), 3.25 and 3.30 (m, furyl C 3 -H and C4-H), 3.44 (broad s, COHH2), 4.34 (dd, J 5 and 8 Hz, C? -H), 4.92 (d, J 5 Hz, C6-H), 5, 15 (q, J 13 Hz, C₂-CHg), 6.07 (s, NOCH₂) and 6.58 (q, J 18 Hz, C₂-H2).
Beregnet for U^H^N^NaOgS.0.5H20 (455,37): C 42,2 H 3,5 N 12,3 S 7,0 fundet: C 42,0 H 3,8 N 12,1 S 7,2%.Calcd. For U 2 H 3 N 3 NaO 2 S.0.5H 2 O (455.37): C 42.2 H 3.5 N 12.3 S 7.0 Found: C 42.0 H 3.8 N 12.1 S 7 , 2%.
Eksempel 2 (6R,7R)-3-Karbamoyloxymetyi-7(fur-2-yl)-2-metoxy- iminoacetamido7~ceph-3-em-4-karboxylsyre (syn-isomer)Example 2 (6R, 7R) -3-Carbamoyloxymethyl-7 (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid (syn isomer)
En under omrøring værende blanding af 75 ml N,N-dimetyl-acetamid, 75 ml acetonitril, 42 ml (0,3 mol) triætylamin og 16,40 g (0,06 mol) (6R,7R)-7-amino-3-karbamoyloxymetylceph-3-em-4-karboxylsyre nedsænkedes i et isbad og der tilsattes 10 ml vand. Blandingen omrørtes ved 0-2°C i 45 minutter, hvorved det faste stof langsomt opløste sig og gav en gul opløsning.A stirring mixture of 75 ml of N, N-dimethylacetamide, 75 ml of acetonitrile, 42 ml (0.3 mol) of triethylamine and 16.40 g (0.06 mol) of (6R, 7R) -7-amino 3-carbamoyloxymethylceph-3-em-4-carboxylic acid was immersed in an ice bath and 10 ml of water was added. The mixture was stirred at 0-2 ° C for 45 minutes, slowly dissolving the solid to give a yellow solution.
I mellemtiden afkøledes en under omrøring værende suspension af 14,99 g (0,072 mol) fosforpentaklorid i 150 ml tør di-klormetan til 0°c og der tilsattes 27,5 ml N,N-dimetylacetamid.Meanwhile, a stirred suspension of 14.99 g (0.072 mol) of phosphorus pentachloride in 150 ml of dry dichloromethane was cooled to 0 ° C and 27.5 ml of N, N-dimethylacetamide was added.
Den resulterende opløsning afkøledes påny til -10°C og der tilsattes 12,17 g (0,072 mol) 2-(fur-2-yl)-2-metoxyiminoeddikesyre (syn- 147683 42 isomer). Blandingen omrørtes ved -10°C i 15 minutter og der tilsattes 35 g knust is. Blandingen omrørtes ved 0°C i ti minutter hvorefter den nedre diklormetanfase i løbet af· ti minutter sattes til den i henhold til det ovenstående tilberedte cephalosporinop-løsning afkølet til -10°c, således at reaktionstemperaturen roligt Steg til 0°C. Blandingen omrørtes ved 0-2°C i en time hvorefter kølebadet fjernedes og man lod reaktionstemperaturen stige til 20°C i løbet af en time. Reaktionsblandingen sattes derefter langsomt til 100 ml 2N saltsyre fortyndet med koldt vand (l,15 liter) ved 5°C. Den tofasede blandings pH-værdi reguleredes til under 2 med 10 ml 2N saltsyre og blandingen omrørtes og afkøledes påny til 5°C. Det faste stof som udfældedes filtreredes, vaskedes med 100 ml diklormetan og 250 ml vand og tørredes i vakuum ved 40°C natten over, hvorved der fremkom 22,04 g (86,6%) af den i overskriften an-givne forbindelse. aD =+58° (c = 1,08 i Me2S0); Xmax (pH 6 fosfatpuffer) 274 nm (ε = 17,500); Vmax (nujol) 3480, 344o, 3367, 3255 og 3133 (bundet NH og NH2), 2725 og 2590 (C02H), 17,60 (azetidin- 2-on)-, 1728, 1712 og 1698 (OCONHg og COOH), 1655 og 1530 cm"1 (CONH); (Me2S0-d6) 0,25 (d, J 8 Hz; CONH), 2,18 (s, furyl C5-H), 3,28 og 3,4 (m, furyl C4-H og C3-H), 3,42 (s, C0NH2), 4,19 (dd, J 8 og 5 Hz; C?-H), 4,80 (d, J 5 Hz; Cg-H), 5,06 og 5,39 (q, J 13 Hz; Cg-CHg), 6,09 (s; NOCH^), 6,44 (kollaberet ABq; Cg-H;?) 7,99 (0,03 mol CH3CON(CH3)2).The resulting solution was again cooled to -10 ° C and 12.17 g (0.072 mol) of 2- (fur-2-yl) -2-methoxyiminoacetic acid (syn isomer) was added. The mixture was stirred at -10 ° C for 15 minutes and 35 g of crushed ice was added. The mixture was stirred at 0 ° C for ten minutes and then the lower dichloromethane phase was added over a period of ten minutes to the cephalosporin solution cooled to -10 ° C in accordance with the above, so that the reaction temperature slowly increased to 0 ° C. The mixture was stirred at 0-2 ° C for one hour after which the cooling bath was removed and the reaction temperature was allowed to rise to 20 ° C over one hour. The reaction mixture was then slowly added to 100 ml of 2N hydrochloric acid diluted with cold water (1.15 liters) at 5 ° C. The pH of the biphasic mixture was adjusted to below 2 with 10 ml of 2N hydrochloric acid and the mixture was stirred and cooled again to 5 ° C. The solid which precipitated was filtered, washed with 100 ml of dichloromethane and 250 ml of water and dried in vacuo at 40 ° C overnight to give 22.04 g (86.6%) of the title compound. aD = + 58 ° (c = 1.08 in Me 2 SO); Λmax (pH 6 phosphate buffer) 274 nm (ε = 17,500); Vmax (nujol) 3480, 344o, 3367, 3255 and 3133 (linked NH and NH 2), 2725 and 2590 (CO 2 H), 17.60 (azetidin-2-one) -, 1728, 1712 and 1698 (OCONHg and COOH), 1655 and 1530 cm "1 (CONH); (Me₂SO-d6) 0.25 (d, J 8 Hz; CONH), 2.18 (s, furyl C5-H), 3.28 and 3.4 (m, furyl C4-H and C3-H), 3.42 (s, COHH2), 4.19 (dd, J 8 and 5 Hz; C? -H), 4.80 (d, J 5 Hz; Cg-H ), 5.06 and 5.39 (q, J 13 Hz; Cg-CHg), 6.09 (s; NOCH ^), 6.44 (collapsed ABq; Cg-H;?) 7.99 (0, 03 mol CH3CON (CH3) 2).
Eksempel 3 a) (6R,7R)-7-(R-5-Benzoylamino-5-karboxypentanamido)-3-hydroxymetylceph-3-em-4-karboxylsyre-monokinolinium-salt-monohydratExample 3 a) (6R, 7R) -7- (R-5-Benzoylamino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid monoquinolinium salt monohydrate
En under omrøring værende opløsning af 18,45 g (30 mmol) (6R,7K)-7-(R-5-amino-5-karboxypentanamido)-3-hydroxymetylceph-3-em- 4-karboxylsyre-monokaliumsalt i 93 ml vand afkøledes til 0-5°c (is/ vandbad) og behandledes med en opløsning af 5,19 ml (45 mmol) ben-zoylklorid i 63 ml acetone i løbet af 25 minutter. Reaktionsblandingens pH holdtes på 8,5 ί 0,1 ved kontrolleret tilsætning af ca.A stirred solution of 18.45 g (30 mmol) (6R, 7K) -7- (R-5-amino-5-carboxypentanamido) -3-hydroxymethylceph-3-em-4-carboxylic acid monocalcium salt in 93 ml water was cooled to 0-5 ° C (ice / water bath) and treated with a solution of 5.19 ml (45 mmol) of benzoyl chloride in 63 ml of acetone over 25 minutes. The pH of the reaction mixture was maintained at 8.5 µl 0.1 by controlled addition of ca.
147683 43 100 ml 30%s v/r vandigt trikaliumortofosfat. Blandingen omrørtes i yderligere fem minutter og dækkedes med 150 ml ætylacetat, hvorefter pH nedsattes til 5,6 med ortofosforsyre. Lagene adskiltes og den vandige del vaskedes med yderligere 2 x 300 ml ætylacetat. De forenede vaskevæsker ekstraheredes med 200 ml vand. Den vandige fase forenedes med vaskevæskeme og de således forenede væsker fortyndedes med 600 ml vand og dækkedes med 600 ml ætylacetat, hvorpå den under omrøring værende blandings pH reguleredes til 2,0 med ortofosforsyre. Det organiske lag fraskiltes og der tilsattes 10,64 ml (45 mmol) kinolin i 25 ml ætylacetat under omrøring, hvorved der fremkom et hvidt bundfald. Den vandige del ekstraheredes med yderligere 3 x 300 ml ætylacetat og disse sattes til suspensionen indeholdende kinolin. Blandingen omrørtes i en time ved ca. 18°C og koncentreredes derefter i vakuum til ca. 500 ml. Der tilsattes 900 ml æter under omrøring og efter 30 minutters forløb opsamledes det faste stof ved filtrering, vaskedes med 5 x 100 ml æter og tørredes i vakuum (1 mm Hg) for at give den i overskriften angivne forbindelse som et hvidt pulver i en mængde på 19,20 g (104,1%), aj8 = +78° (c = 1,00 i dioxan). kmax (pH 6 puffer) 258 nm (inflektion, E^cjn = 185). IR og NMR-data bekræftede strukturen som den i overskriften angivne forbindelses struktur indeholdende ca. 15% lakton-urenhed og spormængder af æter og ætylacetat.100 ml of 30% s / v aqueous tricalcium orthophosphate. The mixture was stirred for a further five minutes and covered with 150 ml of ethyl acetate, then the pH was reduced to 5.6 with orthophosphoric acid. The layers were separated and the aqueous portion was washed with an additional 2 x 300 ml of ethyl acetate. The combined washings were extracted with 200 ml of water. The aqueous phase was combined with the washing liquids and the liquids thus combined were diluted with 600 ml of water and covered with 600 ml of ethyl acetate and the pH of the stirred mixture was adjusted to 2.0 with orthophosphoric acid. The organic layer was separated and 10.64 ml (45 mmol) of quinoline added in 25 ml of ethyl acetate with stirring to give a white precipitate. The aqueous portion was extracted with an additional 3 x 300 ml of ethyl acetate and these were added to the quinoline-containing suspension. The mixture was stirred for one hour at ca. 18 ° C and then concentrated in vacuo to ca. 500 ml. 900 ml of ether were added with stirring and after 30 minutes the solid was collected by filtration, washed with 5 x 100 ml of ether and dried in vacuo (1 mm Hg) to give the title compound as a white powder in an amount of 19.20 g (104.1%), aj8 = + 78 ° (c = 1.00 in dioxane). kmax (pH 6 buffer) 258 nm (inflection, E ^ cjn = 185). IR and NMR data confirmed the structure as the title compound structure containing ca. 15% lactone impurity and trace amounts of ether and ethyl acetate.
b) (6R,7R)-7-(R-5-Benzoylamino-5-karboxypentanamido)-3 trikloracetylkarbamoyloxymetylceph-3-em-4-karboxyl-syre-monokino1iniumsalt 4,24 g af produktet fra eksempel 3 a), svarende til 7 mmol, behandledes med 100 ml tør dioxan hvori produktet delvis opløste sig. Til den under omrøring værende blanding sattes 2,90 ml (24,5 mmol) trikloracetylisocyanat. Den resulterende opløsning omrørtes i 30 minutter og klaredes derefter ved filtrering og inddampedes i vakuum til et gult skum. Dette opløstes i ca. 10 ml acetone og udhældtes i ca. 100 ml omrørt isopropylæter. Den resulterende hvide udfældning opsamledes ved filtrering og tørredes i vakuum (l mm), hvorved der fremkom 6,26 g (147,8%) af den i overskriften 147683 44 angivne forbindelse som et hvidt pulver. NMR-data bekræftede at strukturenvar den i overskriften angivne forbindelses struktur og udviste også tilstedeværelse af lakton (ca. 22%), isopropylæter (0,75 mol), dioxan (0,2 mol) og en ringe mængde acetone.b) (6R, 7R) -7- (R-5-Benzoylamino-5-carboxypentanamido) -3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid monoquinoline salt 4.24 g of the product of Example 3 a), corresponding to 7 mmol, treated with 100 ml of dry dioxane in which the product partially dissolved. To the stirred mixture was added 2.90 ml (24.5 mmol) of trichloroacetyl isocyanate. The resulting solution was stirred for 30 minutes and then clarified by filtration and evaporated in vacuo to a yellow foam. This dissolved in ca. 10 ml of acetone and poured into ca. 100 ml stirred isopropyl ether. The resulting white precipitate was collected by filtration and dried in vacuo (1 mm) to give 6.26 g (147.8%) of the title compound as a white powder. NMR data confirmed that the structure was the structure of the title compound and also showed the presence of lactone (about 22%), isopropyl ether (0.75 mol), dioxane (0.2 mol) and a small amount of acetone.
c) (6R, 7E )-7-Amino-3-trikloracetylkarbamoyloxymetylceph- 3-em—4-karboxylsyrec) (6R, 7E) -7-Amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid
En opløsning af 4,77 g af produktet fra eksempel 3b), • svarende til 6 mmol, i 40 ml tørt metylenklorid under nitrogen afkøledes til ca. 10°C under omrøring. Der tilsattes 2,20 ml (27,3 mmol) pyridin og derefter 2,10 ml (17,4 mmol) diklordimetylsilan, og den brune opløsning omrørtes ved ca. 17°C i tyve minutter og afkøledes derefter til -17°C. Der tilsattes 1,355 g (6,5 mmol) fosforpentaklorid og blandingen omrørtes ved ca. -16°C i to timer. Der tilsattes 0,81 ml (10 mmol) pyridin og blandingen sattes til metanol (13 ml + 2,5 ml vaskevæsker, forud afkølet til -35ec) med en sådan hastighed at den omrørte opløsnings temperatur ikke oversteg -10°c. Man lod den under omrøring værende opløsnings temperatur nå +9°C i løbet af 25 minutter, hvorefter der tilsattes 11 ml vand og blandingens pH-værdi førtes fra 0,3 til 3,8 med ammoniakvand (massefylde 0,880). Den resulterende tofasede blanding indeholdende et udfældet fast stof køledes i køleskab i en time og filtreredes derefter. Det faste stof vaskedes successivt med 12 ml 50%s vandig metanol, 10 ml metanol og 5 ml metylenklorid og tørredes derefter i vakuum (l mm), hvorved der fremkom 1,22 g (25,6%) af den i overskriften angivne forbindelse som et flødefarvet pulver, aD = +44° (c = 1,02 i MeoS0); \max (pH 6 puffer) 240 nm (b}* = 133), 263 nm (B^ ^ = 140). NMR-data bekræftede at produktets struktur var den i overskriften angivne forbindelses.A solution of 4.77 g of the product of Example 3b), corresponding to 6 mmol, in 40 ml of dry methylene chloride under nitrogen was cooled to ca. 10 ° C with stirring. 2.20 ml (27.3 mmol) of pyridine and then 2.10 ml (17.4 mmol) of dichlorodimethylsilane were added and the brown solution was stirred at ca. 17 ° C for twenty minutes and then cooled to -17 ° C. Phosphorus pentachloride (1.355 g (6.5 mmol)) was added and the mixture was stirred at ca. -16 ° C for two hours. 0.81 ml (10 mmol) of pyridine was added and the mixture was added to methanol (13 ml + 2.5 ml washing liquids, pre-cooled to -35 ° C) at such a rate that the temperature of the stirred solution did not exceed -10 ° c. The stirring solution temperature was allowed to reach + 9 ° C over 25 minutes, then 11 ml of water was added and the pH of the mixture was adjusted from 0.3 to 3.8 with ammonia water (density 0.880). The resulting two-phase mixture containing a precipitated solid was refrigerated in the refrigerator for one hour and then filtered. The solid was washed successively with 12 ml of 50% aqueous methanol, 10 ml of methanol and 5 ml of methylene chloride and then dried in vacuo (1 mm) to give 1.22 g (25.6%) of the title compound. as a cream colored powder, α D = + 44 ° (c = 1.02 in MeoSO); \ max (pH 6 buffer) 240 nm (b} + = 133), 263 nm (B + = 140). NMR data confirmed that the structure of the product was the title compound.
d) (6R,7R)-3-Karbamoyloxymetyl-7-/2-(f ur-2-yl)-2-metoxy-iminoacetamido7-ceph-3-em-4-karboxylsyre (syn-isomer) 4,5 g (21,5 mmol) fosforpentaklorid opløstes i 90 ml tørt metylenklorid og afkøledes under omrøring til -15°C. Der tilsattes langsomt 9 ml Ν,Ν-dimetylacetamid idet temperaturen holdtes under U7683 45 -10°C, og blandingen omrørtes i ti minutter. Derefter tilsattes der 3,66 g svarende til 21,5 mmol af syn-isomeren af 2-(fur-2-yl)- 2-metoxyiminoeddikesyre, og blandingen omrørtes ved -15°C i 15 minutter. Der tilsattes forsigtigt 18 g knust is så at blandingens temperatur ikke oversteg -7°C. Derefter omrørtes blandingen i ti minutter og den organiske del fraskiltes og sattes dråbevis til en opløsning af 7,52 g svarende til 18 mmol, (6 R, 7 R )-7-amino-3-trikloracetylkarbamoyloxymetylceph-3-em-4-karboxylsyre i 90 ml tørt metylenklorid og 5,5 ml (40 mmol) triætylamin, i forvejen afkølet til -10°C. Syrekloridopløsningen tilsattes i løbet af 20 minutter idet reaktionsblandingens temperatur holdtes mellem -10 og -8°C. Derefter omrørtes blandingen i 80 minutter i løbet af hvilken periode man tillod temperaturen at stige til +3°C, og der tilsattes 6 ml metanol. Efter yderligere fem minutters omrøring ekstra-heredes opløsningen med 2 x 120 ml 3%s vandigt natriumhydrogenkar-bonat og 250 ml vand. De forenede ekstrakter henstod ved ca. 20°C i 3 1/2 time og vaskedes derefter med 100 ml ætylacetat og syrnedes til pH 1,5 med koncentreret saltsyre. Den resulterende afsatte olie ekstraheredes med 2 x 300 ml ætylacetat. De forenede organiske dele vaskedes med 2 x 100 ml vand, tørredes over MgSO^ og inddampedes i vakuum til 7,1 g gult fast stof som omrørtes med 150 ml æter, filtreredes og tørredes i vakuum på 1 mm Hg for at give den i overskriften angivne forbindelse i en mængde på 5,20 g (68,2%) af et lysegult fast stof med \max (pH 6 puffer) 275 nm (E^ = 385).d) (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxy-iminoacetamido7-ceph-3-em-4-carboxylic acid (syn isomer) 4.5 g Phosphorus pentachloride (21.5 mmol) was dissolved in 90 ml of dry methylene chloride and cooled to -15 ° C with stirring. 9 ml of Ν, Ν-dimethylacetamide was slowly added keeping the temperature below -7 ° C -10 ° C and the mixture stirred for ten minutes. Then, 3.66 g corresponding to 21.5 mmol of the syn isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid was added and the mixture was stirred at -15 ° C for 15 minutes. Carefully add 18 g of crushed ice so that the temperature of the mixture did not exceed -7 ° C. Then the mixture was stirred for ten minutes and the organic part was separated and added dropwise to a solution of 7.52 g corresponding to 18 mmol, (6R, 7R) -7-amino-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylic acid in 90 ml of dry methylene chloride and 5.5 ml (40 mmol) of triethylamine, pre-cooled to -10 ° C. The acid chloride solution was added over 20 minutes keeping the temperature of the reaction mixture between -10 and -8 ° C. Then the mixture was stirred for 80 minutes during which time the temperature was allowed to rise to + 3 ° C and 6 ml of methanol was added. After a further five minutes of stirring, the solution was extracted with 2 x 120 ml of 3% aqueous sodium hydrogen carbonate and 250 ml of water. The combined extracts were allowed to stand at ca. 20 ° C for 3 1/2 hours and then washed with 100 ml of ethyl acetate and acidified to pH 1.5 with concentrated hydrochloric acid. The resulting deposited oil was extracted with 2 x 300 ml of ethyl acetate. The combined organic parts were washed with 2 x 100 ml of water, dried over MgSO 4 and evaporated in vacuo to 7.1 g of yellow solid which was stirred with 150 ml of ether, filtered and dried in vacuo at 1 mm Hg to give the title the compound of 5.20 g (68.2%) of a light yellow solid with λ max (pH 6 buffer) 275 nm (E + = 385).
IR og NMR-data bekræftede at produktets struktur var strukturen af den i overskriften angivne forbindelse indeholdende spor af æter.IR and NMR data confirmed that the structure of the product was the structure of the title compound containing traces of ether.
Eksempel 4 (6R,7R)-3-Karbamoyloxymetyl-7-/2-metoxyimino-2-(tien-2- yl)-acetamido7-ceph-3-em-4-karboxylsyre (syn-isomer)Example 4 (6R, 7R) -3-Carbamoyloxymethyl-7- / 2-methoxyimino-2- (thien-2-yl) -acetamido7-ceph-3-em-4-carboxylic acid (syn isomer)
Ved samme fremgangsmåde som beskrevet i eksempel 2 fremstilledes der 888 mg (50$) af den i overskriften angivne forbindelse ud fra 1,09 g (4 mmol) (6R,7R)-7-amino-3-karbamoyloxymetylceph- 3-em-4-karboxylsyre og 923 mg (4,8 mmol) af syn-isomeren af natrium- 147683 46 2-metoxyimino-2-(tien-2-yl)-acetat. Forbindelsens egenskaber er: smeltepunkt 157-163°C, αβ = 57,3° (c = 1,0 i dioxan), EpAC 0,8, opløsningsmiddelsystem A (se noter efter omstående tabel l), Xmax (pH 6 puffer) 262,5 nm (ε = 15,550) og inflektion ved 235 nm (e = 10.350),<ir(DMS0-dg) 0,20 (d, J 8 Hz, NH), 2,29 (dd, J 2 og 5 Hz, tienyl C^-H), 2,7-2,9 (m, tienyl Cg-H og C4-H), 3,40 (s, C0NH2), 4,13 (dd, J 5 og 8 Hz, C7-H), 4,75 (d, J 5 Hz, Cg-H), 5,01 og 5,34 (AB-q, J 13 Hz, Cg-CHg), 6,08 (s, NOCH^), og 6,42 (kollaberet AB-q, C2-H2), Vmax (nujol) 3700 til 2100 (COOH), 3480, 3440, 3365 og 3255 (NH og NH2), 1760 (azetidin-2-on), 1722 (COOH), 1709 (0C0NH2), 1652 og 1530 cm-1 (amid).By the same procedure as described in Example 2, 888 mg (50 $) of the title compound was prepared from 1.09 g (4 mmol) (6R, 7R) -7-amino-3-carbamoyloxymethylceph-3-em. 4-carboxylic acid and 923 mg (4.8 mmol) of the sodium isomer of sodium 2-methoxyimino-2- (thien-2-yl) acetate. The properties of the compound are: mp 157-163 ° C, αβ = 57.3 ° (c = 1.0 in dioxane), EpAC 0.8, solvent system A (see notes following Table 1), Xmax (pH 6 buffer) 262 , 5 nm (ε = 15,550) and inflection at 235 nm (e = 10,350), δ ir (DMSO-dg) 0.20 (d, J 8 Hz, NH), 2.29 (dd, J 2 and 5 Hz) , thienyl C ^-H), 2.7-2.9 (m, thienyl Cg-H and C4-H), 3.40 (s, CONH₂), 4.13 (dd, J 5 and 8 Hz, C7 -H), 4.75 (d, J 5 Hz, Cg-H), 5.01 and 5.34 (AB-q, J 13 Hz, Cg-CHg), 6.08 (s, NOCH and 6.42 (collapsed AB-q, C2-H2), Vmax (nujol) 3700 to 2100 (COOH), 3480, 3440, 3365 and 3255 (NH and NH2), 1760 (azetidin-2-one), 1722 ( COOH), 1709 (OCNH 2), 1652 and 1530 cm -1 (amide).
Eksempel 5 (6R,7R)-3-Karbamoyloxymetyl-7-^S-(fur-2-yl)-2-metoxyimino- acetamido7-ceph-3-em-4-karboxylsyre (syn-isomer) 1,5 ml Ν,Ν-dimetylacetamid sattes til en opløsning 750 mg (3,6 mmol) fosforpentaklorid i 15 ml vandfrit diklormetan afkølet til —10°C. Efter ti minutter sattes der 612 mg, 3,6 mmol, af syn-isomeren af 2-(fur-2-yl)-2-metoxyiminoeddikesyre til den resulterende suspension, der hurtigt blev en klar opløsning og omrørt es ved 10°C i 15 minutter. Der tilsattes 3 g is^Sfter ti minutters forløb lod man lagene skille sig ad i en dråbetragt. Den organiske fase overførtes langsomt, i løbet af fem minutter, til en til —10°C afkølet opløsning af 1,05 g (3 mmol) (6R,7R)-7-amino-3-kloracetylkarbamoyloxymetylceph-3-em-4-karboxylsyre i 15 ml diklormetan indeholdende 0,9 ml, 6,5 mmol, triætylamin. Der tilsattes 1 ml metanol efter 40 minutters forløb og fem minutter senere ek-straheredes reaktionsblandingen to gange med 150 ml 3%s vandig na-triumbikarbonatopløsning. Den vandige ekstrakt vaskedes med 25 ml ætylacetat og henstod ved 20eC i fire timer. Opløsningen vaskedes to gange med ætylacetat, syrnedes med 2N saltsyre og ekstraheredes tre gange med ætylacetat. De forenede organiske lag tørredes over magniumsulfat, affarvedes med aktiveret trækul og inddampedes i vakuum til 1,15 g, 87%, af et lysegylt fast stof. Dette vaskedes med 147683 47 diætylæter og frafiltreredes, hvorved der fremkom 0,91 g, 71%» af den i overskriften angivne forbindelse. Amax (pH 6 puffer) 274 nm (e = 17*300). Produktets IR- og NMR-spektre stemte med spektrene for en autentisk prøve af forbindelsen.Example 5 (6R, 7R) -3-Carbamoyloxymethyl-7- [5- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid (syn isomer) 1.5 ml ml Ν-Dimethylacetamide was added to a solution of 750 mg (3.6 mmol) of phosphorus pentachloride in 15 ml of anhydrous dichloromethane cooled to -10 ° C. After ten minutes, 612 mg, 3.6 mmol, of the syn-isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid was added to the resulting suspension, which quickly became a clear solution and stirred at 10 ° C for 10 min. 15 minutes. 3 g of ice was added. After ten minutes, the layers were allowed to separate into a dropping funnel. The organic phase was slowly transferred, over five minutes, to a solution cooled to -10 ° C of 1.05 g (3 mmol) (6R, 7R) -7-amino-3-chloroacetylcarbamoyloxymethylceph-3-em-4- carboxylic acid in 15 ml of dichloromethane containing 0.9 ml, 6.5 mmol, triethylamine. After 40 minutes, 1 ml of methanol was added and five minutes later the reaction mixture was extracted twice with 150 ml of 3% aqueous sodium bicarbonate solution. The aqueous extract was washed with 25 ml of ethyl acetate and left at 20 ° C for four hours. The solution was washed twice with ethyl acetate, acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, decolorized with activated charcoal and evaporated in vacuo to 1.15 g, 87%, of a light yellow solid. This was washed with diethyl ether and filtered off to give 0.91 g, 71% of the title compound. Amax (pH 6 buffer) 274 nm (e = 17 * 300). The product's IR and NMR spectra matched the spectra for an authentic sample of the compound.
Eksempel 6 (6R,7R)-3-Karbamoyloxymetyl-7-^2-(fur-2-yl)-2-metoxy- iminoacetamido7-ceph-3-em-4-karboxylsyre (syn-isomer)Example 6 (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid (syn isomer)
Metode IMethod I
750 ml acetone afkøledes til 0°C og behandledes med 28,8 ml, 240 mmol, trikloracetylisocyanat hvorefter opløsningen påny afkøledes til 0°C. Der sattes 45,6 g, 120 mmol, (6R,7R)-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-3-hydroxymetylceph-3-em-4-karboxylsyre (syn-isomeren) til den under omrøring værende isocyanatopløsning i portioner i løbet af fem minutter på en sådan måde at reaktionstemperaturen ikke oversteg 6°c. Den gule opløsning omrørtes i yderligere 15 minutter og der tilsattes 4,5 ml metanol. Opløsningen koncentreredes til 60 ml og koncentratet opløstes i 750 ml metanol. Der tilsattes 45,3 g (540 mmol) natriumbikarbonat i 600 ml vand efterfulgt af 4,5 g aktiveret trækul, og den resulterende suspension omrørtes ved stuetemperatur i to timer. Trækullene fjernedes ved filtrering gennem kiselgur og det lysegule filtrat reguleredes til pH750 ml of acetone was cooled to 0 ° C and treated with 28.8 ml, 240 mmol of trichloroacetyl isocyanate and the solution was again cooled to 0 ° C. 45.6 g, 120 mmol, (6R, 7R) -7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-3-hydroxymethylceph-3-em-4-carboxylic acid (the syn isomer) were added to the stirred isocyanate solution in portions over five minutes in such a way that the reaction temperature did not exceed 6 ° C. The yellow solution was stirred for a further 15 minutes and 4.5 ml of methanol was added. The solution was concentrated to 60 ml and the concentrate dissolved in 750 ml of methanol. 45.3 g (540 mmol) of sodium bicarbonate was added in 600 ml of water followed by 4.5 g of activated charcoal and the resulting suspension was stirred at room temperature for two hours. The charcoal was removed by filtration through diatomaceous earth and the pale yellow filtrate was adjusted to pH
4,5 ved tilsætning af fortyndet saltsyre. Opløsningen koncentreredes til det halve rumfang under nedsat tryk og der tilsattes en lige så stor mængde vand. pH reguleredes til 2,0 med fortyndet saltsyre og produktet isoleredes ved filtrering, vaskedes med 3 x 150 ml vand og tørredes ved 40°C i 16 timer i vakuum, hvorved der fremkom 37,46 g svarende til 73,5% af den i overskriften angivne forbindelse, ap® = +63,7° (c = 1,0 i 0,2 M pH 7 fosfatpuffer). Amax (pH 6 fosfatpuffer) 274 nm (e - 17.600).4.5 by the addition of dilute hydrochloric acid. The solution was concentrated to half the volume under reduced pressure and an equal amount of water was added. The pH was adjusted to 2.0 with dilute hydrochloric acid and the product isolated by filtration, washed with 3 x 150 ml of water and dried at 40 ° C for 16 hours in vacuo to give 37.46 g corresponding to 73.5% of the title compound, ap® = + 63.7 ° (c = 1.0 in 0.2 M pH 7 phosphate buffer). Amax (pH 6 phosphate buffer) 274 nm (e - 17,600).
IR, NMR og mikroanalytiske data bekræftede at strukturen var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure was the title compound.
Metode IIMethod II
48 16768348 167683
En opslæmning af 3,81 g, 9,55 mmol, af syn-isomeren af (6R,7R)-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-3-hydroxymetylceph- 3-em-4-karboxylsyre i en blanding af 70 ml diklormetan og 25 ml tetrahydrofuran ved 5°C behandledes med 2,5 ml, 25 mmol, diklor-acetylisocyanat. Reaktionsblandingen behandledes derefter på samme måde som beskrevet foran under metode I, hvorved der fremkom 3,36 g svarende til 83,0% af den i overskriften angivne forbindelse. ct^° = +63®, Xmax 273,5 nm (e = 17.800). IR- og NMR-spektre var som spektrene af det ved metode I frembragte produkt.A slurry of 3.81 g, 9.55 mmol, of the syn isomer of (6R, 7R) -7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-3-hydroxymethylceph-3-em-4 -carboxylic acid in a mixture of 70 ml of dichloromethane and 25 ml of tetrahydrofuran at 5 ° C was treated with 2.5 ml, 25 mmol, dichloroacetyl isocyanate. The reaction mixture was then treated in the same manner as described above under Method I to yield 3.36 g, corresponding to 83.0% of the title compound. = + 63®, λmax 273.5 nm (e = 17,800). IR and NMR spectra were like the spectra of the product produced by Method I.
Metode IIIMethod III
En opslæmning af 19,05 g, 50 mmol, af syn-isomeren af (6R,7 R)-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-3-hydroxymetylceph- 3-em-4-karboxylsyre i 250 ml tør acetonitril behandledes ved en temperatur mellem 5 og 10°C med 6,33 ml, 75 mmol, klorsulfonylisocya-' nat i 80 ml acetonitril.A slurry of 19.05 g, 50 mmol, of the syn isomer of (6R, 7R) -7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-3-hydroxymethylceph-3-em-4 carboxylic acid in 250 ml dry acetonitrile was treated at a temperature between 5 and 10 ° C with 6.33 ml, 75 mmol, chlorosulfonylisocyanate in 80 ml acetonitrile.
Reaktionsblandingen omrørtes ved temperaturer mellem 0 og 5°C i ti minutter og der tilsattes 50 ml vand. Blandingen omrørtes ved ca. 20°c og efter tyve minutter udskilte der sig et hvidt krystallinsk fast stof. Inddampning og filtrering gav 18,17 g (85,7%) 20 af den i overskriften angivne forbindelse, ctD = +62,5®; \max 273,5 nm (ε = 17.820). IR- og NMR-spektre var som dem der fandtes for produktet ifølge metode I. Et næste udbytte på 1,88 g, 8,6%, af produktet med lignende konstanter vandtes ved inddampning af modervæskerne.The reaction mixture was stirred at temperatures between 0 and 5 ° C for ten minutes and 50 ml of water was added. The mixture was stirred at ca. 20 ° C and after twenty minutes a white crystalline solid separated. Evaporation and filtration gave 18.17 g (85.7%) of the title compound, ctD = + 62.5®; ν max 273.5 nm (ε = 17.820). IR and NMR spectra were similar to those found for the product of Method I. A next yield of 1.88 g, 8.6%, of the product of similar constants was obtained by evaporation of the parent liquids.
Eksempel 7Example 7
Form I af syn-isomeren af natrium-(6R,7R)-3-karbamoyloxy- metyl-7-72-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em- 4-karboxylatForm I of the syn isomer of sodium (6R, 7R) -3-carbamoyloxymethyl-7-72- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate
Metode IMethod I
49 U7683 100 g af syn-isomeren af (6R,7 R)-3-karbamoyloxymetyl-7-^2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylsyre i en blanding af 400 ml Ν,Ν-dimetylacetamid og 1 liter acetone behandledes med 40 g natrium-2-ætylhexanoat i 200 ml acetone. Blandingen podedes og omrørtes ved stuetemperatur i 1 1/4 time. Produktet frafiltreredes og vaskedes med 500 ml acetone, opslæmmedes derefter med 3 x 300 ml acetone og opslæmmedes til slut med æter, hvorved der fremkom 101,4 g (92,5%) af den i overskriften angivne forbindelse der efter at være kommet i ligevægt i atmosfæren indeholdt 0,65 molækvivalenter vand. Produktet har aD = +61° (c = 0,5 i pH 4,5 fosfatpuffer) og \max 273 nm (E^cm = 412) (HgO).49 g of the syn isomer of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid in a mixture of 400 ml of Ν, Ν-dimethylacetamide and 1 liter of acetone were treated with 40 g of sodium 2-ethyl hexanoate in 200 ml of acetone. The mixture was seeded and stirred at room temperature for 1 1/4 hour. The product was filtered off and washed with 500 ml of acetone, then slurried with 3 x 300 ml of acetone and finally slurried with ether to give 101.4 g (92.5%) of the title compound which, after reaching equilibrium, in the atmosphere contained 0.65 molar equivalents of water. The product has α D = + 61 ° (c = 0.5 in pH 4.5 phosphate buffer) and λ max 273 nm (E + cm = 412) (HgO).
IR- og NMR-data bekræftede at strukturen var den i overskriften angivne forbindelsesstruktur, og IR-spektret viste at forbindelsen var saltet af Form I.IR and NMR data confirmed that the structure was the titled compound structure and the IR spectrum indicated that the compound was salt of Form I.
Metode liMethod li
Fremgangsmåden i metode I gentoges med den forskel at cephalosporinsyren oprindelig opløstes i en blanding N,N~dimetyl-formamid og industrieltmetyleret ætanol i stedet for en blanding af Ν,Ν-dimetylacetamid og acetone, hvorved der fremkom den i overskriften angivne forbindelse i et udbytte på 80% med lignende egenskaber som produktet ifølge metode I. Det infrarøde spektrum viste at forbindelsen var saltet af Form I.The method of method I was repeated with the difference that the cephalosporic acid was initially dissolved in a mixture of N, N ~ dimethylformamide and industrial methylated ethanol instead of a mixture of Ν, Ν-dimethylacetamide and acetone to give the title compound in a yield of 80% with similar properties to the product of Method I. The infrared spectrum showed that the compound was the salt of Form I.
Metode IIIMethod III
4,24 g, 10 mmol, af syn-isomeren af (6R,7R)-3-karbamoyl-oxymetyl-7-^2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karb-oxylsyre opløstes i 20 ml Ν,Ν-dimetylacetamid som var blevet tørret over et molekylsigtemateriale ('‘Linde 4A") i 24 timer. Hertil sattes der en opløsning af 2,0 g, 12 mmol, natrium-2-ætylhexanoat, omkrystalliseret fra dioxan og tørret over fosforpentoxyd, i 80 ml ætylacetat der var blevet tørret over et molekylsigtemateriale 147683 50 ("Linde 4A") i 24 timer. Opløsningen omrørtes i en lukket beholder i ca. 15 minutter indtil der begyndte krystallisation hvorefter den afkøledes til 4°C i en time. Produktet filtreredes, vaskedes med ca. 100 ml tørt ætylacetat og overførtes, i en tilstand hvor det endnu var vådt af sidstnævnte opløsningsmiddel, til en ovn hvor det tørredes ved 20°c i vakuum over fosforpentoxyd natten over; der fremkom herved 3»84 g* 87%, af den i overskriften angivne forbindelse .4.24 g, 10 mmol, of the syn isomer of (6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -ceph-3-em-4 Carboxylic acid was dissolved in 20 ml of Ν, Ν-dimethylacetamide which had been dried over a molecular sieve material ("Linde 4A") for 24 hours. To this was added a solution of 2.0 g, 12 mmol, sodium 2-ethyl hexanoate, was recrystallized from dioxane and dried over phosphorus pentoxide, in 80 ml of ethyl acetate which had been dried over a molecular sieve material ("Linde 4A") for 24 hours. The solution was stirred in a closed vessel for about 15 minutes until crystallization began, then cooled to The product was filtered, washed with about 100 ml of dry ethyl acetate and transferred, in a state still wet by the latter solvent, to an oven where it was dried at 20 ° C in vacuo over phosphorus pentoxide overnight; thus obtained 3 »84 g * 87% of the title compound.
Produktets IR- og NMR-spektre stemte med de tilsvarende spektre for en autentisk prøve af stoffet.The product's IR and NMR spectra matched the corresponding spectra for an authentic sample of the fabric.
Eksempel 8Example 8
Form II af syn-isomeren af natrium-(6R,7R)-3-karbamoyl- oxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3- em-4-karboxy1atForm II of the syn isomer of sodium (6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate
Metode IMethod I
0,2 g trækul sattes til en opløsning af 4,00 g, 9,42 mmol, af syn-isomeren af (6R, 7R )-3-karbamoyloxymetyl-7-/2-(fur-2-yl )-2-metoxyiminoacetamido/-ceph-3-em-4-karboxylsyre i en blanding af 132 ml acetone og 1,33 ml vand. Suspensionen omrørtes i 30 minutter og filtreredes gennem et kiselgurleje som vaskedes med 10 ml acetone. Der tilsattes en filtreret opløsning af 1,66 g, 10 mmol, 2-ætylhexanoat i 20 ml acetone i løbet af en time til det under omrøring værende filtrat. Den resulterende suspension omrørtes i yderligere ti minutter og det hvide faste stof frafiltreredes, vaskedes med 2 x 25 ml acetone og tørredes i vakuum til 4,06 g, 93,0%, af ΛΛ den i overskriften angivne forbindelse med = +60° (c =0,91 i H20). \max (H20) 274 nm (ε = 17,400).0.2 g of charcoal was added to a solution of 4.00 g, 9.42 mmol, of the syn isomer of (6R, 7R) -3-carbamoyloxymethyl-7- / 2- (fur-2-yl) -2- methoxyiminoacetamido / ceph-3-em-4-carboxylic acid in a mixture of 132 ml of acetone and 1.33 ml of water. The suspension was stirred for 30 minutes and filtered through a diatomaceous earth bed which was washed with 10 ml of acetone. A filtered solution of 1.66 g, 10 mmol, 2-ethylhexanoate in 20 ml of acetone was added over one hour to the stirred filtrate. The resulting suspension was stirred for a further ten minutes and the white solid was filtered off, washed with 2 x 25 ml of acetone and dried in vacuo to 4.06 g, 93.0%, of the title compound at = + 60 ° ( c = 0.91 in H2 O). λ max (H 2 O) 274 nm (ε = 17,400).
Beregnet for Cl6H15N4Na08S, 0,7 HgO (459,0): G 41,8, H 3,6, N 12,2, Na 5,0, S 7,0, H20 2,7%; fundet C 41,0, 41,2; H 3,45, 3,6; N 12,3, 12,4; Na 5,2; S 6,6, 6,85; H20 2,7, 2,7. Renhed ved HPLC: 99,4%. Produktets NMR-spektrum lignede spektret for en autentisk prøve og IR-spektret viste at produktet var saltet af Form II.Calcd for C16 H15 N4 Na08S, 0.7 HgO (459.0): G 41.8, H 3.6, N 12.2, Na 5.0, S 7.0, H2 O 2.7%; found C 41.0, 41.2; H, 3.45; 3.6; N, 12.3, 12.4; Na 5.2; S, 6.6, 6.85; H2 O 2.7, 2.7. Purity by HPLC: 99.4%. The NMR spectrum of the product was similar to the spectrum of an authentic sample and the IR spectrum showed that the product was salt of Form II.
147683 51!147683 51!
Metode IIMethod II
16»98 g, 40 nunol, af syn-isomeren af (6R,7R)-3-karbamoyl-o:xymetyl-7-^2-(fur-2-yl )-2-metoxyiminoacetamido7-ceph-3-em-4-karb-oxylsyre sattes til en under omrøring værende blanding af 333 ml acetone og 8,5 ml vand. Efter behandling med trækul og filtrering af denne opløsning tilsattes der langsomt i løbet af en time 7,32 g, 44 mmol, natrium-2-ætylhexanoat i 85 ml acetone. Reaktionsblandingen omrørtes i 15 minutter og filtreredes og produktet vaskedes med 2 x 65 ml acetone og tørredes i vakuum ved 20°C natten over for at give 17»95 g, 98,5%, af den i overskriften angivne forbindelse indeholdende 0,5 mol H^O. Produktets NMR-spektrum stemte med en autentisk prøves, og IR-spektrum viste at produktet var saltet af Form II.16 »98 g, 40 nunol, of the syn isomer of (6R, 7R) -3-carbamoyl-o: xymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em. 4-carboxylic acid was added to a stirring mixture of 333 ml of acetone and 8.5 ml of water. After treatment with charcoal and filtration of this solution, 7.32 g, 44 mmol sodium 2-ethyl hexanoate in 85 ml of acetone was slowly added over one hour. The reaction mixture was stirred for 15 minutes and filtered and the product washed with 2 x 65 ml of acetone and dried in vacuo at 20 ° C overnight to give 17 »95 g, 98.5% of the title compound containing 0.5 mole H ^ O. The NMR spectrum of the product matched an authentic sample, and the IR spectrum indicated that the product was salt of Form II.
Eksempel 9Example 9
Form III af syn-isomeren af natrium-(6R,7R)-3-karbamoyl- oxymetyl-7-^2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3- em-4-karboxylat 4»0 g af syn-isomeren af natrium-(6R,7R)-3-karbamoyloxy-mety1-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxy-lat opløstes i 20 ml vand. Der tilsattes 20 ml industriel metyleret ætanol og 160 ml dioxan og opløsningen filtreredes og stilledes derefter til side ved 4°C for at krystallisere. De meget hvide nåleformede krystaller frafiltreredes, vaskedes med 100 ml dioxan og overførtes i en tilstand hvor de endnu var våde med dioxan til en ovn og tørredes ved 20°C i vakuum natten over; der fremkom herved 13,96 g, 78,5%, af den i overskriften angivne forbindelse. Produktets IR-og NMR-spektre stemte med dem fra en autentisk prøve.Form III of the syn isomer of sodium (6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate 40 g of the syn isomer of sodium (6R, 7R) -3-carbamoyloxy-methyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate was dissolved in 20 ml of water. 20 ml of industrial methylated ethanol and 160 ml of dioxane were added and the solution was filtered and then set aside at 4 ° C to crystallize. The very white needle-shaped crystals were filtered off, washed with 100 ml of dioxane and transferred to a state where they were still wet with dioxane in an oven and dried at 20 ° C in vacuo overnight; 13.96 g, 78.5% of the title compound were obtained. The product's IR and NMR spectra matched those of an authentic sample.
Eksempel 10 52 147683Example 10 52 147683
Form IV af syn-isomeren natrium-(6R,7R)-3-karbamoyloxy- metyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em- 4-karboxylatForm IV of the syn-isomeric sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate
Prøver af Form I og Form III af syn-isomeren af natrium- 3- karbaoyloxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat, fremstillet ved metode III i henholdsvis eksempel 7 og eksempel 9, udsattes for fugtighed (75% relativ fugtighed) i tre døgn, hvorved der fremkom den i overskriften angivne forbindelse. Produktets IR- og NMR-spektre stemte med dem fra en autentisk prøve. Vandanalyse efter Karl Fischer gav henholdsvis 4,0 og 3,85% (l mol H20 er ækvivalent med 3,9%).Samples of Form I and Form III of the syn isomer of sodium 3-carbaoyloxymethyl-7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate prepared by Method III in Example 7 and Example 9, respectively, were exposed to humidity (75% relative humidity) for three days to give the title compound. The product's IR and NMR spectra matched those of an authentic sample. Water analysis by Karl Fischer yielded 4.0 and 3.85%, respectively (1 mole of H 2 O is equivalent to 3.9%).
Eksempel 11 a) t-Buty1-(6R,7 R)-3-karbamoyloxymetyl-7-/2-(f ur-2-yl)- 2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat (synis omer )Example 11 a) t-Butyl (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate (synisomer)
En suspension af 4,4 g af syn-isomeren af (6R,7R)-3-kar-bamoyloxymetyl-7-/2- (fur-2-yl )-2-metoxyiminoacetamido7-ceph-3-em- 4- karboxylsyre i 200 ml tørt metylenklorid behandledes med 6,6 ml O-t-butyl-N,N*-dicyklohexylisourinstof, hvorved der dannedes en lysegul opløsning. Efter 24 timer ved 23°C var der udgangsmateriale tilbage og der tilsattes yderligere 3,3 ml af isourinstoffet. Efter 48 timer filtreredes blandingen og filtratet inddampedes under nedsat tryk. Det resulterende materiale opslæmmedes med æter/ ætylacetat for at fjerne tilbageværende dicyklohexylurinstof. Filtratet vaskedes med mættet vandigt natriumhydrogenkarbonat og vand og tørredes derefter og inddampedes til et skum i en mængde på 5,2 g. Kromatografi på silikagel med toluen/ætylacetat 2:1 som opløsningsmiddel gav 3,9 g af den i overskriften angivne forbindelse som et lysegult skum, \max (ætanol) 275,5 nm (ε = 18.400).A suspension of 4.4 g of the syn isomer of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid in 200 ml of dry methylene chloride was treated with 6.6 ml of Ot-butyl-N, N * -dicyclohexylisourea to give a pale yellow solution. After 24 hours at 23 ° C, starting material was left and an additional 3.3 ml of the isour substance was added. After 48 hours, the mixture was filtered and the filtrate was evaporated under reduced pressure. The resulting material was slurried with ether / ethyl acetate to remove residual dicyclohexylurea. The filtrate was washed with saturated aqueous sodium bicarbonate and water, then dried and evaporated to a foam in an amount of 5.2 g. Chromatography on silica gel with toluene / ethyl acetate 2: 1 as solvent gave 3.9 g of the title compound pale yellow foam, \ max (ethanol) 275.5 nm (ε = 18,400).
IR- og NMR-data bekræftede at strukturen var den i overskriften angivne forbindelses.IR and NMR data confirmed that the structure was the title compound.
147683 53 b) t-Butyl-(IR,6R,7R)-3-karbamoyloxymetyl-7-^2-(fur-2-yl)- 2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat-l-oxyd (syn-isomer) 0,3 ml t-butylhypoklorit sattes til en under kraftig omrøring værende opløsning af 0,98 g t-butyl-(6R,7R)-3-karbamoyloxy-metyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxy-lat i 25 ml pyridin og 1 ml vand ved -45°C. Efter omrøring i to minutter sattes der 1 ml 2N svovlsyrling til opløsningen og blandingen udhældtes øjeblikkelig i 100 ml 20%s vandig ortofosforsyre. Opløsningen ekstraheredes med 2 x 100 ml ætylacetat og de forenede organiske ekstrakter vaskedes med 100 ml vandigt NaHCO^ og 100 ml vand og tørredes derefter over MgSO^ og koncentreredes i vakuum.B) t-Butyl (IR, 6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate-1-oxide (syn isomer) 0.3 ml of t-butyl hypochlorite was added to a solution with vigorous stirring of 0.98 g of t-butyl (6R, 7R) -3-carbamoyloxy-methyl-7- / 2- (fur-2 -yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylate in 25 ml of pyridine and 1 ml of water at -45 ° C. After stirring for two minutes, 1 ml of 2N sulfuric acid was added to the solution and the mixture was immediately poured into 100 ml of 20% aqueous orthophosphoric acid. The solution was extracted with 2 x 100 ml of ethyl acetate and the combined organic extracts washed with 100 ml of aqueous NaHCO 3 and 100 ml of water and then dried over MgSO 4 and concentrated in vacuo.
Råproduktet kromatograferedes præparative plader af si-likagel med ætylacetat som elueringsmiddel, og den mindre komponent af S-oxydet løb forud for R-oxydet. Ekstraktion af den langsomste komponent med ætylacetat gav 0,27 g (27$) af den i overskriften angivne forbindelse.The crude product was chromatographed on silica gel preparative plates with ethyl acetate as the eluent, and the minor component of the S-oxide preceded the R-oxide. Extraction of the slowest component with ethyl acetate gave 0.27 g (27 $) of the title compound.
IR- og NMR-data bekræftede at strukturen var den i overskriften angivne forbindelses.IR and NMR data confirmed that the structure was the title compound.
c) (IR,6R,7R)-3-Karbamoyloxymetyl-7-^2-(fur-2-yl)-2-me-toxyiminoacetamido7-ceph-3-em-4-karboxylsyre-l-oxyd (syn-isomer) 0,42 g af syn-isomeren af t-butyl-(lR,6R,7R)-3-karbamoyl-oxymetyl-7-^2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karb-oxylat-l-oxyd opløstes i 5 ml trifluoreddikesyre og omrørtes ved stuetemperatur i otte minutter. Opløsningen inddampedes til en rød olie i vakuum, opløstes i 5 ml ætylacetat/acetone 1:1 og sattes dråbevis under omrøring til 50 ml petroleumsæter (kp. 6o-80°C). Det afsatte faste stof opsamledes og tørredes i en ekssikkator. Råproduktet opslæmmedes med ætylacetat og den flydende fase dekanteredes og sattes dråbevis til 50 ml petroleumsæter (kp. 60-80°C), hvorved der vandtes 150 mg, 40$, af den i overskriften angivne forbindelse som et farveløst fast stof. \max (0,25N NaHCO^) 263,5 nm (ε = 15.000) og 281 nm (ε = 13,700). max (nujol) 1799 (β-laktam), 1727 og 1716 147683 54 (COOH og OCONH2)f 1684 og 1538 (CONH) og 1060 og 1050 cm"1 (s—>0). C(Me2SO-cl6) værdier indbefatter 0,02 (d, J 8 Hz, CONH), 4,17 (dd, J 4 og 8 Hz, 7-H), 4,99 (d, J 4 Hz, 6-H) og 6,09 (s, N-0CH3).c) (IR, 6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em-4-carboxylic acid 1-oxide (syn isomer ) 0.42 g of the syn isomer of t-butyl (1R, 6R, 7R) -3-carbamoyl-oxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em -4-Carboxylate-1-oxide was dissolved in 5 ml of trifluoroacetic acid and stirred at room temperature for eight minutes. The solution was evaporated to a red oil in vacuo, dissolved in 5 ml of ethyl acetate / acetone 1: 1 and added dropwise with stirring to 50 ml of petroleum ether (bp 6o-80 ° C). The deposited solid was collected and dried in a desiccator. The crude product was slurried with ethyl acetate and the liquid phase decanted and added dropwise to 50 ml of petroleum ether (bp 60-80 ° C) to give 150 mg, $ 40, of the title compound as a colorless solid. \ max (0.25N NaHCO3) 263.5 nm (ε = 15,000) and 281 nm (ε = 13,700). max (nujol) 1799 (β-lactam), 1727 and 1716 147683 54 (COOH and OCONH2) f 1684 and 1538 (CONH) and 1060 and 1050 cm -1 (s -> 0). C (Me2SO-cl6) values include 0.02 (d, J 8 Hz, CONH), 4.17 (dd, J 4 and 8 Hz, 7-H), 4.99 (d, J 4 Hz, 6-H) and 6.09 (s , N-OCH 3).
Eksempel 12 (IS,6R,7E)-3-Karbamoyloxymetyl-7-{2-(fur-2-yl)-2-metoxy-iminoacetamido7-cepii-3-em-4-lcarboxylsyre-l-oxyd (syn-isomer)Example 12 (1S, 6R, 7E) -3-Carbamoyloxymethyl-7- {2- (fur-2-yl) -2-methoxy-iminoacetamido7-cepi-3-em-4-carboxylic acid 1-oxide (syn isomer )
Til en under omrøring værende opløsning af 2,59 g af syn-isomeren af natrium-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur-2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylat i 25 ml vand sattes der 1,93 g natriummetaperjodat. Opløsningen omrørtes i 30 minutter ved stuetemperatur og syrnedes derefter ved dråbevis tilsætning af 2N vandig saltsyre. Det resulterende bundfald opsamledes, vaskedes successivt med vand, ætanol og æter og tørredes derefter i vakuum for at give 1,63 g af den i overskriften angivne forbin-delse som et hvidt pulver, = +113° (c = 0,86 i dimetylsulfoxyd). Xmax (pH 6 puffer) 264,5 nm (ε = 17,200) og 279 nm (ε = 15.600).To a stirred solution of 2.59 g of the syn isomer of sodium (6R, 7R) -3-carbamoyloxymethyl-7- / 2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em -4-carboxylate in 25 ml of water was added 1.93 g of sodium metaperiodate. The solution was stirred for 30 minutes at room temperature and then acidified by dropwise addition of 2N aqueous hydrochloric acid. The resulting precipitate was collected, washed successively with water, ethanol and ether and then dried in vacuo to give 1.63 g of the title compound as a white powder, = + 113 ° (c = 0.86 in dimethyl sulfoxide). ). Xmax (pH 6 buffer) 264.5 nm (ε = 17,200) and 279 nm (ε = 15,600).
>7max (nujol) 1770 (β-laktam), 1740 og 1716 (COOH), 1688, 1654, 1589 og 1530 (CONH og 0C0NH2) og 1030 cm"1 (S-» 0).^(Me2SO-d6) 0,60 (d, J 8 Hz, NH), 2,11, 3,19, 3,31 (multipletter, furylproto-ner), 4,08 (q, J 5 og 8 Hz, C-7H), 4,87 og 5,45 (ABq, J 13 Hz, CH20C0NH2), 4,96 (d, J 5 Hz, C-6H), 6,08 (s, 0CH3), 6,10 og 6,42 (ABq, J 18 Hz, C-2CH2).> 7max (nujol) 1770 (β-lactam), 1740 and 1716 (COOH), 1688, 1654, 1589 and 1530 (CONH and OCNH2) and 1030 cm -1 (S-O). ^ (Me2SO-d6) 0 , 60 (d, J 8 Hz, NH), 2.11, 3.19, 3.31 (multiplets, furyl protons), 4.08 (q, J 5 and 8 Hz, C-7H), 4, 87 and 5.45 (ABq, J 13 Hz, CH 2 CONH 2), 4.96 (d, J 5 Hz, C-6H), 6.08 (s, OCH 3), 6.10 and 6.42 (ABq, J 18 Hz, C-2CH 2).
Eksempel 13 55 147683 (1R,6r,7R)- og (1S, 6 R, 7 R) -3-Karbamoyloxymety1-7-^2-(fur- 2-yl)-2-metoxyiminoacetamido7-ceph-3-em-4-karboxylsyre- 1-oxyd (syn-isomerer)EXAMPLE 13 (1R, 6R, 7R) - and (1S, 6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido7-ceph-3-em] 4-carboxylic acid 1-oxide (syn isomers)
En opløsning af 1,93 g natriumperjodat i 10 ml vand sattes til en under omrøring værende opløsning af 2,59 g natrium-(6R, 7R)-3-karbamoyloxymety1-7-^2- (fur-2-yl )-2-metoxyiminoacetamido7-ceph-3~em-4-karboxylat i 25 ml vand. Omrøringen fortsattes i 30 minutter ved stuetemperatur og opløsningen syrnedes så med 2 ml 2N HC1. Det aflejrede lS-oxyd frafiltreredes, vaskedes med 5 ml ætanol og 20 ml æter og tørredes i en ekssikkator hvorved der fremkom I, 55 g farveløst fast stof, aD = +110° (c = l i Me2S0), og produktet lignede det der er beskrevet i eksempel 12.A solution of 1.93 g of sodium periodate in 10 ml of water was added to a stirred solution of 2.59 g of sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2 -methoxyiminoacetamido7-ceph-3 ~ em-4-carboxylate in 25 ml of water. Stirring was continued for 30 minutes at room temperature and the solution was then acidified with 2 ml of 2N HCl. The precipitated 1S oxide was filtered off, washed with ethanol (5 ml) and ether (20 ml) and dried in a desiccator to give 1.5 g of colorless solid, aD = + 110 ° (c = 1e Me 2 SO). described in Example 12.
Modervæskerne mættedes med natriumklorid og filtreredes og filtratet ekstraheredes med 2 x 100 ml ætylacetat. De organiske ekstrakter forenedes, tørredes over MgSO^ og koncentreredes i vakuum hvorved der fremkom et gult fast stof. Råproduktet vaskedes med acetone og det uopløselige materiale fjernedes ved filtrering. Filtratet inddampedes til tørhed og acetonen vaskedes gentagne gange, hvorved der fremkom 380 mg af lR-oxydet med aD = -88° (c = 1 i Me2S0), ΙΓ-værdier (Me2S0-dg) lignede dem der er anført i eksempel II.The mother liquors were saturated with sodium chloride and filtered and the filtrate was extracted with 2 x 100 ml of ethyl acetate. The organic extracts were combined, dried over MgSO 4 and concentrated in vacuo to give a yellow solid. The crude product was washed with acetone and the insoluble material removed by filtration. The filtrate was evaporated to dryness and the acetone washed repeatedly to give 380 mg of the 1R oxide with aD = -88 ° (c = 1 in Me2S0), ΙΓ values (Me2S0-dg) similar to those listed in Example II.
Eksempel 14 a) Difenylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur-2-yl)-2-fenoxyiminoacetamido7-ceph-3-em-4-karboxylat (syn-isomer)Example 14 a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-phenoxyiminoacetamido7-ceph-3-em-4-carboxylate (syn isomer)
En opløsning af 7»75 g (0,382 mol) DL-dicyklohexylkarbo-diimid i 50 ml tørt diklormetan sattes i løbet af ti minutter til en opløsning af 13»7 g» 0,312 mol, difenylmetyl-(6R,7R)-7-amino-3-karbamoyloxymetylceph-3-em-4-karboxylat og 8,8 g, 0,382 mol, af syn-isomeren af 2-(fur-2-yl)-2-fenoxyiminoeddikesyre i 200 ml tørt 147683 56 « diklormetan ved 0°C. Efter 45 minutter frafiltreredes et fast stof (antagelig Ν,Ν'-dicyklohexylurinstof), og filtratet vaskedes med vandig natriumbikarbonatopløsning og vand, tørredes over magniumsulfat og inddampedes på en roterende evaporator. Remanensen kroma tograf eredes på en kolonne med 1 kg silikagel. Urenheder som var mindre polære end det ønskede produkt elueredes med 1 liter diklormetan og 1 liter acetone/diklormetan 2:98 samt 4 liter acetone/di-klormetan 5:95. Fraktioner som elueredes med acetone/diklormetan 10:90 og acetone/diklormetan 15:85 inddampedes til en gummi i en mængde på 11 g, og den tritureredes med diætylæter til frembringelse af 8,35 g (41$) af et fast stof. Dette frafiltreredes og rensedes yderligere ved krystallisation fra vandig ætanol, hvorved der fremkom 7,6 g af den i overskriften angivne forbindelse med smelte- 00 punkt 143-146°C, aD = +48° (c = 1,0 i Me2S0). Xmax (ætanol) 273 nm (ε = 18.700). Xinfl. (ætanol) 271 nm (ε = 17,600) og Xmax (ætanol) 254 nm (ε = 16.500).A solution of 7 »75 g (0.382 mol) of DL-dicyclohexylcarbodiimide in 50 ml of dry dichloromethane was added over 10 minutes to a solution of 13» 7 g »0.312 mol, diphenylmethyl (6R, 7R) -7-amino -3-carbamoyloxymethylceph-3-em-4-carboxylate and 8.8 g, 0.382 mol, of the syn isomer of 2- (fur-2-yl) -2-phenoxyiminoacetic acid in 200 ml of dry dichloromethane at 0 ° C. After 45 minutes, a solid (presumably Ν, Ν'-dicyclohexylurea) was filtered off and the filtrate washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated on a rotary evaporator. The residue was chromatographed on a column of 1 kg of silica gel. Impurities less polar than the desired product were eluted with 1 liter of dichloromethane and 1 liter of acetone / dichloromethane 2:98 and 4 liters of acetone / dichloromethane 5:95. Fractions eluted with acetone / dichloromethane 10:90 and acetone / dichloromethane 15:85 were evaporated to a gum in an amount of 11 g and triturated with diethyl ether to give 8.35 g ($ 41) of a solid. This was filtered off and further purified by crystallization from aqueous ethanol to give 7.6 g of the title compound, mp 143-146 ° C, α D = + 48 ° (c = 1.0 in Me₂SO). Xmax (ethanol) 273 nm (ε = 18.700). Xinfl. (ethanol) 271 nm (ε = 17,600) and Xmax (ethanol) 254 nm (ε = 16,500).
IR-, NMR- og mikroanalytiske data bekræftede at strukturen var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure was the title compound.
b) Natrium-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur-2-yl)- 2-fenoxyiminoacetamido7-ceph-3-em-4-karboxylat (syn-isomer) 30 ml trifluoreddikesyre sattes i løbet af ti minutter til en isafkølet blanding af 8 ml anisol og 7,4 g, 11,4 mmol, af syn-isomeren af difenylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-/2-(fur- 2-yl)-2-fenoxyiminoacetamidoT-ceph-3-em-4-karboxylat. Efter yderligere fem minutter ved 0°C udhældtes den mørke opløsning forsigtigt i en blanding af en mættet vandig opløsning af natriumbikarbonat og æteracetat. Den vandige opløsning fraskiltes og behandledes med aktiveret trækul. Ætylacetatlaget vaskedes med vand og den vandige vaskevæske forenedes med natriumbikarbonatekstrakten og syrnedes med koncentreret saltsyre. Denne sure opløsning ekstraheredes med en blanding af ætylacetat og diætylæter som derefter vaskedes fem gange med vand, tørredes over magniumsulfat og inddampedes i vakuum. Remanensen vaskedes med diætylæter og diisopropylæter og gav 4,5 g (82$) af cephalosporinsyren som et fast stof.b) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-phenoxyiminoacetamido7-ceph-3-em-4-carboxylate (syn isomer) 30 ml trifluoroacetic acid was added over ten minutes to an ice-cooled mixture of 8 ml of anisole and 7.4 g, 11.4 mmol, of the syn isomer of diphenylmethyl- (6R, 7R) -3-carbamoyloxymethyl-7- / 2- (fur-2 yl) -2-fenoxyiminoacetamidoT-ceph-3-em-4-carboxylate. After another five minutes at 0 ° C, the dark solution was gently poured into a mixture of a saturated aqueous solution of sodium bicarbonate and ether acetate. The aqueous solution was separated and treated with activated charcoal. The ethyl acetate layer was washed with water and the aqueous wash liquid combined with the sodium bicarbonate extract and acidified with concentrated hydrochloric acid. This acidic solution was extracted with a mixture of ethyl acetate and diethyl ether which was then washed five times with water, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether and diisopropyl ether to give 4.5 g (82 $) of the cephalosporic acid as a solid.
147683 57147683 57
Denne syre opløstes i 150 ml ætylacetat og der tilsattes en opløsning af natrium-2-hexylhexanoat i ætylacetat (10 ml indeholdende 10 mmol). Opløsningen afkøledes i et isbad og omrørtes i 1 1/2 time i løbet af hvilken periode der udkrystalliserede 2,84 g af produktet, mens uomdannet syre efterlodes i opløsning (1,1 g genvandtes ved fældning med petroleumsæter, kp. 60-80°C). Det faste stof filtreredes til dannelse af den i overskriften angivne forbindelse.This acid was dissolved in 150 ml of ethyl acetate and a solution of sodium 2-hexylhexanoate in ethyl acetate (10 ml containing 10 mmol) was added. The solution was cooled in an ice bath and stirred for 1 1/2 hours during which time 2.84 g of the product crystallized while leaving unchanged acid in solution (1.1 g recovered by precipitation with petroleum ether, bp 60-80 ° C). The solid was filtered to give the title compound.
Fysiske konstanter for den i overskriften angivne forbindelse er anført i omstående tabel l.Physical constants for the title compound are given in Table 1 below.
Eksempel 15 a) Difenylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-(2-metoxy-imino-2-fenylacetamido)-ceph-3-em-4-karboxylat (syn-isomer) 1,83 g, 3 mmol, difenylmetyl-(6R,7R)-7-amino-3-harbamoyl-oxymetylceph-3-em-4-karboxylat-p-toluensulfonsyresalt sattes til en blanding af 50 ml mættet vandig natriumbikarbonatopløsning og 100 ml diklormetan. Blandingen rystedes for at opløse det faste stof og det organiske lag fraskiltes, vaskedes to gange med vand, tørredes over natriumsulfat og koncentreredes under nedsat tryk til ca. 15 ml. Denne opløsning afkøledes til 0°C og der tilsattes opløsninger af 824 mg, 4 mmol, DL-dicyklohexylkarbodiimid i 10 ml tørt diklormetan og 716 mg, 4 mmol, af syn-isomeren af 2-metoxyi-mino-2-fenyleddikesyre i 10 ml tørt diklormetan. Reaktionsblandingen omrørtes ved 0°C i 70 minutter hvorefter den filteredes, vaskedes med 2N svovlsyre, vand, mættet vandig natriumbikarbonatopløsning, vand og saltlage, tørredes over natriumsulfat og inddampedes til 2,05 g af et gult fast stof. Dette opløstes i 25 ml varm metylacetat som afkøledes, og dicyklohexylurinstof frafiltreredes. Tilsætning af diisopropylæter til filtratet bevirkede udfældning af et fast stof som frafiltreredes, omrørtes og vaskedes med diisopropylæter, filtreredes og til slut vaskedes med ætylæter; herved fremkom 1,10 g (61,5%) af den i overskriften angivne forbindelse med smeltepunkt 178-182°C. aD = +22,5° (c = 1 i CHClg). \max (ætanol) 258,5 nm (ε = 18.500), Xinfl. (ætanol) 295 nm (ε = 3120).Example 15 a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl 7- (2-methoxy-imino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn-isomer) 1.83 g, 3 mmol, diphenylmethyl (6R, 7R) -7-amino-3-harbamoyl-oxymethylceph-3-em-4-carboxylate-p-toluenesulfonic acid salt was added to a mixture of 50 ml of saturated aqueous sodium bicarbonate solution and 100 ml of dichloromethane. The mixture was shaken to dissolve the solid and the organic layer was separated, washed twice with water, dried over sodium sulfate and concentrated under reduced pressure to ca. 15 ml. This solution was cooled to 0 ° C and solutions of 824 mg, 4 mmol, DL-dicyclohexylcarbodiimide in 10 ml of dry dichloromethane and 716 mg, 4 mmol of the syn-isomer of 2-methoxy-mino-2-phenylacetic acid were added in 10 ml. dry dichloromethane. The reaction mixture was stirred at 0 ° C for 70 minutes, then filtered, washed with 2N sulfuric acid, water, saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated to 2.05 g of a yellow solid. This was dissolved in 25 ml of hot methyl acetate which was cooled and the dicyclohexylurea was filtered off. Addition of diisopropyl ether to the filtrate caused the precipitation of a solid which was filtered, stirred and washed with diisopropyl ether, filtered and finally washed with ethyl ether; There was thus obtained 1.10 g (61.5%) of the title compound, mp 178-182 ° C. aD = + 22.5 ° (c = 1 in CHCl 3). \ max (ethanol) 258.5 nm (ε = 18,500), Xinfl. (ethanol) 295 nm (ε = 3120).
147683 58 IR, NMR og mikroanalytiske data bekræftede at strukturen var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure was the title compound.
b) (6R,7R)-3-Karbamoyloxymetyl-7-(2-metoxyimino-2-fenyl-acetamido)-ceph-3-em-4-karboxylsyre (syn-isomer)b) (6R, 7R) -3-Carbamoyloxymethyl-7- (2-methoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)
Behandling af produktet fra eksempel 15 a) i overensstemmelse med den metode der er beskrevet i eksempel lb) gav 75% af den i overskriften angivne forbindelse, og den rensedes ved triturering af råproduktet med 10 ml ætylacetat efterfulgt af 2 ganges vask under omrøring med diætylæter, henholdsvis 25 ml og 10 ml.Treatment of the product of Example 15 a) in accordance with the method described in Example 1b) provided 75% of the title compound and was purified by trituration of the crude product with 10 ml of ethyl acetate followed by washing twice with stirring with diethyl ether. , 25 ml and 10 ml respectively.
Fysiske konstanter for den i overskriften angivne forbindelse er anført i omstående tabel 1.Physical constants for the title compound are listed in Table 1 below.
Eksempel 16 a) Difenylmetyl-(6 R,7 R)-3-karbamoyloxymetyl-7-(2-fen-ojcyimino-2-fenylacetamido)-ceph-3-em-4-karboxylat (syn-isomer)Example 16 a) Diphenylmethyl (6 R, 7 R) -3-carbamoyloxymethyl-7- (2-phenylimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)
Fremgangsmåden ifølge eksempel 15 a) gentoges med den forskel at der brugtes syn-isomeren af 2-fenoxyimino-2-fenyleddikesyre i stedet for syn-isomeren af 2-metoxyimino-2-fenyleddikesy-re, og der vandtes et rødt klæbrigt skum. Dette råprodukt krystalliseredes fra vandig acetone hvorved der fremkom 1,3 g af et rødt fast stof som vaskedes to gange under omrøring med diætylæter; herved fremkom der 675 mg (34%) af den i overskriften angivne forbindelse med smeltepunkt 138-140°C. aD = +44,5° (c = 1 i CHCl^). Xmax (ætanol) 264 nm (ε = 12,400), \infl. (ætanol) 268 og 281 nm (ε = 16,850 og 14.000); produktet var et hvidt fast stof. Den remanens der vandtes efter inddampning af modervæskerne og vaskevæskerne krystalliseredes fra ætanol og gav yderligere 431 mg (17%) af den i overskriften angivne forbindelse i to udbytter, som vaskedes med diætylæter under omrøring.The procedure of Example 15 a) was repeated with the difference that the syn isomer of 2-phenoxyimino-2-phenylacetic acid was used instead of the syn isomer of 2-methoxyimino-2-phenylacetic acid and a red sticky foam was obtained. This crude product was crystallized from aqueous acetone to give 1.3 g of a red solid which was washed twice with stirring with diethyl ether; there was obtained 675 mg (34%) of the title compound, mp 138-140 ° C. aD = + 44.5 ° (c = 1 in CHCl3). Xmax (ethanol) 264 nm (ε = 12,400), \ infl. (ethanol) 268 and 281 nm (ε = 16,850 and 14,000); the product was a white solid. The residue obtained after evaporation of the mother liquors and washings was crystallized from ethanol to give an additional 431 mg (17%) of the title compound in two yields which were washed with diethyl ether with stirring.
IR, NMR og mikroanalytiske data bekræftede at produktets struktur var den i overskriften angivne forbindelses.IR, NMR and microanalytical data confirmed that the structure of the product was the title compound.
147683 59 b) Natrium-(6R,7R)-3-karbamoyloxymetyl-7-(2-fenoxyimino-2-fenylacetamido)-ceph-3-em-4-karboxylat (syn-isomer)B) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- (2-phenoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn-isomer)
Behandling af produktet fra eksempel 16 a) ved den metode der er beskrevet i eksempel 1 b) gav den rå cephalosporinsyre, og den omrørtes med ætylacetat og mættet vandig natriumbikarbonat-opløsning. Det resulterende bundfald frafiltreredes og vaskedes med acetone og æter for at give den i overskriften angivne forbindelse (66%) med de fysiske egenskaber som er vist i omstående tabel l.Treatment of the product of Example 16 a) by the method described in Example 1 b) gave the crude cephalosporic acid and it was stirred with ethyl acetate and saturated aqueous sodium bicarbonate solution. The resulting precipitate was filtered off and washed with acetone and ether to give the title compound (66%) having the physical properties shown in Table 1 below.
Eksempel 17 a) Difenylmetyl-( 6r,7R)-3-karbamoyloxymetyl-7-/2-cyklo-pentyloxyimino-2-(fur-2-yl)-acetamido7-ceph-3-em-4-karboxylat (syn-isomer)Example 17 a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- / 2-cyclo-pentyloxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em-4-carboxylate (syn-isomer) )
Fremgangsmåden i eksempel 15 a) blev gentaget med en forskel at der brugtes syn-isomeren af 2-cyklopentyloxyimino-2-(fur-2-yl)-eddikesyre i stedet for syn-isomeren af 2-metoxyimino-2-fenyl-eddikesyre, og der fremkom 1,77 g af et skum som tritureredes med ætylacetat og gav 1,30 g (67%) af den i overskriften angivne forbindelse som et lysegult fast stof med smeltepunkt 102-108 °C. <*D = +12,5° (c = 1 i CHClg). Xmax (ætanol) 278 nm (e = 16,650).The procedure of Example 15 a) was repeated with the difference that the syn isomer of 2-cyclopentyloxyimino-2- (fur-2-yl) acetic acid was used instead of the syn isomer of 2-methoxyimino-2-phenyl acetic acid. and 1.77 g of a foam was obtained which was triturated with ethyl acetate to give 1.30 g (67%) of the title compound as a pale yellow solid, mp 102-108 ° C. <* D = + 12.5 ° (c = 1 in CHCl 3). Xmax (ethanol) 278 nm (e = 16,650).
b) (6R,7R)-3-Karbamoyloxymetyl-7-/2-cyklopentyloxyimino-2-(fur-2-yl)-acetamido7-ceph-3-em-4-karboxylsyre (syn-isomer)b) (6R, 7R) -3-Carbamoyloxymethyl-7- / 2-cyclopentyloxyimino-2- (fur-2-yl) -acetamido7-ceph-3-em-4-carboxylic acid (syn isomer)
Behandling af produktet fra eksempel 17 a) i overensstemmelse med den metode der er beskrevet i eksempel 1 b) gav den rå cephalosporinsyre som udfældedes fra ætylacetat med diisopropylæter; herved vandtes den i overskriften angivne forbindelse (55%) med fysiske konstanter som vist i omstående tabel 1.Treatment of the product of Example 17 a) in accordance with the method described in Example 1 b) gave the crude cephalosporic acid which precipitated from ethyl acetate with diisopropyl ether; thereby winning the title compound (55%) with physical constants as shown in Table 1 below.
Eksempel 18 60 147683 a) Di£enylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-(2-ætoxy-imino-2-fenylacetamido)-ceph-3-em-4-karboxylat (syn-isomer)Example 18 60 147683 a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- (2-ethoxy-imino-2-phenylacetamido) -ceph-3-em-4-carboxylate (syn isomer)
Fremgangsmåden ifølge eksempel 15 a) gentoges med den forskel at der brugtes syn-isomeren af 2-ætoxyimino-2-fenyleddike-syre i stedet for syn-isomeren af 2-metoxyimino-2-£enyleddikesyre. Krystallisation af råproduktet fra metanol gav 1,30 g (53%) af den i overskriften angivne forbindelse i tre udbytter, smeltepunkt 199-202°G, aD = +9,7° (c = 1 i dioxan). Xmax (ætanol) 259 nm (ε = 20.000). \infl. (ætanol) 295 nm (ε = 3700).The procedure of Example 15 a) was repeated except that the syn isomer of 2-ethoxyimino-2-phenylacetic acid was used instead of the syn isomer of 2-methoxyimino-2-enylacetic acid. Crystallization of the crude product from methanol afforded 1.30 g (53%) of the title compound in three yields, mp 199-202 ° G, α D = + 9.7 ° (c = 1 in dioxane). Xmax (ethanol) 259 nm (ε = 20,000). \ Infl. (ethanol) 295 nm (ε = 3700).
b) (6R,7R)-3-Karbamoyloxymetyl-7-(2-ætoxyimino-2-fenyl-acetamido)-ceph-3-em-4-karboxylsyre (syn-isomer)b) (6R, 7R) -3-Carbamoyloxymethyl-7- (2-ethoxyimino-2-phenylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)
Behandling af produktet fra eksempel 18 a) på den måde der er beskrevet i eksempel lb) gav den rå cephalosporinsyre, og den tritureredes med 3 ml ætylacetat, frafiltreredes og vaskedes under omrøring med 5 ml ætylacetat og derefter med 2 x 10 ml diæ-tylæter; herved fremkom 413 mg (64%) af den i overskriften angivne forbindelse som et hvidt fast stof. En yderligere mængde på 180 mg (27%) krystalliserede fra filtraterne og frafiltreredes og vaskedes med diætylæter. Fysiske konstanter for den i overskriften angivne forbindelse er vist i omstående tabel 1.Treatment of the product of Example 18 a) in the manner described in Example 1b) gave the crude cephalosporic acid and it was triturated with 3 ml of ethyl acetate, filtered and washed with stirring with 5 ml of ethyl acetate and then with 2 x 10 ml of diethyl ether. ; 413 mg (64%) of the title compound was obtained as a white solid. An additional amount of 180 mg (27%) crystallized from the filtrates and filtered off and washed with diethyl ether. Physical constants for the title compound are shown in Table 1 below.
Eksempel 19 a) Difenylmetyl-(6R,7R)-3-karbamoyloxymetyl-7-^2-t-bu-toxyimino-2-(tien-2-yl)-acetamido7-ceph-3-em-4-karb-oxylat (syn-isomer)Example 19 a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxyimino-2- (thien-2-yl) -acetamido7-ceph-3-em-4-carb oxylate (syn isomer)
Fremgangsmåden ifølge eksempel 15 a) gentoges med den forskel at der brugtes syn-isomeren af 2-t-butoxyimino-2-(tien-2-yl)-eddikesyre i stedet for syn-isomeren af 2-metoxyimino-2-fenyleddike- 147683 61 syre. Råproduktet rensedes ved omrøring af en suspension i 2 x 25 ml diisopropylæter, og den i overskriften angivne forbindelse vandtes som et ganske lyserødt fast stof i en mængde på 1,90 g (73¾), smeltepunkt 148-152°C. aD = +8,5° (c = 1 i CHClg). kmax (ætanol) 262 og 282 nm (ε * 14.500 og 13.200).The procedure of Example 15 a) was repeated except that the syn isomer of 2-t-butoxyimino-2- (thien-2-yl) acetic acid was used instead of the syn isomer of 2-methoxyimino-2-phenylacetic acid. 61 acid. The crude product was purified by stirring a suspension in 2 x 25 ml of diisopropyl ether and the title compound was watered as a quite pink solid in an amount of 1.90 g (73¾), mp 148-152 ° C. aD = + 8.5 ° (c = 1 in CHCl 3). kmax (ethanol) 262 and 282 nm (ε * 14,500 and 13,200).
b) Natrium-(6R,7R)-3-karbamoyloxymetyl-7-/2-t-butoxyimi-no-2-(tien-2-yl)-acetajnido7-ceph-3-em-4-karboxylat (syn-isomer)b) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- / 2-t-butoxyimino-2- (thien-2-yl) -acetajnido7-ceph-3-em-4-carboxylate (syn isomer) )
Behandling af produktet fra eksempel 19 a) på den måde der er beskrevet i eksempel lb) gav cephalosporinsyren som en gummi der størknede ved triturering med diisopropylæter; herved vandtes der 1,20 g (94¾) af et råprodukt. En portion på 811 mg (1,68 mmol) af denne syre og 282 mg (1,68 mmol) 2-ætylhexanoat omrørtes i 5 ml n-butanol ved 20°C i ti minutter og ved 0°C i tyve minutter. Det resulterende gule faste stof frafiltreredes og vaskedes med kold n-butanol (3 ml) og diisopropylæter (7 ml), hvorved der fremkom 495 mg (58¾) af den i overskriften angivne forbindelse med de fysiske konstanter som er vist i tabel 1.Treatment of the product of Example 19 a) in the manner described in Example 1b) gave the cephalosporic acid as a gum which solidified upon trituration with diisopropyl ether; 1.20 g (94¾) of a crude product were obtained. A portion of 811 mg (1.68 mmol) of this acid and 282 mg (1.68 mmol) of 2-ethyl hexanoate was stirred in 5 ml of n-butanol at 20 ° C for ten minutes and at 0 ° C for twenty minutes. The resulting yellow solid was filtered off and washed with cold n-butanol (3 ml) and diisopropyl ether (7 ml) to give 495 mg (58¾) of the title compound with the physical constants shown in Table 1.
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(ti i t n I OO(ti i t n I OO
VJ I O !>1 "i ffl XS S _J Opj ·. I-l /-V 0<rv ri N o n O r-N I—I /—sVJ I O!> 1 "i ffl XS S _J Opj ·. I-l / -V 0 <rv ri N o n O r-N I — I / —s
m I N_r v[ <l)r-N · <J · PQ * · ·<1 · <1 · CQm I N_r v [<l) r-N · <J · PQ * · · <1 · <1 · CQ
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ΰΑΌ ^ 'r' 'r' WWWΰΑΌ ^ 'r' 'r' WWW
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. © © © © O O. © © © © O O
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C, Nr' VC, No. V
« H <j m© γν. οοσ URr-lr-lr-l r—l r-l r-l 147683 63 Μ cη — •η Ο Ν«H <j m © γν. οοσ URr-lr-lr-l r — l r-l r-l 147683 63 Μ cη - • η Ο Ν
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W <--- ΗΝΠ Γ0 N N H CM (N Π Π CMCH CM CMW <--- ΗΝΠ Γ0 N N H CM (N Π Π CMCH CM CM
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«I r—I CM rsN CM CM <f +jj-H S· «ro. · · · οίΓ«Ι ? ° ^ ° ° ° <H I ly> Zi tih H ! Λ /-s ^«I r — I CM rsN CM CM <f + jj-H S ·« ro. · · · ΟίΓ «Ι? ° ^ ° ° ° <H I ly> Zi tih H! Λ / -s ^
ni S λ g £ £ Sni S λ g £ £ S
(Dl · ^ ^ ^ fik I (fl · al I X Sh viinvo r* oo σ>(Dl · ^ ^ ^ got I {fl · al I X Sh viinvo r * oo σ>
Em I H f3 . H r-( i—i ·-< ^ 147883 64Em I H f3. H r- (i-i · - <^ 147883 64
Tabel 1 fortsatTable 1 continued
Eks. nr. Mikroanalyse (%) Empirisk formel fundet/beregnet (solvat)Ex. No. Microanalysis (%) Empirical formula found / calculated (solvate)
C Η N SC Η N S
14 (b) 48.2 3.8 10.5 5.9 C H J SO.14 (b) 48.2 3.8 10.5 5.9 C H J SO.
48.2 3.6 10.7 6.1 ^ 15 (b) 50.1 4.3 12.4 7.2 C10H.„N.S07 49.8 4.2 12.9 7.4 18 18 4 7 16 (b) 49.5 3.65 9.6 5.8 C„_H pN SO?Na 49.9 4.15 10.0 5.8 (fm^ H'0) 17 (b) 50.6 5-4 10.5 C„nH„N.SOfl 51.8 5.2 10.8 1 2 3,22 4 8 LO.4 mol (i-Pr)20] (b) 52.6 4.3 11.9 7.1 C1QHonN.S0, 52.2 4.3 11.9 6.8 ,}9,20 4 7 . , .48.2 3.6 10.7 6.1 ^ 15 (b) 50.1 4.3 12.4 7.2 C10H. "N.S07 49.8 4.2 12.9 7.4 18 18 4 7 16 (b) 49.5 3.65 9.6 5.8 C" _H pN SO? After 49.9 4.15 10.0 5.8 (fm ^ H '0) 17 (b) 50.6 5-4 10.5 C "nH" N.SOfl 51.8 5.2 10.8 1 2 3.22 4 8 LO.4 mol (i-Pr) 20] (b) 52.6 4.3 11.9 7.1 C1QHonN.S0 , 52.2 4.3 11.9 6.8,} 9.20 4 7. ,.
(0.2 mol anisol ) 2 (b) C19H21N4S2°7Na 3(0.2 mol of anisole) 2 (b) C19H21N4S2 ° 7Na 3
Fodnoter (1) for forbindelsen *D = _£_Footnotes (1) for the compound * D = _ £ _
PACPAC
R^ af (6R,7R)-3-acetoxymetyl-7-fenylacet-amido-ceph-3-em-4-karboxy1syre Opløsningsmiddelsystem A er n-butanol/ætanol/vand 4:1:5. Opløsningsmiddelsystem B er n-propanol/vand 7:3.R 1 of (6R, 7R) -3-acetoxymethyl-7-phenylacetamido-ceph-3-em-4-carboxylic acid Solvent system A is n-butanol / ethanol / water 4: 1: 5. Solvent system B is n-propanol / water 7: 3.
(2) inf. angiver en inflektion.(2) inf. indicates an inflection.
(3) Trifluoreddikesyre-spektrum.(3) Trifluoroacetic acid spectrum.
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB3964573A GB1453049A (en) | 1973-08-21 | 1973-08-21 | Cephalosporing antibiotics |
GB3964573 | 1973-08-21 |
Publications (3)
Publication Number | Publication Date |
---|---|
DK443274A DK443274A (en) | 1975-04-28 |
DK147683B true DK147683B (en) | 1984-11-12 |
DK147683C DK147683C (en) | 1985-05-13 |
Family
ID=10410683
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK443274A DK147683C (en) | 1973-08-21 | 1974-08-20 | METHOD OF ANALOGY FOR THE PREPARATION OF CEPHALOSPORINE COMPOUNDS OR TOXIC SALTS, BIOLOGICAL ACCEPTABLE ESTERS, 1-OXYDS OR SOLVATES THEREOF |
Country Status (32)
Country | Link |
---|---|
JP (2) | JPS562077B2 (en) |
AR (2) | AR212076A1 (en) |
AT (1) | AT340042B (en) |
AU (1) | AU473550B2 (en) |
BE (1) | BE819004R (en) |
BG (2) | BG23903A3 (en) |
CA (1) | CA1057283A (en) |
CH (2) | CH613975A5 (en) |
CS (2) | CS204989B2 (en) |
CY (1) | CY945A (en) |
DD (1) | DD114417A5 (en) |
DE (2) | DE2462376A1 (en) |
DK (1) | DK147683C (en) |
ES (2) | ES429388A1 (en) |
FI (1) | FI65623C (en) |
FR (1) | FR2241318B2 (en) |
GB (1) | GB1453049A (en) |
GT (1) | GT198302370A (en) |
HK (1) | HK17378A (en) |
HU (1) | HU170000B (en) |
IE (1) | IE39764B1 (en) |
IL (1) | IL45505A (en) |
KE (1) | KE2816A (en) |
LU (2) | LU70765A1 (en) |
MY (1) | MY7800188A (en) |
NL (1) | NL154741B (en) |
NO (1) | NO152751C (en) |
PL (2) | PL115805B1 (en) |
RO (2) | RO69607A (en) |
SU (1) | SU633483A3 (en) |
YU (2) | YU36737B (en) |
ZA (1) | ZA745331B (en) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1555471A (en) * | 1975-06-19 | 1979-11-14 | Glaxo Lab Ltd | 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof |
CA1093549A (en) * | 1976-02-16 | 1981-01-13 | Michael Gregson | Cephalosporin antibiotics |
FR2345153A1 (en) * | 1976-03-25 | 1977-10-21 | Roussel Uclaf | NEW ALCOYLOXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
FI771866A (en) * | 1976-06-28 | 1977-12-29 | Fujisawa Pharmaceutical Co | |
GB1598568A (en) * | 1977-04-19 | 1981-09-23 | Glaxo Lab Ltd | Esters of(6r,7r)-3-carbamoyloxymethyl-7-((z)-2-(fur-2-yl)-2-methoxyiminoacetamido)-ceph-3-em-4-carboxylic acid |
IT1162442B (en) * | 1978-01-17 | 1987-04-01 | Glaxo Group Ltd | PROCEDURE FOR PREPARING THE CRYSTALLINE SHAPED SODIUM SALT OF CEFUROSSIMA |
DE2804040C3 (en) * | 1978-01-31 | 1981-03-19 | Hoechst Ag, 6000 Frankfurt | Process for the preparation of cephem compounds |
US4341777A (en) * | 1979-09-10 | 1982-07-27 | Glaxo Group Limited | Cephalosporin antibiotic |
IT1190734B (en) * | 1982-03-11 | 1988-02-24 | Opos Biochimica Srl | PROCEDURE FOR THE PREPARATION OF CEFUROXIMA AND INTERMEDIATES USED IN SUCH PROCEDURE |
GB8320520D0 (en) * | 1983-07-29 | 1983-09-01 | Glaxo Group Ltd | Chemical process |
GB8400024D0 (en) * | 1984-01-03 | 1984-02-08 | Glaxo Group Ltd | Cephalosporin antibiotics |
GB8810394D0 (en) * | 1988-05-03 | 1988-06-08 | Glaxo Group Ltd | Chemical process |
WO2000053609A1 (en) * | 1999-03-09 | 2000-09-14 | Ranbaxy Laboratories Limited | Process for the preparation of cefuroxime |
EP1567674A4 (en) * | 2002-11-22 | 2007-09-26 | Univ Johns Hopkins | Target for therapy of cognitive impairment |
WO2004050663A2 (en) * | 2002-12-05 | 2004-06-17 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefuroxime sodium |
JP2008275173A (en) * | 2008-08-04 | 2008-11-13 | Toshiba Corp | Branch pipe |
EP2741750A1 (en) | 2011-08-12 | 2014-06-18 | Dhanuka Laboratories Ltd. | Pharmaceutical composition comprising cefuroxime |
WO2013038323A1 (en) | 2011-09-13 | 2013-03-21 | Unimark Remedies Ltd. | Taste masked pharmaceutical compositions of cefuroxime axetil |
KR101497420B1 (en) | 2013-07-05 | 2015-03-03 | 삼성중공업 주식회사 | LNG transportation Apparatus for reducing Boil-Off Gas |
CN105884799A (en) * | 2015-09-23 | 2016-08-24 | 石药集团中诺药业(石家庄)有限公司 | Novel cefuroxime sodium compound |
-
1973
- 1973-08-21 GB GB3964573A patent/GB1453049A/en not_active Expired
-
1974
- 1974-08-13 CY CY945A patent/CY945A/en unknown
- 1974-08-19 RO RO7486148A patent/RO69607A/en unknown
- 1974-08-19 RO RO7479828A patent/RO64129A/en unknown
- 1974-08-20 YU YU2283/74A patent/YU36737B/en unknown
- 1974-08-20 FI FI2456/74A patent/FI65623C/en active
- 1974-08-20 CS CS745783A patent/CS204989B2/en unknown
- 1974-08-20 PL PL1974196434A patent/PL115805B1/en unknown
- 1974-08-20 ES ES429388A patent/ES429388A1/en not_active Expired
- 1974-08-20 CH CH1135374A patent/CH613975A5/en not_active IP Right Cessation
- 1974-08-20 DD DD180622A patent/DD114417A5/xx unknown
- 1974-08-20 CS CS745783A patent/CS204988B2/en unknown
- 1974-08-20 DK DK443274A patent/DK147683C/en active
- 1974-08-20 IL IL45505A patent/IL45505A/en unknown
- 1974-08-20 DE DE19742462376 patent/DE2462376A1/en active Pending
- 1974-08-20 BG BG031288A patent/BG23903A3/en unknown
- 1974-08-20 CA CA207,441A patent/CA1057283A/en not_active Expired
- 1974-08-20 BE BE147745A patent/BE819004R/en active
- 1974-08-20 DE DE2439880A patent/DE2439880C3/en not_active Expired
- 1974-08-20 JP JP9545674A patent/JPS562077B2/ja not_active Expired
- 1974-08-20 IE IE1735/74A patent/IE39764B1/en unknown
- 1974-08-20 NL NL747411095A patent/NL154741B/en not_active IP Right Cessation
- 1974-08-20 AU AU72531/74A patent/AU473550B2/en not_active Expired
- 1974-08-20 BG BG027524A patent/BG25801A3/en unknown
- 1974-08-20 PL PL1974173581A patent/PL98962B1/en unknown
- 1974-08-20 ZA ZA00745331A patent/ZA745331B/en unknown
- 1974-08-20 NO NO742986A patent/NO152751C/en unknown
- 1974-08-20 LU LU70765A patent/LU70765A1/xx active Protection Beyond IP Right Term
- 1974-08-20 LU LU88269C patent/LU88269I2/xx unknown
- 1974-08-20 AR AR255247A patent/AR212076A1/en active
- 1974-08-20 AT AT676374A patent/AT340042B/en not_active IP Right Cessation
- 1974-08-21 HU HUGA1166A patent/HU170000B/hu unknown
- 1974-08-21 FR FR7428750A patent/FR2241318B2/fr not_active Expired
-
1975
- 1975-04-30 ES ES437269A patent/ES437269A1/en not_active Expired
- 1975-05-13 AR AR258764A patent/AR212156A1/en active
-
1976
- 1976-04-08 SU SU762343055A patent/SU633483A3/en active
-
1978
- 1978-02-06 KE KE2816A patent/KE2816A/en unknown
- 1978-03-30 HK HK173/78A patent/HK17378A/en unknown
- 1978-09-28 CH CH1013378A patent/CH615931A5/en not_active IP Right Cessation
- 1978-12-31 MY MY1978188A patent/MY7800188A/en unknown
-
1980
- 1980-05-28 JP JP7210780A patent/JPS5649388A/en active Pending
-
1981
- 1981-02-05 YU YU307/81A patent/YU41231B/en unknown
-
1983
- 1983-05-30 GT GT198302370A patent/GT198302370A/en unknown
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