DK151338B - Analogifremgangsmaade for the preparation of racemic or optically active penicillins or cephalosporins - Google Patents

Analogifremgangsmaade for the preparation of racemic or optically active penicillins or cephalosporins Download PDF

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DK151338B
DK151338B DK201975A DK201975A DK151338B DK 151338 B DK151338 B DK 151338B DK 201975 A DK201975 A DK 201975A DK 201975 A DK201975 A DK 201975A DK 151338 B DK151338 B DK 151338B
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Isamu Saikawa
Shuntaro Takano
Chosaku Yoshida
Okuta Takashima
Kaishu Momonoi
Seietsu Kuroda
Miwako Komatsu
Takashi Yasuda
Yutaka Kodama
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Toyama Chemical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D499/00Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Description

* * ·\ 151338 * * · \ 151,338

Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte penicilliner eller cephalosporiner med den i krav l's indledning angivne almene formel (I). The invention relates to a process for preparing novel penicillins or cephalosporins having in the preamble to claim indicated general formula (I).

De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har et bredt antibakterielt spektrum overfor Gram-positive og Gram-negative bakterier, og de er især effektive overfor arterne Pseudomonas aeruginosa, Klebsiella pneumoniae og Proteus. The process of the invention compounds prepared have a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, and are particularly effective against the species Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus. Endvidere har de omhandlede forbindelser høj bestandighed overfor (3-lactamase, som produceres af bakterier, og de har en effektiv an-tibakteriel aktivitet selv overfor kliniske isolater af bakterier, 2 15133; som i klinisk henseende er signifikante. Som følge deraf er de omhandlede forbindelser ganske effektive som terapeutiske midler for mennesker og dyr, som har infektionssygdomme, der skyldes de ovennævnte pathogene mikroorganismer. Furthermore, these compounds have high resistance to the (3-lactamase produced by bacteria, and they have an effective An antibacterial activity even against clinical isolates of bacteria, 2 15133; as clinically significant. As a result, the subject compounds are quite effective as therapeutic agents for humans and animals, which have infectious diseases caused by the above-mentioned pathogenic microorganisms.

Det er allerede kendt, at 6-aeylaminopenicillansyre og 7-aeylamino cephalosporansyre med en aminogruppe ved α-positionen af acylgrup-pen udviser kraftig antibakteriel aktivitet ikke blot overfor gram-positive bakterier, men også overfor gram-negative bakterier. It is already known that the 6-and 7-aeylaminopenicillansyre aeylamino cephalosporanic acid with an amino group at α-position of the acyl group exhibit potent antibacterial activity not only against Gram-positive bacteria but also against Gram-negative bacteria. De beskrevne kendte forbindelser lider dog af den ulempe, at de ikke blot ikke har nogen effektiv antibakteriel aktivitet overfor Pseudomonas aeruginosa, Klebsiella pneumoniae og Proteus arter, son har forårsaget mange klinisk alvorlige infektionssygdomme, men også overfor resistente bakterier, der hyppigt isoleres på mange kliniske hospitaler. The described known compounds, however, suffer from the disadvantage that they not only have no effective antibacterial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, son has caused many clinically severe infectious diseases, but also against resistant bacteria frequently isolated in many clinical hospitals. De har endvidere tilbøjelighed til at blive hydrolyseret af /3-lactamase, der produceres af mange lægemiddelresistente bakterier. They also tend to be hydrolyzed by / 3-lactamase produced by many drug-resistant bacteria.

De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser udviser et bredt antibakterielt spektrum, de har høj resistens overfor £>-lactamase, der produceres af bakterier, og de er effektive over for kliniske isolater af bakterier. The process of the invention prepared compounds show a broad antibacterial spectrum, they have high resistance to £> lactamase produced by bacteria and are effective against clinical isolates of bacteria.

De udmærkede egenskaber hos forbindelserne med den almene formel (I) og ikke-toxiske salte deraf er afledt af den følgende del i molekylet (0) /Ή AN N — C-NH- 2^ 3 “ The excellent properties of the compounds of general formula (I) and non-toxic salts derived from the following part of the molecule (0) / Ή AN N - C-NH 2 ^ 3 "

RZ K R K

2 3 hvori A, R , R og n har den i krav 1 angivne betydning. 2 3 wherein A, R, R and n are as given in claim 1 importance. Det ses klart, at disse forbindelser har en ureido-binding repræsenteret ved formlen ^ NC-NH- It is clearly seen that these compounds have a ureido bond represented by the formula ^ NC-NH-

/ «I / 'In

O ISLAND

og er karakteriseret ved, at denne ureido-binding er dannet i forbindelse med oxo- eller dioxopiperazin-ringen ovenfor. and is characterized in that this ureido-bond is formed in connection with oxo or dioxopiperazin-ring above.

3 151338 3 151338

Der kendes nogle penicillinforbindelser af ureido-typen, f.eks. There are known some penicillin compounds of the ureido-type, for example. Mezlocillin-natrium med formlen JK (01 -c. /00¾ CH,S0,lf N-CONHCHCONH—i- \ / A 1 I 3 V / [Q] cr COONa Mezlocillin sodium JK of formula (01-c. / 00¾ CH, S0, N-CONHCHCONH LF-I \ / A 1 I 3 V / [Q] cr COONa

Denne forbindelse indeholder en ureido-binding og er den nærmest beslægtede i kemisk struktur med de ifølge opfindelsen fremstillede forbindelser, selv om der også er afgørende, forskelle som forklaret nedenfor. This compound containing a ureido bond and is the most closely related in chemical structure to the compounds of this invention, although there are also essential differences as explained below. Forbindelserne af Mezlocillin-typen indeholder den følgende gruppe 0 0' -ncnc-nh- I_l 0 «V " nemlig en ureido-binding repræsenteret ved formlen ->NC-NH-og også en cyclisk ureido-binding i 2-oxoimidazolidin-ringen repræsenteret ved formlen -b- The compounds of Mezlocillin type contains the following group 0 0 '-ncnc-NH- I_l 0 "V" namely, a ureido bond represented by the formula -> NC-NH-and also a cyclic ureido-bond in the 2-oxoimidazolidine ring represented by the formula -B-

Det vil sige, at der dannes en biureido-binding, og det karakteristiske træk ved denne type forbindelser ligger i denne kemiske struktur. That is, to form a biureido-bond and the characteristic feature of this type of compounds lies in this chemical structure. Derfor er de ifølge opfindelsen fremstillede forbindelser og ureido-forbindelserne af Mezlocillin-typen afgjort forskellige. Therefore, the compounds of this invention and the compounds of the ureido-type Mezlocillin definitely different.

Endvidere har det ved sammenligning af den nyttige virkning af de her omhandlede penicilliner med virkningen af Mezlocillin, som er en typisk repræsentant for forbindelserne af biureido-typen, vist sig, at de ifølge opfindelsen fremstillede forbindelser, f.eks. Further, it has by comparison of the effectiveness of the claimed effect of penicillins with Mezlocillin, which is a typical representative of the compounds of biureido type, been found that the compounds of this invention, for example. Piperacillin med formlen (I), hvori A er ethyl, 2 3 5 R og R er H, og R er phenyl, har et meget bredere anti-bakte-rielt spektrum end Mezlocillin, som det fremgår af referaterne fra 18th Interscience (1-4. oktober 1978), Session 6, No. Piperacillin of formula (I) wherein A is ethyl, 2 3 5 R and R are H and R is phenyl, have a much broader anti-bacterial hydroactivated spectrum than Mezlocillin, as shown by the notes of 18th Interscience (1- 4 October 1978), Session 6, No. 39 og Session 12, No. 39 and Session 12, No. 116. 116th

Det er en selvfølge, at de her omhandlede cephalosporiner med formlen (i) er helt forskellige i kemisk henseende fra Mezlocil- 4 1513 3 ί lin. It is a matter of course that the present cephalosporins of formula (I) are quite different chemically from Mezlocil- 4 1513 3 ί lin. De Omhandlede cephalosporiner har udmærkede egenskaber, som aldrig er blevet opnået af konventionelle cephalosporiner. The Referred cephalosporins have excellent properties which has never been achieved by conventional cephalosporins.

De omhandlede forbindelser med formlen (I) har deres optiske isomere, og alle D-isomere, L-isomere og racemiske forbindelser deraf kan fremstilles ved fremgangsmåden ifølge opfindelsen. The present compounds of formula (I) have their optical isomers, and all the D-isomers, L-isomers and racemic compounds thereof can be prepared by the method of the invention.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del anførte. The inventive method is characterized by the features of claim 1's characterizing part indicated.

13 I formlerne (II),(IV) og (VI) betyder R et hydrogenatom, en saltdannende kation eller en beskyttende gruppe, som er kendt inden for penicillin- eller cephalosporin-området. 13 In the formulas (II), (IV) and (VI), R represents a hydrogen atom, a salt-forming cation or a protective group which is known in the penicillin or cephalosporin art. De beskyttende grupper kan mere konkret være (1) esterdannende grupper, der kan fjernes ved katalytisk reduktion, kemisk reduktion eller hydrolyse under milde betingelser, f.eks. The protecting groups may more specifically be (1) ester-forming groups that can be removed by catalytic reduction, chemical reduction or hydrolysis under mild conditions, for example. arylsulfonylalkylgrupper, såsom toluen-sulfonylethyl; arylsulphonylalkyl groups, such as toluene-sulfonylethyl; substituetede eller usubstituerede aralkylgrupper, såsom benzyl, 4-nitrobenzyl, diphenylmethyl, trityl eller 3,5-di-(tert.-butyl)-4-hydroxybenzyl; substituetede or unsubstituted aralkyl groups such as benzyl, 4-nitrobenzyl, diphenylmethyl, trityl, or 3,5-di- (t-butyl) -4-hydroxybenzyl; substituerede eller usubstituerede alkylgrupper, såsom tert.-butyl eller trichlorethyl; substituted or unsubstituted alkyl groups such as tert-butyl or trichloroethyl; phenacyl-grupper; phenacyl groups; alkoxyalkylgrupper, såsom methoxymethyl; alkoxyalkyl groups such as methoxymethyl; eller usubstituerede eller alkyl-substituerede cycliske aminoalkylgrupper, såsom piperidinoethyl, 4-methylpyperidinoethy1, morpholinoethyl eller pyrrolidinoethyl; or unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethyl, 4-methylpyperidinoethy1, morpholinoethyl or pyrrolidinoethyl; (2) esterdannende grupper, der let kan fjernes af enzymer i levende organismer, f.eks. (2) ester-forming groups that can be readily removed by enzymes in living organisms, for example. acyloxyalkylgrupper, såsom pivaloyloxymethyl; acyloxyalkyl groups such as pivaloyloxymethyl; phthalidyl eller indanyl; phthalidyl or indanyl; (3) sili-ciumholdige grupper, phosphorholdige grupper eller tinholdige grupper, som let fjernes ved behandling med i^O eller en alkohol, såsom (CH..) -jSi-, —CL Ο,,Η,-Ο. (3) silica ciumholdige groups, phosphorus-containing groups or the tin-containing groups which are readily removed by treatment with I ^ O, or an alcohol, such as (CH ..) -jSi-, -Cl ,, Η Ο, -Ο.

P-, ^ P- eller (C.H0),Sn-. P, ^ P or (C.H0), Sn.

/ / 4 y 3 0 C2H5° / / 4 y 3 0 C2H5 °

De beskyttende grupper, der er nævnt ovenfor under (1), (2) og (3) er typiske, og andre eksempler fremgår af US patentskrifterne nr. The protecting groups mentioned above under (1), (2) and (3) are typical, and other examples are found in U.S. Patent Nos.

3 499 909, 3 573 296 og 3 641 018 samt DE offentliggørelsesskrifterne nr. 2 301 014, 2 253 287 og 2 337 105. Den saltdannende kation kan være af samme art, som anvendes i penicillin- eller cephalosporin- forbindelser·,· fortrinsvis sådanne, som danner ikke-giftige salte. 3,499,909, 3,573,296 and 3,641,018 as well as DE Published Specifications Nos. 2,301,014, 2,253,287 and 2 337 105. The salt-forming cation may be of the same type as used in penicillin or cephalosporin compounds ·, · preferably those which form non-toxic salts. Saltene kan være alkalimetalsalte, såsom natriumsalte eller 5 151338 kaliumsalte, jordalkalimetalsalte, såsom calciumsalte og magnesium-salte, ammoniumsalte og sålte med nitrogenholdige organiske forbindelser, såsom procain, dibenzylamin, N-benzyl-$-phenethylamin, 1-ephenamin og .Ν,Ν-dibenzylethylendiamin. The salts may be alkali metal salts, such as sodium salts, or 5 151338 potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts and sålte with nitrogen-containing organic compounds such as procaine, dibenzylamine, N-benzyl - $ - phenethylamine, 1-ephenamine and .Ν, Ν dibenzylethylenediamine. Udover de ovennævnte kationer kan der anvendes sådanne kationer, som er i stand til at danne salte med andre nitrogenholdige organiske baser, såsom tri-methylamin, triethylamin, tributylamin, pyridin, dimethylanilin, N-methylpiperidin, N-methylmorpholin, diethylamin og dicyclohexyl-amin. In addition to the above-mentioned cations may be used such cations, which are capable of forming salts with other nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine . Kationen kan også være en kvaternær ammoniumgruppe dannet i 3-positionen af cephemringen, såsom pyridinium, quinolinium, isoquinolinium eller pyrimidinium. The cation can also be a quaternary ammonium group formed at the 3-position of the cephemringen such as pyridinium, quinolinium, isoquinolinium or pyrimidinium. I dette tilfælde dannes en be-tain-struktur i molekylet. In this case, the BE form a betaine-structure in the molecule.

7 I formlerne (II) og (IV) betyder R hydrogen eller en konventionel beskyttende siliciumholdig eller phosphorholdig gruppe, som let kan fjernes ved behandling med vand eller en alkohol. 7 In the formulas (II) and (IV), R is hydrogen or a conventional protecting silicon-containing or phosphorus-containing group, which are readily removable by treatment with water or an alcohol. Disse grup-per kan f.eks. These can be grouped per example. være de samme som nævnt for R ovenfor under (3). be the same as mentioned for R in the above (3).

I formlen (VI) under fremgangsmådens variant (c) repræsenterer B en substituent, der let erstattes af et nucleophilt reagens, og eksempler herpå er halogenatomer, såsom chlor og brom; In the formula (VI) in the process variant (c) B represents a substituent that can be easily replaced by a nucleophilic reagent, exemplified by halogen atoms such as chlorine and bromine; lavere al-kanoyloxygrupper, såsom formyloxy, acetoxy, propionyloxy, buty-tyloxy og pivaloyloxy; lower al-kanoyloxygrupper, such as formyloxy, acetoxy, propionyloxy, butyl-pentyloxy and pivaloyloxy; arylcarbonyloxygrupper, såsom benzoyloxy eller naphthoyloxy; arylcarbonyloxy groups such as benzoyloxy or naphthoyloxy; arylcarbonylthiogrupper, såsom benzoylthio eller naphthoylthio; arylcarbonylthiogrupper such as benzoylthio or naphthoylthio; carbamoyloxygrupper; carbamoyloxy groups; heteroaromatiske amin-N-oxid-thiogrupper med en thiogruppe ved carbonatomet op til N-oxidgruppen i molekylet, såsom pyridin-l-oxid-2-ylthio eller py-ridazin-l-oxid-6-ylthio. heteroaromatic amine N-oxide-thio groups with a thio group at the carbon atom up to the N-oxide group in the molecule, such as pyridine-l-oxide-2-ylthio, or py-pyridazine-l-oxide-6-ylthio.

Hver af de ovennævnte grupper for B kan være substitueret med en vilkårlig af sådanne.substituenter som f. eks. halogenatomer, nitrogrupper, alkylgrupper, alkoxygrupper, alkylthiogrupper eller acylgrupper. Each of the above groups of B may be substituted with any of sådanne.substituenter as f. Eg. Halogen atoms, nitro groups, alkyl groups, alkoxy groups, alkylthio groups or acyl groups.

Som forbindelse (II) under fremgangsmådens variant (a) kan der anvendes enhver D-isomer, L-isomer eller racemisk forbindelse. As compound (II) in the process variant (a) may be used any D-isomer, L-isomer or racemic compound.

6 151338 6 151338

Som reaktivt derivat af carboxylgruppen af forbindelsen med formlen (III) kan der anvendes et reaktivt derivat af en carboxylsyre, som sædvanligvis anvendes til syntese af syreamidforbindel-ser. As the reactive derivative of the carboxyl group of the compound of formula (III) may be used a reactive derivative of a carboxylic acid, which are commonly used for the synthesis of syreamidforbindel-Ser. Eksempler på sådanne reaktive derivater er syrehalogenider, syreazid, syrecyanid, blandede syreanhydrider, aktive estere og aktive amider. Examples of such reactive derivatives are acid halides, acid azide, acid cyanide, mixed acid anhydrides, active esters and active amides. Særligt foretrukne eksempler derpå er syrehalogenider, såsom syrechlorider og syrebromider, og aktive estere, såsom cyanmethylester eller trichlormethylester. Particularly preferred examples thereof are acid halides such as acid chlorides and acid bromides, and active esters such as cyanomethyl or trichloromethyl ester.

Det reaktive derivat af carboxylgruppen i forbindelsen med formlen (III) kan let fås ved f.eks. The reactive derivative of the carboxyl group in the compound of formula (III) can easily be obtained by, for example. at omsætte en oxopiperazin med formlen AU ]JH (VIII) 2/3 3 reacting an oxo-piperazine of formula AU] H (VIII) 2/3 3

R R

2 3 hvori A, R , R og n har den i krav 1 angivne betydning, syntetiseret på i og for sig kendt måde som angivet i de efterfølgende litteraturreferencer, med phosgen eller trichlormethylesteren af chlormyresyre. 2 3 wherein A, R, R and n are as in claim 1, defined above, was synthesized in a per se known manner as indicated in the following literature references, with phosgene or chloroformic of trichlormethylesteren.

Litteraturreferencer: VG Granik, Khim-Farm. Literature Reference: VG Granik, Khim-Farm. Zh., KV), 16-19 (1967) (Russ); Zh., KV), 16-19 (1967) (Russ);

Samuel R. Aspinall, J. An. Samuel R. Aspinall, J. An. Chem. Chem. Soc., 62, 1202-V (19V0); Soc., 62, 1202-V (19V0);

Kuniyoshi MASUZAWA, Pharm. Kuniyoshi Masuzawa, Pharm. Bull. Bull. (Japan), 38 2078-2081 (1966); (Japan), 38 2078-2081 (1966);

Arthur P. Phillips, Ger. Arthur P. Phillips, Ger. 1135V72, Aug. 1135V72, August 30 (1962); 30 (1962); JL Riebsomer, J. Org. JL Riebsomer, J. Org. Chem., l£ 68-73 (1950); Chem., L £ 68-73 (1950); 151338 7 151 338 7

Litteraturreference: (fortsat) Literature Reference: (continued)

Jongkees, Rec. Jongkees, Rec. trav. trot. Chim., 2£ 305; Chim., 2 £ 305;

Patric T. Izzo, J. Am. Patric T. Izzo, J. Am. Chem. Chem. Soc., 8l k668-k670 (1959); Soc., 8l k668-k670 (1959); og BH Chase & AM Downes, J. Chem. and BH & Chase AM Downes, J. Chem. Soc., 387^-3877 (1953). Soc., 387 ^ -3877 (1953).

Konkrete eksempler på forbindelser med formlen (VIII) og de reaktive derivater af carboxylgruppen af forbindelsen med formlen (III) er anført i henholdsvis tabel 1 og tabel 2. Concrete examples of the compounds of formula (VIII) and the reactive derivatives of the carboxyl group of the compound of formula (III) are set forth in Table 1 and Table 2.

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Tabel 1 table 1

Forbindelser med formlen (VIII) --- , Compounds of formula (VIII) ---,

Smp. Mp. (omkrystal- (omkrystal-

Forbindelse lisationsmiddel) (cm-1) 1 Compound crystallization agent)? (Cm-1) 1

0 o Jc=0 1640 I 0 o 0 J c = 1640 In

rA 136°C (( )) , ΗΪΓ^ΝΗ . rA 136 ° C (()), ΗΪΓ ^ ΝΗ. 0 Vhh ' 3450 - 3250 0 kp. 0 V HH '3450-3250 0 kp. 122 - , V-% 125°C/2 mmHg Yn=0 1650 - 1630 ! 122 -, V% 125 ° C / 2 mmHg Y n = 0 1650-1630! mm . mm.

140 - 14-1°C (IPA) Vuh 3260, 3170 CH3 0 _ ^ ^G=Q 1645' 1625 A 112 - 113°C ((O) ) ) ° CH3C0F^JIH ^ YM 3380, 3220 o γ*π_η 1650, 1630 A 129 - 130°C (IPA) , cicHaCQE^jm vm 3270 0 ^0=0 1660-1630 r< 134 - 135°C (IPA) j C12CHC0N HH Vm 3280 0 Vc=0 1670, 1640 , λ A 96 - 97°C (CC1J j 0Η5(0Η2)ΐ30Η200Ι^Μ ^ YM 3200 0 \/n_n 1660, 1620 A 80 - 8l°C (IPE) , 0Η3(0Η2)50Η200ΪΓ^ΚΗ vm 3250 0 . Vp_ri 1660, 1620 140 - 14-1 ° C (IPA) Vuh 3260, 3170 CH 3 _ ^ 0 ^ G = Q 1645 '1625 A 112 to 113 ° C ((O))) ° CH3C0F JIH ^ ^ YM 3380, 3220 o γ * π_η 1650, 1630 A 129 to 130 ° C (IPA), cicHaCQE ^ jm World Cup 3270 0 ^ 0 = 0 1660-1630 r <134-135 ° C (IPA) C12CHC0N J ​​HH Vm Vc = 0 3280 0 1670, 1640, λ A 96 to 97 ° C (CC1J j 0Η5 (0Η2) ΐ30Η200Ι ^ Μ ^ YM 3200 0 \ / n_n 1660, 1620 A 80 - 8L ° C (IPE), 0Η3 (0Η2) 50Η200ΪΓ ^ ΚΗ VM 3250 0th Vp_ri 1660, 1620

, . ,. A 83 - 84°c (IPE) J A 83 to 84 ° C (IPE) J

CH3(CH2)4CH2C01Sr HH )/m 3250 0 Vn=n 1660, 1620 . CH 3 (CH 2) 4CH2C01Sr HH) / 3250 m = 0 n V n 1660, 1620th . . A 99 - 100°C (CC14) , ch3(ch2)3ch2copv_jih 4 vM 3250 o ^0=0 χ680 A 167 - 168°C (EtOH) Vim 3200 A 99 to 100 ° C (CC14), CH 3 (CH 2) 4 3ch2copv_jih VM 3250 o ^ 0 = 0 A χ680 167-168 ° C (EtOH) 3200 Vim

CH^SOpU HH CH ^ SOpU HH

2 2 w_ Vs02N< 1310, 1140 9 151338 2 2 W_ Vs02N <1 310, 1140 9 151338

Tabel 1 (fortsat) /? Table 1 (continued) /? o Vn_o 1650, 1620 rA 189 - 190°c (IPA) , u (ΟΗ·^) 3 TCH2-, NH V jjj-g 525Ο 0 Vc=0 1650 - 1650 r4 olieagtigt materi- , CH3(CH2)4CH2-N NH ale ' ym 3270 P 3250 rJ( olieagtigt materi- . o Vn_o 1650, 1620 rA 189-190 ° C (IPA), u (· ΟΗ ^) 3 TCH2-, NH V-jjj g 525Ο 0? c = 0 1650 to 1650 r4 oily in material, CH3 (CH2) 4CH2-N NH ale 'ym 3270 P 3250 RJ (oily in material.

CH3(CH2)2CH2-N_NH ale Yc=0 1650 - 1630 -- - ...... — A ' ^ ^ . CH3 (CH2) 2CH2-N_NH ALE? C = 0 1650 to 1630 - - ...... - A '^ ^. 4=0 1650 - 1620 CH,(CHo)o0Ho-N NH olieagtigt maten- 5 2 2 2 ale _cb____ 0 fe, 1650 - 16J0 rA olieagtigt materi- Hydrochloride CH3(CH2)6CH2-N NH ale Vc=o 1680 ' ' Vjjjj 3200, 3080 ______ _______ — — — ----« — ......... M ----1 o ^c=o 1620 V\ kp · 104°C/4 mmHg , ch3nwnh vm 5275 0 Vq-o 1610 }~y olieagtigt materi- , CH3CH2-N NH ale VNH 3250 olieagtigt materi- ^0=0 ^10 ch3(ch2)2ch2-\_nh ale v'jju 3250 ..... .. .... . 4 = 0 1650 to 1620 CH (CHO) o0Ho-N NH oily maten- 5 2 2 2 ale _cb____ 0 Fe, 1650 - 16J0 rA oily in material Hydrochloride CH3 (CH2) 6CH2-N NH ale Vc = o 1680 '' Vjjjj 3200, 3080 ______ _______ - - - ---- '- ......... 1 ---- M o ^ c = o 1620 V \ · bp 104 ° C / 4 mmHg, ch3nwnh VM 5275 0 Vq-1610} o ~ y oily in material, CH3CH2-N NH VNH 3250 ale oily in material ^ 0 ^ = 0 10 CH3 (CH2) 2CH2 - \ _ NH ale v'jju 3250 ..... .. .. ... .. .... .... - 1 —ft — -.....—— - 0 olieagtigt materi- V^O 1610 V-\ ale . .. .... .... - 1 ft - -.....-- - 0 oily in material V ^ O 1610 N \ ale. 1 (CH3)2CH-N_jm vm 3400 - 3200 0 , . 1 (CH 3) 2 CH-N_jm vm 3400-3200 0. 4..4. 4..4. 4. . 4. vL0 1620 ^ olieagtigt materi- wu CH3(CH2)3CH2-N__NH ale ' )lm 3270 0 ^ . vL0 1620 ^ oily in material Wu CH3 (CH2) 3CH2-N__NH ale ') LM 3270 ^ 0. ^0-0 1620 CH rA olieagtigt materi- ^CHCH2CH2-N NH ale Vjjh 3270 CH3 " j _:_____ _:_! 10 151338 0-0 1620 CH ^ rA oily in material CHCH2CH2-N ^ NH ale Vjjh 3270 CH3 "j _ _____ _: _! 10 151 338

Tabel 1 (fortsat) 0 , Vc=0 1620 olieagtigt materi- , CH5(CH2)4CH2-N_JIH ale Vm 3270 ^ olieagtigt materi- ^0=0 1620 CH5(CH2)5CH2-N NH ale 3270 0 _. Table 1 (continued) 0, Vc = 0 1620 oily in material, CH5 (CH2) 4CH2-N_JIH ale Vm 3270 ^ oily in material ^ 0 = 0 1620 CH5 (CH2) 5CH2-N NH ale 3270 0 _. .. , . ..,. Vn—n 1620 olieagtigt materi- CH3(CH2)6CH2-FJJH al® ' \)m 3270 0 olieagtigt materi- Vø_o ^20 y—N. VN-1620 N in material oily CH3 (CH2) 6CH2-FJJH Al® '\) 0 3270 m oily in material Vø_o y ^ 20-N. ale i CH3 (CH2) 10CH2-NJJH Vm 3270 0 Vn n 1620 V olieagtigt materi- bu ale Vrø 5300 0 · i K V1630 CH-z (CHp) nCHp-U NH olieagtigt materi- ' 2 2 2 H ale J 3300 ch5 m ALE in CH3 (CH2) 10CH2-NJJH Vm 3270 0 Vn n 1620 V oily in material bu ale Vroe 5300 0 · K V1630 CH-Z (CHP) nCHp-U NH oily in material '2 2 2 H ale J 3300 ch5 m

0 I 0 I

. . . . ^ olieagtigt materi- ^C=0 1630 CH3(CH2)2CH2-E ER ale - ) M Vra 3200 ch5 0 or'0', ^C=0 1650 /-\ K 157 - 158°C (Γ J ) j (O/-0H2-]i ffl Ό Vjih 3300 0 i ^ kp. 183- l85°C/2mmHg ^0=0 1620 HOCHgCHg-F BH * JJ ' 6 °N olieagtigt materi- ^0=0 1650 y—s. ' pip - ) CH2=CHCH2-ir MH Vm 3300 n 151338 ^ Oily in material ^ C = 0 1 630 CH3 (CH2) 2CH2-E is ale -) M Vra 3200 CH5 or'0 0 ', ^ C = 0 1650 / - \ K 157-158 ° C (Γ J) j ( O / -0H2-] ffl in Ό Vjih 3300 0 ^ kp. 183- L85 ° C / 2mmHg ^ 0 = 0 1620 HOCHgCHg-F BH * JJ 'N 6 ° oily in material ^ 0 = 0 y 1650 p. 'pip -) CH 2 = CH CH 2-ir MH Vm 3300 N 151 338

Tabel 1 (fortsat) °K ^0=0 1620 0Η?=0Η0Η-1ί EH olieagtigt materi- , I ^ ale Vm 3300 CH3 Vn ^0=0 1640 CHp=CCH2-E EH olieagtigt materi- , I ^ ale Vjjjj 3300 CH3 0 , 0H=0HCH2-H ra Olieagtigt materi- '0=° 1660 I w ale Vm 3350 CH5 0 0 ^0=0 1695, 1660 Vf . Table 1 (continued) ° K ^ 0 = 0 1620 0Η? = 0Η0Η-1ί EH oily in material, I ^ ale Vm 3300 CH3 Vn ^ 0 = 0 1640 CHP = CCH2-E EH oily in material, I ^ ale Vjjjj 3300 CH 3 0, 0H-H = 0HCH2 Oily in material ra '= 0 ° In 1660 w V m ale 3350 CH5 0 0 ^ 0 = 0 1695, 1660 Vf. 158°C (IPA) » CH^-EMffl Vlffi 3220 ° ,° olieagtigt materi- ^C=0 I730 - 1650 158 ° C (IPA) 'CH ^ -EMffl Vlffi 3220 °, oily ° C in material ^ 0 = I730 - 1650

alp I alp In

CH5C00CH2CH2-H HH Υ^Η 3300 - 3200 00 n ,0s ^0=0 1680, 1650 W 124°C (( ]) , CH^CHp-E EH 0^ V^j 3250 00 Vp=o 1680, 1650 V/ 98 - 100°C {( j) , CH3CH2CH2-N HH 0 VNH 3200, 3100 00 n VC=o 1695, 1670 W7 Hl - 113 C (CClr) , CH5(CH2)2CH2-N HH ^ YNH 3240, 3150 0 0 ^C-0 1650 S-4 166 - 167°C (( ] ) , (CH5)2CH-H HH ^0^ Vm 3300 - 3200 0 0 VC=0 1700, 1660 CH5C00CH2CH2-H HH Υ ^ Η 3300-3200 00 n, 0s ^ 0 = 0 1680, 1650 W 124 ° C ((]), CH = CHP-E EH 0 ^ V ^ j 3250 00 V p = o 1680, 1650 V / 98 - 100 ° C, {(j) CH3CH2CH2-N HH 0 VNH 3200, 3100 00 n? C = O 1695, 1670 W7 Hl - 113 C (CClr), CH5 (CH2) 2CH2-N HH ^ y NH 3240, 3150 0 0 0 ^ C-1650 S-4166 to 167 ° C ((]), (CH5) 2 CH-H HH ^ 0 ^ Vm 3300 to 3200 0 0 C = 0 1700, 1660

Vf 104 - 106°C (IPE) , CH3(CH2)3CH2-N HH vm 3200, 3100 12 151338 _ _Tabel 1 (fortsat) 0 0 Vq_q 1700, 1660 Vf 104-106 ° C (IPE), CH3 (CH2) 3CH2-N HH VM 3200, 3100 12 151 338 _ _Tabel 1 (cont'd) 0 0 Vq_q 1700, 1660

'M' 111 - 115°G (ΙΡΞ) I 'M' 111-115 ° G (ΙΡΞ) In

ΟΗ5(ΟΗ2)4ΟΗρ-Ν HH VM 3200, 3100 0 0 Vc=o 1700, 1660 ΟΗ5 (ΟΗ2) 4ΟΗρ Ν-HH VM 3200, 3100 0 0? C = o 1700, 1660

YJf 112 - Π 5°Π (TPP) I YJF 112 - 5 ° Π Π (TPP) in

CH5(CH2)5CH2-N^NH Vhh 3200, 3100 00 n Vn=0 1700, 1660 \-4 116 - 120°C (IPE) \ CH5(CH2)6CH2-H HH Vm 3225, 3100 OO ^C=0 1680, 1655 VT 136 - I37°c » CH2=CHCH2-NJM (Acetone) 3200, 3100 OO Vc=o 1690, 1645 ΓΛ ^ 202 - 20H-°C (IPA) . CH5 (CH2) 5CH2-N ^ NH VHH 3200, 3100 00 n V n = 0 1700, 1660 \ -4116 to 120 ° C (IPE) \ CH5 (CH2) 6CH2-H HH Vm 3225, 3100 OO ^ C = 0 1680, 1655 VT 136 - I37 ° C 'CH 2 = CHCH 2-NJM (acetone) 3200, 3100 OO? c = o 1690, 1645 ΓΛ ^ 202 - 20H- ° C (IPA).

(0)-NJSIH VkH 3260 j OO ^0=0 !700 - I650 M 128 - 129°C (EtOH) , CICHgCHglSr HH Vjjfj 3200 - 3100 OO } 'M' 0 »0=0 1660 CH5CH2-N HH 127 - I280C (AcOEt) , M Vm 3200, 3080 CH3 OO ) M' n *0=0 1660 CH3-N NH 146 - 1^7 C (il) . (0) -NJSIH VKH 3260 J OO ^ 0 = 0! 700 - I650 M 128-129 ° C (EtOH), CICHgCHglSr HH Vjjfj 3200 to 3100 OO} 'M' 0 '= 0 0 1 660 N-CH5CH2 HH 127 - I280C (AcOEt), M Vm 3200, 3080 CH 3 OO) M 'n * 0 = 0 1660-CH3 N NH 146-1 C ^ 7 (IL).

M Oy Vra 3200, 3100 -ch5 ---jJ- " ------- M Oy Vra 3200, 3100 -ch5 --- jJ- "-------

Note: IPA = (CH5)2CH0H Note: IPA = (CH5) 2CH0H

ipe = (ch3)2choch(ch3)2 IPE = (CH 3) 2choch (CH 3) 2

AcOEt = CH3C00CH2CH3 AcOEt = CH3C00CH2CH3

EtOH = CH3CH2OH EtOH = CH3CH2OH

13 151338 13 151338

Tabel 2 table 2

Reaktive derivater af forbindelser med formlen (III) Reactive derivatives of compounds of formula (III)

Forbindelse. Connection. Fysiske egenskaber I*R· (cm-1) 0 · , rA ....... Vø_0 1790, 1710, CH^CO-N N-C0C1 .olieagtigt materi- ^ w · ale 1640 0 ' ^C=0 1790, Physical properties I * R · (cm-1) · 0, R ....... Vø_0 1790, 1710, CH ^ CO-N N-C0C1 .olieagtigt in material ale ^ w · 1640 0 '^ C = 0 1790

rA raw

ciCH2oo-ir ir-coci 1730 - 1650 o 4=0 1790, Λ C12CHC0-N N-C0C1 1730 - 1650 0 Vc=0 1740, 1.660, CH3(CH2)13CH2CO-Nwli-COCl " 1640 0 Vc=0 1740, rA " ch5(ch2)5ch2co-it w-σοσι i680 - 1640 o 1=0 1740, iH " CH5(CH2)4CH2C0-N_^N-C0C1 1680 - 1640 \ o Vc=o 1790, 1710, ciCH2oo-na na-COCl 1730-1650 o 4 = 0 1790, Λ C12CHC0-N, N-C0C1 1730-1650 0? c = 0 1740, 1660, CH 3 (CH 2) 13CH2CO-Nwli -COCl "1640 0? c = 0 1740, rA "CH5 (CH 2) w 5ch2co-it-σοσι i680 - o 1640 1 0 = 1740, H" CH5 (CH2) 4CH2C0-N_ ^ N-C0C1 1680-1640 \ o? c = o 1790, 1710,

rA raw

CH5(CH2)3CH2CO-li N-C0C1 1640 --, 0 Vc=o 1790, 1700 CE5S02-ir N-C0C1 f VSo2 2.320, 1140 14 151338 CH5 (CH2) 3CH2CO-Li N-C0C1 1640 -, 0? C = o 1790, 1700 CE5S02 ir-N-C0C1 f VSo2 2320, 1140 14 151 338

Tabel 2 (fortsat) 0 VC=o 1740 - 1720, t^ olieagtigt (CH5)3CC00CH2-N N-C0C1 materiale 1670 „ ^0=0 1790, 1720 CH5 (CH2) 4CH2-I'Tjl-C0Cl 0 ) A " VC=0 1790, 1720 CHj (CH2) 2CH2~U^j:T-C0Cl o Table 2 (cont'd) 0? C = O from 1740 to 1720, t ^ oily (CH5) 3CC00CH2-N N-C0C1 material 1670 "^ 0 = 0 1790, 1720 CH5 (CH2) 4CH2-I'Tjl-C0Cl 0) A" VC = 0 1790, 1720 CH (CH2) 2CH2 ~ U ^ j: t-C0Cl o

A A

CH3(0H2)2CH2-K 1T-C0C1 " YCz=Q 1790, 1720 CH 3 (0H2) 2CH2-K-1T C0C1 "YCz = Q 1790, 1720

M M

ch5 0 \ A " Vc=0 1790, 1720 CH5 (CH2) 6CH2-1'I_rl-COCl 0 smp.= 115 - 116°C j (dekomp.) M1=0 1720, 1660 “U'0001 (fra (6) ) 0 ^ ) HN N-C0C1 krystal Yc=;q 1720, 1660 ge3 K olieagtigt m0 16;0 CH^-F K-C0C1 materiale 0 uw 0 K " VG=0 1750, 1650 CH5(CH2)2CH2-N N-C0C1 -1—-1- 15 CH5 0 \ A "is? c = 0 1790, 1720 CH5 (CH 2) 6CH2-1'I_rl -COCl 0 mp. = 115-116 ° C j (dec.) M 1 = 0 1720, 1660" U'0001 (from (6 )) 0 ^) HN N-C0C1 crystal Yc =; q 1720, 1660 GE3 K oily M0 16; 0 CH ^ -F K-C0C1 material 0 UW 0 K "VG = 0 1750, 1650 CH5 (CH2) 2CH2-N N-C0C1 -1--1- 15

Tabel 2 (fortsat) K olieagtict ^C=0 ^30, 1650 ch3ch2-hwij-coci 0 ) K " vc=0 1720, 1640 (CH^CH-I^Ji-CGCl 0 ) K « vq_o 1730, 1640 ch3(0H2)5ch2-n N-C0C1 0 ) K " VC=0 1720, 1640 (ch3)2CHCH2CH2-N N-C0C] 0 ) K " vc=0 1730, 1640 ch3(CH2)4CH2-N N-C0C1 0 j \-y " Vc=0 1730, 1640 ch3 ( ch2 ) 5CH2-N N-C0C1 0 ) K " YC=0 1720, 1640 CH3 (CH2) gCH2-lT_N-C0C1 0 i K " VQ—π 1720, 1640 CH3(CH2)10CH2-N N-C0C1 —\ K ” Vc=o 1730, 1640 H>-1 1T-C0C1 —' \_f 16 151338 Table 2 (continued) K olieagtict ^ C = 0 ^ 30, 1650 CH3CH2-hwij-COCl 0) K "? C = 0 1720, 1640 (CH = CH-I ^ Ji-CGCl 0) K 'vq_o 1730, 1640 CH 3 ( 0H2) 5ch2-n N-C0C1 0) K 'C = 0 1720, 1640 (CH3) 2CHCH2CH2-N N-C0C] 0) K "? c = 0 1730, 1 640 CH3 (CH2) 4CH2-N, N-C0C1 0 j \ -y "? c = 0 1730, 1 640 CH3 (CH2) 5CH2-N, N-C0C1 0) K" YC = 0 1720, 1640 CH 3 (CH 2) gCH2 lT_N-C0C1-0 in the K "VQ-π 1720, 1640 CH 3 (CH 2) 10CH2 N-N-C0C1 - \ K "Vc = o 1730, 1640 H> 1T-C0C1 -1 - '\ 16 151 338 _F

Tabel 2 (fortsat) Table 2 (continued)

0 r H 0 r H

0¾ (CHo) oCHo-H N-C0C1 olieagtigt } 7 yt materiale Yq=q 1720, 1540 CH^, 0¾ (CHO) ocho-H N-C0C1 oily material yl} 7 y q = Q 1720, 1540 CH ^,

S S

0 0

Υ“λ « I Υ "λ" In

CH5(CH2 )2CH2-W BT-COCl vc=o 1730, 1650 CH3 y-, · ' " ^C=0 1720, 1645 (O/-CH2-N_N-C0Cl 0 Vc=0 1730, )-Λ " HOCH2CH2-IT Έ-C0C1 ' 1660 - 1630 0 ) K " Vq_o 1720, 1640 CH2=CHCH2-N N-C0C1 0 K · ) CH2=CHCM N-C0C1 " Vc=o 1730, 1650 I v—1 CH3 0 ^—v ) CH2=CCH2-ir IT-C0C1 " Vc=0 1730, 1650 CH3 CH-zCH 0 CHCH^N^JT-COCl ' Vc=0 173Ο, 1650 (trans-) 17 151338 CH5 (CH2) 2CH2 BT-W-COCl? C = o 1730, 1650 y CH 3, · ' "^ C = 0 1720, 1645 (O / -CH2-n_n C0Cl 0? C = 0 1730,) -Λ" HOCH2CH2 -IT Έ-C0C1 '1660-1630 0) K "Vq_o 1720, 1640 CH 2 = CHCH 2 N-N 0-C0C1 · K) CH 2 = CHCM N-C0C1" Vc = o 1730, 1650 in the v-CH 3 1 0 ^ - v) CH 2 = CCH 2-IT-IR C0C1 "? c = 0 1730, 1650 ZCH-CH 3 CH CH CH 0 ^ N ^ JT-COCl 'Vc = 0 173Ο, 1650 (trans) 17 151 338

Tabel 2 (fortsat) π η smp. Table 2 (continued) π η mp. 94 - 95°C , 0 (dekqmp.) ^0=0 1790, 1680 CH3-N_N-C0C1 (fra CH2Et|0) olieagtigt materi- ^C=0 Π90, 17^0, / \ o'] λ CH5C00CH2CH2-N N-C0C1 axe 1670 O π snip. 94-95 ° C, 0 (dekqmp.) ^ 0 = 0 1790, 1680 CH3 n_n-C0C1 (from CH 2 Et | 0) oily in material ^ C = 0 Π90, 17 ^ 0, / \ O '] λ CH5C00CH2CH2- N, N-C0C1 ax 1670 O π snip. 95 - 96°cuu (dekomp.) Vc=0 1780, 1660 ch3ch2-n^n-coci (fra Ac0Bu^ olieagtigt materi- ^C=0 4780 > CH3CH2 CH2-C0C1 ale 1710 - 1640 0 0 j " Vc_0 1780, 1660 CH3(CH2)2CH2-N N-G0C1 0 0 smp. 130 - 131°C \ M VC=0 1780, 1660 (CH3) 2CH-ir N-C0C1 (dekDmp.) olieagtigt materi- ^0=0 1790, CH3(CH2)3CH2-Njr-COCl ale 1720 _ 1665 0 0 Vr_n 1780, 95-96 ° Cuu (decomp.) V c = 0 1780, 1660 CH3CH2-N ^ N-COCl (from Ac0Bu ^ oily in material ^ C = 0 4780> CH3CH2 CH2-C0C1 ale 1710 to 1640 0 0 j "Vc_0 1780, 1660 CH3 (CH2) 2CH2-N N-G0C1 0 0 mp. 130-131 ° C \ M? C = 0 1780, 1660 (CH 3) 2 CH-ir N-C0C1 (dekDmp.) oily in material ^ 0 = 0 1790, CH3 (CH2) 3CH2-NJR -COCl ale _ 1720 1665 0 0 Vr_n 1780,

M M

CH3(CH2)4CH2-I^ir-C0Cl 1720 - 1640 0 0 Vq=0 1780, M' CH5(CH2)5CH2-N N-C0C1 1720 - 1640 i8 151338 CH3 (CH2) 4CH2-I ^ IR C0Cl 1720 to 1640 0 0 0 Vq = 1780, M 'CH5 (CH2) 5CH2-N, N-C0C1 1720-1640 i8 151338

Tabel 2 (fortsat) 0 0 Vc=0 1780, CH3(CH2)6CH2-hMt-C0C1 1720 - 1640 0 0 V^o 1775, i( krystal CH2=CHCH2-N^N-C0C1 1660 - 1620 i OO \ic=0 1785, /—\ krystal (OZ-N^JT-COCl 1720 - 1650 olieagtigt materi- ^c=0 1790 * 1720 ' C1CH2CH2-N N-C0C1 a±e 1680 00 hi smpl 65 - 70 C . Table 2 (cont'd) 0 0? C = 0 1780, CH3 (CH2) 6CH2-HMT C0C1 1720 to 1640 0 0 V ^ o 1775 in (crystal CH 2 = CH CH 2-N ^ N-C0C1 1660-1620 in OO \ ic = 0 1785 / - \ crystal (OZ-N ^ JT-COCl 1720-1650 oily in material ^ C = 0 1790 * 1 720 'C1CH2CH2-N, N-C0C1 a ± 00 1680 e hi SMPL 65-70 C.

CH3CH2-F N-C0C1 VC=Q 1785, 1680 ^-( . (dekomp.) ch5 CH3CH2-N-C0C1 F? C = Q 1785, 1680 ^ - (. (Decomp.) CH5

Note: Et20 = CH3CH20CH2CH3 Note: ET20 = CH3CH20CH2CH3

AcOBu = CH3C00(CH2)3CH3 19 151338 AcOBu CH3C00 = (CH2) 3CH3 151 338 19

Forbindelsen med den almene formel (V) under fremgangsmådens variant (b) kan let fås ved omsætning af f.eks. The compound of the general formula (V) in the process variant (b) can easily be obtained by reacting for example. et alkalimetal- eller jordalkalimetalsalt eller salt med en nitrogenholdig organisk base af en aminosyre (enhver D-isomer, L-isomer eller racemisk forbindelse) med den almene formel (IX): H„N-CH-COOH (IX) an alkali metal or alkaline earth metal salt or salt with a nitrogen-containing organic base of an amino acid (any D-isomer, L-isomer or racemic compound) of the general formula (IX): H "N-CH-COOH (IX)

Δ 15 R Δ R 15

5 hvor R har den i krav 1 angivne betydning, med et reaktivt derivat i henseende til carboxylgruppen af en forbindelse med den almene formel (III) i et opløsningsmiddel, som er inert overfor reaktionen, i nærvær af et syrebindende middel. 5 wherein R is as stated in claim 1, is reacted with a reactive derivative with respect to the carboxyl group of a compound of general formula (III) in a solvent which is inert to the reaction, in the presence of an acid binding agent.

Som reaktivt derivat i henseende til carboxylgruppen af forbindelsen med dei almene formel (V) anvendes et reaktivt derivat af en carboxylsyre, som sædvanligvis anvendes til syntese af syreamider. As the reactive derivative with respect to the carboxyl group of the compound of dei general formula (V) is used a reactive derivative of a carboxylic acid, which are commonly used for the synthesis of acid amides. Sådanne reaktive derivater omfatter f. eks. syrehalogenider, syre-anhydrider, blandede syreanhydrider med organiske eller uorganiske syrer, aktive syreamider, syrecyanider og aktive estere. Such reactive derivatives include f. Eg., Acid halides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, active amides, active esters and acid cyanides. Særligt foretrukne er syrechlorider, blandede syreanhydrider og aktive syreamider. Particularly preferred are acid chlorides, mixed acid anhydride and active acid amides. Eksempler på blandede syreanhydrider er blandede syre- · anhydrider med substitueret eddikesyre, alkylcarbonsyre, arylcar-bonsyre og aralkylcarbonsyre; Examples of mixed acid anhydrides are mixed acid anhydrides with substituted · acetic acid, alkylcarbonic, arylcar-bonsyre and aralkylcarbonsyre; eksempler på de aktive estere er cyanomethylestere,' substituerede phenylestere, substituerede ben-zylestere, substituerede thienylestere; Examples of the active esters are cyanomethyl esters, 'substituted phenyl esters, substituted leg-zylestere, substituted thienylestere; og eksempler på aktive syreamider er N-acyl-sacchariner, N-acylimidazoler, N-acyl-benzoyl-amider, N,N-dicyclohexyl-N-acylurinstoffer og N-acyl-sulfonamider. and examples of active acid amides are N-acyl saccharins, N-acyl imidazoles, N-acyl-benzoyl-amides, N, N-dicyclohexyl-N-acyl ureas and N-acyl-sulfonamides.

Forbindelser med formlen (VI) under fremgangsmådens variant (c) kan fås f.eks. Compounds of formula (VI) in the process variant (c) can be obtained, for example. ifølge varianterne (a) eller (b). according to variants (a) or (b). Nogle af forbindelserne dannet ved variant (c) kan yderligere anvendes som udgangsmateriale ved variant (c). Some of the compounds formed by the variant (c) may further be used as starting material in the variant (c). Enhver D-, L- og racemisk forbindelse med formlen (VI) kan anvendes. Any D-, L- and racemic compound of formula (VI) may be used.

Den praktiske gennemførelse af fremgangsmådevarianterne (a), (b) og (c) er forklaret i det efterfølgende. The practical implementation of the process variants (a), (b) and (c) is explained below.

Varianterne (a) og (b) kan udføres under i det væsentlige samme 20 1 5 1 3 3 8 ' betingelser. The variants (a) and (b) may be carried out in substantially the same 20 1 5 1 3 3 8 'conditions. Således kan forbindelsen med formlen (II) eller (IV) opløses eller suspenderes i mindst et af opløsningsmidlerne: vand, acetone, tetrahydrofuran, dioxan, acetonitrile, dimethylformamid, methanol, ethanol, methoxyethanol, diethylether, isopropylether, benzen, toluen, methylenchlorid, chloroform, ethylacetat og methyl-isobutylketon. Thus, the compound of formula (II) or (IV) is dissolved or suspended in at least one of the solvents are: water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxy ethanol, diethyl ether, isopropyl ether, benzene, toluene, methylene chloride, chloroform , ethyl acetate and methyl isobutyl ketone. Den dannede opløsning eller suspension omsættes med et reaktivt derivat af forbindelsen med formlen (III) eller med forbindelsen med formlen (V) eller et reaktivt derivat i henseende til carboxylgruppen af forbindelsen med formlen (V) i nærværelse eller fraværelse af en base ved en temperatur mellem -r60° og 80°C, fortrinsvis mellem -t40° og 30°Cj reaktionstiden er sædvanligvis 5 minutter til 5 timer. The resulting solution or suspension is reacted with a reactive derivative of the compound of formula (III) or with the compound of formula (V) or its reactive derivative with respect to the carboxyl group of the compound of formula (V) in the presence or absence of a base at a temperature between -r60 ° and 80 ° C, preferably between -t40 ° and 30 ° C the reaction time is usually 5 minutes to 5 hours. Eksempler på baser, der anvendes ved ovennævnte reaktion, er uorganiske baser, såsom alkalihydroxider, alka-lihydrogencarbonater, alkalicarbonater og alkaliacetater; Examples of bases used in the above reaction are inorganic bases such as alkali hydroxides, alkali lihydrogencarbonater, alkali carbonates and alkaliacetater; tertiære aminer, såsom trimethylamin, triethylamin, tributylamin, pyridin, N-methylpiperidin, N-methylmorpholin, lutidin eller collidin; tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine or collidine; og sekundære aminer, såsom dicyclohexylamin eller diethylamin. and secondary amines such as dicyclohexylamine or diethylamine. Når forbindelsen med formlen (V) anvendes i form af en fri syre eller et salt ved fremgangsmådevarianten (a), kan reaktionen ifølge variant (a) udføres i nærvær af et dehydratiserende kondensationsmiddel, såsom Ν,Ν-dicyclohexylcarbodiimid, N-cyclohexyl-N'-morpho-liniethylcarbodiimid, N,N1-diethylcarbodiimid, N,N1-carbonyl-(2-methylimidazol), en trialkylester af phosphorsyre, ethylester af polyphosphorsyre, phosphorixychlorid, phosphortrichlorid, 2-chlor- 1,3,2-dioxaphospholan eller oxazolylchlorid. When the compound of formula (V) is used in the form of a free acid or a salt in process variant (a), the reaction may be according to variant (a) is conducted in the presence of a dehydrating condensing agent such as Ν, Ν-dicyclohexylcarbodiimide, N-cyclohexyl-N 'morpholin-liniethylcarbodiimid, N, N1-diethylcarbodiimide, N, N 1-carbonyl- (2-methylimidazole), a trialkyl ester of phosphoric acid, ethyl ester of polyphosphoric acid, phosphorixychlorid, phosphorus trichloride, 2-chloro-1,3,2-dioxaphospholane or oxazolyl chloride . Saltet af forbindelsen med formlen (V) omfatter alkalimetalsalte, jordalkalimetalsal-te, ammoniumsalte og salte med organiske baser, såsom trimethylamin eller dicyclohexylamin. The salt of the compound of formula (V) include alkali metal salts, alkaline earth metal salts, ammonium salts and salts with organic bases such as trimethylamine or dicyclohexylamine.

Praktiske udførelsesformer for variant (c) er som følger: Når B i formel (VI) er forskellig fra en hetero-aromatisk N-oxid-thio-gruppe med en thiogruppe ved carbonatomet ved siden af N-oxid-gruppen i molekylet, omsættes forbindelsen med formlen (VI) med en forbindelse med formlen (VII) eller en tertiær amin i mindst et opløsningsmiddel, f.eks. Practical embodiments of variant (c) are as follows: When B in formula (VI) is other than a hetero-aromatic N-oxide-thio group with a thio group at the carbon atom next to the N-oxide group in the molecule, the compound of formula (VI) with a compound of formula (VII) or a tertiary amine in at least one solvent, eg. vand, methanol, ethanol, propanol, isopropanol, butanol, acetone, methylethylketon, methylisobutylketon, tetrahydrofuran, dioxan, acetonitril, ethylacetat, methoxyethanol, dimethoxyethan, dimethylformamid, dimethyl- 21 151338 sulfoxid, dichlormethan, chloroform eller dichlorethan. water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, methoxyethanol, dimethoxyethane, dimethyl formamide, dimethyl sulfoxide 21 151338, dichloromethane, chloroform or dichloroethane. Ovennævnte reaktion udføres fortrinsvis i et stærkt polært opløsningsmiddel, såsom vand. The above reaction is preferably conducted in a highly polar solvent such as water. I dette tilfælde er det hensigtsmæssigt at indstille pH værdien af reaktionsblandingen til 2-10, fortrinsvis 4-8. In this case, it is appropriate to adjust the pH value of the reaction mixture to 2-10, preferably 4-8. Den ønskede pH værdi kan opnås ved tilsætning af en pufferopløsning, såsom natriumphosphat. The desired pH value can be achieved by adding a buffer solution such as sodium phosphate. Reaktionsbetingelserne er ikke særlig begrænsede, men reaktionen udføres sædvanligvis mellem 0°C og 100°C i løbet af flere timer indtil 10 timer. The reaction conditions are not particularly limited, but the reaction is usually carried out between 0 ° C and 100 ° C over several hours up to 10 hours. Når B i fprmlen (Vi) er en heteroaromatisk N-oxid-thio-gruppe med en thiogruppe ved car-bonatomet nær N-oxidgruppen i molekylet, omsættes forbindelsen med formlen (VI) med forbindelsen (VII) i ovennævnte opløsningsmiddel i nærvær af en cupriforbindelse. When B in fprmlen (Vi) is a heteroaromatic N-oxide-thio group with a thio group at the carbon bonatomet near the N-oxide group in the molecule, the compound of formula (VI) with the compound (VII) in the above solvent in the presence of a cupriforbindelse. Denne reaktion er særlig velegnet, hvis en alkohol, såsom methylalkohol, ethylalkohol, propylalkohol, isopropylalkohol, n-butylalkohol, benzylalkohol eller ethylenglycol, anvendes som forbindelsen med formlen (VII). This reaction is particularly suitable if an alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol or ethylene glycol, is used as the compound of formula (VII).

I dette tilfælde forløber reaktionen glat ved anvendelse af overskud af alkohol, idet denne også virker som reaktionsmedium. In this case, the reaction proceeds smoothly by use of excess of alcohol and the latter also acts as the reaction medium. Den ved fremgangsmåden anvendte cupriforbindelse kan være organisk eller uorganisk, såsom cuprichlorid, -bromid, -fluorid, -nitrat, -sulfat, -borat, -phosphat, -cyanid, -formiat, -acetat, propio-nat, -citrat, -tartrat, -benzoat eller -salicylat. The cupriforbindelse used in the process can be organic or inorganic, such as cupric chloride, bromide, fluoride, nitrate, sulfate, borate, phosphate, cyanide, formate, acetate, propionate, citrate, tartrate , benzoate or salicylate. Mængden af anvendt cupriforbindelse er fortrinsvis et halvt mol pr. The amount of cupriforbindelse is preferably one-half mole per. mol af forbindelsen med formlen (VI). mole of the compound of formula (VI). Reaktionstemperaturen og reaktionstiden kan varieres i afhængighed af arten af forbindelsen med formlen (VI), cupriforbindelsen og forbindelsen med formlen (VII), men som regel foretrækkes temperaturer mellem 0 °C og 100 °C, og reaktionstiden kan hensigtsmæssigt ligge mellem flere minutter og flere dage. The reaction temperature and the reaction time may be varied depending upon the nature of the compound of formula (VI), cupriforbindelsen and the compound of formula (VII), but usually it is preferable temperatures between 0 ° C and 100 ° C, and the reaction time may conveniently be between several minutes and several days.

Reaktionsbetingelserne ved fremgangsmådevarianterne (a), (b) og (c) er ikke begrænset til de ovennævnte, men kan varieres i afhængighed af arten af reagenser. The reaction conditions in the process variants (a), (b) and (c) are not limited to those mentioned above, but may be varied depending upon the nature of the reagents.

Endvidere kan man let fremstille ugiftige salte med den ovennævnte formel (I), hvori er en saltdannende kation, på i og for sig kendt måde ud fra forbindelser med formlen (I), hvori R1 er et hydrogenatom eller en blokerende gruppe. Furthermore, one can readily prepare non-toxic salts of the above formula (I) wherein is a salt forming cation, in a per se known manner from compounds of formula (I) wherein R 1 is a hydrogen atom or a blocking group.

22 1 5 1 3 3 8 22 1 5 1 3 3 8

Blandt forbindelserne med formlen (I) kan penicillinerne let fås ved en af de ovennævnte fremgangsmådevarianter (a) og (b), medens cephalosporinerne let kan fås ved enhver af varianterne (a), (b) eller (c). Among the compounds of formula (I) may be the penicillins easily obtained by one of the above process variants (a) and (b) while the cephalosporins can be readily obtained by any of the variants (a), (b) or (c).

I det efterfølgende er beskrevet undersøgelsesmetoden for aktiviteten af de omhandlede forbindelser. In the following is described the method of examination for the activity of the subject compounds.

(1) De minimale inhiberende koncentrationer (MIC) af forbindelserne over for forskellige standardstammer er vist i tabellerne 3 og 4. (1) The minimum inhibitory concentrations (MIC) of the compounds against various standard strains are shown in Tables 3 and 4.

Den minimale inhiberende koncentration (MIC) blev bestemt ved en plade-metode, som er offentliggjort i "Chemotherapy" (Japan), The minimum inhibitory concentration (MIC) was determined by a plate method, as published in "Chemotherapy" (Japan),

Vol. Vol. 16, (1968), sider 98-99. 16 (1968), pages 98-99. Dyrkningsmediet var hjerteinfusionsagar (pH = 7,4). The culture medium was heart infusion (pH = 7.4). Antal celler pr. Number of cells per well. plade i podematerialet var ΙΟ4 (106 celler/ml). plate in the inoculum was ΙΟ4 (106 cells / ml).

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40 151338 (2) De minimale inhiberende koncentrationer (MIC) af forbindelserne over for kliniske isolater af bakterier er vist i tabellerne 5 og 6, hvor numrene i tabel 5 henviser til forbindelserne i tabel 3, og numrene i tabel 6 henviser til forbindelserne i tabel. 40 151338 (2) The minimum inhibitory concentrations (MIC) of the compounds against clinical isolates of bacteria are shown in Tables 5 and 6, where the numbers in Table 5 refer to the compounds in Table 3, and the numbers in Table 6 refers to the compounds in Table .

4. 4th

MIC blev bestemt på samme måde som beskrevet i ovennævnte afsnit (1). MIC was determined in the same manner as described in the above item (1).

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57 151338 _Tabel 6-5_ 57 151338 _Tabel 6-5_

Proteus Proteus

Forbindelse mirabilis morganii vulgaris rettgeri Compound mirabilis morganii vulgaris rettgeri

Nairiv™r , 3.13 1.56 50 50 Nairiv ™ s, 3.13 1.56 50 50

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Forbindelse nr,· 1 3-13 3.13 1.56 6.25 " . 2 1.56 1.56 0.8 3.13 ' " 3 6.25 3.13 3.13 6.25 " 4 3.13 3.13 1.56 3.13 (3) Resistent aktivitet overfor β-lactamase, Pseudomonas aeruginosa GN 238: Compound No, 1 · 3-13 3.13 1.56 6.25 ". 2 1.56 1.56 3.13 0.8 '" 3 6.25 3.13 3.13 6.25 "4 3.13 3.13 1.56 3.13 (3) resistant activity against β-lactamase, Pseudomonas aeruginosa GN 238:

Den resistente aktivitet for hver forbindelse overfor β-lactamase blev målt som beskrevet i det efterfølgende, β-lactamase fremstilledes ud fra Pseudomonas aeruginosa CEN 238, The resistant activity of each compound against β-lactamase was measured as described below, β-lactamase was prepared from Pseudomonas aeruginosa CEN 238,

Denne mikroorganisme blev dyrket i 100 ml af et dyrkningsmedium indeholdende 2 g gærekstrakt, 10 g polypepton, 2 g glucose, 7 g dinatriumhydrogenphosphat, 2 g kaliumdihydrogenphosphat, 1,2 g ammoniumsulfat og 0,4 g magnesiumsulfat pr. This microorganism was cultured in 100 ml of a culture medium containing 2 g of yeast extract, 10 g of polypeptone, 2 g of glucose, 7 g of disodium hydrogen phosphate, 2 g of potassium dihydrogenphosphate, 1.2 g of ammonium sulfate and 0.4 g of magnesium sulfate per. liter i en 500 ml konisk kolbe i 6 timer ved rystning ved 37°C. liters in a 500 ml conical flask for 6 hours by shaking at 37 ° C. De dannede celler blev opsamlet ved centrifugering (5.000 omdr./min. i 10 minutter), vaskedes 3 gange med 0,1 M phosphatpuffer (pH = 7,0). The resulting cells were collected by centrifugation (5000 rpm. For 10 minutes), washed 3 times with 0.1 M phosphate buffer (pH = 7.0). Derefter blev cellerne underkastet lydbehandling (20 KHz, 20 minutter) og derefter centrifugeret ved 15.000 omdr./min. The cells were then subjected to sonication (20 kHz, 20 minutes) and then centrifuged at 15,000 rpm. i 60 minutter. for 60 minutes. Ved anvendelse af den ovenstående enzymvæske blev resistensen af hver forbindelse overfor β-lactamase bestemt ved iodometrisk prøve. By use of the above enzyme liquid was the resistance of each compound against β-lactamase was determined by iodometric test. De opnåede resultater er angivet i tabel 7, hvor numrene henviser til forbindelserne i tabel 3. Hvert tal i tabel 7 angiver en 'relativ aktivitetsverdi, beregnet ved at antage en aktivitet på 100 for kalium penicillin G, der blev benyttet som kontrol. The results obtained are given in Table 7, where the numbers refer to the compounds in Table 3. Each number in Table 7 indicates a 'relative activity Verdi, calculated by assuming an activity of 100 for potassium penicillin G, which was used as a control.

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Tabel 7 table 7

Sammenligning af resistent aktivitet overfor β-lactamase Comparison of activity against resistant β-lactamase

Forbindelse Relativ aktivitet (%) Compound Relative activity (%)

Kalium Penicillin G 100 Potassium penicillin G 100

Natrium-Amp ic illin 115 Sodium Amp ic illin 115

Natrium-Carbenicillin 116 Sodium Carbenicillin 116

Natrium-Sulbenicillin 50 Sodium sulbenicillin 50

Forbindelse nr. 49 3 » » 2 14 » » 1 15 » » 3 15 n η 4 15 Η tf . Compound no. 49 3 '' 2 14 '' 1 15 '' 3 15 15 4 n η Η tf. 5 15 » " 10 16 i » .· »11 1 12 » «12 ,1 5 15 "" 10 16 ". ·" 11 1 12 »« 12 1

Af tabellerne 3-6 forstås, at de omhandlede forbindelser har et bredere antibakterielt spektrum og en højere antibakteriel aktivitet overfor ikke blot Pseudomonas aeruginosa, Klebsiella pneumoniae og Proteus-arter, men også mange lægemiddelresistente bakterier, end tilfældet er med ampicillin og cephaloglycin, der anvendes til kontrol, dvs i forbindelse med en aminogruppe i a-stilling til acylgruppen. Tables 3-6 understood that the subject compounds have a wider antibacterial spectrum and a higher antibacterial activity against not only Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, but also many drug-resistant bacteria than is the case with ampicillin and cephaloglycin used to control, that is to say in relation to an amino group in alpha to the acyl group. Det fremgår også af tabel 7, at forbindelsen ifølge opfindelsen har en langt højere resistens overfor β-lactamase end sammenligningsforbindelserne. It is also apparent from Table 7 that the compound of the invention has a much higher resistance to β-lactamase than the comparison compounds.

Det fremgår af de ovennævnte resultater, at forbindelserne med formlen (I)» som indeholder to oxygenatomer knyttet til henholdsvis 2- og 3-positionen i piperazinringen, udviser særlige fremragende egenskaber, og særlig foretrukne forbindelser er sådanne, hvori A betyder et hydrogenatom, en (C2_4)alkenylgruppe, en phenylgruppe, en benzylgruppe eller en )alkylgruppe, som kan være substitueret med chlor, hydroxy eller carboxyl; It is clear from the above results that the compounds of formula (I) 'which contains two oxygen atoms attached to the 2- and 3-position of the piperazine ring, exhibit particular excellent properties, and especially preferred compounds are those wherein A is a hydrogen atom, (C2-4) alkenyl group, a phenyl group, a benzyl group or a) alkyl group which may be substituted by chloro, hydroxy or carboxyl; og 3 og R hver for sig betyder et hydrogenatom eller en (C^_g)alkyl-gruppe. and 3 and R are each independently a hydrogen atom or a (C ^ _g) alkyl group. De mest foretrukne forbindelser er 6-Q)(-)-o&-(4-ethyl- 59 1 5 1 3 3 8 2,3-dioxo-l-piperazinocarbonylamino)-phenylacetamidq] penicillan-syre og 7-£p(-)-dr(4-ethyl~2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetamidoj —3—^*5— (1-methyl-1 ,2,3,4-tetrazolyl)thio-methylJ-^-cephem-4-carboxylsyre og farmaceutisk acceptable syre-additionssalte deraf. The most preferred compounds are 6-Q) (-) - O & - (4-ethyl 59 1 5 1 3 3 8 2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamidq] penicillanic acid and 7-£ p (- ) -DR (4-ethyl ~ 2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetamidoj -3 - ^ * 5- (1-methyl-1, 2,3,4-tetrazolyl) thio-methylJ - ^ - cephem-4-carboxylic acid and pharmaceutically acceptable acid addition salts thereof.

De omhandlede penicilliner og cephalosporiner har sædvanligvis lav toxicitet. They provided penicillins and cephalosporins usually have low toxicity. F.eks. Eg. har 6-[D(-)-a-(4-methyl-2,3-dioxo-l-piper-azinocarbonylamino)-phenylacetamido]penicillansyre og 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-penicillansyre en LD^0 (iv på mus af en vægt på 19 - 1 g) større end 5 g/kg. the 6- [D (-) - a- (4-methyl-2,3-dioxo-piperidin-l-azinocarbonylamino) -phenylacetamido] penicillanic acid and 6- [D (-) - a- (4-ethyl-2, 3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -penicillanic acid LD ^ 0 (IV on mice weighing from 19 to 1 g) of greater than 5 g / kg.

Forbindelserne med formel (i) kan indgives enten i form af de frie syrer eller i form af ikke-giftige salte eller fysiologisk acceptable estere. The compounds of formula (I) may be administered either in the form of the free acids or in the form of non-toxic physiologically acceptable salts or esters. Endvidere kan de forbindelser, som har form af fysiologisk uacceptable estere, sædvanligvis bringes i anvendelse ved omdannelse til de frie syrer eller ikke-giftige salte ved fjernelse af den esterdannende gruppe på i og for sig kendt måde. Furthermore, the compounds which have the form of physiologically unacceptable esters, usually are applied by conversion to the free acids or non-toxic salts by removal of the ester-forming group in a per se known manner.

De ifølge opfindelsen fremstillede forbindelser kan indgives mennesker og dyr i form af tabletter, kapsler, sirupper eller injektioner, på samme måde som de kendte penicilliner og cephalosporiner. The compounds of this invention can be administered human and animals in the form of tablets, capsules, syrups or injections, the same way as the known penicillins and cephalosporins.

Fremgangsmåden ifølge opfindelsen belyses nærmere ved de efterfølgende eksempler. The process of the invention is illustrated by the following examples.

EKSEMPEL 1 (l) Til en blanding af 2,5 g l-acetyl-3-oxo-piperazin, 3,45 g triethylamin og 20 ml vandfrit dioxan blev sat en opløsning af 3,71 g trimethylchlorsilan i 10 ml vandfri dioxan. Example 1 (l) To a mixture of 2.5 g of l-acetyl-3-oxo-piperazine, 3.45 g of triethylamine and 20 ml of anhydrous dioxane was added a solution of 3.71 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. Den dannede blanding blev kogt under tilbagesvaling i 17 timer og afkølet til udfældning af triethylamin-hydrochlorid, som derefter blev frafiltreret. The resulting mixture was boiled under reflux for 17 hours and cooled to precipitate triethylamine hydrochloride which was then filtered off. Filtratet blev ved T40°C til -30°C dryppet til en opløsning af 1,8 g phosgen i 30 ml vandfrit methylenchlorid. The filtrate was at T40 ° C to -30 ° C dropwise to a solution of 1.8 g of phosgene in 30 ml of anhydrous methylene chloride. Efter tildryp-ningen hævedes temperaturen af den dannede blanding til stuetemperatur, som opretholdtes i 30 minutter. After tildryp solution raised the temperature of the resulting mixture to room temperature, which was maintained for 30 minutes. Derefter blev overskud af 60 151338 phosgen og opløsningsmiddel fjernet ved.destillation under reduceret tryk til dannelse af 3,5 g lysebrunt olieagtigt 4-acetyl-2-oxo- 1- piperazinocarbonylchlorid. Then, the excess of phosgene and 60 151338 ved.destillation solvent removed under reduced pressure to give 3.5 g of light brown oily 4-acetyl-2-oxo-1- piperazinocarbonylchlorid.

IR (film) cm-1: ^C=o 1790» 1710» 1640 · (2) En suspension af 1,0 g 6-[D(-)-a-aminophenylacetamido]-penicillansyre i 20 ml tetrahydrofuran indeholdende 20 rumfangsprocent vand, indstilledes til pH =8,0 til 8,5 ved gradvis tilsætning af triethylamin under omrøring, og derpå afkøledes til 0°C. IR (film) cm-1: C = o ^ 1790 '1710' 1640 · (2) A suspension of 1.0 g of 6- [D (-) - alpha-aminophenylacetamido] -penicillanic acid in 20 ml of tetrahydrofuran containing 20 volume percent water , adjusted to pH = 8.0 to 8.5 by gradual addition of triethylamine with stirring, and then cooled to 0 ° C. Til den således behandlede suspension dryppedes en opløsning af 900 mg af ovennævnte 4-acetyl-2-oxo-l-piperazinocarbonylchl0rid i 5 ml tetrahydrofuran ved den nævnte temperatur i løbet af 30 minutter. To the thus treated suspension was added dropwise a solution of 900 mg of the above 4-acetyl-2-oxo-l-piperazinocarbonylchl0rid in 5 ml of tetrahydrofuran at said temperature over 30 minutes. I dette tidsrum blev pH-værdien af suspensionen opretholdt på 7,5 til 8,0 ved gradvis tilsætning af triethylamin. During this time, the pH of the suspension was maintained 7.5 to 8.0 by gradual addition of triethylamine. Derefter blev temperaturen af den dannede blanding hævet til 5°C til 10°C, og blandingen blev omsat ved den nævnte temperatur i 1 time, medens pH-værdien opretholdtes på 7,5 til 8,0 ved tilsætning af triethylamin. Then, the temperature of the resulting mixture was raised to 5 ° C to 10 ° C and the mixture was reacted at said temperature for 1 hour, while the pH was maintained at 7.5 to 8.0 by the addition of triethylamine. Efter koncentrationen blev tetrahydrofuranen af-destilleret ved reduceret tryk, og remanensen blev opløst i et blandet opløsningsmiddel bestående af 30 ml ethylacetat og 10 ml vand. After concentration of the tetrahydrofuran was distilled at reduced pressure and the residue was dissolved in a mixed solvent consisting of 30 ml of ethyl acetate and 10 ml of water. Den dannede opløsning blev indstillet på en pH-værdi på 1,5 til 2 ved tilsætning af fortyndet saltsyre under isafkøling, og derefter blev det organiske lag fraskilt. The resulting solution was adjusted to a pH value of 1.5 to 2 by addition of dilute hydrochloric acid under ice-cooling, and then the organic layer was separated. Det vandige lag blev genekstraheret med 20 ml ethylacetat, og det dannede organiske lag blev forenet med ovennævnte organiske lag. The aqueous layer was re-extracted with 20 ml of ethyl acetate, and the formed organic layer was combined with the above organic layer. De forenede organiske lag blev vasket med vand, tørret over vandfrit magnesiumsulfat og derefter isafkølet. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and then ice-cooled. I dette organiske lag blev dryppet en opløsning af 470 mg af et natriumsalt af 2-ethylhexansyre i 20 ml ethylacetat til udfældning af hvide krystaller. This organic layer was dropped a solution of 470 mg of a sodium salt of 2-ethylhexanoic acid in 20 ml of ethyl acetate to precipitate white crystals. De udfældede krystaller blev opsamlet ved filtrering, vasket med ethylacetat og derefter tørret til dannelse af 1,4 g natriumsalt af 6 - [D (-) - a- (4-acetyl- 2- oxo-l-piperazinocarbonylamino)phenylacetamido]penicillansyre, smp.: 2050 C (dekomp.), udbytte: 94%. The precipitated crystals were collected by filtration, washed with ethyl acetate and then dried to give 1.4 g of the sodium salt of 6 - [D (-) - a- (4-acetyl-2-oxo-l-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp .: 2050 C (decomp.), yield: 94%.

151338 IR (KBr) cm”1; 151,338 IR (KBr) cm "1; yc=Q 1760 (lactam), 1600 - 1700 (-C00®, -CON<0 NMR: [(CD^)2S0 + D20] ^ værdier: 2,73 (5H), 4,35 (IH), 4,75 (2H), 5,75 (IH), 5,84 (2H), 6,42 (4H), 8,03 (3H), 8,52 (3H), 8,64 (3H). ? C = Q 1760 (lactam), 1600 to 1700 (-C00®, -CON <0 NMR: [(CD ^) 2S0 + D20] ^ values: 2.73 (5H), 4.35 (IH), 4, 75 (2H), 5.75 (IH), 5.84 (2H), 6.42 (4H), 8.03 (3H), 8.52 (3H), 8.64 (3H).

Ovennævnte operation blev gentaget med den ændring, at 4-acetyl-2-oxo-l-piperazinocarbonylchlorid blev erstattet med de i efterfølgende tabel 8 nævnte reaktive derivater af forbindelser med formlen (III), til dannelse af de i tabel 8 nævnte forbindelser. The above operation was repeated with the modification that 4-acetyl-2-oxo-l-piperazinocarbonylchlorid was replaced by the following Table 8 in said reactive derivatives of compounds of formula (III), to form in Table 8, the compounds. Strukturen af hvert af de dannede slutprodukter blev bekræftet ved IR og NMR. The structure of each of the resulting final products were confirmed by IR and NMR.

62 151338 62 151338

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^ w to to to aaaooo ^ J--- 65 1 5 1 3 3 8 EKSEMPEL 2 (1) I en opløsning af 1,74 g natriumsalt af D(-)-a-aminophenyl-eddikesyre i 30 ml tetrahydrofuran indeholdende 20 rumfangsprocent vand, som er afkølet til 0°C, dryppedes en opløsning af 2,5 g 4-acetyl-2~oxo-l-piperazinocarbonyl i 5 ml tetrahydrofuran ved den nævnte temperatur i løbet af 30 minutter. ^ W two two two aaaooo ^ J --- 65 1 5 1 3 3 8 EXAMPLE 2 (1) In a solution of 1.74 g of sodium salt of D (-) - a-amino-phenyl-acetic acid in 30 ml of tetrahydrofuran containing 20 volume percent water, which is cooled to 0 ° C, was added dropwise a solution of 2.5 g of 4-acetyl-2-oxo-l-piperazinocarbonyl in 5 ml of tetrahydrofuran at said temperature over 30 minutes. I dette tidsrum blev pH-værdi en af reaktionsopløsningen holdt mellem 11,0 og 12.0 ved gradvis tilsætning af en 10% vandig natriumhydroxidopløsning. In this time, the pH of one of the reaction solution was maintained between 11.0 and 12.0 by gradual addition of a 10% aqueous sodium hydroxide solution. Derefter blev temperaturen af den dannede blandede opløsning hævet til 5 - 10°C, og opløsningen blev omsat ved stuetemperatur i 2 timer, medens pH-værdi en blev holdt mellem 10,0 og 11.0 ved tilsætning af 10% vandig natriumhydroxidopløsning. Then, the temperature of the resulting mixed solution was raised to 5 - 10 ° C and the solution was reacted at room temperature for 2 hours, while the pH-value one was maintained between 10.0 and 11.0 by addition of 10% aqueous sodium hydroxide solution. Efter reaktionen blev tetrahydrofuranet afdestilleret ved reduceret tryk. After the reaction, the tetrahydrofuran is distilled off at reduced pressure. Remanensen blev opløst i et blandet opløsningsmiddel indeholdende 20 ml vand og 50 ml ethylacetat, og den dannede opløsning blev ind·?· stillet på en pH-værdi af 1,0 til 1,5 ved tilsætning af fortyndet saltsyre under isafkøling. The residue was dissolved in a mixed solvent containing 20 ml of water and 50 ml of ethyl acetate, and the resulting solution was zoom ·? · Set to a pH value of 1.0 to 1.5 by addition of dilute hydrochloric acid under ice-cooling. Derefter blev det organiske lag fraskilt, vasket med vand og derefter tørret over vandfrit magnesiumsulfat. Then, the organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. Til dette organiske lag sattes en opløsning af 1,66 g natriumsalt af 2-ethyl-hexansyre i 20 ml ethylacetat til udfældning af hvide krystaller. To this organic layer was added a solution of 1.66 g of sodium salt of 2-ethyl-hexanoic acid in 20 ml of ethyl acetate to precipitate white crystals. De udfældede krystaller blev opsamlet ved filtrering, vasket grundigt med ethylacetat og derefter tørret til dannelse af 1,89 g af et natriumsalt af D(-)-a-(4-acetyl-2-oxo-l-piperazinocarbonylamino)phenyleddikesyre, smp.: 115°C (dekomp.), udbytte 52%. The precipitated crystals were collected by filtration, washed well with ethyl acetate and then dried to give 1.89 g of a sodium salt of D (-) - a- (4-acetyl-2-oxo-l-piperazinocarbonylamino) phenyl acetic acid, mp. : 115 ° C (dec.), yield 52%.

IR (KBr) cm”1: 1690, 1650 - 1600 (2) Til en suspension i 15 ml vandfri acetone af 833 mg af ovennævnte natrimsalt af D(-)-a-(4-acetyl-2-oxo-l-piperazinocarbonyl-amino) phenyl-eddike syre sattes 10 mg N-methylmorpholin. IR (KBr) cm "1: 1690, 1650-1600 (2) To a suspension in 15 ml of anhydrous acetone of 833 mg of the above natrimsalt of D (-) - a- (4-acetyl-2-oxo-l-piperazinocarbonyl amino) phenyl-acetic acid was added 10 mg of N-methylmorpholine. Den dannede blanding opsamledes ved -20°C til -15°C, og en opløsning af 286 mg ethylchlorcarbonat i 5 ml vandfri acetone tildryppedes blandingen i løbet af 5 minutter. The resulting mixture was collected at -20 ° C to -15 ° C, and a solution of 286 mg of ethyl chlorocarbonate in 5 ml of anhydrous acetone was added dropwise to the mixture over 5 minutes. Derefter omrørtes blandingen ved den nævnte temperatur i 60 minutter. Then, the mixture was stirred at said temperature for 60 minutes. I den således behandlede blanding dryppedes en opløsning af 646 mg triethylaminsalt af 6-aminopeni-cillansyre i 30 ml vandfrit methylenchlorid ved -40°C til -30°C i løbet af 10 minutter. Into the thus treated mixture was added dropwise a solution of 646 mg of triethylamine salt of 6-aminopeni-cillansyre in 30 ml of anhydrous methylene chloride at -40 ° C to -30 ° C over 10 minutes. Derefter omsattes blandingen under omrøring ved -30° C til -20° C i 60 minutter og ved -20° C til -1.0° C i 30 minutter og ved -10°C til 0°C i 30 minutter. Then, the mixture was reacted with stirring at -30 ° C to -20 ° C for 60 minutes and at -20 ° C to -1.0 ° C for 30 minutes and at -10 ° C to 0 ° C for 30 minutes. Efter reaktionen blev det ,ί 66 1513.38 organiske opløsningsmiddel afdestilleret under reduceret tryk. After the reaction, it ί 66 1513.38 organic solvent is distilled off under reduced pressure. Remanensen blev opløst i et blandet opløsningsmiddel bestående af 50 ml ethylacetat og 20 ml vand, og den dannede opløsning indstilledes på en pH-værdi på 1,5 til 2,0 ved tilsætning af fortyndet saltsyre under isafkøling. The residue was dissolved in a mixed solvent consisting of 50 ml of ethyl acetate and 20 ml of water, and the resulting solution was adjusted to a pH of 1.5 to 2.0 by addition of dilute hydrochloric acid under ice-cooling. Derefter fraskiltes det organiske lag, der vaskedes grundigt med vand og tørredes derefter over vandfrit magnesiumsulfat, og ethylacetatet afdestilieredes ved reduceret tryk. Then, the separated organic layer was washed thoroughly with water and then dried over anhydrous magnesium sulfate, and the ethyl acetate afdestilieredes at reduced pressure. Remanensen blev opløst i 50 ml acetone, og den dannede opløsning blev blandet med en opløsning af 340 mg natriumsalt af 2-ethylhexansyre i 20 ml acetone under isafkøling til udfældning af hvide krystaller. The residue was dissolved in 50 ml of acetone, and the resulting solution was mixed with a solution of 340 mg of sodium salt of 2-ethylhexanoic acid in 20 ml of acetone under ice-cooling to precipitate white crystals. De udfældede krystaller opsamlede.· ved filtrering, vaskedes grundigt med acetone og tørredes derefter til dannelse af 1,16 g natriumsalt af 6-[D(-)-a-(4-acetyl-2-oxo-1-piperazinocarbonylamino)phenylacetamido]penicillansyre, smp.: 205°C (dekomp.), udbytte 94%. The precipitated crystals are collected. · By filtration, washed thoroughly with acetone and then dried to give 1.16 g of sodium salt of 6- [D (-) - a- (4-acetyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p .: 205 ° C (dec.), yield 94%.

i EKSEMPEL 5 In Example 5,

Cl) Til en blanding af 1,0 g l-palmitoyl-3-oxo-piperazin, 0,6 g triethylamin og 20 ml vandfrit dioxan sattes en opløsning af 0,65 g trimethylchlorsilan i 10 ml vandfrit dioxan. Cl) To a mixture of 1.0 g of l-palmitoyl-3-oxo-piperazine, 0.6 g of triethylamine and 20 ml of anhydrous dioxane was added a solution of 0.65 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. Den dannede blanding kogtes under tilbagesvaling i 16 timer og afkøledes til udfældning af triethylaminhydrochlorid, som derefter frafiltreredes. The resulting mixture was refluxed for 16 hours and cooled to precipitate triethylamine hydrochloride which was then filtered off. Filtratet dryppedes ved -40°C til -30°C i en opløsning af 0,6 g phosgen i 30 ml vandfrit methylenchlorid. The filtrate was added dropwise at -40 ° C to -30 ° C in a solution of 0.6 g of phosgene in 30 ml of anhydrous methylene chloride. Efter tildrypningen blev temperaturen af den dannede blanding hævet, og blandingen omsattes til stuetemperatur i 30 minutter. After the dropwise addition, the temperature of the resulting mixture was closed and allowed to react to room temperature over 30 minutes. Derefter blev overskud af phosgen og opløsningsmiddel afdestilleret ved reduceret tryk til dannelse af 1,1 g lysegul olieagtig 4-palmitoyl-2-ox0-l-piperazinocarbonyl-chlorid. Then, the excess of phosgene and the solvent distilled off at reduced pressure to give 1.1 g of pale yellow oily 4-palmitoyl-2-ox0-l-piperazino- carbonyl chloride.

IR (film) cm“^: Y^c=0 -*-740, 1660, 1640 (2) En suspension af 1,0 g 6-[D(-)-a-aminophenylacetamido]peni-cillansyre i 20 ml tetrahydrofuran indeholdende 20 rumfangsprocent vand indstilledes på en pH-værdi af 8,0 til 8,5 ved gradvis tilsætning af triethylamin under omrøring og afkøledes derefter til 0°C. IR (film) cm "^ Y ^ c = 0 - * - 740, 1660, 1640 (2) A suspension of 1.0 g of 6- [D (-) - alpha-aminophenylacetamido] peni-cillansyre in 20 ml of tetrahydrofuran containing 20 volume percent water adjusted to a pH of 8.0 to 8.5 by gradual addition of triethylamine with stirring and then cooled to 0 ° C.

I den således behandlede suspension dryppedes en opløsning af 1,27 g af det ovennævnte palmitoyl-2-oxo-l-piperazinocarbonylchlorid i 5 ml tetrahydrofuran ved den nævnte temperatur i løbet af 30 minut- 67 1 5 1 3 3 8 ter. Into the thus treated suspension was added dropwise a solution of 1.27 g of the above palmitoyl-2-oxo-l-piperazinocarbonylchlorid in 5 ml of tetrahydrofuran at said temperature over 30 The minutes 1 5 67 1 3 3 8 ter. I dette tidsrum opretholdtes pH-værdien af suspensionen på 7,5 til 8,0 ved gradvis tilsætning af triethylamin. During this time, maintaining the pH of the suspension to 7.5 to 8.0 by gradual addition of triethylamine. Derefter hævedes temperaturen af den dannede blanding til 5°C til 10°C, og blandingen omsattes ved den nævnte temperatur i 1 time, medens pH-værdien opretholdtes på 7,5 til 8,0 ved tilsætning af triethylamin. Then, the temperature was raised to the resulting mixture to 5 ° C to 10 ° C and the mixture was reacted at said temperature for 1 hour, while the pH was maintained at 7.5 to 8.0 by the addition of triethylamine. Efter reaktionen afdestilleredes tetrahydrofuranen ved reduceret tryk, og remanensen opløstes i et blandet opløsningsmiddel indeholdende 30 ml ethylacetat og 10 ml vand. After the reaction, the tetrahydrofuran was distilled off at reduced pressure and the residue was dissolved in a mixed solvent containing 30 ml of ethyl acetate and 10 ml of water. Den dannede opløsning indstilledes til en pH-værdi på 1,0 til 2,0 ved tilsætning af fortyndet saltsyre under isafkøling, og derefter fraskiltes det organiske lag. The resulting solution was adjusted to a pH of 1.0 to 2.0 by addition of dilute hydrochloric acid under ice-cooling, and then separated the organic layer. Det vandige lag blev genekstraheret med 20 ml ethy-acetat, og det dannede organiske lag forenedes med det ovennævnte organiske lag. The aqueous layer was re-extracted with 20 ml of ethyl acetate, and the formed organic layer was combined with the above organic layer. Det forenede organiske lag blev vasket med vand og tørret over vandfrit magnesiumsulfat. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. Dette organiske lag koncentreredes under reduceret tryk til fjernelse af opløsningsmidlet, og koncentratet blev indført i 10 ml diisopropylether til udfældning af krystaller. This organic layer was concentrated under reduced pressure to remove the solvent, and the concentrate was introduced into 10 ml of diisopropyl ether to precipitate crystals. Derefter opsamledes krystallerne ved filtrering til dannelse af 1,65 g hvide krystaller af 6-[D(-)-a-(4-palmitoyl-2-oxo-l-piperazinocarbonylamino)phenylacetamido]penicillansyre, smp.: 121 - 123°C (dekomp.), udbytte 80%. Then, the crystals were collected by filtration to give 1.65 g of white crystals of 6- [D (-) - a- (4-palmitoyl-2-oxo-l-piperazinocarbonylamino) phenylacetamido] penicillanic acid, mp .: 121 - 123 ° C (dec.), yield 80%.

IR (KBr) cm"1: ^ C=Q 1770 (lactam), 1730 (-C00H), 1660 - 1630 (-CON O- IR (KBr) cm "1: ^ C = Q 1770 (lactam), 1730 (-C00H), 1660-1630 (-CON O-

Ovennævnte operation gentoges med den ændring at 4-palmitoyl-2-oxo-l-piperazinocarbonylchloridet erstattedes med de reaktive derivater af forbindelser med formlen (III), som er vist i tabel 9, til dannelse af de ligeledes i tabel 9 viste slutprodukter. The above operation was repeated with the modification that 4-palmitoyl-2-oxo-l-piperazinocarbonylchloridet was replaced by the reactive derivatives of compounds of formula (III), shown in Table 9, to form the likewise in Table 9, the final products. Strukturen af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of the resulting compounds were confirmed by IR and NMR.

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(1) Til en opløsning af 6,4 g l-formyl-3-oxo-piperazin i 10 ml vandfrit dimethylformamid sattes 2,7 g natriumhydrid (renhed 53%) under isafkøling, og den dannede blanding omsattes ved stuetemperatur i 1 time. (1) To a solution of 6.4 g of l-formyl-3-oxo-piperazine in 10 ml of anhydrous dimethylformamide was added 2.7g sodium hydride (purity 53%) under ice-cooling, and the resulting mixture was reacted at room temperature for 1 hour. Derefter indførtes blandingen i 7,1 g methyl-iodid, og der omsattes i 10 timer. Then the mixture was introduced into 7.1 g of methyl iodide, and they were reacted for 10 hours. Efter reaktionen afdestilleredes dimethylformamidet under reduceret tryk til dannelse af l-formyl-4-methyl-3-oxo-piperazin. After the reaction, the dimethylformamide was distilled off under reduced pressure to yield l-formyl-4-methyl-3-oxo-piperazine. Denne piperazin-forbindelse opløses i 70 ml af en 50% vandig acetoneopløsning indeholdende 2,2 g natriumhydroxid, og den dannede opløsning omsattes ved stuetemperatur i 3 timer. Piperazine This compound was dissolved in 70 ml of a 50% aqueous acetone solution containing 2.2 g of sodium hydroxide, and the resulting solution was reacted at room temperature for 3 hours. Derefter afdestilleredes opløsningsmidlet under reduceret tryk, og remanensen blev indført i acetone til udfældning af uopløselige stoffer. Then distilled off the solvent under reduced pressure and the residue was added to acetone to precipitate the insolubles. De uopløselige stoffer frafil-treredes, og acetonen afdestilleredes fra filtratet under reduceret tryk. The insolubles frafil-treredes and the acetone was distilled off from the filtrate under reduced pressure. Derefter underkastedes remanensen en destillation ved reduceret tryk til dannelse af 5,2 g l-methyl-2-oxo-piperazin, kp. Then, the residue was subjected to distillation at reduced pressure to give 5.2 g of l-methyl-2-oxo-piperazine, bp. 104°C/4 mmHg, udbytte 91%. 104 ° C / 4 mmHg, yield 91%.

(2) I en opløsning af 1,9 g phosgen i 20 ml vandfrit dioxan dryp-· pedes ved 10°C 20 ml af en vandfri dioxanopløsning indeholdende 2,0 g l-methyl-2-oxo-piperazin og 1,95 g triethylamin, hvorefter reaktionen forløb til udfældning af hvide krystaller af triethyl-amin-hydrochlorid. (2) In a solution of 1.9 g of phosgene in 20 ml of anhydrous dioxane drip · pedes at 10 ° C, 20 ml of an anhydrous dioxane solution containing 2.0 g of l-methyl-2-oxo-piperazine and 1.95 g of triethylamine, and then the reaction proceeded to precipitate white crystals of triethylamine hydrochloride. De udfældede krystaller frafiltreredes, og filtratet inddampedes til tørhed til dannelse af 3,0 g lysegult olie-agtigt 4-methyl-3-oxo-l-piperazinocarbonylchlorid. The precipitated crystals were filtered, and the filtrate was evaporated to dryness to give 3.0 g light yellow oil-like 4-methyl-3-oxo-l-piperazinocarbonylchlorid.

IR (film) cm”^: 1710, 1630 (3) En suspension af 4,0 g 6-[D(-)-a-aminophenylacetamido]peni-cillansyre i 40 ml tetrahydrofuran, indeholdende 20 rumfangsprocent vand, indstilledes på en pH-værdi på 8,0 til 8,5 ved gradvis tilsætning af triethylamin under omrøring, og derefter afkøledes til 0°C. IR (film) cm "^: 1710, 1630 (3) A suspension of 4.0 g of 6- [D (-) - alpha-aminophenylacetamido] peni-cillansyre in 40 ml of tetrahydrofuran containing 20 volume percent water, adjusted to a pH value of 8.0 to 8.5 by gradual addition of triethylamine with stirring, and then cooled to 0 ° C. Til den således behandlede suspension dryppedes 10 ml af en tetrahydrofuranopløsning indeholdende 2,2 g af ovennævnte 4-methyl- 3-oxo-l-piperazinocarbonylchlorid. To the thus treated suspension was added dropwise 10 ml of a tetrahydrofuran solution containing 2.2 g of the above 4-methyl-3-oxo-l-piperazinocarbonylchlorid. I dette tidsrum opretholdtes pH-værdien af suspensionen på 7,5 til 8,5 ved gradvis tilsætning af triethylamin. During this time, maintaining the pH of the suspension to 7.5 to 8.5 by gradual addition of triethylamine. Derefter omsattes den dannede blanding ved den nævnte temperatur i 30 minutter, og temperaturen hævedes til 10°C til 15°C, hvorefter blandingen yderligere omsattes ved den nævnte temperatur i 90 minutter, medens pH værdien holdtes på 7,5 til 8,0 7i 151338 ved tilsætning af triethylamin. Then the resulting mixture was reacted at that temperature for 30 minutes and the temperature was raised to 10 ° C to 15 ° C, after which the mixture was further reacted at that temperature for 90 minutes, while the pH value was maintained at 7.5 to 8.0 7i 151338 by the addition of triethylamine. Efter reaktionen afdestilleredes tetrahydrof uranet under reduceret tryk, og remanensen opløstes i 30 ml vand. After the reaction was distilled off tetrahydrof uranium under reduced pressure and the residue was dissolved in 30 ml of water. Den dannede opløsning vaskedes med ethylacetat, hvorefter det vandige lag fraskiltes. The resulting solution was washed with ethyl acetate, and the aqueous layer was separated. Dette vandige lag isafkøledes og indstilledes derefter til en pH værdi på 1,5 ved tilsætning af fortyndet saltsyre til udfældning af hvide krystaller. This aqueous layer was ice-cooled and then adjusted to a pH value of 1.5 by addition of dilute hydrochloric acid to precipitate white crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes flere gange med små mængder vand, tørredes og opløstes derefter i 100 ml acetone. The precipitated crystals were collected by filtration, washed several times with small amounts of water, dried and then dissolved in 100 ml of acetone. Til den dannede opløsning sattes 1,9 g af et natriumsalt af 2- ethylhexansyre under isafkøling til udfældning af krystaller, som derefter opsamles ved filtrering til opnåelse af 5,4 g af et natriumsalt af 6-[D(-)-a-(4-methyl-3-oxo-l-piperazinocarbonylamino)-phenylacetamido]penicillansyre, smp.: 195°C (dekomp.), udbytte 92%. To the resulting solution was added 1.9 g of a sodium salt of 2-ethylhexanoic acid under ice-cooling to precipitate crystals which was then collected by filtration to obtain 5.4 g of a sodium salt of 6- [D (-) - a- ( 4-methyl-3-oxo-l-piperazinocarbonylamino) -phenylacetamido] penicillanic acid, m.p .: 195 ° C (dec.), yield 92%.

IR (KBr) cm"1: C=Q 1760 (lactam), 1600 - 1660 (-CON , -C00 " ), NMR [(CD^^SO + D2O] værdier: 2.62 (5H), 4,48 (IH), 4,56 (2H), 5,97 (3H), 6.63 - 6,39 (4H), 7,13 (3H), 8,46 (3H), 8,55 (3H). IR (KBr) cm "1: C = Q 1760 (lactam), 1600 to 1660 (-CON, -C00"), NMR [(CD ^^ SO + D 2 O] values: 2.62 (5H), 4.48 (IH ), 4.56 (2H), 5.97 (3H), 6.63 to 6.39 (4H), 7.13 (3H), 8.46 (3H), 8.55 (3H).

Ovennævnte operation blev gentaget med den ændring, at 4-methyl- 3- oxo-l-piperazinocarbonylchlorid blev erstattet med hver af de i efterfølgende tabel 10 nævnte reaktive derivater af forbindelser med formlen (III) til dannelse af de ligeledes i tabel 10 nævnte respektive slutprodukter. The above operation was repeated with the modification that 4-methyl-3- oxo-l-piperazinocarbonylchlorid was replaced with each of the following Table 10 in the mentioned reactive derivatives of compounds of formula (III) to form the table 10 also in said respective end products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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di °v 75 151338 EKSEMPEL 5 (1) I en opløsning af 0,5 g phosgen i 10 ml vandfrit dioxan dryppedes ved 10°C 10 ml vandfrit dioxan indeholdende 0,56 g 1-allyl- 2-oxo-piperazin og 0,5 g triethylamin, hvorved der indledtes en reaktion til udfældning af hvide krystaller af triethylamin-hydro-chlorid. di v ° 75 151338 Example 5 (1) Into a solution of 0.5 g of phosgene in 10 ml of anhydrous dioxane was added dropwise at 10 ° C 10 ml of anhydrous dioxane containing 0.56 g of 1-allyl 2-oxo-piperazine, and 0, 5 g of triethylamine, which launched a reaction to precipitate white crystals of triethylamine hydro-chloride. Derefter opsamledes de hvide krystaller ved filtrering, og filtratet inddampedes til tørhed til dannelse af 800 mg lysegult olieagtigt 4-allyl-3-oxo-l-piperazino-carbonylchlorid. Then the white crystals were collected by filtration, and the filtrate was evaporated to dryness to give 800 mg of pale yellow oily 4-allyl-3-oxo-l-piperazino-carbonyl chloride.

IR (film) cm"1: VC=Q 1720,.1640 (2) En suspension af 1,4 g 6-[D(-)-a-amino-phenylacetamido]penicil-lansyre i tetrahydrofuran indeholdende 20 rumfangsprocent vand, indstilledes til en pH-værdi af. 8,0 til 8,5 ved gradvis tilsætning af triethylamin under omrøring, og derefter afkøledes til 0°C. I den således behandlede dryppedes 10 ml tetrahydrofuranopløsning indeholdende 800 mg af ovennævnte 4-allyl-3-oxo-l-piperazinocarbonyl-chlorid. I dette tidsrum opretholdtes pH-værdien af suspensionen ved 7,5 til 8,5 ved gradvis tilsætning af triethylamin. Derefter omsattes den dannede blanding ved den nævnte temperatur i 30 minutter, og temperaturen hævedes til 10° til 15°C, hvorefter blandingen yderligere omsattes ved den nævnte temperatur i 90 minutter, medens pH-værdien indstilledes på 7,5 til 8,0 ved tilsætning af triethylamin. Efter reaktionen afdestilieredes tetrahydrofuranet under reduceret tryk, og remanensen opsamledes i 20 ml vand. Den dannede opløsning vaskedes med et IR (film) cm "1:? C = Q 1720, 0.1640 (2) A suspension of 1.4 g of 6- [D (-) - alpha-amino-phenylacetamido] penicillin lansyre in tetrahydrofuran containing 20 volume percent water, adjusted to a pH of. 8.0 to 8.5 by gradual addition of triethylamine with stirring, and then cooled to 0 ° C. Into the thus treated dropwise with 10 ml of tetrahydrofuran solution containing 800 mg of the above 4-allyl-3-oxo -L-piperazinocarbonyl chloride. During this time, maintaining the pH of the suspension at 7.5 to 8.5 by gradual addition of triethylamine. Then, the resulting mixture was reacted at that temperature for 30 minutes and the temperature was raised to 10 ° to 15 ° C, after which the mixture was further reacted at that temperature for 90 minutes, while the pH was adjusted to 7.5 to 8.0 by addition of triethylamine. After the reaction, afdestilieredes the tetrahydrofuran under reduced pressure and the residue was collected in 20 ml water. the resulting solution was washed with a hylacetat, og det vandige lag fraskiltes. hylacetat and the aqueous layer was separated. Dette vandige lag isafkøledes og indstilledes på en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre til udfældning af hvide krystaller. This aqueous layer was ice-cooled and adjusted to a pH of 1.5 by addition of dilute hydrochloric acid to precipitate white crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes grundigt med vand og tørredes derefter til opnåelse af 1,8 g 6-[p(-)-(K-(4-allyl-3-oxo-l-piperazinocarbonylamino) phenylac etami do] penicillansyre, smp. 92°C (dekomp.), udbytte 90%. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to give 1.8 g of 6- [p (-) - (K- (4-allyl-3-oxo-l-piperazinocarbonylamino) phenylac etami do] penicillanic mp. 92 ° C (dec.), yield 90%.

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76 151338 76 151338

Ovennævnte operation blev gentaget med den ændring, at 4-allyl-3-oxo-l-piperazinocarbonylchloridet blev erstattet af hver af de i tabel 11 angivne reaktive derivater af forbindelserne med formlen (III) til dannelse af de respektive slutprodukter, der ligeledes er vist i tabel 11 <> Strukturen af hver forbindelse blev bekræftet . The above operation was repeated with the modification that 4-allyl-3-oxo-l-piperazinocarbonylchloridet was replaced by each of the in Table 11 indicated reactive derivatives of the compounds of formula (III) to form the respective end products, also shown in table 11 <> the structure of each compound was confirmed. ved IR og NMR. by IR and NMR.

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(2) Til en suspension af 0,71 g af ovennævnte l-ethyl-2,3-dioxo-piperazin i 15 ml vandfrit dioxan sattes under omrøring 0,70 g trimethylsilylchlorid og 0,83 ml triethylamin. (2) To a suspension of 0.71 g of the above l-ethyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane was added with stirring 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine. Den dannede blanding omrørtes ved stuetemperatur i 20 timer til udfældning af tri-ethylamin-hydrochlorid. The resulting mixture was stirred at room temperature for 20 hours to precipitate triethylamine hydrochloride. Dette hydrochlorid blev frafiltreret, og filtratet dryppedes.ved 5° til 10°C i en opløsning af 0,70 g phosgen i 10 ml vandfrit tetrahydrofuran. This hydrochloride was filtered off and the filtrate dryppedes.ved 5 ° to 10 ° C in a solution of 0.70 g phosgene in 10 ml of anhydrous tetrahydrofuran. Derpå omsattes den dannede blanding ved 5° til 10°C i 30 minutter og ved stuetemperatur i 2 timer, hvorefter opløsningsmidlet afdestilléredes under reduceret tryk til dannelse af 1,0 g lysegule krystaller af 4-ethyl-2,3-dioxo-l-piperazinocarbonylchlorid. Is then reacted the resulting mixture at 5 ° to 10 ° C for 30 minutes and at room temperature for 2 hours, then the solvent afdestilléredes under reduced pressure to give 1.0 g of light yellow crystals of 4-ethyl-2,3-dioxo-L- piperazinocarbonylchlorid.

(3) En suspension af 1,75 g 6-[d(-)-a-aminophenylacetamidcTjpeni-cillansyre i 50 ml tetrahydrofuran indeholdende 20% efter volumen vand indstilledes på pH 8,0 til 8,5 ved tilsætning af triethylamin under omrøring til dannelse af en opløsning. (3) A suspension of 1.75 g of 6- [D (-) - a-aminophenylacetamidcTjpeni-cillansyre in 50 ml of tetrahydrofuran containing 20% ​​by volume of water was adjusted to pH 8.0 to 8.5 by addition of triethylamine with stirring to form a solution. Denne opløsning afkøledes til 0° til 5°C, hvorefter 7 ml vandfrit tetrahydrofuranopløsning indeholdende 1,0 g af ovennævnte 4-ethyl-2,3-dioxo-l-piper-azinocarbonylchlorid dryppedes i opløsningen. This solution was cooled to 0 ° to 5 ° C, after which 7 ml of anhydrous tetrahydrofuran solution containing 1.0 g of the above 4-ethyl-2,3-dioxo-piperidin-l-azinocarbonylchlorid was dropped into the solution. I denne periode opretholdtes pH-værdien af reaktionsopløsningen ved 7,5 til 8,0 ved gradvis tilsætning af'triethylamin. During this period, maintaining the pH of the reaction solution at 7.5 to 8.0 by the gradual addition af'triethylamin. Den dannede blandede opløsning omsattes ved den nævnte temperatur i 30 minutter og derefter ved 5° til 10°C i en time, medens pH-værdien holdtes ved 7,5 til 8,0. The resulting mixed solution was reacted at said temperature for 30 minutes and then at 5 ° to 10 ° C for one hour, while the pH was maintained at 7.5 to 8.0. Efter reaktionen fjernedes tetrahydrofuranen ved destillation under reduceret tryk, og remanensen opløstes i 20 ml vand og vaskedes derefter to gange med 20 ml ethylacetat. After the reaction, the tetrahydrofuran was removed by distillation under reduced pressure and the residue was dissolved in 20 ml of water and then washed twice with 20 ml of ethyl acetate. Til det vandige 81 151358 lag sattes igen 50 ml ethylacetat, og den dannede blanding indstilledes på en pH-værdi på 1,5 ved gradvis tilsætning af fortyndet saltsyre under isafkøling. To the aqueous layer was added 81 151358 again 50 ml of ethyl acetate, and the resulting mixture was adjusted to a pH of 1.5 by gradual addition of dilute hydrochloric acid under ice-cooling. Derefter fraskiltes ethylacetatlaget, som Vaskedes grundigt med vand og derpå tørredes over vandfrit magnesiumsulfat. Then, the ethyl acetate layer was separated, which was washed thoroughly with water and then dried over anhydrous magnesium sulfate. Til det således behandlede lag dryppedes 10 ml af en ethylacetatopløsning indeholdende 0,85 g natrium-2-ethyl-hexanoat til udfældning af hvide krystaller. To the thus treated layer was added dropwise 10 ml of an ethyl acetate solution containing 0.85 g of sodium 2-ethyl hexanoate to precipitate white crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes grundigt med ethylacetat, vaskedes derefter med diethylether og tørredes til dannelse af 2,4 g natriumsalt af 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocar-bonylamino)phenylacetamido]penicillansyre, smp. The precipitated crystals were collected by filtration, washed well with ethyl acetate, then washed with diethyl ether and dried to give 2.4 g of the sodium salt of 6- [D (-) - a- (4-ethyl-2,3-dioxo-L- piperazinocar-bonylamino) phenylacetamido] penicillanic acid, mp. 183-185°C (dekomp.), udbytte 89%. 183-185 ° C (dec.), Yield 89%.

IR (KBr) cm”1: V^c=0 (lactam), 1720 - 1670 (-C0N<), 1600 (-C00®) NMR ((01)3)280 + D20) Έ værdier: 2.62 (5H), 4.31 (IH), 4.50 (IH), 4.70 (1E), ' 6.05 (IH), 6.35 - 6.65 (6H), 8.49 (3H), 8.60 (3H), 8.91 (3H) IR (KBr) cm "1: V ^ c = 0 (lactam), 1720 to 1670 (-C0N <), 1600 (-C00®) NMR ((01) 3) 280 + D 20) Έ values: 2.62 (5H) , 4.31 (IH), 4.50 (IH), 4.70 (1 E), '6.05 (IH), 6.35 to 6.65 (6H), 8.49 (3H), 8.60 (3H), 8.91 (3H)

Ovennævnte operation gentoges med den ændring, at 4-ethyl-2,3-dioxo-1-piperazinocarbonylchlorid erstattedes med hvert af de i tabel 12 angivne reaktive derivater af forbindelser med formlen (III) til dannelse af de ligeledes i tabel 12 nævnte slutprodukter. The above operation was repeated with the modification that 4-ethyl-2,3-dioxo-1-piperazinocarbonylchlorid was replaced with each of the 12 indicated in Table reactive derivatives of compounds of formula (III) to form the likewise in Table 12, the end-products. Strukturen af hver fremstillet forbinuelse blev bekræftet ved IR og NMR. The structure of each forbinuelse prepared was confirmed by IR and NMR.

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Eksempel 7 85 151338 Example 7 85 151338

En suspension af 1,4 g 6-jp(-)-oc-aminophenylacetamidoj[penicillansyre i 30 ml tetrahydrofuran indeholdende 20% efter volumen vand indstilledes til pH = 8,0 til 8,5 ved tilsætning af triethylamin under omrøring til dannelse af en opløsning. A suspension of 1.4 g of 6-JP (-) - oc-aminophenylacetamidoj [penicillanic acid in 30 ml of tetrahydrofuran containing 20% ​​by volume of water adjusted to pH = 8.0 to 8.5 by addition of triethylamine with stirring to form a resolution. Denne opløsning afkøledes til 0° til 5°C, og 10 ml af en tetrahydrofuranopløsning indeholdende 1,2 g af 4-n-pentyl-2,3-d.ioxo-l-piperazinocarbonylchlorid til-dryppedes til opløsningen. This solution was cooled to 0 ° to 5 ° C, and 10 ml of a tetrahydrofuran solution containing 1.2 g of 4-n-pentyl-2,3-d.ioxo-l-to-piperazinocarbonylchlorid added dropwise to the solution. I denne periode opretholdtes pH-værdien af reaktionsblandingen på 7,5 til 8,5 ved gradvis tilsætning af triethylamin. During this period, maintaining the pH of the reaction mixture of 7.5 to 8.5 by gradual addition of triethylamine. Derefter omsattes den dannede blanding ved den nævnte temperatur i 30 minutter og derpå ved 10° til 15°C i 90 minutter, medens pH-værdien holdtes på 7,5 til 8,5» Efter reaktionen afdestilléredes tetrahydrofuranet under reduceret tryk, og remanensen opløstes i 20 ml vand og vaskedes derefter to gange med 20 ml ethylacetat. Then the resulting mixture was reacted at that temperature for 30 minutes and then at 10 ° to 15 ° C for 90 minutes, while the pH was maintained at 7.5 to 8.5 »afdestilléredes After the reaction, the tetrahydrofuran under reduced pressure, and the residue dissolved in 20 ml of water and then washed twice with 20 ml of ethyl acetate. Til det vandige lag sattes yderligere 30 ml ethylacetat, og den dannede blanding indstilledes på en pH-vær-•di på 1,5 ved tilsætning af fortyndet saltsyre under isafkøling. To the aqueous layer was added an additional 30 ml of ethyl acetate, and the resulting mixture was adjusted to a pH-value-• di of 1.5 by addition of dilute hydrochloric acid under ice-cooling. Derefter fraskiltes ethylacetatlaget, som vaskedes grundigt med vand, tørredes over magnesiumsulfat og derefter befriedes for opløsningsmidlet ved destillation under reduceret tryk. Then, the ethyl acetate layer was separated, which was washed well with water, dried over magnesium sulphate and then freed from the solvent by distillation under reduced pressure. Remanensen omkrystalliseredes ved tilsætning af diisopropylether til opnåelse af 1,8 g krystaller af 6- 0>( -)-a-(4-pentyl-2,3-dioxo-l-piper-azinocarbonylamino)phenylacetamidoJ penicillansyre, smp. The residue was crystallized by addition of diisopropyl ether to give 1.8 g of crystals of 6- 0> (-) - a- (4-pentyl-2,3-dioxo-piperidin-l-azinocarbonylamino) phenylacetamidoJ penicillanic acid, mp. 96°C (dekomp.), udbytte 80,5%. 96 ° C (dec.), Yield 80.5%.

IR (KBr) cm-1; IR (KBr) cm-1; ^C=Q i770 (lactam), 1720 - 1660 (-CrøC, -C00H) MR ((CD^SO + D20) T værdier: 2.62 (5H), 4.31 (IH), 4.51 - 4.69 (2H), 6.04 (IH), 6.20 - 6.90 (6H), 8.50 (3H), 8.60 (3H), 8.75 (6H), 8.90 (3H) 86 151338 ^ C = Q i770 (lactam), 1720-1660 (-CrøC, -C00H) MR ((CD ^ SO + D20) T values: 2.62 (5H), 4.31 (IH), 4.51 to 4.69 (2H), 6.04 ( H), 6.20 to 6.90 (6H), 8.50 (3H), 8.60 (3H), 8.75 (6H), 8.90 (3H) 86 151338

Ovennævnte operation gentoges med den ændring, at 4-n-pentyl- 2,3-dioxo-l- piperazinocarbonylchlorid erstattedes med enhver af de i efterfølgende tabel 13 nævnte reaktive derivater af forbindelser med formlen (III) til dannelse af de ligeledes i tabel 13 nævnte slutprodukter. The above operation was repeated with the modification that 4-n-pentyl-2,3-dioxo-L- piperazinocarbonylchlorid was replaced with any of the in the following Table 13 mentioned reactive derivatives of compounds of formula (III) to form the likewise in Table 13 said final products. Strukturen af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of the resulting compounds were confirmed by IR and NMR.

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Med 1,7 g triethylaminsalt af 6-[p(-)-a-amino-p-hydroxyphenyl-acetamidojpenicillansyre og 0,7 g 4-methyl-2,3--dioxo-l-piperazino-carbonylchlorid gentoges fremgangsmåden ifølge eksempel 7 til” dannelse af 1,2 g natriumsalt af 6-jD(-)-a-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetamido] penicillansyre, smp. With 1.7 g of triethylamine salt of 6- [p (-) - alpha-amino-p-hydroxyphenyl-acetamidojpenicillansyre and 0.7 g of 4-methyl-2,3 - dioxo-l-piperazino-carbonyl chloride, was repeated the procedure of Example 7 to "give 1.2 g of the sodium salt of 6-IO N (-) - a- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid, mp. 170-172°C (dekomp.), udbytte 75%. 170-172 ° C (dec.), Yield 75%.

IR (KBr) cm-1: vfø.Q 1760 (lactam), 1710 - 1660 (-COirO, 1600 (-000Θ) fflR ((CD^)2SO) 'X værdier: 2*8 - 3.3 (4H), 4.45 (IH), 4.65 (2H), 6.05 (IH), 6.2 (4H), 6.97 (3H), 8.48 (3H), 8.60 (3Ξ) På samme måde som angivet ovenfor dannedes natriumsaltet af 6-[d(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxy-phenylacetamidojpenicillansyre, smp0 175°C (dekomp.), udbytte 72%, ud fra 4-ethyl-2,3-'dioxo-l-piperazinocarbonylchlorid og et triethylaminsalt af 6-[p(-)-α-amino-p-hydroxyphenylacetamidoj penicillansyre. IR (KBr) cm-1: vfø.Q 1760 (lactam), 1710 to 1660 (-COirO, 1600 (-000Θ) fflR ((CD ^) 2 SO) 'X values: 2 * 8 to 3.3 (4H), 4.45 (IH), 4.65 (2H), 6.05 (IH), 6.2 (4H), 6.97 (3H), 8.48 (3H), 8.60 (3Ξ) In the same manner as set forth above forming the sodium salt of 6- [d (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxy-phenylacetamidojpenicillansyre, smp0 175 ° C (dec.), yield 72%, from 4-ethyl-2,3-'dioxo- L-piperazinocarbonylchlorid and a triethylamine salt of 6- [p (-) - α-amino-p-penicillanic hydroxyphenylacetamidoj.

Eksempel 9 example 9

Til en opløsning af 0,8 g phthalidester af 6-[p(-)-a-aminophenyl-acetamidoj penicillansyre i 10 ml tetrahydrofuran sattes 0,25 ml triethylamin. To a solution of 0.8 g of 6- phthalidester [P (-) - a-aminophenyl acetamidoj-penicillanic acid in 10 ml of tetrahydrofuran was added 0.25 ml of triethylamine. I den dannede blanding dryppedes 0,32 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid med isafkøling, og blandingen omsattes ved stuetemperatur i 2 timer. In the resulting mixture was added dropwise 0.32 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid with ice-cooling, and the mixture was reacted at room temperature for 2 hours. Efter reaktionen afdestilleredes opløsningsmidlet under reduceret tryk. After the reaction, distilled off the solvent under reduced pressure. Remanensen blev opløst i et blandet opløsningsmiddel bestående af 20 ml ethylace-tat og 20 ml vand, og den dannede opløsning indstilledes på pH-værdi af 2 ved tilsætning af fortyndet saltsyre. The residue was dissolved in a mixed solvent consisting of 20 ml of ethyl acetate and 20 ml of water, and the resulting solution was adjusted to pH of 2 by addition of dilute hydrochloric acid. Derefter fra- 89 151338 skiltes det organiske lag, som vaskedes med vand, vaskedes med en 2% vandig natriumhydrogencarbonatopløsning, vaskedes med vand, tørredes over magnesiumsulfat og derefter inddampedes til en væske på 2 ml. Then from- 89 151338 was separated the organic layer, which was washed with water, washed with a 2% aqueous sodium hydrogen carbonate solution, washed with water, dried over magnesium sulfate and then concentrated to a liquid of 2 ml. Til koncentratet sattes 20 ml diisopropylether til udfældning af krystaller, som derefter opsamledes til dannelse af 0,95 g krystaller af phthalidester af 6-[jD (-) -oc- (4-methy 1-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido] penicillansyre, smp. To the concentrate was added 20 ml of diisopropyl ether to precipitate crystals which was then collected to give 0.95 g of crystals of phthalidester of 6- [JD (-) -OC- (4-methyl-1-2.3-dioxo-l-piperazinocarbonylamino ) phenylacetamido] penicillanic acid, mp. 157-l60°C (dekomp.), udbytte 90,0^. 157-l60 ° C (dec.), Yield 90.0 ^.

IR (KBr) cm -'-i V^,_q 1780 (lactam), 1715 (ester), 1680 (-COnC) MR ((01)3)200 + D2O) 71 værdier: 2.12 (4H), 2.40 (IH), 2.58 (5H), 4.25 - 4.60 (3H), 5.45 (IH), 5.85 - 6.42 (4H), 6.90 (3H), 8.50 (6H) IR (KBr) cm -'- of V ^, _ Q 1780 (lactam), 1715 (ester), 1680 (-COnC) MR ((01) 3) 200 + D 2 O) 71 values: 2.12 (4H), 2.40 (IH ), 2.58 (5H), 4.25 to 4.60 (3H), 5.45 (IH), 5.85 to 6.42 (4H), 6.90 (3H), 8.50 (6H)

Ovennævnte operation gentoges med den ændring, at :4-methy 1-2,3-dioxo-1-piperazinocarbonylchlorid erstattedes med hver af de reaktive derivater af forbindelser med formlen (III), som er angivet i tabel 14, til dannelse af de ligeledes i tabel 14 nævnte slutprodukter. The above operation was repeated with the modification that 4-methyl-1-2.3-dioxo-1-piperazinocarbonylchlorid was replaced with each of the reactive derivatives of compounds of formula (III), which is set forth in Table 14, to form the likewise in table 14 above end products. Strukturen af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of the resulting compounds were confirmed by IR and NMR.

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Eksempel 10 example 10

En opløsning af 0,86 g hydrochloric! A solution of 0.86 g of hydrochloric! af methoxymethylester af 6-[d (-)-a-aminophenylac etamido] -penicillansyre i 15 ml tetrahydro-furan indeholdende 20 rumfangsprocent vand, indstilledes på en pH-værdi på 8,0 til 8,5 ved tilsætning af triethylamin ved 0° til 5°C. the methoxymethyl ester of 6- [D (-) - a-aminophenylac etamido] -penicillanic acid in 15 ml of tetrahydrofuran containing 20 volume percent water, adjusted to a pH of 8.0 to 8.5 by addition of triethylamine at 0 ° to 5 ° C. Til denne opløsning dryppedes en opløsning af 0,38 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid i 10 ml tetrahydro-furan i løbet af 10 minutter. To this solution was added dropwise a solution of 0.38 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid in 10 ml of tetrahydrofuran over 10 minutes. I denne periode opretholdtes reaktionsblandingens pH-værdi på 7,5 til 8,0 ved gradvis tilsætning af triethylamin. During this period, maintaining the reaction mixture pH of 7.5 to 8.0 by gradual addition of triethylamine. Den dannede blandede opløsning omsattes i 30 minutter, medens pH-værdien opretholdtes til 7,5 til 8,0. The resulting mixed solution was reacted for 30 minutes while the pH was maintained at 7.5 to 8.0. Efter reaktionens afslutning fjernedes tétrahydrofuranet ved destillation under reduceret tryk. After completion of the reaction the tetrahydrofuran was removed by distillation under reduced pressure. Remanensen opløstes i et blandet opløsningsmiddel indeholdende 50 ml vand og 50 ml ethylacetat, og den dannede opløsning indstilledes på en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre under isafkøling. The residue was dissolved in a mixed solvent containing 50 ml of water and 50 ml of ethyl acetate, and the resulting solution was adjusted to a pH of 1.5 by addition of dilute hydrochloric acid under ice-cooling. Derefter fraskiltes det organiske lag, som vaskedes med vand, tørredes over vandfrit magnesiumsulfat og derefter befriedes for opløsningsmidlet ved destillation under reduceret tryk til dannelse af krystaller. Then, the organic layer was separated, which was washed with water, dried over anhydrous magnesium sulfate, and then freed from the solvent by distillation under reduced pressure to give crystals.

De således dannede krystaller vaskedes med diethylether til dannelse af 0,9 g methoxymethylester af 6-{p(-)-a-(4-methyl-2,3-dioxo-1-piperazinocarbonylamino)-phenylacetamido]penicillansyre, smp. The crystals thus formed were washed with diethyl ether to give 0.9 g of the methoxymethyl ester 6- {p (-) - a- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] penicillanic acid, mp.

111-115°C (dekomp.), udbytte 82,5%. 111-115 ° C (dec.), Yield 82.5%.

IR (KBr) cm-1; IR (KBr) cm-1; vfø_Q 1780 (lactam), 1740 (ester), 1700 - 1660 '(-CONCC) NMR ((CDj )200) 'Z værdi: 0.15 (IH), 2.0 (IH), 2.67 (5H), 4.3 - 4.5 (3H), 4.75 (2H), 5.7 (IH), 6.55 (4H), 6.97 (3H), 7.25 (3H), 8.84 (3H), 8.60 (3H) 92 1 5 1 3 3 8 vfø_Q 1780 (lactam), 1740 (ester), 1700-1660 '(-CONCC) NMR ((CDJ) 200), Z value: 0.15 (IH), 2.0 (IH), 2.67 (5H), 4.3 to 4.5 (3H ), 4.75 (2H), 5.7 (IH), 6.55 (4H), 6.97 (3H), 7.25 (3H), 8.84 (3H), 8.60 (3H) 92 1 5 1 3 3 8

Ovennævnte operation gentoges med den ændring, at 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid erstattedes med hver af de i tabel 15 viste reaktive derivater af forbindelserne med formlen (III) til dannelse af de ligeledes.i tabel 15 viste slutproduk ter. The above operation was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid was replaced with each of the 15 shown in Table reactive derivatives of the compounds of formula (III) to form the ligeledes.i Table 15 showed the final product ter. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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Eksempel li « 151338 Example li '151 338

Med 1,5 g hydrochlorid af pivaloyloxymetiiylester af 6-[l)(-)-a-aminophenylacetamido] -penicillansyre og 0,6 g 4-methyl-2,3-dioxo-1-piperazinocarbonylchlorid gentoges fremgangsmåden ifølge eksempel 10 til dannelse af en pivaloyloxymetiiylester af 6-[d(-)-oc-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoJ penicillansyre, smp. With 1.5 g of hydrochloride of pivaloyloxymetiiylester of 6- [l) (-) - alpha-aminophenylacetamido] -penicillanic acid and 0.6 g of 4-methyl-2,3-dioxo-1-piperazinocarbonylchlorid was repeated the procedure of Example 10 to give one pivaloyloxymetiiylester of 6- [d (-) - oc- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoJ penicillanic acid, mp. 108-111°C (dekomp.), udbytte 75%. 108-111 ° C (dec.), Yield 75%.

t IR (KBr) cm"!-: Vc-0 ^780 (lactam), 1750 (ester), T IR (KBr) cm "! -: Vc-0 ^ 780 (lactam), 1750 (ester),

1710 - 1660 (-CORO 1710 - 1660 (-CORO

Ovennævnte fremgangsmåde gentoges med den ændring, at 4-methyl- 2,3-dioxo-l-piperazinocarbonylchloridet erstattedes med hver af de reaktive derivater af forbindelser med formlen (III) vist i tabel 16, til dannelse af de respektive forbindelser, som er vist i tabel 16. Strukturen af hver forbindelse blev bekræftet ved IR og NMR. The above procedure was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchloridet was replaced with each of the reactive derivatives of compounds of formula (III) shown in Table 16, to give the respective compounds shown in table 16. the structure of each compound was confirmed by IR and NMR.

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Eksempel 12 97 15.1338 Example 12 97 15.1338

Med 0,81 g hydrochlorid af β-piperidinoethylester af 6-[ρ(-)-α-aminophenylacetamidojpenicillansyre og 0,3 g 4-methyl-2,3-dioxo-1-piperazinocarbonylchlorid, gentoges fremgangsmåden ifølge eksempel 10 til dannelse af 0,75 g β-piperidinoethylester af 6-[p(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidojpeni-cillansyre, smp. With 0.81 g of hydrochloride of β-piperidinoethylester of 6- [ρ (-) - α-aminophenylacetamidojpenicillansyre and 0.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonylchlorid, was repeated the procedure of Example 10 to give 0 , 75 g of β-piperidinoethylester of 6- [p (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidojpeni-cillansyre, mp. l66-l69°C (dekomp.), udbytte 78%. L66-L69 ° C (dec.), yield 78%.

IR (KBr) cm"l; Vq_q· 1780 (lactam), 1740 (ester), IR (KBr) cm "l; Vq_q · 1780 (lactam), 1740 (ester),

1710 - 1670 (-C0nO 1710 - 1670 (-C0nO

HMR (CDCl·^) X værdier: 2.7 (5H), 4.5 - 4.6 (3H), 5-7 (IH), 5.75 (2H), 6.0 (2H), 6.4 (2H), 6.9 (3H), 7.45 (2H), 7.6 (4H), 8.5 (12H) HMR (CDCl · ^) X values: 2.7 (5H), 4.5 to 4.6 (3H), 5-7 (IH), 5.75 (2H), 6.0 (2H), 6.4 (2H), 6.9 (3H), 7.45 ( 2H), 7.6 (4H), 8.5 (12H)

Ovennævnte fremgangsmåde gentoges med den ændring, at 4-methyl- 2.3- dioxo-l-piperazinocarbonylchloridet erstattedes med 4-n-octyl- 2.3- dioxo-l-piperazinocarbonylchlorid til dannelse af β-piperidino-ethylester af 6-[b(-)-a-(4-n-octyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenylacetamido]penicillansyre, smp. The above procedure was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchloridet was replaced with 4-n-octyl-2,3-dioxo-l-piperazinocarbonylchlorid to form β-piperidino-ethyl ester of 6- [B (-) -a- (4-n-octyl-2,3-dioxo-l-piperazinocarbonyl-amino) phenylacetamido] penicillanic acid, mp. 110-115°C (dekomp.), udbytte 73,58%. 110-115 ° C (dec.), Yield 73.58%.

Eksempel 13 example 13

Med 0,93 g hydrochlorid af β-morpholinoethylester af 6-[p(-)~a-amino-phenylacetamido]-penicillansyre og 0,39 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid gentoges samme fremgangsmåde som i eksempel 10 til dannelse af 0,8 g β-morpholinoethylester af 6-{p(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoJ-penicillansyre, smp. With 0.93 g of hydrochloride of β-morpholinoethyl ester of 6- [p (-) ~ a-amino-phenylacetamido] -penicillanic acid and 0.39 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid was repeated the same procedure as in example 10 to yield 0.8 g of β-morpholinoethyl ester of 6- {p (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoJ-penicillanic acid, mp. 150-153°C (dekomp.), udbytte 73%. 150-153 ° C (dec.), Yield 73%.

98 151338“- IR (KBr) cm-1: ^q~q 1780 (lactam), 1740 (ester), 98 151338 "- IR (KBr) cm -1: q ^ q ~ 1780 (lactam), 1740 (ester),

1710 - 1680 (-COtfO 1710 - 1680 (-COtfO

MMR (CDCI3) X værdier; MMR (CDCl 3) X values; 2.55 (5H), 4.5 - 4.55 (3H), 5.6 (IH), 5.7 (3H), 6.0 (2H), 6.3 (2H), 7.4 (2H), 7.5 (4Ξ), 8.5 (6H) 2.55 (5H), 4.5 to 4.55 (3H), 5.6 (IH), 5.7 (3H), 6.0 (2H), 6.3 (2H), 7.4 (2H), 7.5 (4Ξ), 8.5 (6H)

Ovennævnte fremgangsmåde gentoges med den ændring, at 4-methyl-2,3-dioxo-l-piperazinocarbonylchloridet erstattedes med 4-n-octyl- 2,3-dioxo-l-piperazinocarbonylchlorid til dannelse af β-morpholino-ethylester af 6- [D(-)-a -(4-n-octyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenylacetamidojpenicillansyre, smp. The above procedure was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchloridet was replaced with 4-n-octyl-2,3-dioxo-l-piperazinocarbonylchlorid to form the β-morpholino-ethyl ester of 6- [ D (-) - a - (4-n-octyl-2,3-dioxo-l-piperazinocarbonyl-amino) phenylacetamidojpenicillansyre, mp. 103-105°C (dekomp.), udbytte 70%. 103-105 ° C (dec.), Yield 70%.

Eksempel 14 <D - - # λ Example 14 <D - - # λ

Til en opløsning af 8,7 g natriumsalt af D(-)-a-phenylglycin i 50 ml vand sattes 50 ml ethylacetat og 5,05 g triethylamin. To a solution of 8.7 g of sodium salt of D (-) - a-phenylglycine in 50 ml of water was added 50 ml of ethyl acetate and 5.05 g of triethylamine. Til den dannede blanding sattes gradvis 9,5 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid ved 0° til 5°C i løbet af 15 minutter, hvorefter blandingen omsattes ved 5° til 15°C i 30 minutter. To the resulting mixture was gradually added 9.5 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid at 0 ° to 5 ° C over 15 minutes, after which the mixture was reacted at 5 ° to 15 ° C for 30 minutes. Efter reaktionen fraskiltes det vandige lag, som vaskedes med diethylether, og derefter indstilledes pH-værdien på 1,5 ved tilsætning af fortyndet saltsyre til udfældning af krystaller. After the reaction, the aqueous layer was separated, which was washed with diethyl ether, and then adjusted pH to 1.5 by addition of dilute hydrochloric acid to precipitate crystals. De udfældede kry-- staller opsamledes ved filtrering,', vaskedes med vand og tørredes til dannelse af 14,1 g D(-)-oc-(4-methyl-2,3-dioxo-l-piperazino-carbonylamino)phenyleddikesyre, smp. The precipitated kry-- crystals were collected by filtration, 'washed with water and dried to give 14.1 g of D (-) - oc- (4-methyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetic acid, mp. 138-14l°C (dekomp.), udbytte 87%. 138-14l ° C (dec.), Yield 87%. Omkrystallisationen af vandigt butanol gav hvide krystaller, smp. The recrystallization from aqueous butanol gave white crystals, mp. 14o-142°C (dekomp.). 14o-142 ° C (dec.).

99' 151338 99 '151338

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Beregnet - : {<?») C: 52.01 H: 5.30 Ή: 13.00 Fundet- (<fo) C: 52.24 H: 5-32 N: 12.87 IR (KBr) cm-1: Vq=q 1710, 1700, 1660 . Calculated -: {<? ') C: 52.01 H: 5.30 Ή: 13.00 Fundet- (<fo) C: 52.24 H: 5-32 N: 12.87 IR (KBr) cm-1: V q = Q 1710, 1700, 1660 .

(2) I en opløsning af 10 g af ovennævnte D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre i 200 ml acetone dryppedes en opløsning af 5,2 g natriumsalt af 2-ethylhexansyre i 50 ml acetone med omrøring til udfældning af krystaller. (2) In a solution of 10 g of the above D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid in 200 ml of acetone was added dropwise a solution of 5.2 g of sodium salt of 2- ethylhexanoic acid in 50 ml of acetone with stirring to precipitate crystals. De udfældede krystaller opsamledes ved filtrering og vaskedes derefter med acetone til dannelse af 9,6 g natriumsalt af D(-)-a-(4-methyl- 2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre, smp. The precipitated crystals were collected by filtration and then washed with acetone to give 9.6 g of sodium salt of D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid, mp. 165°C (dekomp.), udbytte 95%· (3) Til en suspension af 8,8 g af ovennævnte natriumsalt af D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre i 80 ml methylenchlorid sattes 20 mg N-methylmorpholin. 165 ° C (dec.), Yield 95% · (3) To a suspension of 8.8 g of the above sodium salt of D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid in 80 ml of methylene chloride was added 20 mg of N-methylmorpholine. Til den dannede blanding dryppedes en opløsning af 3,1 g ethylchlorcarbo-nat i 20 ml methylenchlorid ved -r20° til -HL5°C i løbet af 5 minutter, og blandingen omsattes ved den nævnte temperatur i en time. To the resulting mixture was added dropwise a solution of 3.1 g ethylchlorcarbo-night in 20 ml of methylene chloride at -R20 ° to -HL5 ° C over 5 minutes and the mixture was reacted at that temperature for one hour.

Til denne reaktionsvæske dryppedes en opløsning af 9,4 g af et triethylaminsalt af 6-aminopenicillansyre i 40 ml methylenchlorid ved -r40° til -i-30oC i løbet af 10 minutter, og den dannede blanding omsattes ved -f40° til -r20°C i løbet af en time. To this reaction liquid was added dropwise a solution of 9.4 g of a triethylamine salt of 6-aminopenicillanic acid in 40 ml of methylene chloride at -r40 ° to -i-30 ° C over 10 minutes and the resulting mixture was reacted at -f40 ° to -R 20 ° C over one hour. Efter reaktionen blev temperaturen af reaktionsvæsken gradvis hævet til 0°C i løbet af en time, og blandingen underkastedes ekstraktion med 100 ml vand. After the reaction, the temperature of the reaction liquid was gradually raised to 0 ° C over one hour and the mixture was subjected to extraction with 100 ml of water. Derefter fraskiltes det vandige lag, og methylen-chloridlaget underkastedes yderligere ekstraktion med 50 ml vand, og det dannede vandige lag forenedes med det ovennævnte vandige lag. Then, the aqueous layer was separated, and the methylene chloride layer was further subjected to extraction with 50 ml of water and the resulting aqueous layer was combined with the above aqueous layer. De forenede vandige lag indstilledes på en pH-værdi på 2 ved tilsætning af fortyndet saltsyre under isafkøling til udfældning af krystaller. The combined aqueous layer was adjusted to a pH value of 2 by addition of dilute hydrochloric acid under ice-cooling to precipitate crystals. De udfældede krystaller opsameldes ved filtrering, vaskedes grundigt med vand, tørredes og opløstes derefter i 200 ml acetone. The precipitated crystals opsameldes by filtration, washed well with water, dried and then dissolved in 200 ml of acetone. Til den dannede opløsning dryppedes en opløsning af 4 g natriumsalt af 2-ethylhexansyre i 40 ml acetone i løbet af 10 minutter til udfældning af krystaller. To the resulting solution was added dropwise a solution of 4 g of sodium salt of 2-ethylhexanoic acid in 40 ml of acetone over 10 minutes to precipitate crystals. De udfældede loo 151338 krystaller opsamledes ved filtrering, vaskedes med acetone og tørredes derefter til dannelse af 11,4 g natriumsalt af 6—Qd(—)— (4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoj peni-cillansyre, smp. The precipitated loo 151 338 crystals were collected by filtration, washed with acetone and then dried to give 11.4 g of the sodium salt of 6-Q d (-) - (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoj peni-cillansyre mp. 170°C (dekomp.), udbytte 80,8%. 170 ° C (dec.), Yield 80.8%.

Ovennævnte operation blev gentaget med den ændring, at (4-methy1-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyren erstattedes med de i tabel 17 angivne forbindelser med formlen (V) til dannelse af de ligeledes i tabel 17 viste slutprodukter. The above operation was repeated with the modification that (4-methy1-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with those in Table 17 indicated compounds of formula (V) to form the likewise shown in Table 17. final products. Strukturen af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of the resulting compounds were confirmed by IR and NMR.

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Eksempel 15 102 151338 (1) Til en opløsning af 2,28 g D(-)-a-amino-l,4-cyclohexadienyl-eddikesyre i 15 ml N NaOH sattes 20 ml ethylacetat og 2,1 ml tri-ethylamin, og den dannede blanding afkøledes til 0°C. Example 15 102 151338 (1) To a solution of 2.28 g of D (-) - a-amino-l, 4-cyclohexadienyl-acetic acid in 15 mL of N NaOH was added 20 ml of ethyl acetate and 2.1 ml of triethylamine, and the resulting mixture was cooled to 0 ° C. Til denne blanding sattes gradvis 1,69 g 4-methyl-2,3-dioxo-l-piperazino~ carbonylchlorid i løbet af 10 minutter. To this mixture was gradually added 1.69 g of 4-methyl-2,3-dioxo-l-piperazino ~ carbonyl chloride in 10 minutes. Derefter omsattes blandingen i 30 minutter under isafkøling, og det vandige lag fraskiltes. Then, the mixture was reacted for 30 minutes under ice-cooling, and the aqueous layer was separated. Til det vandige lag sattes yderligere 20 ml ethylacetat. To the aqueous layer was added another 20 ml of ethyl acetate. Den dannede blanding indstilledes på en pH-værdi på 2 ved tilsætning af 2N saltsyre under isafkøling, og ethylacetatlaget fraskiltes. The resulting mixture was adjusted to a pH value of 2 by addition of 2N hydrochloric acid under ice-cooling, and the ethyl acetate layer was separated. Det organiske lag vaskedes grundigt med vand, tørredes over vandfrit magnesiumsulfat, befriedes for opløsningsmiddel ved destillation under reduceret tryk og indførtes derefter i isopropanol til udfældning af krystaller. The organic layer is washed well with water, dried over anhydrous magnesium sulfate, freed from the solvent by distillation under reduced pressure and was then introduced in isopropanol to precipitate crystals. De udfældede krystaller opsamledes ved filtrering til dannelse af 2,5 g hvide krystaller af D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-l,4-cyclohexadienyl-eddikesyre, smp. The precipitated crystals were collected by filtration to give 2.5 g of white crystals of D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -l, 4-cyclohexadienyl-acetic acid, mp. 140-145°C (dekomp.), udbytte lk%. 140-145 ° C (dec.), Yield lk%.

IR (KBr) cm”1: 3300, ^Q=0 1715, 1660 MR (dg-DMSO) Z værdiers 0.57 (IH, d), 4.26 (IH, s), 4.36 (2H, s), 5.29 (IH, d), 6.07 - 6.18 (2H, m), 6.38 - 6.49 (2H, m), 7.05 (3H, s), 7.35 (4H, s) (2) Til en suspension af 0,45 g af ovennævnte D(-)-cc-(4-methyl- 2,3-dioxo-l-piperazinocarbonylamino) -1,4-cyclohexadienyleddikesyre i 15 ml vandfrit methylenchlorid sattes 0,24 ml N-methyl-morpho-lin under omrøring til dannelse af en opløsning. IR (KBr) cm "1: 3300, ^ Q = 0 1715, 1660 MR (d₆-DMSO) Z values ​​0.57 (IH, d), 4.26 (IH, s), 4.36 (2H, s), 5.29 (H, d), 6.07 to 6.18 (2H, m), 6.38 to 6.49 (2H, m), 7.05 (3H, s), 7.35 (4H, s) (2) To a suspension of 0.45 g of the above d (- ) -CC- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -1,4-cyclohexadienyleddikesyre in 15 ml of anhydrous methylene chloride was added 0.24 ml of N-methyl-morpholine with stirring to form a solution. Efter afkøling af opløsningen til -HL0°C tildryppedes 3 ml af en vandfri methylen-chloridopløsning indeholdende 0,4 g ethylchlorcarbonat, og den dannede blanding omsattes ved den nævnte temperatur i 90 minutter. After cooling the solution to -HL0 ° C was added dropwise 3 ml of an anhydrous methylene chloride solution containing 0.4 g of ethyl chlorocarbonate, and the resulting mixture was reacted at that temperature for 90 minutes. Derefter afkøledes reaktionsvæsken til t20°C, og 5 ml af en methy- 103 1 5 1 3 38 lenchloridopløsning indeholdende 0,70 g triethylaminsalt af 6-aminopenicillansyre og 0,31 ml triethylamin dryppedes gradvis i reaktionsvæsken. Then the cooled reaction liquid to t20 ° C and 5 ml of a methylene 103 1 5 1 3 38 chloride solution containing 0.70 g of triethylamine salt of 6-aminopenicillanic acid and 0.31 ml of triethylamine was dropped gradually in the reaction liquid. Den dannede blanding omsattes ved +20°C i en time, ved -^20° til 0°C i en time og ved 0° til 5°C i en time. The resulting mixture was reacted at 20 ° C for one hour, at - ^ 20 ° to 0 ° C for one hour and at 0 ° to 5 ° C for one hour. Derefter befriedes reaktionsvæsken for opløsningsmidlet ved destillation under reduceret tryk. Then freed the reaction liquid from the solvent by distillation under reduced pressure. Remanensen opløstes i 10 ml vand og vaskedes derefter med 10 ml ethylacetat. The residue was dissolved in 10 ml of water and then washed with 10 ml of ethyl acetate. Det vandige lag indførtes atter i 15 ml ethylacetat, og blandingen indstilledes på en pH-værdi på 2,0 ved tilsætning af 2N HC1 under isafkøling. The aqueous layer was introduced again in 15 ml of ethyl acetate, and the mixture was adjusted to a pH of 2.0 by addition of 2N HC1 under ice cooling. Derefter fraskiltes ethylacetatlaget, som vaskedes med vand, tørredes over vandfrit magnesiumsulfat og befriedes for opløsningsmidlet ved destillation under reduceret tryk til dannelse af 0,74 g hvide krystaller af 6- [d (-) -oc- (4-methyl-2,3-dioxo-l-piperazinocarbonyl-amino)-1,4-cyclohexadienylacetamidcTjpenicillansyre, smp. Then, the ethyl acetate layer was separated, which was washed with water, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure to give 0.74 g of white crystals of 6- [D (-) -OC- (4-methyl-2,3 dioxo-l-piperazinocarbonyl-amino) -1,4-cyclohexadienylacetamidcTjpenicillansyre, mp. 84-87°C (dekomp.), udbytte 87%. 84-87 ° C (dec.), Yield 87%.

UMR (dg-DMSO) X værdier: 0.55 (IH, d), 0.95 (IH, d), 4.22 (IH, s), 4.35 (2H, s), 4.'41 - 4.61 (2H, s), 4.92 (IH, d), 5.75 (IH, s), 6.05 (2H, bs), 6.40 (2H, bs), 7.03 (3H, s), 7.35 (4H, s), 8.40 (3H, s), 8.52 (3H, s) UMR (d₆-DMSO) X values: 0.55 (IH, d), 0.95 (IH, d), 4.22 (IH, s), 4.35 (2H, s), 4.'41 - 4.61 (2H, s), 4.92 (IH, d), 5.75 (IH, s), 6.05 (2H, bs), 6.40 (2H, bs), 7.03 (3H, s), 7.35 (4H, s), 8.40 (3H, s), 8.52 ( 3H, s)

Det således dannede produkt indstilledes på en pH-værdi på 7,0 ved neutralisation med vandig natriumhydrogencarbonatopløsning og underkastedes derefter en filtrering og frysetørring til dannelse af natriumsaltet deraf. The product thus formed was adjusted to a pH of 7.0 by neutralization with aqueous sodium bicarbonate solution and was then subjected to a filtering and freeze-drying to form the sodium salt thereof.

Den ovennævnte operation blev gentaget med den ændring, at D(-)-oc- (4-me thyl-2,3-dioxo-l-piperazinocarbonylamino) -1,4-cyclohexa-dienyleddikesyre blev erstattet med hver af de i tabel 18 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 18 viste slutprodukter. The above operation was repeated with the modification that the D (-) - oc- (4-me thyl-2,3-dioxo-l-piperazinocarbonylamino) -1,4-cyclohexane-dienyleddikesyre was replaced with each of the in Table 18 yielded compounds of formula (V) to form the likewise in table 18 showed the final products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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Eksempel 16 105 151338 (1) Til en opløsning af 2,2 g DL-oc-amino-2-thieny 1 eddikesyre i 14 ml N natriumhydroxidopløsning sattes ved 0°C 2,2 g triethylamin. Example 16 105 151338 (1) To a solution of 2.2 g of DL-.alpha.-amino-2-thienyl 1 acetic acid in 14 ml of N sodium hydroxide solution was added at 0 ° C 2.2 g of triethylamine.

Til den dannede blanding sattes yderligere 3,6 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid lidt efter lidt ved nævnte temperatur. To the resulting mixture was further added 3.6 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid gradually at said temperature. Derefter omsattes blandingen ved 0°C i 30 minutter og derpå ved stuetemperatur i 30 minutter. Then, the mixture was reacted at 0 ° C for 30 minutes and then at room temperature for 30 minutes. Efter reaktionen indstilledes reaktionsvæsken på en pH-værdi på 1,0 ved tilsætning af fortyndet saltsyre til udfældning af krystaller. After the reaction, the reaction liquid was adjusted to a pH value of 1.0 by addition of dilute hydrochloric acid to precipitate crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes med vand og tørredes derefter til dannelse af 3,5 g DL-a-(4-methyl-2,3-dioxo-l~piperazino-carbonylamino)-2-thienyleddikesyre, smp. The precipitated crystals were collected by filtration, washed with water and then dried to give 3.5 g of DL-a- (4-methyl-2,3-dioxo-l ~ piperazino-carbonylamino) -2-thienylacetic acid, mp. 2l4-215°C (dekomp.), udbytte 80,5#!· IR (KBr) cm"1: \^c=0 ^10^ ^80 " (2) I en opløsning af 3,5 g af ovennævnte DL-oc-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-2-thienyleddikesyre i 100 ml acetone dryppedes en opløsning af 1,86 g natriumsalt af 2-ethylhexansyre i 50 ml acetone, hvorefter krystallerne udfældedes. 2l4-215 ° C (dec.), Yield 80.5 #! · IR (KBr) cm "1: \ ^ C = 0 ^ 10 ^ 80 ^" (2) In a solution of 3.5 g of the above-mentioned DL -OC- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -2-thienylacetic acid in 100 ml of acetone was added dropwise a solution of 1.86 g of sodium salt of 2-ethylhexanoic acid in 50 ml of acetone, and the crystals precipitated. De udfældede krystaller opsamledes ved filtrering og vaskedes derefter med a-cetone til dannelse af 3,5 g natriumsalt af DL-oc-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-2-thienyleddikesyre, smp. The precipitated crystals were collected by filtration and then washed with alpha-cetone to give 3.5 g of the sodium salt of DL-octyl (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -2-thienylacetic acid, mp. 175-176°C (dekomp.) (3) Til en suspension af 3,3 g af. 175-176 ° C (decomp.) (3) To a suspension of 3.3 g of. ovennævnte natriumsalt af DL-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-2-thienyleddike-syre i 50 ml methylenchlorid sattes 30 mg N-methylmorpholin, og den dannede blanding afkøledes til -ί-20ο til -HL5°C. the above sodium salt of DL-a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -2-thienyleddike acid in 50 ml of methylene chloride was added 30 mg of N-methylmorpholine, and the resulting mixture was cooled to-20ο to -ί -HL5 ° C. Til den dannede blanding dryppedes en opløsning af 1,3 g ethylchlorcarbonat i 20 ml methylenchlorid i løbet af 5 minutter, og blandingen om-rørtes ved den nævnte temperatur i 90 minutter. To the resulting mixture was added dropwise a solution of 1.3 g of ethyl chlorocarbonate in 20 ml of methylene chloride over 5 minutes and the mixture re-touched at said temperature for 90 minutes. Derefter dryppedes en opløsning af 3,3 g triethylaminsalt af 6-aminopenicillansyre i 50 ml methylenchlorid i blandingen ved -r50° til -r40°C i løbet af 20 minutter, og den dannede blanding omsattes under omrøring ved -f40° til -r30°C i 30 minutter, ved -^30° til -r-20°C i 30 minutter 106 1 5 1 3 3 8 og derefter ved τ·20° til 0°C i 30 minutter. Then added dropwise a solution of 3.3 g of triethylamine salt of 6-aminopenicillanic acid in 50 ml of methylene chloride in the mixture by -R 50 ° to -r40 ° C over 20 minutes and the resulting mixture was reacted with stirring at -f40 ° to -R 30 ° C for 30 minutes, at - ^ 30 ° for s-20 ° C for 30 minutes 106 1 5 1 3 3 8 and subsequently by τ · 20 ° to 0 ° C for 30 minutes. Efter reaktionen af-destilleredes opløsningsmidlet under reduceret tryk, og remanensen opløstes i vand. After the reaction, by-the solvent was distilled under reduced pressure and the residue was dissolved in water. Den dannede vandige opløsning indstilledes på en pH-værdi på 2,0 ved tilsætning af fortyndet saltsyre under isafkøling til udfældning af krystaller. The resulting aqueous solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid under ice-cooling to precipitate crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes grundigt med vand og tørredes derefter til opnåelse af 4,1 g 6-jj)La-(4-methyl-2,3-dioxo-l-pi-perazinocarbonylamino)-2-thienylacetamidoj penicillansyre, smp. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to obtain 4.1 g of 6-JJ) La- (4-methyl-2,3-dioxo-l-pi-perazinocarbonylamino) -2-thienylacetamidoj penicillanic acid, mp.

185°C (dekomp.), udbytte 80,5%. 185 ° C (dec.), Yield 80.5%.

IR (nujol) cm-1: Vc=0 1780 (lactam), 1715 (-C00H), 1685 - 1675 (-C0NO MR ((CD3) 2CO) T værdier: 0.5 (IH), 1.8 (IH), 2.6 (IH), 2.85 - 3.05 (2H), 4.0 (IH), 4.2 - 4.5 (2H), 5.7 (IH), 5.8 - 6.0 (2H), 6.2 - 6.4 (2H), 6.95 (3H), 8.4 (3H), 8.45 (3H) IR (nujol) cm-1:? C = 0 1780 (lactam), 1715 (-C00H), 1685-1675 (-C0NO MR ((CD 3) 2 CO) T values: 0.5 (IH), 1.8 (IH), 2.6 ( H), 2.85 to 3.05 (2H), 4.0 (IH), 4.2 to 4.5 (2H), 5.7 (IH), 5.8 to 6.0 (2H), 6.2 to 6.4 (2H), 6.95 (3H), 8.4 (3H) , 8.45 (3H)

Det således dannede produkt indstilledes på en pH-værdi på 7,0 ved neutralisation med en vandig natriumhydrogencarbonatopløs-ning og filtreredes derefter og frysetørredes til opnåelse af natriumsaltet deraf. The product thus formed was adjusted to a pH of 7.0 by neutralization with an aqueous sodium bicarbonate solution, filtered and then freeze dried to give the sodium salt thereof.

Ovennævnte operation gentoges med den ændring, at natriumsaltet af DL-oc- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -2-thienyleddi-kesyre erstattedes med hver af de i tabel 19 nævnte forbindelser med formlen (V) til dannelse af de ligeledes i tabel 19 viste slutprodukter. The above operation was repeated with the modification that the sodium salt of DL-octyl (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -2-thienyleddi-acetic acid was replaced with each of the table 19 in the said compounds of formula (V) to form the likewise in table 19 showed the final products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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Eksempel 17 108 151338 Example 17 108 151338

Til en suspension af 0,9 g 6- [d(-)-ct-aminophenylacetamidoj peni-cillansyre i 30 ml vandfrit ethylacetat sattes ved 5° til 10°C 0,55 g triethylamin og 0,6 g trimethylsilylchlorid. To a suspension of 0.9 g of 6- [D (-) - ct-aminophenylacetamidoj peni-cillansyre in 30 ml of anhydrous ethyl acetate was added at 5 ° to 10 ° C 0.55 g triethylamine and 0.6 g of trimethylsilyl chloride. Den dannede blanding omsattes ved 15° til 20°C i 3 timer til dannelse af tri-methylsilyleret 6-|jD( - )-a-aminophenylacet amidojpenicillansyre. The resulting mixture was reacted at 15 ° to 20 ° C for 3 hours to form the tri-methylsilyleret 6- | IO N (-) -a-aminophenylacet amidojpenicillansyre.

Til denne syre sattes derpå 1 g 4-ethyl-2,3-dioxo-l-piperazino-carbonylchlorid, og den dannede blanding omsattes ved 15° til 20°C i 2 timer. To this acid was then added 1 g of 4-ethyl-2,3-dioxo-l-piperazino-carbonyl chloride, and the resulting mixture was reacted at 15 ° to 20 ° C for 2 hours. Efter reaktionen udskiltes et bundfald af triethyl-amin-hydrochlorid ved filtrering, og filtratet indførtes i 0,4 g n-butanol til udfældning af krystaller. After the reaction, separated a precipitate of triethyl amine hydrochloride by filtration, and the filtrate was introduced into 0.4 g of n-butanol to precipitate crystals. De udfældede krystaller opsamledes ved filtrering til dannelse af 1,25 g hvide krystaller r* af 6-|D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenyl-acetamidojpenicillansyre. The precipitated crystals were collected by filtration to give 1.25 g of white crystals of 6- r * | D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetamidojpenicillansyre. I en opløsning af de nævnte krystaller i 30 ml tetrahydrofuran dryppedes en opløsning af 0,38 g af natriumsaltet af 2-ethylhexansyre i 10 ml tetrahydrofuran, hvorefter hvide krystaller blev udfældet. In a solution of the said crystals in 30 ml of tetrahydrofuran was added dropwise a solution of 0.38 g of the sodium salt of 2-ethylhexanoic acid in 10 ml of tetrahydrofuran, after which white crystals were precipitated. De udfældede krystaller opsamledes ved filtrering, vaskedes grundigt med tetrahydrofuran og tørredes derefter til opnåelse af 1,25 g natriumsalt af 6-[p(-)-oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino )phenylacetamidoJ penicillansyre, smp. The precipitated crystals were collected by filtration, washed thoroughly with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6- [p (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoJ penicillanic mp. 183-185°C (dekomp·), udbytte 90%. 183-185 ° C (dec ·), yield 90%.

Eksempel 18 example 18

Til en suspension af 4 g trihydrat af 6-[i)(-)-a-aminophenylaceta-midoj penicillansyre i 40 ml vand sattes 20 ml ethylacetat, og den dannede blanding afkøles til 2°C. To a suspension of 4 g of trihydrate of 6- [i) (-) - a-aminophenylaceta midoj-penicillanic acid in 40 ml of water was added 20 ml of ethyl acetate, and the resulting mixture is cooled to 2 ° C. Derefter forenedes blandingen ned 1,37 g kaliumcarbonat, og der omrørtes ved 2° til 3°C i 2 minutter. Then, the mixture was combined into 1.37 g of potassium carbonate and stirred at 2 ° to 3 ° C for 2 minutes. Derefter sattes 1,89 g 4-methyl-2,3-dioxo-l-piperazinocar-bonylchlorid til blandingen ved den nævnte temperatur i løbet af 10 minutter, og den dannede blanding omsattes ved den nævnte temperatur i 15 minutter. Then was added 1.89 g of 4-methyl-2,3-dioxo-l-piperazinocar-bonylchlorid to the mixture at said temperature over 10 minutes and the resulting mixture was reacted at that temperature for 15 minutes. Efter reaktionen udskiltet små mængder uopløseligt stof ved filtrering, og filtratet indførtes i 80 ml ethylacetat. After the reaction, udskiltet small amounts of insoluble matter by filtration, and the filtrate was introduced into 80 ml of ethyl acetate. I den dannede blanding dryppedes 5 ml 2N saltsyre ved 20° til 22°C i løbet af 5 minutter, og blandingen omrørtes ved den nævnte temperatur i 5 timer til udfældning af krystaller. In the resulting mixture was added dropwise 5 ml of 2N hydrochloric acid at 20 ° to 22 ° C over 5 minutes and the mixture was stirred at said temperature for 5 hours to precipitate crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes to gange 109 151338 med 4 ml vand, vaskedes yderligere to gange med 4 ml isopropanol og tørredes derefter til opnåelse af 4,0 g dihydrat af 6-{jD(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoj penicillansyre, smp. The precipitated crystals were collected by filtration, washed twice with 109 151338 4 ml of water, washed twice more with 4 ml of isopropanol and then dried to obtain 4.0 g of dihydrate of 6- {IO N (-) - a- (4- methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoj penicillanic acid, mp. 156-157°C (dekomp.), udbytte 75,4%· IR (KBr) cm-lj JQ=Q 1775, 1740, 1695, 1670 MR (ds-DMSO) T værdier: 0.18 (IH, d), 0.77 (IH, d), 2.66 (5H, s), 4.30 (IH, d), 4.40 (3H, br), 4-48 (IH, g), 4.65 (IH, d), 5.80 (IH, s), 6.12 (2H, bs), 6.45 (2H, bs), 7.06 (3H, s), 8.48 (3H, s), 8.60 (3H, s) 156-157 ° C (dec.), Yield 75.4% · IR (KBr) cm-lj JQ = Q 1775, 1740, 1695, 1670 MR (d-DMSO) T values: 0.18 (IH, d), 0.77 (IH, d), 2.66 (5H, s), 4.30 (IH, d), 4.40 (3H, br), 4-48 (H, g), 4.65 (IH, d), 5.80 (IH, s), 6.12 (2H, bs), 6.45 (2H, bs), 7.06 (3H, s), 8.48 (3H, s), 8.60 (3H, s)

Ovennævnte fremgamgsmåde gentoges idet 4-methyl-2,3-dioxo-l-pi-perazinocarbonylchloridet erstattedes med 4-ethyl-2,3-dioxo-l-piperazinocarbonylchlorid til dannelse af et monohydrat af 6-{d(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenylacetamidoj penicillansyre, smp· 154-156°C (dekomp.), udbytte 84,8%· IR (KBr) cm-1: JQ=Q 1775, 1735, 1705, 1680, 1665 NMR (dg-DMSO) Z værdier: 0.20 (IH, d), *0.76 (IH, d), 2.69 (5H, s), 4.32 (IH, d), 4.53 (IH, q), 4.64 (IH, d), 5.00 (3H, br), 5.83 (IH, s), 6.13 (2H, bs), 6.49 (2H, bs), 6.62 (2H, q), 8.44 (3H, s), 8.58 (3H, s), 8.91 (3H, t) Fremgamgsmåde The above was repeated with 4-methyl-2,3-dioxo-l-pi-perazinocarbonylchloridet was replaced with 4-ethyl-2,3-dioxo-l-piperazinocarbonylchlorid to form a monohydrate of 6- {D (-) - octyl (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamidoj penicillanic acid, m.p. · 154-156 ° C (dec.), yield 84.8% · IR (KBr) cm-1: 1775 JQ = Q, 1735, 1705, 1680, 1665 NMR (d-DMSO) Z values: 0.20 (IH, d), * 0.76 (IH, d), 2.69 (5H, s), 4.32 (IH, d), 4.53 (IH, q ), 4.64 (IH, d), 5.00 (3H, br), 5.83 (IH, s), 6.13 (2H, bs), 6.49 (2H, bs), 6.62 (2H, q), 8.44 (3H, s) , 8.58 (3H, s), 8.91 (3H, t)

Det således dannede monohydrat neutraliseredes med en vandig natriumhydrogencarbonatopløsning, og derefter filtreredes blandingen, og filtratet frysetørredes til dannelse af natriumsaltet af 6-[p(-)-<x-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoj -penicillansyre· 110 151338 The monohydrate thus formed was neutralized with an aqueous sodium bicarbonate solution, and then the mixture was filtered and the filtrate was freeze-dried to give the sodium salt of 6- [p (-) - <x- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoj pennicillanic · 110 151338

Yderligere henstilledes en opløsning af 2 g af det ovennævnte dihydrat af 6-[p(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidojpenicillansyre i 18 timer til udfældning af krystaller, som frafiltreredes til dannelse af 2 g monohydrat af et nitromethan-additionsprodukt af 6-[p (-) -a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino )phenylacetamidoj| Further allowed to stand, a solution of 2 g of the above dihydrate of 6- [p (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidojpenicillansyre for 18 hours to precipitate crystals, which were collected by filtration to give 2 g of the monohydrate of a nitromethane adduct of 6- [p (-) -a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoj | penicillansyre, smp. penicillanic acid, mp. 128-130°C (dekomp.), udbytte 92,2%. 128-130 ° C (dec.), Yield 92.2%.

Elementær analyse (for 022^25^5^7^0^1^02 '^O): Elemental analysis (for 022 ^ 25 ^ 5 ^ 7 ^ 0 ^ 1 ^ 02 '^ O):

Beregnet^ (%) C: 47.42 Η: 5·19 H: 14.43 Fundet - (%) C: 47-94 H: 5.13 N: 14.53 IR (KBr) cm"1: ^0=0 1770 ' 1755' 1700 ' 1680 NMR (d6-DMS0) X værdier: 0.22 (IH, d), 0.80 (IH, d), 2.69 (5H, s), 3.3Ο (3H, hr), 4.30 {IH, d), 4.46 - 4.70 (2H), 5.67 (3H, s), 5.81 (IH, s), 6.13 (2H, bs), 6.46 (2H, bs), 7.07 (3H, s), 8.45 (3H, s), 8.58 (3H, s) ^ Calculated (%) C: 47.42 Η: 5 · 19 H: 14.43 Found - (%) C: 47-94 H: 5.13 N: 14.53 IR (KBr) cm "1: ^ 0 = 0 1770 '1755' 1700 ' 1680 NMR (d 6 DMS0) X values: 0.22 (IH, d), 0.80 (IH, d), 2.69 (5H, s), 3.3Ο (3H, hr), 4.30 {IH, d), 4.46 to 4.70 ( 2H), 5.67 (3H, s), 5.81 (IH, s), 6.13 (2H, bs), 6.46 (2H, bs), 7.07 (3H, s), 8.45 (3H, s), 8.58 (3H, s )

Eksempel 19 example 19

Til en suspension af 1,6 g trihydrat af D(-)-a-aminobenzyl-peni-cillin i 20 ml vand sattes ved 2° til 3°C 0,54 g kaliumcarbonat, og den dannede blanding omrørtes i 3 minutter. To a suspension of 1.6 g of trihydrate of D (-) - a-aminobenzyl penicillin in 20 ml water was added at 2 ° to 3 ° C, 0.54 g of potassium carbonate, and the resulting mixture was stirred for 3 minutes. Til blandingen sattes gradvis 0,81 g 4-ethyl-2,3-dioxo-l-piperazinocarbonylchlorid ved den nævnte temperatur i løbet af 10 minutter, og blandingen omsattes i 15 minutter. To the mixture was gradually added 0.81 g of 4-ethyl-2,3-dioxo-l-piperazinocarbonylchlorid at said temperature over 10 minutes and the mixture was reacted for 15 minutes. Efter reaktionen blev små mængder uopløselige stoffer frafiltreret, og filtratet indførtes i 10 ml methyl-n-propyl-keton. After the reaction, small amounts of insoluble matters were filtered off and the filtrate was introduced into 10 ml of methyl n-propyl ketone. Til den dannede blanding dryppedes 1,98 ml 2N saltsyre ved 15° til 20°C i løbet af 2 minutter, og blandin- 111 151338 gen omrørtes ved den nævnte temperatur i to timer til udfældning af krystaller. To the resulting mixture was added dropwise 1.98 ml of 2N hydrochloric acid at 15 ° to 20 ° C over 2 minutes and the mixtures 111 151 338 gene was stirred at that temperature for two hours to precipitate crystals. De udfældede krystaller opsamledes ved filtrering, vaskedes to gange med 2 ml vand, vaskedes yderligere to gange med 2 ml methyl-n-propyl-keton, og tørredes derefter til dannelse af 1,7 g monohydrat af D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocar-bonylamino)benzylpenicillin, smp. The precipitated crystals were collected by filtration, washed twice with 2 ml of water, washed twice with 2 ml of methyl n-propyl ketone, and then dried to give 1.7 g of monohydrate of the D (-) - a- ( 4-ethyl-2,3-dioxo-l-piperazinocar-bonylamino) benzylpenicillin, mp. 152-154°C (dekomp.), udbytte 80,2%. 152-154 ° C (dec.), Yield 80.2%.

Det således dannede produkt neutraliseredes med en vandig natrium-hydrogencarbonatopløsning og underkastedes derefter en filtrering og frysetørredes til dannelse af et natriumsalt af det nævnte produkt. The product thus formed was neutralized with an aqueous sodium bicarbonate solution and was then subjected to a filtering and freeze-dried to give a sodium salt of said product.

Eksempel 20 example 20

En suspension af 4,0 g monohydrat af 7-(D(-)-a-aminophenylaceta-midoj-3-methyl- A^-cephem-4-carboxylsyre i 60 ml tetrahydrofuran indeholdende 20 rumfangsprocent vand, indstilledes på en pH-vær-di på 8,0 til 8,5 ved gradvis tilsætning af triethylamin under omrøring til dannelse af en opløsning, som derefter afkøledes til 0°C. Til denne opløsning sattes gradvis 2,5 g krystaller af 4-methyl-2,3-dioxo-lp.iperazLino-cår.bOnylchlorid i løbet af 10 minut ter. Under denne periode opretholdtes reaktionsblandingens pH-værdi på 7,5 til 8,0 ved gradvis tilsætning af triethylamin. Derefter omsattes den dannede blanding ved 0° til 5°C i 15 minutter, medens pH-værdien opretholdtes ved 7,5 til 8,0. Efter reaktionen omrørtes reaktionsblandingen sammen med 60 ml diethylether og 70 ml vand, og derefter fraskiltes det vandige lag. Det således dannede vandige lag vaskedes med 30 ml ethylacetat, afkøledes til 0° til 5°C og indstilledes derefter på en pH-værdi på 1,5 ved tilsætning A suspension of 4.0 g of monohydrate of 7- (D (-) - a-aminophenylaceta-midoj-3-methyl-N, -cephem-4-carboxylic acid in 60 ml of tetrahydrofuran containing 20 volume percent water, adjusted to a pH-Be -di of 8.0 to 8.5 by gradual addition of triethylamine with stirring to give a solution which was then cooled to 0 ° C. to this solution was gradually added 2.5 g of crystals of 4-methyl-2,3- lp.iperazLino-dioxo-cår.bOnylchlorid over ter 10 minutes. during this period, maintaining the reaction mixture pH of 7.5 to 8.0 by gradual addition of triethylamine. Then, the resulting mixture was reacted at 0 ° to 5 ° C for 15 minutes, while the pH was maintained at 7.5 to 8.0. After the reaction, the reaction was stirred together with 60 ml of diethyl ether and 70 ml of water, was separated and then the aqueous layer. the thus formed aqueous layer was washed with 30 ml of ethyl acetate, was cooled to 0 ° to 5 ° C and was then adjusted to a pH of 1.5 by addition af fortyndet saltsyre til udfældning af hvide krystaller. of dilute hydrochloric acid to precipitate white crystals.

De udfældede krystaller opsamledes ved filtrering, vaskedes grundigt med vand og tørredes derefter til dannelse af 4,7 g hvide krystaller af 7- (p(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-phenylacet amido] -3-methyl- A^-cephem-4-carboxylsyre, smp. 185-186°C (dekomp.), udbytte 86%. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to give 4.7 g of white crystals of 7- (p (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) - phenylacet amido] -3-methyl-N, -cephem-4-carboxylic acid, mp. 185-186 ° C (dec.), yield 86%.

r 112 151338 IR (KBr) cm-1: v\j=0 1770 - 1760 (lactam), 1720 - 1660 (-COUCT» -C00H) MR (dg-DMSO) T værdier: 0.1 (IH, d), 0.56 (1H, d), 2.62 (5H, s), 4.26 - 4.37 (2H, dd.), 5.05 (1H, d), 6.1 (2H, bs), 6.47 (2H, bs), 6.63 (2H, s), 7.05 (3H, s), 8.02 (3H, s) r 112 151338 IR (KBr) cm -1: v \ j = 0 1770 to 1760 (lactam), 1720 to 1660 (-COUCT '-C00H) MR (d₆-DMSO) T values: 0.1 (IH, d), 0.56 (1H, d), 2.62 (5H, s), 4.26 to 4.37 (2H, dd.), 5.05 (1H, d), 6.1 (2H, bs), 6.47 (2H, bs), 6.63 (2H, s) , 7.05 (3H, s), 8.02 (3H, s)

Ovennævnte operation blev gentaget med den ændring, at 4-methyl- 2,3-dioxo-l-piperazinocarbonylchloridet erstattedes med hver af de i tabel .20 viste reaktive derivater af forbindelser med formlen (III) til dannelse af de ligeledes i tabel 20 viste slutprodukter. The above operation was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchloridet was replaced with each of the .20 shown in Table reactive derivatives of compounds of formula (III) to form the likewise shown in Table 20 end products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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Eksempel 21 (1) Til en opløsning af 0,92 g ln-pentyl-2,3-dioxo-piperazin i 15 ml vandfrit dioxan sattes 1,1 ml triethylamin og 1,08 g trimethyl-silylchlorid. Example 21 (1) To a solution of 0.92 g of n-pentyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane was added 1.1 ml of triethylamine and 1.08 g of trimethyl-silyl chloride. Den dannede blanding omrørtes ved stuetemperatur i 20 timer til dannelse af triethylamin-hydrochlorid. The resulting mixture was stirred at room temperature for 20 hours to give the triethylamine hydrochloride. Dette hydro-chlorid frafiltreredes, og filtratet dryppedes ved 0° til 5°C i en opløsning af 0,6 g phosgen i 10 ml vandfrit tetrahydrofuran. This hydro-chloride was filtered off and the filtrate was added dropwise at 0 ° to 5 ° C in a solution of 0.6 g of phosgene in 10 ml of anhydrous tetrahydrofuran. Derefter omsattes den dannede blanding ved 5° til 10°C i 30 minutter og derpå ved stuetemperatur i 2 timer. Then, the resulting mixture was reacted at 5 ° to 10 ° C for 30 minutes and then at room temperature for 2 hours. Derefter afdestille-redes opløsningsmidlet under reduceret tryk til dannelse af 1,21 g lysegult olieagtigt 4-n-pentyl-2,3-dioxo-l-piperazinocarbonylchlo-rid. Then distilling off-the solvent was removed under reduced pressure to give 1.21 g of light yellow oily 4-n-pentyl-2,3-dioxo-l-piperazinocarbonylchlo chloride.

IR (film) cm-1: Vc=o 1790' 1720 ~ 1665 (2) En suspension af 1,70 g monohydrat af 7-{p(-)-a-aminophenyl-acetamido] -3-methyl-A?-cephem-4-carboxylsyre i 50 ml tetrahydro-furan indeholdende 20 rumfangsprocent vand, indstilledes til en pH-vær di på 8,0 til 8,5 ved tilsætning af triethylamin vinder omrøring til dannelse af en opløsning. IR (film) cm-1:? C = o 1790 '1720 ~ 1665 (2) A suspension of 1.70 g of monohydrate of 7- {p (-) - a-aminophenyl-acetamido] -3-methyl-A? - cephem-4-carboxylic acid in 50 ml of tetrahydrofuran containing 20 volume percent water, was adjusted to a pH-di Be of 8.0 to 8.5 by addition of triethylamine eventually stirring to form a solution. Denne opløsning afkøledes til 0° til 5°C, og 7 ml af en vandfri tetradydrofuranopløsning indeholdende 1,21 g 4-n-pentyl-2,3-dioxo-piperazinocarbonylchlorid fra trin (l) dryppedes i opløsningen. This solution was cooled to 0 ° to 5 ° C, and 7 ml of an anhydrous tetradydrofuranopløsning containing 1.21 g of 4-n-pentyl-2,3-dioxo-piperazinocarbonylchlorid of step (l) was dropped into the solution. Under denne periode indstilledes pH-værdien af opløsningen på 7,5 til 8,0 ved tilsætning af triethylamin.Derefter omsattes den dannede blanding ved 0° til 5°C i 1 time og derefter ved 5° til 10°C i 2 timer, medens pH-værdien holdtes på 7,5 til 8,0. During this period was adjusted the pH of the solution to 7.5 to 8.0 by the addition of triethylamin.Derefter the resulting mixture was reacted at 0 ° to 5 ° C for 1 hour and then at 5 ° to 10 ° C for 2 hours, while the pH was maintained at 7.5 to 8.0. Efter reaktionen afdestilleredes tetrahydro-furanet under reduceret tryk, og remanensen opløstes i 20 ml vand og vaskedes derpå to gange med 20 ml ethylacetat. After the reaction was distilled off tetrahydro-furanet under reduced pressure and the residue was dissolved in 20 ml of water and then washed twice with 20 ml of ethyl acetate. Det vandige lag blandedes derpå igen med 40 ml ethylacetat og indstilledes på en pH-værdi på 1,5 ved gradvis tilsætning af fortyndet saltsyre vinder isafkøling. The aqueous layer was then mixed again with 40 ml of ethyl acetate, and adjusted to a pH of 1.5 by gradual addition of dilute hydrochloric acid eventually ice cooling. Derefter fraskiltes ethylacetatlaget, som vaskedes med vand og derpå tørredes over vandfrit magnesiumsvuLfat. Then, the ethyl acetate layer was separated, which was washed with water and then dried over anhydrous magnesiumsvuLfat. Derefter dryppedes 10 ml af en ethylacetatopløsning indeholdende 0,75 g 115 151338 natrium-2-ethylhexanoat i laget ved 0° til 5°C til udfældning af hvide krystaller. Then added dropwise 10 ml of an ethyl acetate solution containing 0.75 g 115 151 338 sodium 2-ethylhexanoate in the layer at 0 ° to 5 ° C to precipitate white crystals. De udfældede krystaller opsamledes ved filtrering og vaskedes med ethylacetat og derpå med diethylether til dannelse af 1,95 g natriumsalt af 7- [p (-)-a-(4-n-pentyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-methyl- Λ^-cephem-4-carboxylsyre, smp. The precipitated crystals were collected by filtration and washed with ethyl acetate and then with diethyl ether to give 1.95 g of the sodium salt of 7- [P (-) - a- (4-n-pentyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-methyl Λ ^ -cephem-4-carboxylic acid. 164-166°C (dekomp.), udbytte 75%. 164-166 ° C (dec.), Yield 75%.

IR (KBr) cm-1: VC=Q 1750 (lactam), 1720 - • 1660 (-C0RO, 1-590 (-C009) NMR (dg-DMSO + D20) T værdier: 2.58 (5H,· s), 4.33 (IH, s), 4.49 (IH, d), 5.17 (IH, d), 6.10 (2H, bs), 6.42 - 6.87 (6H, m), 8.09 (3H, s), 8.60 - 8.90 (6H, bs), 9.12 (3H, t) 1 IR (KBr) cm-1:? C = Q 1750 (lactam), 1720 - 1660 • (-C0RO, 1-590 (-C009) NMR (d₆-DMSO + D20) T values: 2.58 (5H, · s), 4.33 (IH, s), 4.49 (IH, d), 5.17 (IH, d), 6.10 (2H, bs), 6.42 to 6.87 (6H, m), 8.09 (3H, s), 8.60 to 8.90 (6H, bs), 9.12 (3H, t) 1

Ovennævnte operation blev gentaget med den ændring, at 4-n-pen-tyl-2,3”dioxo-l-piperazinocarbonylchloridet blev erstattet med hver af de i tabel 21 viste reaktive derivater af forbindelser med formlen (III) til dannelse af de ligeledes i tabel 21 angivne slutprodukter. The above operation was repeated with the modification that 4-n-pen tyl-2,3 'dioxo-l-piperazinocarbonylchloridet was replaced with each of the 21 shown in Table reactive derivatives of compounds of formula (III) to form the likewise in table 21 indicated final products. Strukturen af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of the resulting compounds were confirmed by IR and NMR.

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Eksempel 22 example 22

Med 1,5 g hydrochlorid af methoxymethylester af 7-[D(-)-a-amino-phenylacetamido3-3-methyl-A?-cephem-4-carboxylsyre og 0,65 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid gentoges fremgangsmåden ifølge eksempel 20 til dannelse af 1,6 g methoxymethylester af 7* [b(-) -a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetamidoJ-3-methvl- /\^-cephem-4-carboxylsvre. Hydrochloride with 1.5 g of the methoxymethyl ester of 7- [D (-) - a-amino-phenylacetamido3-3-methyl-A? -cephem-4-carboxylic acid and 0.65 g of 4-methyl-2,3-dioxo- L-piperazinocarbonylchlorid was repeated the procedure of example 20 to give 1.6 g of the methoxymethyl ester 7 * [B (-) -a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetamidoJ-3-methyl- / \ ^ - cephem-4-carboxylic acid. smp. mp. 146-148°C (dekomp.), udbytte 86%. 146-148 ° C (dec.), Yield 86%.

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Eksempel 23 example 23

Til en suspension af 0,20 g 7-[p(-)-a-aminophenylacetamidoj-3-acetoxymethyl-A^-cephem-4-carboxylsyre i 15 ml vandfrit chloroform sattes 0,17 ml triethylamin under omrøring til dannelse af en opløsning, som derefter afkøledes til 0°C. To a suspension of 0.20 g of 7- [P (-) - a-aminophenylacetamidoj-3-acetoxymethyl-A ^ -cephem-4-carboxylic acid in 15 ml of anhydrous chloroform was added 0.17 ml of triethylamine with stirring to form a solution , which is then cooled to 0 ° C. Til denne opløsning sattes 0,11 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid, og den dannede blanding omsattes ved stuetemperatur i 2 timer. To this solution was added 0.11 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid, and the resulting mixture was reacted at room temperature for 2 hours. Ef-. Community. ter reaktionen inddampedes den flydende reaktionsblanding under reduceret tryk, og remanensen blev opløst i 15 ml vand. ter the reaction was concentrated the liquid reaction mixture under reduced pressure and the residue was dissolved in 15 ml of water. Den dannede opløsning vaskedes med 10 ml ethylacetat. The resulting solution was washed with 10 ml of ethyl acetate. Det vandige lag forenedes igen med 20 ml ethylacetat, og derefter indstilledes på en pH-værdi på 1,5 ved tilsætning af 2N saltsyre under isafkøling. The aqueous layer was combined again with 20 ml of ethyl acetate, and then adjusted to a pH of 1.5 by addition of 2N hydrochloric acid under ice-cooling. Derefter fraskiltes ethylacetatlaget, som vaskedes i rækkefølge med vand og en mættet vandig natriumchloridopløsning og derefter tørredes over magnesiumsulfat. Then, the ethyl acetate layer was separated, which was washed successively with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. Derpå fradestilieredes opløsningsmidlet under reduceret tryk til dannelse af 0,22 g hvide krystaller af 7-^D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyl-acetamido3-3-acetoxymethyl-A^-cephem-4-carboxylsyre, smp. Fradestilieredes then the solvent under reduced pressure to give 0.22 g of white crystals of 7- ^ D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetoxymethyl-acetamido3-3 N, -cephem-4-carboxylic acid. 175°C (dekomp.), udbytte 76%. 175 ° C (dec.), Yield 76%.

115 151338 IR (XBr) cm-ΐϊ y^=0 177O (lactam), 1720 - 1650 (-00Ν<, -COOH) MR (dg-DMSO) T værdier: 0.25 (IH, d), 0.65 (IH, d), 2.66 (5H, s), 4.32 (IH, q), 4.43 (IH, d), 5.05 (IH, d), 5.21 (2H, q), 6.15 (2H, bs), 6.40 (2Ξ, bs), 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s) 115 151338 IR (XBR) cm ΐϊ y ^ = 177O 0 (lactam), 1720 to 1650 (-00Ν <, -COOH) MR (d₆-DMSO) T values: 0.25 (IH, d), 0.65 (IH, d ), 2.66 (5H, s), 4.32 (IH, q), 4.43 (IH, d), 5.05 (IH, d), 5.21 (2H, q), 6.15 (2H, bs), 6.40 (2Ξ, bs) , 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s)

Ovennævnte operation blev gentaget med den ændring, at 4-methyl- 2,3-dioxo-l-piperazinocarbonylchlorid blev erstattet med hver af de i tabel 22 viste reaktive derivater af forbindelser med formlen (III) til dannelse af de i tabel 22 viste slutprodukter. The above operation was repeated with the modification that 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid was replaced with each of the 22 shown in Table reactive derivatives of compounds of formula (III) to form in Table 22 showed the final products . Strukturen af hver af de fremstillede forbindelser blev bekræftet ved IR og NMR. The structure of each of the prepared compounds were confirmed by IR and NMR.

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Ovennævnte 7-[ρ(-)-α-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido]-3-acetoxymethyl-Δ^-cephem-A—carboxylsyre, smp. The above 7- [ρ (-) - α- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-Δ ^ -cephem-A-carboxylic acid. 175°C (dekomp.) omkrystalliseredes af vandig acetone til dannelse af hvide krystaller som udviste et smeltepunkt på 198 - 200 °C (dekomp.). 175 ° C (decomp.) Recrystallized from aqueous acetone to give white crystals showing a melting point of 198-200 ° C (dec.).

Eksempel 24 (1) Example 24 (1)

Til en opløsning af 28,2 g natriumsalt af D(-)-phenylglyc in i 150 ml vand sattes 200 ml ethylacetat og 18,2 g triethylamin, og den dannede blanding afkøledes til 0°C. To a solution of 28.2 g of sodium salt of D (-) - phenylglyc in in 150 ml of water was added 200 ml of ethyl acetate and 18.2 g of triethylamine, and the resulting mixture was cooled to 0 ° C. Til denne blanding sattes 34,3 g 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid i løbet af 15 minutter, og blandingen omsattes ved 5° til 10°C i 15 minutter. To this mixture was added 34.3 g of 4-methyl-2,3-dioxo-l-piperazinocarbonylchlorid over 15 minutes and the mixture was reacted at 5 ° to 10 ° C for 15 minutes. Derefter fraskiltes det vandige lag, som indstilledes på en pH-værid på 0,5 ved tilsætning af 2N saltsyre under isafkøling til udfældning af krystaller. Then the aqueous layer was separated, which was adjusted to a pH of 0.5 værid by addition of 2N hydrochloric acid under ice-cooling to precipitate crystals. De udfældede krystaller opsamledes ved filtrering og tørredes derefter til dannelse af 42 g hvide krystaller af D(-)-a-(4-methyl-2,3-dioxo-l-piperazino-carbonylamino)phenyleddikesyre, smp. The precipitated crystals were collected by filtration and then dried to give 42 g of white crystals of D (-) - a- (4-methyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetic acid, mp. 195°C (dekomp.). 195 ° C (dec.).

IR (KBr) cm-1; IR (KBr) cm-1; y)c=0 1700, 1660 NMR (dg-DMSO) T værdier: 0.1 (IH, d), 2.65 (5H, s), 4.60 (IH, d), 6.10 (2H, bs), 6.50 (2H, bs), 7.0 (3H, s) (2) y) C = 0 1700, 1660 NMR (d-DMSO) T values: 0.1 (IH, d), 2.65 (5H, s), 4.60 (IH, d), 6.10 (2H, bs), 6.50 (2H, bs ), 7.0 (3H, s) (2)

Til en suspension i 15 ml vandfrit methylenchlorid af 0,31 g D (-) -oc- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyleddike-syre dannet i ovennævnte trin (l) sattes 0,11 g N-methylmorpholin mider omrøring til dannelse af en opløsning, som derefter afkøledes til 20°C. To a suspension in 15 ml of anhydrous methylene chloride 0.31 g of D (-) -OC- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid formed in the above step (l) was added 0.11 g N-methylmorpholine mites stirring to form a solution which was then cooled to 20 ° C. Til denne opløsning sattes 3 ml af en vandfri methyl enchloridopløsning indeholdende 0,13 g ethylchlorcarbonat, og den dannede blanding omsattes ved fra -10 til 20°C i 60 minutter til dannelse af et blandet syreanhydrid. To this solution was added 3 ml of an anhydrous methylene enchloridopløsning containing 0.13 g of ethyl chlorocarbonate, and the resulting mixture was reacted at -10 to 20 ° C for 60 minutes to form a mixed acid anhydride. I det således dannede syreanhydrid dryppedes en opløsning, dannet ved tilsætning af 0,50 ml triethylamin til en suspension i 5 ml methanol af 0,41 g 122 151338 7-amino-3- [2- ( 5-methyl-l, 3,4-thiadiazolyl)-thiomethylj - A^-cephem- 4-carboxylsyre. In the thus formed acid anhydride is added dropwise a solution formed by adding 0.50 ml of triethylamine to a suspension in 5 ml of methanol 0.41 g 122 151 338 7-amino-3- [2- (5-methyl-l, 3, 4-thiadiazolyl) -thiomethylj - A ^ -cephem- 4-carboxylic acid. Efter tildrypningen omsattes den dannede blanding ved -ί-500 til -r30°C i 30 minutter, ved ^30° til 4-20°C i 30 minutter, ved -r20° til 0°C i 60 minutter og derefter ved stuetemperatur i 30 minutter. After the dropwise addition was reacted the resulting mixture at -ί--R 30 to 500 ° C for 30 minutes, at 30 ^ ° to 4-20 ° C for 30 minutes, by -R 20 ° to 0 ° C for 60 minutes and then at room temperature for 30 minutes. Derefter inddampedes reaktionsvæsken under reduceret tryk, og koncentratet opløstes i 10 ml vand, vaskedes med 5 ml ethylacetat, forenedes atter med 15 ml ethylacetat og blandingen indstilledes på en pH-værdi på 1,5 ved tilsætning af 2N saltsyre under isafkøling. Then the reaction liquid was evaporated under reduced pressure, and the concentrate was dissolved in 10 ml of water, washed with 5 ml of ethyl acetate was combined once more with 15 ml of ethyl acetate and the mixture was adjusted to a pH of 1.5 by addition of 2N hydrochloric acid under ice-cooling. Derefter frafiltreredes uopløselige stoffer, og ethylacetatet fraskiltes, vaskedes i rækkefølge med vand og en mættet natriumchloridopløsning, tørredes over magnesiumsulfat og blev derefter befriet for opløsningsmidlet under reduceret tryk til dannelse af 0,58 g lysegule krystaller af 7-|p(-)-a-(4-methyl- 2.3- dioxo-l-piperazinocarbonylamino)phenylacetamido3 -3-[2-(5-me-thyl-1,3,4-thiadiazolyl) -thiomethyl] - A^-cePhem-4-carboxylsyre, smp. Thereafter insoluble matters were filtered, and the ethyl acetate was separated, washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate and was then freed from the solvent under reduced pressure to give 0.58 g of light yellow crystals of 7- | p (-) - a - (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido3 -3- [2- (5-me-thyl-1,3,4-thiadiazolyl) thiomethyl] - N, -cePhem-4-carboxylic acid, m.p. . 160°C (dekomp.), udbytte 91%. 160 ° C (dec.), Yield 91%.

IR (KBr) cm-1: i780 (lactam), 1650 - 1720 (-C0N< , -C00H) RMR (d6-DMS0) T værdier: 0.2 (IH, d), 0.6 (IH, d), 2.60 (5H, s), 4.35 (IH, q), 4.40 (IH, d), 5.0 (IH, d), 5.70 (2H, q), 6.10 (2H, bs), 6.25 - 6.55 (2H, 2H, bs), 7.0 (3H, s), 7.30 (3H, s) IR (KBr) cm-1: i780 (lactam), 1650 to 1720 (-C0N <, -C00H) RMR (d 6 DMS0) T values: 0.2 (IH, d), 0.6 (IH, d), 2.60 (5H , s), 4.35 (IH, q), 4.40 (IH, d), 5.0 (IH, d), 5.70 (2H, q), 6.10 (2H, bs), 6.25 to 6.55 (2H, 2H, bs), 7.0 (3H, s), 7.30 (3H, s)

Ovennævnte operation gentoges med den ændring, at D(-)-a-(4-methyl- The above operation was repeated with the modification that the D (-) - a- (4-methyl-

2.3- dioxo-l-piperazinocarbonylamino)phenyleddikesyren blev erstattet med de i tabel 23 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 23 viste slutprodukter. 2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with those shown in Table 23, the compounds shown by the formula (V) to form the likewise in Table 23 showed the final products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR The structure of each of the resulting compounds were confirmed by IR

og NMR. and NMR.

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CD. CD. JJ CM CM JJ CM CM

P o^to w ^ P ^ o to w ^

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*W s * W p

CQ CQ

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W μ. W μ. "P "P

o W 43 _J 0 i>, ra~Vo !§ VS 3 -l . 43 _J o W 0 i>, R a ~ V o! § VS 3 -L.

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CO Λ W CO Λ W

H ^ (¾ & a) *-> «5 fi EH _ H ^ (¾ & A) * -> '5 fi EH _

W W

°A ° A

1 o^a 5 § 1 o ^ a 5 §

Eksempel 25 125 151338 Example 25 125 151338

Med 0,3 g D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyleddikesyre og 0,33 g 7-amino-3-[5-(l-methyl-l,2,3,4-tetra-zolyl)-thiomethy:QA^-cephem-4-carboxylsyre gentoges fremgangsmåden ifølge eksempel 24 til dannelse af 0,5 g 7- -(4-methyl- 2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido3-3- Jjp-(l“me-thyl-1,2,3,4-tetrazolyl)-thiomethyl] -^-cephem-4-carboxylsyre, smp. With 0.3 g of D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and 0.33 g of 7-amino-3- [5- (l-methyl-l, 2 , 3,4-tetra-zolyl) -thiomethy: QA ^ -cephem-4-carboxylic acid was repeated the procedure of example 24 to give 0.5 g of 7- - (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido3-3- Jjp- (l "me-thyl-1,2,3,4-tetrazolyl) thiomethyl] - ^ - cephem-4-carboxylic acid. 161-163°C (dekomp.), udbytte 76%. 161-163 ° C (dec.), Yield 76%.

IR (nujol) cm-1: . IR (nujol) cm-1:. y)c=Q 1775 (lactam), 1720 - 1660 (~CQN\ , -C00H) NMR (dg-DMSO) T værdier: 0.02 (IH, d), 0.34 (IH, d), 2.48 (5H, s), 4.17 (IH, q), 4.26 (IH, d), 4.92 (IH, d), 5.66 (2H, s), 6.01 (5H, s), 6.35 (4H, s), 7.0 (3H, s) y) C = Q 1775 (lactam), 1720 to 1660 (cqn ~ \, -C00H) NMR (d₆-DMSO) T values: 0.02 (IH, d), 0.34 (IH, d), 2.48 (5H, s) , 4.17 (IH, q), 4.26 (IH, d), 4.92 (IH, d), 5.66 (2H, s), 6.01 (5H, s), 6.35 (4H, s), 7.0 (3H, s)

Ovennævnte operation blev gentaget med den ændring, at D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre blev erstattet med hver af de i tabel 24 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 24 viste slutprodukter. The above operation was repeated with the modification that the D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid was replaced by each of the table 24 shown in compounds of formula (V) to give of the table 24 also in the turned end-products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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iS1' 5 '»H $ =WS IS1 '5' 'H $ = WS

OK CQ CQ OK CQ CQ

f Ο Φ CM <D CM φ f CM Ο Φ <φ D CM

-. -. / Vi OP K .. *P * W -P / We OP K .. * P * W -P

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•ο “Λ Ώ yj* 3 - 3 I • ο "Λ Ώ yj * 3-3 In

c: op I pi - g C: up to Pi - g

-η k —1 _L «J -η k -1 _L 'J

Q ^ * vv ·* v ^ MOOOO _ 0 O g 0 oo K° Ko o lu K /—V Ο K t°v K to oYo) ^ o C- o ^ Q ^ * vv * · v ^ MOOOO g _ 0 O oo 0 ° K Ko o lu K / -V Ο ° K T V K two Oyo) C- ^ o ^ o

VK \__/ H OH Ο H VK \ __ / H OH H Ο

5 JL ^ >®~ m~ « Η IK ft g& o jj o, j2L .oaoa . 5 JL ^> ® ~ m ~ 'Η IK ft g & o JJ o J2L .oaoa. oacp V^Y oo 9 oos oacp V ^ y oo 9 oos

g °VI °AS 1 Vs 5 I g ° VI ° AS 1 vs 5 In

I Κ* WI · IO^isr 5 In Κ * WI · IO ^ especially 5

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Eh 4J Eh 4J

ra raw

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® o K_0 ο Ο H O ® K_0 ο Ο H

cq yV ο ιλ o +j Η IJ IK- i -H cn I ° r °rY° . cq yV ο ιλ o + j Η IJ IK- in -H cn I ° r ° r Y °. Vs as •HIK^ I CT'^t I Cr'&T β β ,ω-'-'Ο 'T'L ΎΛ. Vs AS • HIK In CT ^ '^ t in CR' & T β β, ω -'- 'Ο' T'L ΎΛ. to tu δ ^ pT ^ w ^ fol > > ft ft O ft O ft 'V/ _ « two tu δ ^ pT ^ w ^ fol>> ft ft ft O O ft 'V / _'

Eksempel 26 127 f 51338 Example 26 127 f 51 338

Med 0,30 g D(-)-α-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyleddikesyre og 0,34 g 7-amino->(5- (1»3,4-thiadiazolyl) -thiomethvlJ-/\^-cephem-4-carboxvlsvre gentoges fremgangsmåden i-følge eksempel 24 til dannelse af 0,47 g 7-* jjD(-)-oc-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)piienylacetamidoj-3-[~5-(1,3» 4-thiadiazolyl ) -thiomethyl Ι-Λ3 -cephem-4-carboxylsyre, smp. 158-159°C (dekomp.), udbytte 71,5%. With 0.30 g of D (-) - α- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and 0.34 g of 7-amino -> (5- (1 '3,4-thiadiazolyl) -thiomethvlJ - / \ ^ - cephem-4-carboxylic acid the procedure was repeated at follow-example 24 to give 0.47 g of 7- JJD * (-) - oc- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino ) piienylacetamidoj-3- [~ 5- (1,3 '4-thiadiazolyl) thiomethyl-Ι Λ3 -cephem-4-carboxylic acid, mp. 158-159 ° C (dec.), yield 71.5%.

IR (nujol) cm"l: Vc=0 -^75 (lsctam), 1720 - 1660 (-C0N<, -C00H) IR (nujol) cm "l: vC = 0 - ^ 75 (lsctam), 1720-1660 (-C0N <, -C00H)

Ovennævnte fremgangsmåde gentoges, idet D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre erstattedes af D(-)-et-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre til dannelse af 7-[p(“)-a-(4-ethyl-2,3-dioxo-l-piperazino-carbonylamino)phenylacetamidq]-3-j5-(1,3,4-thiadiazolyl)-thio-methvlj-A^-cephem-4-carboxylsyre« smp. The above procedure was repeated except that D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid was replaced by D (-) - a- (4-ethyl-2,3-dioxo-L- piperazinocarbonylamino) phenyl acetic acid to give 7- [P ( ") - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidq] -3-j5- (1,3,4-thiadiazolyl) - thio-methvlj-A ^ -cephem-4-carboxylic acid «mp. 123°C (dekomp.), udbytte 64,5%. 123 ° C (dec.), Yield 64.5%.

Eksempel 27 example 27

Med 0,31 g D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyleddikesyre og 0,39 g 7-amino-3-{2-(l-methyl-l,3,4-triazolyl)-thiomethylj-AP-cephem-4-carboxylsyre gentoges fremgangsmåden i-følge eksempel 24, idet dog methanolet erstattedes med vandfrit methylenchlorid til dannelse af 0,43 g 7-jp(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoJ-3{2-(l-methyl-1,3»4—triazolyl)—thiomethyll -A^-cephem-4-carboxylsyre, udbytte 70%. With 0.31 g of D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and 0.39 g of 7-amino-3- {2- (l-methyl-l, 3 , 4-triazolyl) -thiomethylj-AP-cephem-4-carboxylic acid was repeated the procedure of example 24-a result, with the proviso that the methanol was replaced with anhydrous methylene chloride to give 0.43 g of 7-JP (-) - a- (4-methyl -2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoJ-3 {2- (l-methyl-1,3 '4-triazolyl) -thiomethyll -A ^ -cephem-4-carboxylic acid, yield 70%.

IR (nujol) cm-1; IR (nujol) cm-1; 'J q=q ^80 (1ειο1:ειιη) > 1720 “ 1650 (-C0I<, -C00H) 128 151338 'J q = q ^ 80 (1ειο1: ειιη)> 1720 "1650 (-C0I <, -C00H) 128 151 338

Ovennævnte operation blev gentaget med den ændring, at D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino )phenyleddike syre blev erstattet med hver af de i tabel 25 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 25 nævnte slut-' produkter. The above operation was repeated with the modification that the D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with each of the table 25 shown in compounds of formula (V) to they also form in table 25 that the end 'products. Strukturen af hver af de nævnte forbindelser blev bekræftet ved IR og NMR. The structure of each of said compounds was confirmed by IR and NMR.

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1 * Τ=\ a ^ 1 * Τ = \ N?

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φ a> CO___ > V*/ ha Φ o ^ oa 5 IRo) § i § i^® wias °ra] § Φ ° 7 sia™ i cAa' n 7 A 7 Av, o "ponv/ P4 EKSEMPEL 28 . X30 151338 φ a> CO___> V * / ha Φ o ^ oa 5 IRO) § in § I ^ ® wias ° ra] § Φ ° 7 sia ™ in CAA 'N 7 A 7 Av, o "PONV / P4 EXAMPLE 28th X30 151338

Proceduren ifølge eksempel 24 blev gentaget med den ændring, at D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddike-syren blev erstattet med hver af de i tabel 26 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 26 angivne slutprodukter. The procedure of Example 24 was repeated except that the D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with each of the shown in Table 26, compounds of formula ( V) to form the likewise in table 26 indicated final products. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The structure of each of the resulting compounds were confirmed by IR and NMR.

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&2 CQ & 2 CQ

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CM W t CM W t

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Proceduren ifølge eksempel 25 "blev gentaget med den ændring, at D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddike-syren blev erstattet med hver af de i tabel 27 viste forbindelser med formlen (V) til dannelse af de ligeledes i tabel 27 angivne slutprodukter. Strukturen af hver af de dannede forbindelser blev bekræftet ved IR og NMR. The procedure of Example 25 'was repeated except that the D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with each of the shown in Table 27, compounds of formula (V) to form the likewise in table 27 indicated final products. the structure of each of the resulting compounds were confirmed by IR and NMR.

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R jL cAa iai oRJ i a1 ^ O i —- I ^ o II ΡΛ I [<Λ awa ^ apo · popo EKSEMPEL 30 136 151338 På samme måde som angivet i eksempel 27 dannedes 7-[D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenyl-acetamido]-3-[-5-(1-methyl-l,2,3,4-tetrazolyl)-thiomethyl]- Δ?-cephem-4-carboxylsyre ud fra 7-amino-3-[-5-(1-methyl-l,2,3,4-tetrazolyl)-thiomethyl ]-A^-cephem-4-carboxylsyre og D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenyleddike-syre. R JL CAA IAI ORJ in a1 ^ O I - I o II ^ ΡΛ I [<Λ ^ AWA apo · popo Example 30 136 151 338 In the same manner as in Example 27 was formed 7- [D (-) - a- ( 4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenyl acetamido] -3 - [- 5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - Δ? - cephem-4-carboxylic acid from 7-amino-3 - [- 5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] -A ^ -cephem-4-carboxylic acid and D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenyleddike acid.

Smp.: (dekomp.), 147 - 9°C; M.p .: (dec.) 147-9 ° C; udbytte 62,0$. yield 62.0 $.

IR (KBr) cm”1: 1765 (lactam), 1720 - 1660 (-CON—, -C00H) På samme måde som ovenfor fremstilledes 7-[D(-)-a-(4-ethyl-2,3-dioxø-l-piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-Z^-cephem-4-carbo-xylsyre, smp. IR (KBr) cm "1: 1765 (lactam), 1720 to 1660 (-CON, -C00H) In the same manner as above was prepared 7- [D (-) - a- (4-ethyl-2,3-dioxø -L-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] -Z ^ -cephem-4-carboxylic boxylic acid, mp. 188-190°C (decomp.), udbytte 80,7%, ud fra 7-amino-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-/^-cephem-4-carboxylsyre og D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino) -p-hydroxyphenyleddikesyre. 188-190 ° C (decomp.), Yield 80.7%, from 7-amino-3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - / ^ - cephem 4-carboxylic acid and D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino) -p-hydroxyphenylacetic acid.

EKSEMPEL 31 På samme måde som angivet i eksempel 24 dannedes 7~[D(-)-a-(4-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-azidomethyl- -cephem-4-carboxylsyre ud fra D(-)-a-(4-methyl-2,3- dioxo-l-piperazinocarbonylamino)phenyleddikesyre og 7-amino-3- "*5 azidomethyl- Δ -cephem-4-carboxylsyre. Example 31 In the same manner as in Example 24 was formed ~ 7 [D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-azidomethyl- -cephem-4-carboxylic acid from D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and 7-amino-3- "* 5 azidomethyl- Δ -cephem-4-carboxylic acid.

Smp.: (dekomp.), 185 - 8°C; M.p .: (dec.) 185-8 ° C; udbytte 68,0% IR (KBr) cm"1: jc=Q 1775 (lactam), 1720 - 1660 (-C0N—, -C00H) 2090 EKSEMPEL 32 I 10 ml phosphorsyre-puffer med pH = 6,3 suspenderedes 0,57 g 7-[D(—)—a—(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacet- 137 151358 amido]-3-acetoxymethyl-Z^?-cephem-4-carboxylsyre, og 0,07 g na-triumhydrogenc arbonat opløstes heri. Til opløsningen sattes derpå 0,12 g l-methyl-5~mercapto-l,2,3,4-tetrazol til opløsning af sidstnævnte i den førstnævnte, og opløsningen underkastedes en reaktion i 24 timer, medens pH-værdien af opløsningen opretholdtes ved 6,5- 6,7 under anvendelse af fortyndet saltsyre og natriumhydrogencar-bonat. Efter reaktionen opsamledes reaktionsvæsken, som derefter indstilledes på en pH-værdi på 5,0 ved tilsætning af fortyndet saltsyre. Reaktionsblandingen vaskedes med tilstrækkeligt ethyl-acetat, hvorefter det vandige lag blev fraskilt og derpå indstillet på en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre. yield 68.0% IR (KBr) cm "1: jc = Q 1775 (lactam), 1720 to 1660 (-C0N-, -C00H) 2090 Example 32 In 10 ml of phosphoric acid buffer with pH = 6.3 was suspended 0, 57 g of 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) 137 151 358 phenylacet- amido] -3-acetoxymethyl-Z ^? - cephem-4-carboxylic acid, and 0 , 07 g of sodium triumhydrogenc arbonat dissolved therein. to the solution was then added 0.12 g of l-methyl-5 ~ mercapto-l, 2,3,4-tetrazole for the dissolution of the latter in the former, and the solution was subjected to a reaction for 24 hours, while the pH of the solution was maintained at 6.5 X 6.7 using dilute hydrochloric acid and sodium bicarbonate. After the reaction, the reaction liquid was collected, which was then adjusted to a pH value of 5.0 by addition of dilute hydrochloric acid. the reaction mixture was washed sufficiently with ethyl acetate, after which the aqueous layer was separated and then adjusted to a pH of 1.5 by addition of dilute hydrochloric acid.

De udfældede krystaller opsamledesved filtrering og tørredes, hvorefter de tørrede krystaller blev vasket med ethylacetat til dannelse af 0,40 g 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbo-nylamino)phenylacetamido]-3-[5-(l-niethyl-l,2,3,4-tetrazolyl) thiome-thyl-A^-cephem—4—carboxylsyre, smp.: 163-165°C (dekomp.), udbytte 74,5%. The precipitated crystals opsamledesved filtration and dried, after which the dried crystals were washed with ethyl acetate to give 0.40 g of 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbo-nylamino) phenylacetamido] -3- [5- (l-niethyl-l, 2,3,4-tetrazolyl) thiome-^ thyl-A -cephem-4-carboxylic acid, mp .: 163-165 ° C (dec.), yield 74.5%.

IR (KBr) cm"1: gc=Q 1775 (lactam), 1720 - 1660 (-CON^T, -C00H) NMR (dg-DMSO) værdier: 0,18 (IH, d), 0,55 (IH, d), 2,64 (5H, s), 4,3 (IH, q), 4,4 (IH, d), 5,0 (IH, d), 5,75 (2H, s), 6,05 (5H, s), 6,3 - 6,8 (6H), 8,92 (3H, t). IR (KBr) cm "1: Q = GC 1775 (lactam), 1720 to 1660 (-CON ^ T, -C00H) NMR (d₆-DMSO)? Values: 0.18 (IH, d), 0.55 (IH , d), 2.64 (5H, s), 4.3 (IH, q), 4.4 (H, d), 5.0 (H, d), 5.75 (2H, s), 6 , 05 (5H, s), 6.3 to 6.8 (6H), 8.92 (3H, t).

På samme måde som ovenfor angivet fremstilledes de i tabel 28 viste forbindelser ud fra 7-[D(-)-o—(4-methyl-2,3-dioxo-l-piperazinocar-bonyl)phenylacetamido]-3-acetoxymethyl- Δ?-cephem-4-carboxylsyre eller 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenylacetamido]-3-acetoxymethyl-^5_Cephem-4-carboxylsyre og de i tabel 28 viste forbindelser med formel (VII). In the same manner as above was prepared in Table 28, the compounds shown from 7- [D (-) - O- (4-methyl-2,3-dioxo-l-piperazinocar-carbonyl) phenylacetamido] -3-acetoxymethyl Δ ? -cephem-4-carboxylic acid or 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl ^ 5_Cephem-4-carboxylic acid, and in the table 28 showed compounds of formula (VII). Alle de fremstillede forbindelser var D(-)-isomere, og strukturen af forbindelserne blev bekræftet ved IR og HMR. All the compounds prepared had the D (-) - isomer, and the structure of the compounds was confirmed by IR and HMR.

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144 151338 EKSEMPEL 33 I 10 ml vand suspenderedes 1,15 g 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-acetoxymethyl-A^-cephem-4-carboxylsyre og 0,17 g natriumhydrogencarbonat blev derefter opløst heri, hvorefter 0,48 g pyridin og 4,1 g kaliumthio-cyanat blev tilsat. 144 151338 Example 33 In 10 ml of water was suspended 1.15 g of 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-A ^ -cephem- 4-carboxylic acid and 0.17 g of sodium bicarbonate was then dissolved therein, after which 0.48 g of pyridine and 4.1 g kaliumthio diisocyanate was added. Den dannede blanding omsattes ved 60°C i 5 ' timer, medens pH-værdien af blandingen holdtes på 6,0 til 6,3 ved tilsætning af fortyndet saltsyre eller natriumhydrogencarbonat. The resulting mixture was reacted at 60 ° C for 5 'hours while the pH of the mixture was maintained at 6.0 to 6.3 by addition of dilute hydrochloric acid or sodium bicarbonate. Efter reaktionen tilsattes 20 ml vand til fortynding af reaktionsblandingen, som derefter blev vasket med chloroform. After the reaction was added 20 ml of water for dilution of the reaction mixture, which was then washed with chloroform. Det vandige lag fraskiltes derefter og indstilledes på en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre. The aqueous layer was separated and then adjusted to a pH of 1.5 by addition of dilute hydrochloric acid. De udfældede krystaller blev opsamlet ved filtrering, tørret og derpå vasket med acetone til dannelse af 1,04 g (udbytte 79,6%) thiocyansyresalt af 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3- •z pyridinpmethyl-.A-cephem-4-carboxylsyre-betain med et smeltepunkt (dekomp.) på 155-160°C, hvilket produkt har formlen: OG. The precipitated crystals were collected by filtration, dried and then washed with acetone to give 1.04 g (yield 79.6%) thiocyansyresalt of 7- [D (-) - a- (4-ethyl-2,3-dioxo -L-piperazinocarbonylamino) phenylacetamido] -3- • z pyridinpmethyl-.A-cephem-4-carboxylic acid betaine, mp (decomp.) at 155-160 ° C, said product having the formula: and.

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OO ISLAND ISLAND

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Smp.: (dekomp.) 180 - 185°C; M.p .: (dec.) 180-185 ° C; udbytte 82,0%. yield 82.0%.

På konventionel måde behandledes ovennævnte to produkter med en ionbytterharpiks til dannelse af det ønskede 7-[D(-)-a-(4-ethyl- 2.3- dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-pyridino-methyl-ZsAcephem-4-carboxylsyrebetain og 7-[D(-)-a-(4-methyl- 2.3- dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-pyridino-me thyl-Δ^- c ephem-4-carb oxyl syr eb e tain. In the conventional manner was treated above two products with an ion exchange resin to form the desired 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-pyridino-methyl-4-ZsAcephem -carboxylsyrebetain and 7- [D (-) - a- (4-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-pyridino-me thyl-Δ ^ - c ephem-4-carb oxyl sewing eb e Tain .

EKSEMPEL 34 I 85 ml vandfrit methanol opløstes 1,5 g natriumsalt af 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]- 3-[2-pyridyl-l-oxid)thiomethyl|-2V'-cephem-4-carboxylsyre. Example 34 In 85 ml of anhydrous methanol was dissolved 1.5 g of sodium salt of 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] - 3- [2-pyridyl-l oxide) thiomethyl | -2V'-cephem-4-carboxylic acid. Til den dannede opløsning sattes 0,65 g vandfrit kuprichlorid, og den dannede blanding omrørtes ved stuetemperatur i 15 minutter og omsattes ved 50°C i 14 timer. To the resulting solution was added 0.65 g of anhydrous cupric chloride, and the resulting mixture was stirred at room temperature for 15 minutes and allowed to react at 50 ° C for 14 hours. Efter reaktionen førtes gasformigt hydrogensulfid gennem reaktionsopløsningen under isafkøling i 20 minutter. After the reaction, was passed gaseous hydrogen sulfide through the reaction solution under ice cooling for 20 minutes. Det dannede uopløselige stof frafiltreredes, og filtratet inddampedes under reduceret tryk. The resulting insoluble substance was filtered off, and the filtrate was evaporated under reduced pressure. Til remanensen sattes 20 ml af en 5% vandig natriumhydrogencarbonatopløsning, og det uopløselige stof frafiltreredes, hvorefter fortyndet saltsyre sattes til filtratet til indstilling af pH-værdien på 6,5. To the residue was added 20 ml of a 5% aqueous sodium hydrogen carbonate solution, and the insoluble matter was filtered off, after which dilute hydrochloric acid was added to the filtrate to adjust the pH to 6.5. Filtratet blev derefter vasket med 10 ml portioner ethylacetat tre gange, hvorefter det vandige lag blev fraskilt og derefter indstillet på en pH-værdi på 1,8 ved tilsætning af fortyndet saltsyre. The filtrate was then washed with 10 ml portions of ethyl acetate three times, after which the aqueous layer was separated and then adjusted to a pH of 1.8 by addition of dilute hydrochloric acid. De således udfældede krystaller opsamledes ved filtrering og tørredes derefter under reduceret tryk og vaskedes med 20 ml af en ethylacetatchloroform-blanding (1:1 efter rumfang) til dannelse af 0,40 g 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-methoxymethyl-£^-c ephem-4-carboxylsyre, smp.: 16 2-6 ° C (dekomp.), udbytte 30,5%. The crystals thus precipitated were collected by filtration and then dried under reduced pressure and washed with 20 ml of a ethylacetatchloroform mixture (1: 1 by volume) to give 0.40 g of 7- [D (-) - a- (4- ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-methoxymethyl £ ^ c ephem-4-carboxylic acid, mp .: 16 2-6 ° C (dec.), yield 30.5%.

146 151338 IR (KBr) cm"1: \jQ=Q 1770 (lactam), 1700 (-C00H), 1666 (-COiO MR (dg-DMSO) H værdier: 0.13 (IH, d), 0.53 (IH, d), 2.61 (5H, s), 4.31 (IH, q), 4.41 (IH, d), 4.96 (IH, d), 5.82 (2H, s), 6.10 (2H, bs), 6.33 (2H, 2H, 2H. bs), 6.79 (3H, s), 8.89 (3H, t). 146 151338 IR (KBr) cm "1: \ jQ = Q 1770 (lactam), 1700 (-C00H), 1666 (-COiO MR (DMSO-dg) H values: 0.13 (IH, d), 0.53 (IH, d ), 2.61 (5H, s), 4.31 (IH, q), 4.41 (IH, d), 4.96 (IH, d), 5.82 (2H, s), 6.10 (2H, bs), 6.33 (2H, 2H, 2H. bs), 6.79 (3H, s), 8.89 (3H, t).

EKSEMPEL 35 Example 35

Til en opløsning af 3,2 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazino-carbonylamino)phenyleddikesyre i 20 ml vandfrit methylenchlorid og 5 ml dimethylformamid sattes 1,33 g Ν,Ν-dimethylanilin. To a solution of 3.2 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetic acid in 20 ml of anhydrous methylene chloride and 5 ml of dimethylformamide was added 1.33 g of Ν, Ν dimethylaniline. Den resulterende blanding blev afkølet til mellem -15 og -10°C, og en opløsning af 1,14 g ethylchlorcarbonat i 5 ml vandfrit methylenchlorid blev tildryppet denne blanding i løbet af 5 minutter. The resulting mixture was cooled to between -15 and -10 ° C, and a solution of 1.14 g of ethyl chlorocarbonate in 5 ml of anhydrous methylene chloride was added dropwise this mixture over 5 minutes. Blandingen fik lov at reagere ved denne temperatur i 60 minutter. The mixture was allowed to react at this temperature for 60 minutes.

Til en suspension af 3,28 g 7-amino-3-[5-(l-methyl-l,2,3,4-tetra-zolyl) thiomethyl ] -^-cephem-4-carboxylsyre i 65 ml vandfrit aceto-nitril sattes på den anden side 3,04 g N,O-bis(trimethylsilyl)-acetamid til opnåelse af en opløsning. To a suspension of 3.28 g of 7-amino-3- [5- (l-methyl-l, 2,3,4-tetra-zolyl) -thiomethyl] - ^ - cephem-4-carboxylic acid in 65 ml of anhydrous acetone nitrile was added on the other hand 3.04 g of N, O-bis (trimethylsilyl) acetamide to obtain a solution. Opløsningen blev afkølet til -20°C og hældt ud i den førnævnte reaktionsblanding. The solution was cooled to -20 ° C and poured into the above reaction mixture. Derefter fik blandingen lov at reagere ved mellem -10 og -5°C i 60 minutter og ved 5-10°C i 60 minutter. Then, the mixture was allowed to react at -10 to -5 ° C for 60 minutes and at 5-10 ° C for 60 minutes. Efter fuldførelse af reaktionen sattes 5 ml methanol til reaktionsblandingen, og blandingen blev befriet for uopløseligt materiale ved filtrering. After completion of the reaction was added 5 ml of methanol to the reaction mixture, and the mixture was freed from insolubles by filtration. Derefter blev opløsningsmidlet fjernet ved destillation under formindsket tryk. Then the solvent was removed by distillation under reduced pressure. Remanensen opløstes i et blandet opløsningsmiddel bestående af 100 ml vand og 50 ml ethylacetat, og den resulterende opløsning blev indstillet til en pH-værdi på 7,5-8,0 ved tilsætning af na-triumhydrogencarbonat, hvorefter der tilsattes 80 ml ethylacetat og 20 ml acetone, og den resulterende opløsning blev indstillet til en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre. The residue was dissolved in a mixed solvent consisting of 100 ml of water and 50 ml of ethyl acetate, and the resulting solution was adjusted to a pH of 7.5-8.0 by the addition of sodium bicarbonate, followed by addition of 80 mL of ethyl acetate and 20 ml of acetone, and the resulting solution was adjusted to a pH of 1.5 by addition of dilute hydrochloric acid.

Derpå blev det organiske lag skilt fra, vasket tilstrækkeligt med vand, og opløsningsmidlet blev fjernet fra ethylacetatlaget 1« 151338 ved destillation under formindsket tryk. Then, the organic layer is separated, washed sufficiently with water, and the solvent was removed from the ethyl acetate layer 1 '151338 by distillation under reduced pressure. Remanensen opløstes i 15 ml acetone, og til denne opløsning sattes 60 ml 2-propanol under omrøring til udfældning af hvide krystaller. The residue was dissolved in 15 ml of acetone and to this solution was added 60 ml of 2-propanol with stirring to precipitate white crystals. De udfældede krystaller blev opsamlet ved filtrering, vasket tilstrækkeligt med 2-propanol og tørret, hvorved der blev opnået 5,26 g 7-[D-(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacet-amido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-4^-cephem- 4-carboxylsyre, smp. The precipitated crystals were collected by filtration, sufficiently washed with 2-propanol and dried, thereby obtaining 5.26 g of 7- [D - (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino ) phenylacet amido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] -4 ^ -cephem- 4-carboxylic acid. 163-165°C (decomp.), udbytte 83,6%. 163-165 ° C (decomp.), Yield 83.6%. Strukturen af denne forbindelse blev bekræftet ved IR og MR. The structure of this compound was confirmed by IR and MR.

Den ovennævnte procedure blev gentaget, undtagen at D(-)-0(.-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyleddikesyre blev erstattet med hver af de i tabel 29 anførte forbindelser med formlen (V) til opnåelse af de respektive ønskede forbindelser som vist i tabel 29. Strukturen af hver fremstillet forbindelse blev bekræftet ved ir og NMR. The above procedure was repeated except that the D (-) - 0 (.- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid was replaced with each of the listed in Table 29 compounds of formula (V) to give the respective title compounds as shown in table 29. the structure of each obtained compound was confirmed by IR and NMR.

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popopo 149 151338 EKSEMPEL 36 PoPoPo 149 151338 Example 36

Proceduren fra eksempel 35 blev gentaget under anvendelse af 3,1 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyl eddike syre og 3,0 g 7-amino-3-[5-(l,2,3-triazolyl)thio-methyl]-å^-cephem-4-carboxylsyre, hvorved der blev opnået 4,5 g 7_[D(_)_a-(4_ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyl-acetamido]-3-[5-(1,2,3-triazolyl)thiomethyl]-Z^-cephem-4-carbo-xylsyre, smp. The procedure of Example 35 was repeated using 3.1 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and 3.0 g of 7-amino-3- [5- (l, 2,3-triazolyl) thio-methyl] -AA ^ -cephem-4-carboxylic acid, there was obtained 4.5 g 7_ [D (_) _ A (4_ethyl-2,3-dioxo -L-piperazinocarbonylamino) phenyl acetamido] -3- [5- (1,2,3-triazolyl) thiomethyl] -Z ^ -cephem-4-carboxylic boxylic acid, mp. 177-180°C (decomp.)» udbytte 76,7%· IR (KBr) cm-1: 1>C=0 1770 (lactam), 1703 (-C00H), 1680, 177-180 ° C (decomp.) '· Yield 76.7% IR (KBr) cm-1: 1> C = 0 1770 (lactam), 1703 (-C00H), 1680,

1667 (-CONO 1667 (-CONO

EKSEMPEL 37 EXAMPLE 37

Proceduren fra eksempel 35 blev gentaget under anvendelse af 1,9 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyleddikesyre og 2,2 g 7-amino-3-[5-(1,3,4-thiadiazolyl)thiomethyl ]-^-cephem-4-carboxylsyre, hvorved der blev opnået 3,1 g 7-[D(-)-oc-( 4- ethyl- 2,3- di oxo -1 -p ip era zino carbony lamino) phenyl-acetamido 3-3-[5-(1,3,4-thiadiazolyl) -thiomethyl ] -/^-cephem-4-carboxylsyre, smp. The procedure of Example 35 was repeated using 1.9 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetic acid and 2.2 g of 7-amino-3- [5 - (1,3,4-thiadiazolyl) thiomethyl] - ^ - cephem-4-carboxylic acid, there was obtained 3.1 g of 7- [D (-) - oc- (4-ethyl-2,3-dioxo -1 -p ip ERA Zino Lamino carbonyl) phenyl acetamido-3-3- [5- (1,3,4-thiadiazolyl) thiomethyl] - / ^ - cephem-4-carboxylic acid. 165-170°C (decomp.), udbytte 82%. 165-170 ° C (decomp.), Yield 82%.

IR (KBr) cm-1: j7c=0 1775 (lactam), I705 (-C00H), 1685, IR (KBr) cm-1: 1775 J7C = 0 (lactam), I705 (-C00H), 1685,

1675 (-CON O 1675 (-CON O

EKSEMPEL 38 Example 38

Proceduren fra eksempel 35 blev gentaget under anvendelse af 1,5 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenyleddikesyre og 1,5 g 7-amino-3-[5-(2-methyl-l,3,4-thiadiazolyl)-thiomethyl]-^-cephem-4-carboxylsyre, hvorved der blev opnået 2,3 g 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazino-carbonylamino)-p-hydroxyphenylacetamido]-3-[5-(2-methyl-l,3,4-thiadiazolyl)thiomethyl]-^-cephem-4-carboxylsyre, smp. The procedure of Example 35 was repeated using 1.5 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and 1.5 g of 7-amino-3- [5- (2-methyl-l, 3,4-thiadiazolyl) thiomethyl] - ^ - cephem-4-carboxylic acid, there was obtained 2.3 g of 7- [D (-) - oc- (4-ethyl -2,3-dioxo-l-piperazino-carbonylamino) -p-hydroxyphenylacetamido] -3- [5- (2-methyl-l, 3,4-thiadiazolyl) thiomethyl] - ^ - cephem-4-carboxylic acid. 172-177°C (decomp.), udbytte 77,7%. 172-177 ° C (decomp.), Yield 77.7%.

150 151338 IR (KBr) cm”1: \) C=0 1780 (lactam)» 1710 (-COOH) 1685, 1672 (-CONC) På samme måde som ovenfor fremstilledes de i tabel 30 anførte forbindelser ud fra D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenyleddikesyre eller D(-)-a-(4-ethyl-2,3-dioxo-l-pipera-zinocarbonylamino)-p-hydroxyphenyleddikesyre og de i tabel 30 viste forbindelser med formlen (IV). 150 151338 IR (KBr) cm "1: \) C = 0 1780 (lactam)" 1710 (-COOH) 1685, 1672 (-CONC) In the same manner as above was prepared in Table 30 listed compounds can be prepared from the D (-) -OC- (4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino) phenylacetic acid or D (-) - a- (4-ethyl-2,3-dioxo-l-piperazine zinocarbonylamino) -p-hydroxyphenylacetic acid and shown in table 30, compounds of formula (IV). Strukturen af hver fremstillet forbindelse blev bekræftet ved IR og NMR. The structure of each obtained compound was confirmed by IR and NMR.

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Til denne opløsning sattes 7,3 g 4-(a-hydroxyethyl)-2,3-dioxo- 1-piperazinocarbonylchlorid ved 0-5°C i løbet af 15 minutter, og den resulterende blanding fik lov at reagere ved 10-15°C i 30 minutter. To this solution was added 7.3 g of 4- (a-hydroxyethyl) -2,3-dioxo-1-piperazinocarbonylchlorid at 0-5 ° C over 15 minutes and the resulting mixture was allowed to react at 10-15 ° C for 30 minutes. Efter fuldførelse af reaktionen blev det vandige lag skilt fra, det tilsattes 100 ml acetonitril, og den resulterende opløsning blev indstillet til en pH-værdi på 1,5 ved tilsætning af fortyndet saltsyre, og blev mættet med natriumchlorid. After completion of the reaction, the aqueous layer was separated, it was added 100 ml of acetonitrile, and the resulting solution was adjusted to a pH of 1.5 by addition of dilute hydrochloric acid and was saturated with sodium chloride. Derefter blev acetonitrillaget skilt fra, vasket to gange med 30 ml af en mættet opløsning af natriumchlorid og derpå tørret ved formindsket tryk. The acetonitrile was then separated, washed twice with 30 ml of a saturated solution of sodium chloride, and then dried at reduced pressure. Remanensen opløstes i et blandet opløsningsmiddel bestående af 50 ml acetone og 10 ml ethanol, og uopløseligt materiale blev skilt fra. The residue was dissolved in a mixed solvent consisting of 50 ml of acetone and 10 ml of ethanol and the insoluble material was separated. Derpå sattes 100 ml isopropyl-alkohol til den resulterende opløsning, og denne blev koncentreret til 2/3 volumen ved formindsket tryk. Then was added 100 ml of isopropyl alcohol to the resultant solution, and this was concentrated to 2/3 volume at reduced pressure. De udfældede krystaller blev opsamlet ved filtrering, vasket med isopropylalkohol og tørret, hvorved der blev opnået 4,5 g 7-[D{-)-a-(4—fp-hydro-xyethyl^ -2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-acetoxymethyl-A^-cephem-4-carboxylsyre, smp. The precipitated crystals were collected by filtration, washed with isopropyl alcohol and dried, thereby obtaining 4.5 g of 7- [D {-) - a- (4-fp-hydro xyethyl ^ -2,3-dioxo-L- piperazinocarbonylamino) phenylacetamido] -3-acetoxymethyl-A ^ -cephem-4-carboxylic acid. 142-144°C (decomp.) udbytte 76,3%· η ·. 142-144 ° C (decomp.), Yield 76.3% · η ·. 1770 (lactam), 1708 (-C0GH) IR (KBr) cm“J' : S) C=0 1680, 1665 (-C0N<) 1770 (lactam), 1708 (-C0GH) IR (KBr) cm "J ': S) C = 0 1680, 1665 (-C0N <)

Den ovenstående procedure blev gentaget, undtagen at 7-[D{-)-a-aminophenylacetamido]-3-acetoxymethyl-fc?-cephem-4-carboxy1syren blev erstattet med hver af de i tabel 31 angivne forbindelser med formlen (II) til fremstilling af de respektive ønskede forbindelser som anført i tabel 31. Strukturen af hver fremstillet forbindelse blev bekræftet ved IR og NMR. The above procedure was repeated except that 7- [D {-) - a-aminophenylacetamido] -3-acetoxymethyl-fc? -cephem-4-carboxy1syren was replaced with each of the in Table 31. The compounds of formula (II) to the production of the respective desired compounds as listed in table 31. the structure of each obtained compound was confirmed by IR and NMR.

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ao V^“° 157 151338 EKSEMPEL 40 . ao ^ V "° 157 151338 EXAMPLE 40th (l) Til en opløsning af 0,63 g D(-)-a-(4-ethyl-2,3“åioxo-l-piperazinocarbonylamino)phenyleddikesyre i 10 ml vandfrit methylenchlorid sattes 0,5 g oxalylchlorid og en dråbe N,N-dimethylformamid, og den resulterende blanding fik lov at rea- 1 gere ved stuetemperatur i 30 minutter. (L) To a solution of 0.63 g of D (-) - a- (4-ethyl-2,3 "åioxo-l-piperazinocarbonylamino) phenyl acetic acid in 10 ml of anhydrous methylene chloride was added 0.5 g of oxalyl chloride and one drop of N, N-dimethylformamide, and the resulting mixture was allowed to react 1 stringent at room temperature for 30 minutes. Efter fuldførelse af reaktionen blev opløsningsmidlet fjernet ved destillation under formindsket tryk. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Remanensen blev vasket med vandfrit benzen, hvorved der blev opnået 0,6 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetylchlorid, smp. The residue was washed with anhydrous benzene, thereby obtaining 0.6 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetyl chloride, mp. 112-116°C (decomp.) udbytte 88,8$. 112-116 ° C (decomp.), Yield 88.8 $.

IR (KBr) cm"1: >)NH 3280 ~)ο=0 179°- 1695 (2) Til en suspension af 0,27 g 7-aminocephalosporansyre i 6 ml vandfrit methanol sattes 0,24 g triethylamin. Den resulterende opløsning blev afkølet til -40°C, og til opløsningen sattes en opløsning af 5 ml vandfrit methylenchlorid indeholdende 0,34 g D(—)-oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylace-tylchlorid, og derpå blev reaktionsvæskens temperatur gradvist hævet til stuetemperatur i løbet af 1 time. Efter fuldførelse af reaktionen blev opløsningsmidlet fjernet ved destillation under formindsket tryk. Remanensen blev fyldt i 20 ml vand, og den resulterende opløsning blev vasket to gange med 5 ml ethyl-acetat. Til det vandige lag sattes 20 ml ethylacetat, og opløsningen blev indstillet til en pH-værdi på 1,5 ved tilsætning af 2N saltsyre under omrøring. Derefter blev det organiske lag skilt fra, vasket med en mættet vandig natriumchloridopløsning, tørret over vandfrit magnesiumsulfat, og opløsningsmid IR (KBr) cm "1:>) NH ~ 3280) ο = 0179 ° - 1695 (2) To a suspension of 0.27 g of 7-aminocephalosporanic acid in 6 ml of anhydrous methanol was added 0.24 g of triethylamine. The resulting solution was cooled to -40 ° C, and to the solution was added a solution of 5 ml of anhydrous methylene chloride containing 0.34 g of D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetyl chloride, and then the reaktionsvæskens temperature gradually raised to room temperature over 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure. the residue was charged in 20 ml of water, and the resulting solution was washed twice with 5 ml of ethyl acetate . to the aqueous layer were added 20 ml of ethyl acetate, and the solution was adjusted to a pH of 1.5 by addition of 2N hydrochloric acid under stirring. Thereafter the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent let fjernet ved destillation under formindsket tryk, hvorved der blev opnået 453 mg 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenylacetamido]-3-acetoxymethyl-^-cephem-4-carboxylsyre, smp. easily removed by distillation under reduced pressure, thereby obtaining 453 mg of 7- [D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl - ^ - cephem -4-carboxylic acid, mp.

165-166°C (decomp.), udbytte 79,0$. 165-166 ° C (decomp.), Yield 79.0 $.

På samme måde som ovenfor fremstilledes 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-acetoxy-A^-cephem-4-carboxylsyre, smp. In the same manner as above was prepared 7- [D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3-acetoxy-N, -cephem-4-carboxylic acid, mp. 168-174°C (decomp.), udbytte 72,3$, ud fra D(-)-a-(4-ethyl-2,3-dioxo-l-piperazino- 158 1 5 1 3 3 8 carbonylamino)-p-hydroxyphenylacetylchlorid og 7-aminocephalo-sporansyre. 168-174 ° C (decomp.), Yield 72.3 $, from D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino 5 158 1 1 3 3 8 carbonylamino) - p-hydroxyphenylacetylchlorid and 7-aminocephalo-sporansyre.

EKSEMPEL 41 Example 41

Til en suspension af 2,16 g 6-aminopenicillansyre i 20 ml methylen-chlorid sattes 2,02 g triethylamin. To a suspension of 2.16 g of 6-aminopenicillanic acid in 20 ml of methylene chloride was added 2.02 g of triethylamine. Til den resulterende opløsning sattes 3,4 g D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-phenylacetylchlorid ved 10-15°C, og den resulterende blanding fik lov at reagere ved 10-15°C i 2 timer. To the resulting solution was added 3.4 g of D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetylchlorid at 10-15 ° C, and the resulting mixture was allowed to react at 10 -15 ° C for 2 hours. Efter fuldførelse af reaktionen blev opløsningsmidlet fjernet ved destillation under formindsket tryk. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Remanensen blev fyldt i 20 ml vand, og til den resulterende opløsning sattes 30 ml ethylacetat. The residue was charged in 20 ml of water, and to the resulting solution was added 30 ml of ethyl acetate. Opløsningen blev indstillet til en pH-værdi på 2,5 ved tilsætning af 2N saltsyre og blev omrørt i 4 timer til udfældning af krystaller. The solution was adjusted to a pH of 2.5 by addition of 2N hydrochloric acid and was stirred for 4 hours to precipitate crystals.

De udfældede krystaller blev omsamlet ved filtrering, hvorved der blev opnået 4,4 g 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazino-carbonylamino)phenylacetamido]penicillansyre, smp. The precipitated crystals were omsamlet by filtration, thereby obtaining 4.4 g of 6- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido] penicillanic acid, mp. 154-156°C (decomp.), udbytte 82,2%. 154-156 ° C (decomp.), Yield 82.2%.

På samme måde som ovenfor fremstilledes 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetamido]-penicillansyre, smp. In the same manner as above was prepared 6- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -penicillanic acid, mp. 160-161°C (decomp.), udbytte 70,5%, ud fra 6-amino-penicillansyre og D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetylchlorid. 160-161 ° C (decomp.), Yield 70.5%, from 6-amino-penicillanic acid and D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetylchlorid .

EKSEMPEL 42 EXAMPLE 42

Proceduren fra eksempel 35. blev gentaget under anvendelse af D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenyl-eddikesyre og 7-amino-3-carbamoyloxymethyl-A.^-cephem-4-carboxyl-syre, hvorved der blev opnået 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-carbamoyloxymethyl-/^-cephem-4-carboxylsyre, smp. The procedure of Example 35 was repeated using D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetic acid and 7-amino-3-carbamoyloxymethyl-A. ^ - cephem 4-carboxylic acid, there was obtained 7- [D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl - / ^ - cephem-4-carboxylic acid mp. 175-180°C (decomp.), udbytte 68,0%. 175-180 ° C (decomp.), Yield 68.0%.

IR (KBr) cm"1: 0 NH? 3430' 3350 0 coSh 3300 ^ c=0 1778, 1710, 1670 159 151338 På samme måde som ovenfor fremstilledes 7-(D(-)-a-(4-ethyl-2,3-di oxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetamido-3-carbamoyloxymethyl-Æ?-cephem-4-carboxylsyre, smp. 178-182° C (decomp.), udbytte 65,090, ud fra D(-)-a-(4-ethyl—2,3-dioxo-l-piperazinocarbonylamino)-p-hydroxyphenyleddikesyre og 7-amino - 3 - c arbamoy 1 oxyme thy 1 -ip-c ephem-4- c arb oxy 1 syre. IR (KBr) cm "1: 0 NH? 3430 '3350 3300 0 cosh ^ c = 0 1778, 1710, 1670 159 151 338 In the same manner as above was prepared 7- (D (-) - a- (4-ethyl-2 , 3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido-3-carbamoyloxymethyl-Æ? -cephem-4-carboxylic acid, mp. 178-182 ° C (decomp.), yield = 65 090, starting from D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and 7-amino - 3 - c 1 arbamoy oxyme Thy 1 -IP-c ephem-4 c 1 piece oxy acid.

EKSEMPEL 43 (1) Til en opløsning af 0,32 g D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre i 15 ml methylen-chlorid sattes 0,1 g N-methylmorpholin. Example 43 (1) To a solution of 0.32 g of D (-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid in 15 ml of methylene chloride was added 0.1 g of N-methylmorpholine . Den resulterende opløsning blev afkølet til -20°C og til opløsningen sattes en opløsning af 0,11 g ethylchlorcarbonat i 2 ml methylenchlorid, hvorefter den resulterende opløsning fik lov at reagere ved mellem -10 og -20°C i 1 time. The resulting solution was cooled to -20 ° C and to the solution was added a solution of 0.11 g of ethyl chlorocarbonate in 2 ml of methylene chloride, and the resulting solution was allowed to react at between -10 and -20 ° C for 1 hour. Derpå blev reaktionsvæsken tildryppet en opløsning af 0,44 g af en benzhydrylester af 7-amino-3-carbamoyloxymethyl-/^-cephem-4-carboxylsyre i 5 ml methylenchlorid ved -20°C. Then, the reaction liquid was added dropwise a solution of 0.44 g of a benzhydryl ester of 7-amino-3-carbamoyloxymethyl - / ^ - cephem-4-carboxylic acid in 5 ml of methylene chloride at -20 ° C. Efter tildrypningen fik den resulterende opløsning lov at reagere ved mellem -lb og -20°C i 1,5 timer, hvorefter temperaturen blev hævet til stuetemperatur. After the dropwise addition, the resulting solution allowed to react at between -lb and -20 ° C for 1.5 hours, after which the temperature was raised to room temperature. Derefter blev opløsningsmidlet fjernet ved destillation under formindsket tryk, og remanensen opløstes i 15 ml ethylacetat. Then the solvent was removed by distillation under reduced pressure, and the residue was dissolved in 15 ml of ethyl acetate. Derefter blev den resulterende opløsning successivt vasket med 10 ml vand, 5 vægt-% natriumhydrogencarbonatopløsning og mættet vandig na-triumchloridopløsning og derpå tørret over vandfrit magnesiumsulfat. Thereafter, the resulting solution successively washed with 10 ml of water, 5% sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Opløsningsmidlet blev fjernet ved destillation under formindsket tryk. The solvent was removed by distillation under reduced pressure. Derpå blev remanensen renset ved søjlechro-matografi (silicagel/chloroform), hvorved der blev opnået 0,53 g benzhydrylester af 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocar-bonylamino)phenylacetamido]-3-carbamoyloxymethyl-Δ^-cephem-4-carboxylsyre, smp. Then the residue purified by column chromatography (silica gel / chloroform), thereby obtaining 0.53 g of benzhydryl 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocar-bonylamino ) phenylacetamido] -3-carbamoyloxymethyl-Δ ^ -cephem-4-carboxylic acid. 120-125°C (decomp.), udbytte 71,6%. 120-125 ° C (decomp.), Yield 71.6%.

160 1 5 1 3 3 8 IR (KSr) cm"1 : ^ ^ 34-80, $$S0, 160 5 1 1 3 3 8 IR (KBr) cm "1: ^ ^ 34 to 80, $$ S0,

Dconh 5500» £)C=0 1780» 1-718, 1680 KKR (CDCl^) <~ζ '.Værdier -0,1 (IH, d), 2;05 ClH, d), 2,64 (15H, bs), 3;19 (IH, s), 4;20 (2H, m), 4,86 (IH, d), 5,20 (2H, s), 5,25 (2H, bs), 6,1 (2H, o), 6,3 - 6,9 (6H, m), 8,9 (3H, t) (2) Til en opløsning af 0,2 g af benzhydrylesteren af 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]- 3-carbamoyloxymethyl-A^-eephem-4-carboxylsyre i 5 ml anisol sattes 5 ml trifluoreddikesyre,Under isafkøling, og den resulterende blandede opløsning fik lov at reagere i 30 minutter under isafkøling. Dconh 5500 »£) C = 0 1780» 1-718, 1680 KKR (CDCl ^) <~ ζ '.Værdier -0.1 (H, d), 2; 05 C. @, d), 2.64 (15H, bs), 3; 19 (IH, s), 4; 20 (2H, m), 4.86 (IH, d), 5.20 (2H, s), 5.25 (2H, bs), 6, 1 (2H, o), 6.3 - 6.9 (6H, m), 8.9 (3H, t) (2) To a solution of 0.2 g of the benzhydryl ester of 7- [D (-) - octyl (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] - 3-carbamoyloxymethyl-A ^ -eephem-4-carboxylic acid in 5 ml of anisole was added 5 ml of trifluoroacetic acid under ice cooling and the resulting mixed solution was allowed to react for 30 minutes under ice-cooling. Efter fuldførelse af reaktionen blev opløsningsmidlet fjernet ved destillation under formindsket tryk. After completion of the reaction, the solvent was removed by distillation under reduced pressure. Derefter opløstes remanensen i 15 ml ethylacetat, og til den resulterende opløsning sattes 10 ml vand, hvorefter opløsningens pH-værdi blev indstillet til 7,5 ved tilsætning af natriumhydrogencarbonat under omrøring. Then, the residue was dissolved in 15 ml of ethyl acetate, and to the resulting solution was added 10 ml water and the pH of the solution was adjusted to 7.5 by addition of sodium bicarbonate with stirring. Derefter blev det vandige lag skilt fra, sat til 20 ml ethylacetat og derpå indstillet til en pH-værdi på 2,0 ved tilsætning af 2N saltsyre. Then, the aqueous layer was separated, added to 20 ml of ethyl acetate and then adjusted to a pH of 2.0 by addition of 2N hydrochloric acid. Det organiske lag blev skilt fra, vasket successivt med vand og mættet vandig natriumchlorid-opløsning og derpå tørret over vandfrit magnesiumsulfat. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Opløsningsmidlet blev fjernet ved destillation under formindsket tryk til udfældning af krystaller. The solvent was removed by distillation under reduced pressure to precipitate crystals. De udfældede krystaller blev opsamlet ved filtrering, hvorved der blev opnået 0,13 g 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino )phenylacetamido ] -3-carbamoyloxymethyl-2^-cephem-4-carboxylsyre, smp. The precipitated crystals were collected by filtration, thereby obtaining 0.13 g of 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3-carbamoyloxymethyl-2 ^ -cephem-4-carboxylic acid. 175-180°C (decomp.), udbytte 83,8%. 175-180 ° C (decomp.), Yield 83.8%.

IR (KBr) cm"1 : pIiH 3450, 3350, ])C0NH2 3500, pCm0 177S, 1710, 1670 161 151338 KKH (d^-DMSO) •ητ Værdier 0,15 (IH, d), 0,55 (IH, c), 2,60 (5H, b), 5-,47 (2H, s), 4,28 (2H, c), 4;95 (Hi, d), 5,25 (2H, q), 6,10 (2H, n>, 6;25 - 6,90 (6H, m), 8,9 (3H, t) EKSEMPEL 44 (1) Til en opløsning af 0,32 g D(-)-a-(4-ethyl-2,3-<iioxo-l-piperazinocarbonylamino)phenyleddikesyre i 15 ml vandfrit methylenchlorid sattes Q,1 g N-methylmorpholin. Den resulterende opløsning blev afkølet til -20°C, og til opløsningen sattes en opløsning af 0,11 g ethylchlorcarbonat i 1 ml ethylenchlorid, hvorpå den resulterende blandede opløsning fik lov at reagere ved mellem -10 og -20°C i 1 time. Derefter blev reaktionsopløsningen tildryppet en opløsning af 0,46 g β,β,β-trichlorethylester af 7-amino-3-cephem-3-carboxylsyre i 5 ml methylenchlorid ved -20°C. Efter til-drypningen fik den resulterende blandede opløsning lov at reagere ved mellem -10 og -20°C i 1 time og ved stuetemperatur i 30 minutter. E IR (KBr) cm "1: pIiH 3450, 3350,]) C0NH2 3500, pCm0 177S, 1710, 1670 161 151 338 KKH (d ^ DMSO) Values ​​• ητ 0.15 (IH, d), 0.55 (IH , c), 2.60 (5H, b), 5, 47 (2H, s), 4.28 (2H, c), 4; 95 (H, d), 5.25 (2H, q), 6.10 (2H, n>, 6; 25 to 6.90 (6H, m), 8.9 (3H, t) Example 44 (1) To a solution of 0.32 g of D (-) - a- (4-ethyl-2,3- <iioxo-l-piperazinocarbonylamino) phenyl acetic acid in 15 ml of anhydrous methylene chloride was added Q, 1 g of N-methylmorpholine. the resulting solution was cooled to -20 ° C, and to the solution was added a solution of 0 , 11 g of ethyl chlorocarbonate in 1 ml of methylene chloride, whereupon the resulting mixed solution was allowed to react at between -10 and -20 ° C for 1 hour. Then, the reaction solution was added dropwise a solution of 0.46 g of β, β, β-trichloroethyl ester of 7-amino-3-cephem-3-carboxylic acid in 5 ml of methylene chloride at -20 ° C. After the no-drip, the resulting mixed solution was allowed to react at between -10 and -20 ° C for 1 hour and at room temperature for 30 minutes. E fter fuldførelse af reaktionen blev opløsningsmidlet fjernet ved destillation under formindsket tryk, remanensen blev successivt vasket med 5 vægt-% vandig natriumhydrogencarbonatopløsning og mættet vandig natrium-chloridopløsning og tørret over vandfrit magnesiumsulfat. fter completion of the reaction, the solvent was removed by distillation under reduced pressure, the residue was washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

Derefter blev opløsningsmidlet fjernet ved destillation under formindsket tryk, remanensen blev renset ved søjlechromatografi (silicagel/benzen-ethylacetat), hvorved der blev opnået 0,53 g β,β,β-trichlorethylester af 7-[D(-)-a-(4-ethyl-2,3-dloxo-l-piperazinocarbonylamino)-phenylacetamido]-3-[5-(1-methyl-1,2,3>4-tetrazolyl)thiomethyl]-A^-cephem-4-carboxylsyre, smp. Then the solvent was removed by distillation under reduced pressure, the residue was purified by column chromatography (silica gel / benzene-ethyl acetate), thereby obtaining 0.53 g of β, β, β-trichloroethyl ester of 7- [D (-) - a- ( 4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -phenylacetamido] -3- [5- (1-methyl-1,2,3> 4-tetrazolyl) thiomethyl] -A ^ -cephem-4-carboxylic acid, mp. 125-135°C (decomp.), udbytte 69,6%. 125-135 ° C (decomp.), Yield 69.6%.

IR (KBr) cm"1: } C=0 1780' 1715 ' 1680 162 151338 (2) Til én opløsning-af 0,5 g β,β,β-trichlorethylester af 7-[D-(-) - oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino )phenylacetamido ] - 3- [ 5- (1-methyl-l ,2,3,4-tetrazolyl) thiomethyl-A^-cephem-4-carboxyl-syre sattes 0,5 g zinkstøv og 0,5 ml eddikesyre, og den resulterende opløsning fik lov at reagere i 1,5 timer. Efter fuldførelse af reaktionen blev reaktionsvæsken filtreret, og filtratet blev befriet for opløsningsmidlet ved destillation under formindsket tryk. Derefter opløstes remanensen i 15 ml vand, og den resulterende opløsning blev indstillet til en pH-værdi på 1,5 ved tilsætning af 2N saltsyre til udfældning af krystaller. De udfældede krystaller blev opsamlet ved filtrering, tørret og derpå vasket med ethylacetat, hvorved der blev opnået 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-^-cephem-4-carboxylsyre , smp. I63-I650C (decomp. IR (KBr) cm "1:} C = 0 1780 '1715' 1 680 162 151 338 (2) To a solution of 0.5 g-β, β, β-trichloroethyl ester of 7- [D - (-) - octyl (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] - 3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl-A ^ -cephem-4-carboxylic acid was added 0.5 g of zinc dust and 0.5 ml of acetic acid, and the resulting solution was allowed to react for 1.5 hours. After completion of the reaction, the reaction liquid was filtered and the filtrate was freed from the solvent by distillation under reduced pressure. Then, the residue was dissolved in 15 ml of water, and the resulting solution was adjusted to a pH of 1.5 by addition of 2N hydrochloric acid to precipitate crystals. the deposited crystals were collected by filtration, dried and then washed with ethyl acetate, there was obtained 7 - [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - ^ -cephem-4-carboxylic acid, mp. I63-I650C (decomp. ), udbytte 82,1%. ), Yield 82.1%.

TCK.qRMPKT . TCK.qRMPKT. 45 10,0 g D (- )-oc- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino ) -p-hydro-xyphenyleddikesyre blev suspenderet i 60 ml vandfrit methylenchlo-rid, og der sattes 6,31 g af trimethylsilylchlorid til denne suspension. 45 10.0 g of D (-) -OC- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydro-xyphenyleddikesyre was suspended in 60 ml of anhydrous methylene chloride, and there was added 6.31 g of trimethylsilyl chloride to this suspension. Blandingen blev afkølet til 5° C efterfulgt af dråbevis tilsætning ag 6,04 g triethylamin ved samme temperatur i løbet af 15 minutter og omrøring ved 10 - 15° C i 90 minutter, indtil reaktionen var fuldført. The mixture was cooled to 5 ° C followed by dropwise addition AG 6.04 g of triethylamine at the same temperature over 15 minutes and stirring at 10-15 ° C for 90 minutes until the reaction was complete. Derpå blev reaktionsblandingen afkølet til -20° C, der tilsattes 2,18 g dimethylformamid, og derpå tilsattes dråbevis 3,25 g trichlormethylchlorformiat i løbet af 15 minutter. Then the reaction was cooled to -20 ° C, was added 2.18 g of dimethylformamide, and then was added dropwise 3.25 g of trichloromethyl chloroformate over 15 minutes. Den resulterende blanding fik lov at reagere ved samme temperatur i 120 minutter. The resulting mixture was allowed to react at the same temperature for 120 minutes.

På den anden side blev 10,0 g af 7-amino-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-Z\ ^-cephem-4-carboxylsyre suspenderet i 90 ml vandfrit methylenchlorid, og der sattes trimethylsilylchlorid til denne suspension under isafkøling. On the other hand, 10.0 g of 7-amino-3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] -Z \ ^ -cephem-4-carboxylic acid was suspended in 90 ml of anhydrous methylene chloride and trimethylsilyl chloride was added to this suspension under ice cooling. Til blandingen sattes dråbevis 7,40 gtriethylamin i løbet af 20 minutter, hvorpå den fik lov at reagere ved samme temperatur i 60 minutter. To the mixture was added dropwise 7.40 gtriethylamin over 20 min and then was allowed to react at the same temperature for 60 minutes. Derefter sattes denne blanding dråbevis til den ovenstående reaktionsblanding ved mellem -15 og 10° C i løbet af 30 minutter, og blandingen fik lov at reagere ved samme temperatur i omkring 90 minutter. Then this mixture was added dropwise to the above reaction mixture at between -15 and 10 ° C over 30 minutes and the mixture was allowed to react at the same temperature for about 90 minutes. Efter at reaktionstemperaturen var hævet til 0° C, tilsattes 6,69 g metha- 163 151338 nol. After the reaction temperature was raised to 0 ° C, was added 6.69 g methanol 163 151 338 nol. Blandingen fik lov at reagere yderligere ved 0° C i 30 minutter og hældtes derpå ud i 280 ml vandig opløsning af 10,0 g natriumhydrogencarbonat. The mixture was allowed to react further at 0 ° C for 30 minutes and then poured out into 280 ml of aqueous solution of 10.0 g of sodium bicarbonate. Den resulterende opløsning blev adskilt i et vandigt lag og et organisk lag. The resulting solution was separated into an aqueous layer and an organic layer. Det organiske lag blev extra-heret med 20 ml 3% vandig natriumhydrogencarbonatopløsning, og ekstrakten sattes til det ovennævnte vandige lag. The organic layer was extra-heret with 20 ml of 3% aqueous sodium hydrogen carbonate solution, and the extract was added to the above aqueous layer. Til den kombinerede vandige opløsning sattes 130 ml acetonnitril. To the combined aqueous solution was added 130 ml acetonnitril. Efter at blandingen var indstillet til pH 5,0 ved tilsætning af 6N saltsyre, tilsattes 4 g aktiv kul, og blandingen blev filtreret. After the mixture was adjusted to pH 5.0 by addition of 6N hydrochloric acid was added 4 g of active carbon, and the mixture was filtered. Filtratet blev opvarmet til 40° C, indstillet til pH 2,0 ved tilsætning af 6N saltsyre, omrørt ved 35° C i 120 minutter og ved 25° C i 60 minutter og derpå afkølet med is til udfældning af krystaller. The filtrate was heated to 40 ° C, adjusted to pH 2.0 by addition of 6N hydrochloric acid, stirred at 35 ° C for 120 minutes and at 25 ° C for 60 minutes and then cooled with ice to precipitate crystals. De udfældede krystaller blev opsamlet ved filtrering, vasket med 20 ml 20% vandig aceonitrilopløsning og tørret, hvorved der blev opnået 15,9 g krystaller af 7-[D(-)-oc-(4-ethyl-2,3-dioxo-l-pi-perazinocarbonylamino)-p-hydroxyphenyl-acetamido]-3-[5-(1-me-thyl-1,2,3,4-tetrazolyl)thiomethyl] -Δ ^-cephem-4-carboxylsyre, smp.(dokomp.) 170 - 171° C, udbytte 78,3%. The precipitated crystals were collected by filtration, washed with 20 ml of 20% aqueous aceonitrilopløsning and dried, thereby obtaining 15.9 g of crystals of 7- [D (-) - oc- (4-ethyl-2,3-dioxo- l-pi-perazinocarbonylamino) -p-hydroxyphenyl acetamido] -3- [5- (1-me-thyl-1,2,3,4-tetrazolyl) thiomethyl] -Δ ^ -cephem-4-carboxylic acid. (dokomp.) 170-171 ° C, yield 78.3%.

NMR (dg-acetone τ D20) værdier 8,9 (3H, t), 6,8 - 6,3 (4H, m), 6,2 - 5,9 (7H, m), 5,78 (2H, ABq), 5,04 (IH, d), 4,58 (IH, s), 4,31 (IH, d), 3,08 (4H, A2B2q) EKSEMPEL 46 i 70 ml methylenchlorid suspenderedes 3,5 g 6-[D(-)-a-aminophenyl-acetamido]penicillansyre, og derpå tilsattes 2,2 g triethylamin for at omdanne suspensionen til opløsning. NMR (d₆-acetone τ D20) values ​​of 8.9 (3H, t), 6.8 to 6.3 (4H, m), 6.2 to 5.9 (7H, m), 5.78 (2H, AB q), 5.04 (IH, d), 4.58 (IH, s), 4.31 (IH, d), 3.08 (4H, A2B2q) Example 46 in 70 ml of methylene chloride was suspended 3.5 g of 6 - [D (-) - a-aminophenyl-acetamido] penicillanic acid, and then treated with 2.2 g triethylamine to convert the suspension to dissolve. Til den resulterende opløsning tilsattes dråbevis en opløsning af 2,28 g 4-ethyl-2-oxo-1-piperazinocarbonylchlorid i 10 ml methylenchlorid ved 5 -10° C. Efter at blandingen havde fået lov at reagere i yderligere en time, blev opløsningsmidlet afdestilleret, og remanensen opløst i 30 ml vandig natriumchlorid opløsning. To the resulting solution was added dropwise a solution of 2.28 g of 4-ethyl-2-oxo-1-piperazinocarbonylchlorid in 10 ml of methylene chloride at 5 -10 ° C. After the mixture had been allowed to react for an additional hour, the solvent was distilled off and the residue is dissolved in 30 ml of aqueous sodium chloride solution. Til den resulterende opløsning tilsattes 50 ml acetonitril, og pH-værdien indstilledes til 3,0 med 2N saltsyre. To the resulting solution was added 50 ml of acetonitrile, and the pH was adjusted to 3.0 with 2N hydrochloric acid. Acetonitrillaget blev vasket med en vandig na-triumchloridopløsning, hvorefter opløsningsmidlet blev afdestilleret 164 151338 til opnåelse af 2,61 g (udbytte 50%) rå krystaller. The acetonitrile was washed with an aqueous sodium chloride solution, after which the solvent was distilled off 164 151338, to give 2.61 g (yield 50%) of crude crystals. Krystallerne blev opløst i tetrahydroforan og derpå renset ved hjælp af "Sepha-dex (S)LH-20" (fremstillet af Fine Chemical Company, udviklingsopløsningsmiddel; tetrahydroforan), hvorved der blev opnået 6-[D (-)-a-(4-ethyl-2-oxo-l-piperazinocarbonylamino)phenylacetamido]-penicillansyre, smp. The crystals were dissolved in tetrahydroforan and then purified using "Sephadex (S) LH-20" (manufactured by Fine Chemical Company, developing solvent; tetrahydro front), thereby obtaining 6- [D (-) - a- (4 ethyl-2-oxo-l-piperazinocarbonylamino) phenylacetamido] -penicillanic acid, mp. 169 - 170° C (dekomp.). 169-170 ° C (dec.).

IR (KBr) cm"1;'^=0 1765, 1700 - 1665 NMR (dg-DMSO) ppm værdier : 1.01 ( 3H, t, CH3CH2), 1,40 (3H, s, C2-CH3), 1,55 ( 3H, s, C2-CH3), 2,50 (2H, m, CH3CH2), 2,70 ( 2H, m, piperazinring C3-CH2), 3,28 (2H, s, piperazinring C3-CH2J, 3,60 (2H, m, piperazinring ^ Cg-CH2), 4,18 (IH, s, C3-H), 5,30 - 5,76 (3H, m, C5>6_Ca aH) 7,35 (5H, s, C6H5), 9,20 (IH, d, NH), 10.1 (IH, d, NH), IR (KBr) cm "1; '^ = 0 1765, 1700-1665 NMR (d₆-DMSO) ppm values ​​1.01 (3H, t, CH3CH2), 1.40 (3H, s, C2-CH3), 1, 55 (3H, s, C2-CH3), 2.50 (2H, m, CH3CH2), 2.70 (2H, m, piperazine ring C3-CH2), 3.28 (2H, s, piperazine ring C3-CH2J, 3 , 60 (2H, m, piperazine ring ^ -C-CH 2), 4.18 (IH, s, C3-H), 5.30 to 5.76 (3H, m, C 5> 6_Ca H) 7.35 (5H, s, C6H5), 9.20 (IH, d, NH), 1.10 (IH, d, NH),

De følgende forbindelser blev fremstillet på samme måde som ovenfor ved passende udvælgelse af udgangsforbindelser med formlen (II) og reaktive derivater af forbindelser med formlen (III): 6-[D(-)-a-(4-methyl-2-0X0-l-piperazinocarbonylamino)-phenylacetamido ]penicillansyre, The following compounds were prepared in the same manner as above by appropriately selecting the starting materials of formula (II) and reactive derivatives of compounds of formula (III): 6- [D (-) - a- (4-methyl-2-0X0- L-piperazinocarbonylamino) -phenylacetamido] penicillanic acid,

Smp.: 160 - 164° C (dekomp.) IR (KBr) cm"1: γ C=0 1765, 1700 -1665; 6-[D(-)-cl-(4-n-propyl-2-oxo-l-piperazinocarbonylamino)-phenylacetamido ]penicillansyre, M.p .: 160 - 164 ° C (dec.) IR (KBr) cm "1: γ C = 0 1765, 1700 -1665; 6- [D (-) - Cl- (4-n-propyl-2-oxo -L-piperazinocarbonylamino) -phenylacetamido] penicillanic acid,

Smp.: 164 - 165° C (dekomp.) IR (KBr) cm"1: γ C=Q 1765, 1700 -1665; 6-[D(-)-a-(4-ethyl-2-oxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetamido jpenicillansyre, M.p .: 164 - 165 ° C (dec.) IR (KBr) cm "1: γ C = Q 1765, 1700 -1665; 6- [D (-) - a- (4-ethyl-2-oxo-l -piperazinocarbonylamino) -p-hydroxyphenylacetamido jpenicillansyre,

Smp.: 167 - 169°C (dekomp.) IR (KBr) cm : γ c=0 17?0> 1?00 _ l665 6- [d( -) -cl- (4-ethyl-2-oxo-l-piperazinocarbonylamino) - 2-thienylacetamido)penicillansyre, K5 151338 M.p .: 167 - 169 ° C (dec.) IR (KBr) cm: γ c = 0 17? 0> 1? 00 _ l665 6- [D (-) -Cl (4-ethyl-2-oxo- L-piperazinocarbonylamino) - 2-thienylacetamido) penicillanic acid, K5 151338

Smp.: 164 - 167° C (dekomp.) IR (KBr) cm 1: ^ c=0 1770, 1700 - 1665 EKSEMPEL 47 I 15 ml 80% vandigt tetrahydrofuran suspenderedes 1,0 g 6-[D (-) -oc-aminophenylacetamido Jpenicillansyre-trihydrat, og der tilsattes dråbevis triethylamin under omrøring til indstilling af pH-værdien til 8,0 - 8,5. M.p .: 164 - 167 ° C (dec.) IR (KBr) cm-1: ^ c = 0 1770, 1700-1665 Example 47 In 15 ml of 80% aqueous tetrahydrofuran were suspended 1.0 g of 6- [D (-) - .alpha.-aminophenylacetamido Jpenicillansyre trihydrate, and triethylamine was added dropwise with stirring to adjust the pH to 8.0 to 8.5. Den resulterende opløsning blev afkølet til 10° C, og der tilsattes 530 mg 4-ethyl-3-oxo-l- piperazinocarbonyl chlorid under tildrypning af triethylamin for at holde pH-værdien ved 7,5 - 8,0. The resulting solution was cooled to 10 ° C, to which was added 530 mg of 4-ethyl-3-oxo-L- piperazinocarbonyl chloride during the dropwise addition of triethylamine to maintain the pH at 7.5 to 8.0. Ved den samme temperatur fik reaktionen lov at forløbe i en time, hvorefter tetra-hydrofuranet blev afdestilleret, og der tilsattes 10 ml vand og 15 ml ethyl acetat til remanensen, hvorved denne opløstes i vandet. At the same temperature, the reaction was allowed to proceed for one hour after which tetra-hydrofuranet was distilled off, to which was added 10 ml of water and 15 ml of ethyl acetate to the residue, which was dissolved in this water. Den resulterende opløsning tilsattes fortyndet saltsyre for at indstille pH-værdien til 2,0. The resulting solution was added dilute hydrochloric acid to adjust the pH to 2.0. Derefter blev ethyl acetatlaget skilt fra, vasket grundigt med vand og koncentreret til 2/3 af begyndelsesvolumenet, hvorefter de udfældede krystaller blev opsamlet ved filtrering, hvorved der blev opnået 1,0 g (udbytte 80%) 6-[D(-)-oc-(4-ethyl-3-oxo-l-piperazi-nocarbonylamino)-phenylacetamido]penicillansyre smp. Then, the ethyl acetate layer separated, washed well with water and concentrated to 2/3 of the initial volume, and the precipitated crystals were collected by filtration, thereby obtaining 1.0 g (yield 80%) of 6- [D (-) - octyl (4-ethyl-3-oxo-piperazin-l-nocarbonylamino) -phenylacetamido] penicillanic mp. 190 -191° C. 190 -191 ° C.

IR (KBr) cm"1: / C=0 1770 (^tam), 1735 (-C00H), 1680 - 1620 (-C0NH-). IR (KBr) cm "1: / C = 0 1770 (^ tam), 1735 (-C00H), 1680-1620 (-C0NH-).

På samme måde som beskrevet ovenfor fremstilledes de følgende forbindelser ved passende udvælgelse af udgangsforbindelser med formlen (II) og reaktive derivater- af forbindelser med formlen (III): 6-[D(-)-a-(3-oxo-l-piperazinocarbonylamino)-phenyl-acetamido ]penicillansyr e, In the same manner as described above were prepared the following compounds by proper selection of the starting compounds of the formula (II) and reactive the derivatives of compounds of formula (III): 6- [D (-) - a- (3-oxo-l-piperazinocarbonylamino ) -phenyl-acetamido] penicillansyr e,

Smp.: 172 - 173° C (dekomp.); M.p .: 172-173 ° C (dec.); 6- [Di -)—ex— (4-methyl-3-oxo-l-piperazinocarbonylami-no) -phenylacetamido ]penicillansyre, 6- [Di -) - ex- (4-methyl-3-oxo-l-piperazinocarbonylami-amino) -phenylacetamido] penicillanic acid,

Smp.: 196 - 197° C (dekomp.); M.p .: 196-197 ° C (dec.); 6-[D(-)-a-(4-n-propyl-3-oxo-l-piperazinocarbonyl-amino )phenylacetamido ]penicillansyre, 166 151338 6- [D (-) - a- (4-n-propyl-3-oxo-l-piperazinocarbonyl-amino) phenylacetamido] penicillanic acid, 166 151,338

Smp.: I65 - 166° C (dekomp.); M.p .: I65 - 166 ° C (dec.); 6-[D(-)-a-(4-benzyl-3-oxo-l-piperazinocarbonylami-no )phenylacetamido )penicillansyr e, 6- [D (-) - a- (4-benzyl-3-oxo-l-piperazinocarbonylami-amino) phenylacetamido) penicillansyr e,

Smp.: 148 - 149° C (dekomp.); M.p .: 148-149 ° C (dec.); 6-[D(-)-a-(4-n-butyl-3-oxo-l-piperazinocarbonylami-no )phenylacetamido ]penicillansyre, 6- [D (-) - a- (4-n-butyl-3-oxo-l-piperazinocarbonylami-amino) phenylacetamido] penicillanic acid,

Smp.: 144 - 146° C (dekomp.); M.p .: 144-146 ° C (dec.); 6-[D(- )-a- (4-ethyl-3-oxo-l-piperazinocarbonylamino)-p-hydroxyphenylacetamido ]penicillansyre, 6- [D (-) -a- (4-ethyl-3-oxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid,

Smp.: 189 - 191° C (dekomp.) IR (KBr) cm"1: / C=Q 1775 (lactam), 1735 (-COGH), 1680 - 1620 (-C0NH-); 6- [D (-) - a- (4-ethyl-3-oxo-l-piperazinocarbonylamino)- 2-thienylaeetamido]penicillansyre, M.p .: 189 - 191 ° C (dec.) IR (KBr) cm "1: / C = Q 1775 (lactam), 1735 (-COGH), 1680-1620 (-C0NH-); 6- [D (- ) - a- (4-ethyl-3-oxo-l-piperazinocarbonylamino) - 2-thienylaeetamido] penicillanic acid,

Smp.: 183 - 187° C (dekomp.) IR (KBr) cm"1: γ C=01775 (laatam)> 1735 (-C0QH), 1680 - 1620 (-CCMH). M.p .: 183-187 ° C (dec.) IR (KBr) cm "1: γ C = 01775 (laatam)> 1735 (-C0QH), 1680-1620 (-CCMH).

EKSEMPEL 48 I en blanding af 25 ml vandfrit methylenchlorid og 6 ml dimethyl-formamid opløses 3>44 g natriumsalt af D(-)-α-(4-ethyl-2-oxo-l-piperazinocarbonylamino ) -p-hydroxyphenyleddikesyre, og der til-sattes en dråbe N-methylmorpholin. Example 48 In a mixture of 25 ml of anhydrous methylene chloride and 6 ml of dimethylformamide is dissolved 3> 44 g of sodium salt of D (-) - α- (4-ethyl-2-oxo-l-piperazinocarbonylamino) -p-hydroxyphenylacetic acid, and to-was added a drop of N-methylmorpholine. Den resulterende opløsning blev afkølet til mellem -15 og - 10° C. Til opløsningen sattes dråbevis 1,14 g ethylchlorcarbonat i løbet af 5 minutter, og reaktionen fik lov at foregå i en time ved samme temperatur. The resulting solution was cooled to between -15 and - 10 ° C. To the solution was added dropwise 1.14 g of ethyl chlorocarbonate over 5 minutes and the reaction was allowed to proceed for one hour at the same temperature. Derefter tilsattes 1,22 ml N,O-bis(trimethylsilyl)acetamid, og den resulterende blanding blev afkølet til -20°C. Then there was added 1.22 ml of N, O-bis (trimethylsilyl) acetamide, and the resulting mixture was cooled to -20 ° C.

På den anden side blev 3,28 g 7- amino-3-[5-(l-methyl-l,2,3, 4-tetrazolyl)thiomethyl]--cephem-4-carboxylsyre suspenderet i 50 ml methylenchlorid, og der tilsattes 3»66 ml N,O-bis(tri-methylsilyl)acetamid til opnåelse af en opløsning, som derefter blev afkølet til -20° C. Denne opløsning sattes til den ovennævnte blanding afkølet til -20°C, og den resulterende blanding fik lov at reagere ved mellel 15 og -10° C i to timer og derpå ved mellem -5 og 0° C i to timer timer. On the other hand, 3.28 g of 7-amino-3- [5- (l-methyl-l, 2,3, 4-tetrazolyl) thiomethyl] - cephem-4-carboxylic acid suspended in 50 ml of methylene chloride and was added 3 '66 ml of N, O-bis (trimethylsilyl) acetamide to obtain a solution, which was then cooled to -20 ° C. This solution was added to the above mixture cooled to -20 ° C, and the resulting mixture was allowed to react at mellel 15 and -10 ° C for two hours and then at between -5 and 0 ° C for two hours hours.

167 1 5 1 3 38 167 1 1 5 3 38

Derefter blev opløsningsmidlet afdestilleret, og remanensen tilsattes 30 ml mættet vandig natriumchloridopløsning og 50 ml acetonitril, og den resulterende blanding blev omrørt i en time, hvorefter der tilsattes natriumhydrogencarbonat for at indstille pH-værdien til 3,0. Then the solvent was distilled off and the residue was added 30 ml of saturated aqueous sodium chloride solution and 50 ml of acetonitrile, and the resulting mixture was stirred for one hour, followed by addition of sodium bicarbonate to adjust the pH to 3.0. Acetonitrillaget blev vasket med en mættet vandig natriumchloridopløsning, opløsningsmidlet blev af destilleret. The acetonitrile was washed with a saturated aqueous sodium chloride solution, the solvent was distilled off. Der sattes ether til remanensen, og blandingen blev filtreret, hvorved der blev opnået 3,3 g (udbytte 52,1%) 7- [D(- )-a- (4-ethyl-2-oxo-l-piperazinocarbonylamino) -p-hydroxy-phenylacetamido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl)thiomethyl]-^^-cephem-4-carboxylsyre, smp. Ether was added to the residue and the mixture was filtered, thereby obtaining 3.3 g (yield 52.1%) of 7- [D (-) -a- (4-ethyl-2-oxo-l-piperazinocarbonylamino) - p-hydroxy-phenylacetamido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - ^^ - cephem-4-carboxylic acid. 120° - 123° C (dekomp.). 120 ° - 123 ° C (dec.).

IR (KBr) cm-1: y'' C=0 1770, 1715 - 1660. IR (KBr) cm-1: y '' C = 0 1770, 1715-1660.

EKSEMPEL· 49 (1) I 20 ml vandfrit methylenchlorid suspenderedes 1,72 g 2,3-di-oxo-l-piperazinoeddikesyre, og der tilsattes dråbesvis 2,38 g trimethylsilylchlorid og 2,22 g triethylamin i. denne rækkefølge ved stuetemperatur, hvorefter den resulterende blanding fik lov at reagere i 1,5 timer ved samme temperatur. · Example 49 (1) In 20 ml of anhydrous methylene chloride was suspended 1.72 g of 2,3-di-oxo-l-piperazinoeddikesyre and added dråbesvis 2.38 g of trimethylsilyl chloride and 2.22 g of triethylamine in. That order at room temperature, then the resulting mixture was allowed to react for 1.5 hours at the same temperature. Derefter blev reaktionsopløsningen afkølet til -50° C, og der tilsattes dråbevis 1,0 g trichlormethylchloroformiat, hvorefter opløsningen fik lov at reagere ved samme temperatur i 30 minutter og ved -30° C i en time. Then, the reaction solution was cooled to -50 ° C and there was added dropwise 1.0 g trichlormethylchloroformiat, after which the solution was allowed to react at the same temperature for 30 minutes and at -30 ° C for one hour. Derefter blev opløsningens temperatur hævet til stuetemperatur i løbet af en time for at fuldføre reaktionen. Thereafter, the solution temperature was raised to room temperature over one hour to complete the reaction. Opløsningsmidlet blev derefter afdestilleret under formindsket tryk til opnåelse af krystaller. The solvent was then distilled off under reduced pressure to obtain crystals.

På den anden side blev 1,5 g D8-)-a-aminophenyleddikesyre suspenderet i 30 ml vandfrit methylenchlorid, og der blev tildryppet 2,4 g trimethylsilylchlorid og 2,1 g triethylamin i denne rækkefølge ved stuetemperatur. On the other hand, 1.5 g of D8 -) - a-aminophenylacetic acid suspended in 30 ml of anhydrous methylene chloride, and there was added dropwise 2.4 g of trimethylsilyl chloride and 2.1 g of triethylamine in that order at room temperature. Den resulterende blanding fik lov at reagere ved denne temperatur i en time til fuldførelse af sily-leringen. The resulting mixture was allowed to react at this temperature for one hour to complete the silyl-control function. Derefter blev reaktionsopløsningen afkølet til -40° C, og der tilsattes dråbevis en opløsning af de ovenfor opnåede krystaller i 40 ml vandfrit methylenchlorid. Then, the reaction solution was cooled to -40 ° C, to which was added dropwise a solution of the above-obtained crystals in 40 ml of anhydrous methylene chloride. Den resulterende blanding fik lov at reagere ved denne temperatur i 30 minutter og ved 0° C i en time, hvorefter blandingens temperatur blev hævet til stuetemperatur i løbet af 30 minutter for at fuldføre reaktionen. The resulting mixture was allowed to react at this temperature for 30 minutes and at 0 ° C for one hour, after which the temperature of the mixture was raised to room temperature over 30 minutes to complete the reaction.

168 1 5 1 3 38 168 1 1 5 3 38

Derefter indførtes reaktionsopløsningen i 30 ml vand, og den resulterende blandings pH-værdi blev indstillet til 1,0 med 2N-saltsyre. Then the reaction solution was introduced into 30 ml of water, and the resulting mixture pH was adjusted to 1.0 with 2N-hydrochloric acid. Det organiske lag blev skilt fra og tilsat 30 ml vand, hvorefter blandingens pH-værdi blev indstillet til 8,0 med en mættet vandig natriumhydrogencarbonatopløsning. The organic layer was separated and added 30 ml water and the mixture pH was adjusted to 8.0 with a saturated aqueous sodium bicarbonate solution. Den resulterende blanding fik lov at stå, og det vandige lag blev skilt fra og tilsat 30 ml ethylacetat, og derpå tilsattes 2Nsaltsyre til indstilling pH-værdien til 1,0. The resulting mixture was allowed to stand, and the aqueous layer was separated and mixed with 30 ml of ethyl acetate, and then was added 2Nsaltsyre to adjust the pH to 1.0. Det organiske lag blev skilt fra, vasket med 20 ml mættet natriumchloridopløsning og tørret over vandfrit magnesiumsulfat. The organic layer was separated, washed with 20 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Opløsningsmidlet blev af destilleret under formindsket tryk, og remanensen blev behandlet med diethylether, hvorved der blev opnået 3,0 g (udbytte 85%) hvide krystaller D(-)-a-(4-carboxymethyl-2,3-dioxo-l-piperazinocarbonylamino )phenyleddikesy-re, smp. The solvent was distilled off under reduced pressure and the residue was treated with diethyl ether, thereby obtaining 3.0 g (yield 85%) of white crystals of D (-) - a- (4-carboxymethyl-2,3-dioxo-L- piperazinocarbonylamino) phenylacetic acid, mp. 70 - 75° C. 70-75 ° C.

IR (KBr) cm"1: / ^3300 Y c=01270 (“C00H)> 1710 -1685 (-CON C) NMR (dg-DMSO) ppm værdier: 3,45 - 4,30 (4H, m >CEZ x 2) 4,17 (2H, s, 3CH2), 5,38 (IH, d, ^CH), 7,40 (5H, s, aromatisk proton), 9,80 (IH, d,^NH). IR (KBr) cm "1: / Y ^ 3300 c = 01270 (" C00H)> 1710 -1685 (-CON C) NMR (d₆-DMSO) ppm values: 3.45 to 4.30 (4H, m> CEZ x 2) 4.17 (2H, s, 3CH2), 5.38 (IH, d, CH ^), 7.40 (5H, s, aromatic proton), 9.80 (H, d, ^ NH).

169 151338 169 151338

Den resulterende blandings pH-værdi blev indstillet til 8,0 med natriumhydrogencarbonat. The resulting mixture pH was adjusted to 8.0 with sodium bicarbonate. Det vandige lag blev skilt fra, der tilsattes 30 ml methylenchlorid, og blandingens pH-værdi blev indstillet til 1,0 med 2Nsaltsyre. The aqueous layer was separated, added with 30 ml of methylene chloride, and the mixture pH was adjusted to 1.0 with 2Nsaltsyre. Det organiske lag blev skilt fra, vasket med 20 ml mættet vandige natriumchloridopløsning, og tørret over vandfrit magnesiumsulfat og inddampet under formindsket tryk. The organic layer was separated, washed with 20 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Remanensen blev renset ved søjlechromatografi (elueret med benzen/ethylacetat), hvorved der blev opnået 2,1 g (udbytte 34,8%) hvide krystaller af 7-[D(-)-oc-(4-carboxymethyl-2,3-dioxo-l-pipe-razinocarbonylamino)-phenylacetamido]-3-acetoxymethyl-A ^-cephem- 4-carboxylsyre, smp. The residue was purified by column chromatography (eluted with benzene / ethyl acetate), thereby obtaining 2.1 g (yield 34.8%) of white crystals of 7- [D (-) - oc- (4-carboxymethyl-2,3- dioxo-l-pipe razinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-A ^ -cephem- 4-carboxylic acid. 185 - 190° C (dekomp.) IR (KBr) cm"1: \f NH 3300 V c=o 1775, 1720 - 1665 185-190 ° C (dec.) IR (KBr) cm "1: \ NH F 3300 V c = o 1775, 1720 to 1665

Forbindelser med formlen (IV) og reaktive derivater af forbindelser med formlen (V) blev udvalgt og omsat på samme måde som beskrevet ovenfor til opnåelse af de følgende forbindelser: 7- [D(- )-oc- [4-(2-carboxyethyl)-2,3-dioxo-l-piperazi-nocarbonylamino]phenylacetamido]-3-acetoxymethyl- Δ cephem-4-earboxylsyre. Compounds of formula (IV) and reactive derivatives of compounds of formula (V) were selected and reacted in the same manner as described above to give the following compounds: 7- [D (-) -OC- [4- (2-carboxyethyl ) -2,3-dioxo-l-piperazino-nocarbonylamino] phenylacetamido] -3-acetoxymethyl Δ cephem-4-earboxylsyre.

Smp.: 150 - 155° C (dekomp.) IR (KBr) cm-1: ^/^^1773 (lactam), ' 1720 - 1685 (-CONO; 7-[D(-)-a-(4-carboxymethyl-2,3-dioxo-l-piperazino-carbonylamino )phenylacetamido ]-3- [5- (l-methyl-1,2,3, 4-tetrazolyl)thiomethyl]- A^-cephem-4-carboxylsyre, M.p .: 150 - 155 ° C (dec.) IR (KBr) cm -1: ^ / ^^ 1773 (lactam), '1720-1685 (-CONO; 7- [D (-) - a- (4- carboxymethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido] -3- [5- (l-methyl-1,2,3, 4-tetrazolyl) thiomethyl] - ^ A -cephem-4-carboxylic acid,

Smp.: 170 - 175° C (dekomp.) IR (KBr) cm-1: \/ ¢=01^0 (lac'tam)> ^ 1720 - 1680 (-CON -); M.p .: 170 - 175 ° C (dec.) IR (KBr) cm -1: \ / ¢ = 01 ^ 0 (lac'tam)> ^ 1720-1680 (-CON -); 7-{D(-)-a-[4-(2-carboxyethyl)-2,3-dioxo-l-piperazi-nocarbonylamino]phenylacetamido}3-[5-(l-methyl-1, 2,3,4-tetrazolyl)thiomethyl]-Δ -cephem-4-carboxyl-syre, 7- {D (-) - a- [4- (2-carboxyethyl) -2,3-dioxo-l-piperazino-nocarbonylamino] phenylacetamido} 3- [5- (l-methyl-1, 2,3,4 -tetrazolyl) thiomethyl] -Δ -cephem-4-carboxylic acid,

Smp.: 162 - 165° C (dekomp.) IR (KBr) cm-1: n n1770 (lactam) 1 υ=υ1710 - 1680 (-C0N<); M.p .: 162 - 165 ° C (dec.) IR (KBr) cm-1: n n1770 (lactam) υ 1 = υ1710 - 1680 (-C0N <); 170 151338 7-(d(-)-a-[4-(3-carboxypropyl)-2,3-dioxo-l-pipera-zinocarbonylamino ]phenylacetamido}-3- [5-(l-methyl- 1,2,3,4-tetrazolyl)thiomethyl]-^ -cephem-4-carb°xyl-syre, 170 151338 7- (D (-) - a- [4- (3-carboxypropyl) -2,3-dioxo-l-piperazine zinocarbonylamino] phenylacetamido} -3- [5- (l-methyl-1,2, 3,4-tetrazolyl) thiomethyl] - ^ -cephem-4-carb ° xyl acid,

Smp.: 145° C (dekomp.) IR (KBr) cm-1: v / c=01775 (lactam)> A ~ 1720 - 1680 (-C0NC). M.p .: 145 ° C (dec.) IR (KBr) cm-1: W / C = 01775 (lactam)> A ~ 1720-1680 (-C0NC).

EKSEMPEL 50 (1) I 70 ml vandfrit methylenchlorid suspenderedes 3,4 g D-(-)-phenylglycin, og der tilsattes 6 ml trimethylsilylchlorid, hvorefter der blev tildryppet 6,26 ml triethylamin. Example 50 (1) In 70 ml of anhydrous dichloromethane was suspended 3.4 g of D - (-) - phenylglycine and treated with 6 ml of trimethylsilyl chloride, after which there were added dropwise 6.26 ml of triethylamine. Den resulterende blanding fik lov at reagere ved stuetemperatur i en time. The resulting mixture was allowed to react at room temperature for one hour. Derefter tilsattes 4-éthyl-6S-methyl-2,3-dioxo-l-piperazinocarbonyl-chlorid under isafkøling, og den resulterende fik lov at reagere ved stuetemperatur i 1,5 timer. Then there was added 4-ethyl-6 S-methyl-2,3-dioxo-l-piperazino- carbonyl chloride under ice-cooling, and the resultant was allowed to react at room temperature for 1.5 hours. Til reaktionsproduktet sattes 50 ml vand, og blandingen blev omrørt i en time. To the reaction product was added 50 ml of water and the mixture was stirred for one hour. De udfældede krystaller blev opsamlet ved filtrering, vasket med vand og tørret, hvorefter de blev underkastet azeotrop dehydratisering med 150 ml toluen, hvorved der blev opnået 6,2 g (udbytte 90,78%) D(-)-a- (4-ethyl-6S-methyl-2,3-dioxo-l-piperazinocarbonylamino )phenyl-eddikesyre, IR (KBr) cm”1: >/μϊι3300 ^J®01710. The precipitated crystals were collected by filtration, washed with water and dried, after which they were subjected to azeotropic dehydration with 150 ml of toluene, thereby obtaining 6.2 g (yield 90.78%) of D (-) - a- (4- ethyl-6 S-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl-acetic acid IR (KBr) cm "1:> / ^ μϊι3300 J®01710. 1660 (2) i 10 ml methylenchlorid suspenderedes 0,6 g D(-)-a-(4-ethyl-6S-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre og der tilsattes 0,189 ml N-methyl-morpholin til dannelse af en opløsning. 1660 (2) in 10 ml of methylene chloride was suspended 0.6 g of D (-) - a- (4-ethyl-6 S-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenyl acetic acid and treated with 0.189 ml of N-methyl-morpholine to form a solution. En blanding af 0,18 ml ethylchlorcarbonat og 1 ml methylenchlorid blev dryppet til blandingen ved -15° C. Opløsningen fik lov at reagere ved samme temperatur i 90 minutter og derpå afkølet til -30° C. Til opløsningen sattes dråbevis en opløsning af 0,7 g af triethylaminsaltet af 6-aminopenicillansyre i 10 ml methylenchlorid ved mellem -25 og -30° C i løbet af 10 minutter, Den resulterende opløsning fik lov at reagere ved mellem -25 og -15° C i 60 minutter og derpå ved mellem -15 og 0° C i 30 minutter, hvorefter opløsningsmidlet blev afdestilleret under formindsket tryk, og remanensen blev opløst i 20 ml 1% vandig na- 151338 171 triumhydrogencarbonat opløsning og vasket med ethylacetat. A mixture of 0.18 ml of ethyl chlorocarbonate and 1 ml of methylene chloride was dropped to the mixture at -15 ° C. The solution was allowed to react at the same temperature for 90 minutes and then cooled to -30 ° C. To the solution was added dropwise a solution of 0 , 7 g of the triethylamine salt of 6-aminopenicillanic acid in 10 ml of methylene chloride at between -25 and -30 ° C for over 10 minutes, the resulting solution was allowed to react at between -25 and -15 ° C for 60 minutes and then at between -15 and 0 ° C for 30 minutes, after which the solvent was distilled off under reduced pressure and the residue was dissolved in 20 ml of 1% aqueous sodium hydrogen carbonate 151 338 171 solution and washed with ethyl acetate. Der tilsattes yderligere 30 ml ethylacetat og den resulterende blandings pH-værdi blev indstillet til 2,0 med 2Nsaltsyre under isafkøling. An additional 30 ml of ethyl acetate and the resulting mixture pH was adjusted to 2.0 with 2Nsaltsyre under ice-cooling. Det organiske lag blev skilt fra, vasket grundigt med vand, tørret over vandfrit magnesiumsulfat, og opløsningsmidlet derefter afdestilleret under formindsket tryk, hvorved der blev opnået 0,7 g (udbytte 72,4%) 6-[D(-)-a-(4-ethyl-6S-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido]-penicillansyre. The organic layer was separated, washed well with water, dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure, thereby obtaining 0.7 g (yield 72.4%) of 6- [D (-) - a- (4-ethyl-6 S-methyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -penicillanic acid.

IR (KBr) cm-1: VC=0 1770 ' 1710' 1680 NMR (dg-DMSO) værdier: 8,88 (3H, t, CH3), 8,75 (3H, d, CH3), 8,58 (3H, s, CH3), 8,44 (3H, s, CH3), 5,85 - 6,85 (4H, m, CH2 x 2), 5,84 (IH, s, CH), 4,60 (IH, m, CH), 4,48 - 5,85 (2H, m, CH x 2), 4,32 (IH, d, CH), 2,67 (5H, s, C6H5), 0,79 (IH, d, NH), 0,15 (IH, d, NH) IR (KBr) cm-1:? C = 0 1770 '1710' 1680 NMR (d₆-DMSO)? Values: 8.88 (3H, t, CH 3), 8.75 (3H, d, CH3), 8.58 ( 3H, s, CH 3), 8.44 (3H, s, CH 3), 5.85 to 6.85 (4H, m, CH 2 x 2), 5.84 (IH, s, CH), 4.60 ( H, m, CH), 4.48 to 5.85 (2H, m, CH x 2), 4.32 (IH, d, CH), 2.67 (5H, s, C6H5), 0.79 ( H, d, NH), 0.15 (IH, d, NH)

Den samme procedure som beskrevet ovenfor blev gentaget, undtagen at der anvendtes andre reaktive derivater af forbindelser med formlen (V) i stedet for D(-)-a-(4-ethyl-6S-methyl-2,3-dioxo-l-piperazinocarbonylamino)phenyleddikesyre til opnåelse af de følgende forbindelser: 6-[D(-)-a-(4-ethyl-6S-ethyl-2,3-dioxo-l-piperazino-carbonylamino )phenylacetamido ]-penicillansyre, The same procedure as described above was repeated except for using other reactive derivatives of compounds of formula (V) instead of D (-) - a- (4-ethyl-6 S-methyl-2,3-dioxo-L- piperazinocarbonylamino) phenyl acetic acid, to give the following compounds: 6- [D (-) - a- (4-ethyl-6 S-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 156° C (dekomp.) IR (KBr) vnf1: Yc=0 1780, 1710» l67°'* 6-[D(-)-a-(4-ethyl-6S-n-propyl-2,3-dioxo-l-pipera-zinocarbonylamino)phenylacetamido]-penicillansyre, M.p .: 156 ° C (dec.) IR (KBr) vnf1:? C = 0 1780, 1710 '° L67' * 6- [D (-) - a- (4-ethyl-6 S-n-propyl-2, 3-dioxo-l-piperazine zinocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 150° C (dekomp.) IR (KBr) cm"1: γQ=Q 1775, 1705, 1670; 6- [d(- )-oc- (4-ethyl-6S-n-butyl-2,3-dioxo-l-piperazi-nocarbonylamino)phenylacetamido]-penicillansyre, M.p .: 150 ° C (dec.) IR (KBr) cm "1: γQ = Q 1775, 1705, 1670; 6- [D (-) -OC- (4-ethyl-6 S-n-butyl-2, 3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 125° C (dekomp.) IR (KBr) cm"1: ^0=01775, 1710» 1680; 6-[D(-)-a-(4-ethyl-6S-n-hexyl-2,3-dioxo-l-piperazi- M.p .: 125 ° C (dec.) IR (KBr) cm "1: ^ 0 = 01775, 1710 '1680; 6- [D (-) - a- (4-ethyl-6 S-n-hexyl-2, 3-dioxo-l-piperazi-

. . I IN

172 151338 nocarbonylamino )phenylacetamido ]-penicillansyre, 172 151338 nocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 125° C (dekomp.) IR (KBr) cm"1: γο=0 1780, 1720 - 1680; 6- [D(-)-cc- (4-eth.yl-5S-meth.yl-2,3-dioxo-l-piperazino-carbonylamido)phenylacetamido]-penicillansyre, M.p .: 125 ° C (dec.) IR (KBr) cm "1: γο = 0 1780, 1720-1680; 6- [D (-) - CC- (4-eth.yl-5S-meth.yl- 2,3-dioxo-l-piperazino-carbonylamido) phenylacetamido] -penicillanic acid,

Smp.: 156 - 157° C (dekomp.) IR (KBr) cm"1: \fc=0 1770 ' 1705' 16705 6- [D(-)-oc- (4-ethyl-6R-methyl-2,3-dioxo-l-piperazi-nocarbonylamino )phenylacetamido ]-penicillansyr e, M.p .: 156 - 157 ° C (dec.) IR (KBr) cm "1: \ fc = 0 1770 '1705' 16705 6- [D (-) - oc- (4-ethyl-6R-methyl-2, 3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillansyr e,

Smp.: 155° C (dekomp.) IR (KBr) cm"1: ^c=0 1780, 17°5, l680; 6- [D (-)-a- (4-ethyl-6R-ethyl-2,3-dioxo-l-piperazino-carbonylamino )phenylacetamido ]-penicillansyr e, M.p .: 155 ° C (dec.) IR (KBr) cm "1: ^ c = 0 1780, 17 no 5, L680; 6- [D (-) - a- (4-ethyl-6R-Ethyl-2 , 3-dioxo-l-piperazino-carbonylamino) phenylacetamido] -penicillansyr e,

Smp.: 154° C (dekomp.) IR (KBr) cm"1: yc=Q 1775, 1705, 1675; 6- [D(- )-a- (4-ethyl-6R-n-propyl-2,3-dioxo-l-piperazi-nocarbonylamino )phenylacetamido ]-penicillansyre, M.p .: 154 ° C (dec.) IR (KBr) cm "1:? C = Q 1775, 1705, 1675; 6- [D (-) -a- (4-ethyl-6 R-n-propyl-2, 3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 155° C (dekomp.) IR (KBr) cm"1: YC=Q 1780, 1705, 1670; 6-[D(-)-a-(4-ethyl-6R-n-butyl-2,3-dioxo-l-piperazi-nocarbonylamino )phenylacetamido ]-penicillansyre, M.p .: 155 ° C (dec.) IR (KBr) cm "1: YC = Q 1780, 1705, 1670; 6- [D (-) - a- (4-ethyl-6 R-n-butyl-2, 3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 125° C (dekomp.) IR (KBr) cm"1: YC=Q 1780, 1705, 1680, 1675; 6-[D(- )-oc- (4-ethyl-6R-n-hexyl-2,3-dioxo-l-piperazi-nocarbonylamino)phenylacetamido]-penicillansyre, M.p .: 125 ° C (dec.) IR (KBr) cm "1: YC = Q 1780, 1705, 1680, 1675; 6- [D (-) -OC- (4-ethyl-6 R-n-hexyl 2,3-dioxo-l-piperazino-nocarbonylamino) phenylacetamido] -penicillanic acid,

Smp.: 121° C (dekomp.) IR (KBr) cm"1: y"c=0 1785» 1710' 1685; M.p .: 121 ° C (dec.) IR (KBr) cm "1: Y 'C = 0 1785' 1710 '1685; 6-[D(-)-a-(4-ethyl-5R-methyl-2,3-dioxo-l-piperazino-carbonylamino )phenylacetamido ]-penicillansyr e, 6- [D (-) - a- (4-ethyl-5R-methyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido] -penicillansyr e,

Smp.: 150 - 152° C (dekomp.) IR (KBr) cm"1: γ C=Q 1780, 1710, 1670. M.p .: 150-152 ° C (dec.) IR (KBr) cm "1: γ C = Q 1780, 1710, 1670.

EKSEMPEL 51 Example 51

Forbindelser med formlen (II) eller (IV) og reaktive derivater af forbindelser med formlen (III) eller (V) blev udvalgt og omsat på samme måde som beskrevet under (1) eller (2) i de ovenstående eksempler til opnåelse af de følgende forbindelser: 173 151338 6-[D(-)-a-(4-benzyl-2-oxo-l-piperazinocarbonylamino)-phenylacetamido jpenicillansyre, Compounds of formula (II) or (IV) and reactive derivatives of compounds of formula (III) or (V) were selected and reacted in the same manner as described in (1) or (2) in the above Examples to give the following compounds: 173 151338 6- [D (-) - a- (4-benzyl-2-oxo-l-piperazinocarbonylamino) -phenylacetamido jpenicillansyre,

Smp.: 146 - 147° C (dekomp.); M.p .: 146-147 ° C (dec.); pivaloyloxymethyl-6-[D(-)-a-(4-acetyl-2-oxo-l-pipe-razinocarbonylamino )phenylacetamido ]-peniclllanat, pivaloyloxymethyl 6- [D (-) - a- (4-acetyl-2-oxo-l-pipe razinocarbonylamino) phenylacetamido] -peniclllanat,

Smp.: 159 - 162° C (dekomp.) IR (KBr) cm"1: '(CaQ 1775 - 1740, 1710 - 1650; 6-[D(-)-a-(4-cyclohexyl-2,3-dioxo-l-piperazinocarbo-nylamino)phenylacetamido]penicillansyre, M.p .: 159 - 162 ° C (dec.) IR (KBr) cm "1: '(CAQ 1775-1740, 1710-1650; 6- [D (-) - a- (4-cyclohexyl-2,3- dioxo-l-piperazinocarbo-nylamino) phenylacetamido] penicillanic acid,

Smp.: 166 - 167° C (dekomp.) IR (KBr) cm”1: ^C=0 1780' 1730' 1710 ' 16705 6-[D(-)-a-(4-benzyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenylacetamido]penicillansyre, M.p .: 166 - 167 ° C (dec.) IR (KBr) cm "1: ^ C = 0 1780 '1730' 1710 '16705 6- [D (-) - a- (4-benzyl-2,3- dioxo-l-piperazinocarbonyl-amino) phenylacetamido] penicillanic acid,

Smp.: 154 - 155° C (dekomp.) IR (KBr) cm"1: \/Q=0 1775, 1705, 1685, 1670; 6- [D(-)-a- (2,3-dioxo-l-piperazinocarbonylamino)-phenylacetamido jpenicillansyre, M.p .: 154 - 155 ° C (dec.) IR (KBr) cm "1: \ / Q = 0 1775, 1705, 1685, 1670; 6- [D (-) - a- (2,3-dioxo- L-piperazinocarbonylamino) -phenylacetamido jpenicillansyre,

Smp.: 154 - 156° C (dekomp.) IR (KBr) cm"1: ^c==0 1770, 1710, 1670; 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino)-2-thienylacetamido jpenicillansyre, M.p .: 154 - 156 ° C (dec.) IR (KBr) cm "1: ^ c == 0 1770, 1710, 1670; 6- [D (-) - a- (4-ethyl-2,3- dioxo-l-piperazinocarbonyl-amino) -2-thienylacetamido jpenicillansyre,

Smp.: 152 - 153° C (dekomp.) IR (KBr) cm"1: '(Q=Q 1775, 1720 - 1660 NMR (dgDMSO)Tvserdier: 8,91 (3H, t, CH3), 8,56 (3H, s, CHj), 8,42 (3H, s, CH3), 6,35 - 6,80 (4H, m, (¾ x 2), 5,95 - 6,20 (2H, m, CH2), 5,80 (IH, s, CH), 4,45 - 4,55 (2H, m, CH x 2), 4,05 (1H, d, CH), 2,89 - 3,13 (2H, m, CH x 2), 2,57 - 2,58 (1H, m, CH), 0,75 (IH, d, NH), 0,25 (IH, d, NH); 1” 151338 IR (KBr) om-1: yc=01765, 1710 - 1630; 6- [d(- )-a- (4-n-dodecyl-2,3-dioxo-l-piperazinocarbo-nylamino )phenylacetamido Jpenicillansyre, M.p .: 152-153 ° C (dec.) IR (KBr) cm "1: '(Q = Q 1775, 1720-1660 NMR (dgDMSO) Tvserdier: 8.91 (3H, t, CH 3), 8.56 (3H, s, CH), 8.42 (3H, s, CH 3), 6.35 to 6.80 (4H, m, (¾ x 2), 5.95 to 6.20 (2H, m, CH 2 ), 5.80 (IH, s, CH), 4.45 to 4.55 (2H, m, CH x 2), 4.05 (1H, d, CH), 2.89 to 3.13 (2H , m, CH x 2), 2.57 to 2.58 (1H, m, CH), 0.75 (IH, d, NH), 0.25 (IH, d, NH); 1 "151,338 IR ( KBr) on-1:? c = 01765, 1710-1630; 6- [d (-) -a- (4-n-dodecyl-2,3-dioxo-l-piperazinocarbo-nylamino) phenylacetamido Jpenicillansyre,

Smp.: 114 - 116° C (dekomp.); M.p .: 114-116 ° C (dec.); indanyl-6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazino-carbonylamino)phenylacetamido]penicillanat, indanyl-6- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido] penicillanate,

Smp.: 95 - 100° C (dekomp.) IR (KBr) cm"1: 3300 ^c=0 1780, 1710, 1690 - 1670; 6-[D(- )-oc-(4-benz oyloxyethyl-2,3-dioxo-1-pip eraz ino-carbonylamino )phenylacetamido ]penicillansyre, M.p .: 95-100 ° C (dec.) IR (KBr) cm "1: 3300 ^ c = 0 1780, 1710, 1690-1670; 6- [D (-) -OC- (4-2 benz-benzoyloxyethyl , 3-dioxo-1-pip eraz ino-carbonylamino) phenylacetamido] penicillanic acid,

Smp.: 175 - 180° C (dekomp.) IR (KBr) om'1; M.p .: 175-180 ° C (dec.) IR (KBr) om'1; yc=0 ^73,.1730, 1720 -1660; yc = 0 ^ 73, .1730, 1720 -1660; 6—[D(—)-a-(4-p-hydroxyethyl-2,3-dioxo-l-piperazino-carbonylamino )phenylacetamido jpenicillansyre, 6- [D (-) - a- (4-p-hydroxyethyl-2,3-dioxo-l-piperazino-carbonylamino) phenylacetamido jpenicillansyre,

Smp.: 183 - 184° C (dekomp.); M.p .: 183-184 ° C (dec.); 6- [D( -) -a- (4-isovaleryloxyethyl-2,3-dioxo-l-pipera-zinocarbonylamino )phenylacetamido ]penicillansyre, 6- [D (-) -a- (4-isovaleryloxyethyl-2,3-dioxo-l-piperazine zinocarbonylamino) phenylacetamido] penicillanic acid,

Smp.: 105 - 110° C (dekomp.) IR (KBr) cm"*1: γσ=0 1775, 1730, 1720 - 1640. M.p .: 105-110 ° C (dec.) IR (KBr) cm "* 1: γσ = 0 1775, 1730, 1720-1640.

EKSEMPEL 52 Example 52

Forbindelser med formlen (V), (IV) eller (VI) og reaktive derivater af forbindelser med formlen (III) eller (V) eller forbindelser med formlen (VII) blev udvalgt og omsat på samme måde som beskrevet under (1), (2) eller (3) i de ovenstående eksempler til opnåelse af de følgende forbindelser: 7- [D(-)-a-(4-n-butylaminocarbonyl-2,3-dioxo-l-pipe-razinocarbonylamino )phenylacetamido ]-3- [5- (l-methyl- 1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylsyre, Compounds of formula (V), (IV) or (VI) and reactive derivatives of compounds of formula (III) or (V) or compounds of formula (VII) were selected and reacted in the same manner as described in (1), ( 2) or (3) in the above examples to give the following compounds: 7- [D (-) - a- (4-n-butylaminocarbonyl-2,3-dioxo-l-pipe razinocarbonylamino) phenylacetamido] -3 - [5- (l-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid,

Smp.: 144° C (dekomp.); M.p .: 144 ° C (dec.); 7_[d(-)(4-ethyl-2,3-dioxo-l-piperazinocarbonyla-mino )phenylacetamido ]-3-n-propylthiomethyl- Δ^-cephem- 4-carboxylsyre, 7. [D (-) (4-ethyl-2,3-dioxo-l-piperazinocarbonyla-Mino) phenylacetamido] -3-n-propylthiomethyl- Δ ^ -cephem- 4-carboxylic acid,

Smp.: 155 - 157° C (dekomp.); M.p .: 155-157 ° C (dec.); 151338 175 7-[D(-)-α-(4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenylacetamido]-3-carboxymethylthiomethyl-Δ3 -cephem-4-carboxylsyre, 151338 175 7- [D (-) - α- (4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino) phenylacetamido] -3-carboxymethylthiomethyl-Δ3 -cephem-4-carboxylic acid,

Smp.: 135 - 137° C (dekomp.); M.p .: 135-137 ° C (dec.); phthalidyl-7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazi-nocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-A^-cephem- 4-carboxylat, phthalidyl 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazino-nocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 , 4-tetrazolyl) thiomethyl] -A ^ -cephem- 4-carboxylate,

Smp.: 152 - 155° C (dekomp.) IR (KBr) cm-1: 3300 yc=0 1780, 1715, 1670; M.p .: 152-155 ° C (dec.) IR (KBr) cm -1: 3300? C = 0 1780, 1715, 1670; 7-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylami-no)-2-thionylacetamido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl )thiomethyl]-å ^-cephem-4-carboxylsyre, 7- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylami-amino) -2-thionylacetamido] -3- [5- (1-methyl-l, 2,3,4 -tetrazolyl) thiomethyl] -AA ^ -cephem-4-carboxylic acid,

Smp.: I60 - 162° C (dekomp.) IR (KBr) cm-1: 1770, 1710 - 1660; M.p .: I60 - 162 ° C (dec.) IR (KBr) cm-1: 1770, 1710-1660; 7-[D(-)-a-(4-p-chlorethyl-2,3-dioxo-l-piperazinocar-bonylami.no) -p-hydroxyphenylacetamido ]-3- [5- (1-methyl- 1,2,3,4-tetrazolyl)thiomethyl]- Δ^-cephem-4-carboxyl-syre, 7- [D (-) - a- (4-p-chloroethyl-2,3-dioxo-l-piperazinocar-bonylami.no) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2 , 3,4-tetrazolyl) thiomethyl] - Δ ^ -cephem-4-carboxylic acid,

Smp.: 193 - 195° C (dekomp.); M.p .: 193-195 ° C (dec.); 7-[D-)-a-(4-allyl-2,3-dioxo-l-piperazinocarbonylami-no)-p-hydroxyphenylacetamido]-3-[5-(1-methyl-l,2,3, 4-tetrazolyl)thiomethyl]- zs3 -cephem-4-carboxylsyre, 7- [D -) - a- (4-Allyl-2,3-dioxo-l-piperazinocarbonylami-amino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-l, 2,3, 4- tetrazolyl) thiomethyl] - ZS3 -cephem-4-carboxylic acid,

Smp.: 183 - 185° C (dekomp.); M.p .: 183-185 ° C (dec.); 7-[D(-)-a-(2,3-dioxo-l-piperazinocarbonylamino) -phe-nylacetamido]-3-[5-(1-methyl-l,2,3,4-tetrazolyl)-thiomethyl]- A ^-cephem-4-carboxylsyre, 7- [D (-) - a- (2,3-dioxo-l-piperazinocarbonylamino) -Phe-nylacetamido] -3- [5- (1-methyl-l, 2,3,4-tetrazolyl) thiomethyl] - A ^ -cephem-4-carboxylic acid,

Smp.: I53 - 157° C (dekomp.); M.p .: I53 - 157 ° C (dec.); valeryloxymethyl-7- [D(-)-oc- (4-ethyl-2,3-dioxo-l-pi-perazinocarbonylamino) -p-hydroxyphenylacetamido ] - 3-[5-(1-methyl-l,2,3»4-tetrazolyl)thiomethyl]-A ^-cephem-4-carboxylat, valeryloxymethyl 7- [D (-) - oc- (4-ethyl-2,3-dioxo-l-pi-perazinocarbonylamino) -p-hydroxyphenylacetamido] - 3- [5- (1-methyl-l, 2,3 '4-tetrazolyl) thiomethyl] -A ^ -cephem-4-carboxylate,

Smp.: 105 - 110° C (dekomp.); M.p .: 105-110 ° C (dec.); pivaloyloxymethyl-7- [D(- )-a- (4-ethyl-2,3-dioxo-i-pi-perazinocarbonylamino) -p-hydroxyphenylacetamido ]- 3- [5- (1-methyl-l ,2,3» 4-tetrazolyl)thiomethyl]-/\ ^-cephem-4-carboxylat, pivaloyloxymethyl 7- [D (-) -a- (4-ethyl-2,3-dioxo-i-pi perazinocarbonylamino) -p-hydroxyphenylacetamido] - 3- [5- (1-methyl-l, 2,3 '4-tetrazolyl) thiomethyl] - / \ ^ -cephem-4-carboxylate,

Smp.: 110 - 115° C (dekomp.); M.p .: 110-115 ° C (dec.); 151338 176 isopropoxymethyl-7-[D(-)-α-(4-ethyl-2,3-dioxo-l-pi-perazinocarbonylamino)-p-hydr oxyphenylacetamido]- 3- [5- (1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-cephem-4-carboxylat, 151338 176 isopropoxymethyl-7- [D (-) - α- (4-ethyl-2,3-dioxo-l-pi-perazinocarbonylamino) -p-hydr oxyphenylacetamido] - 3- [5- (1-methyl-1, 2,3,4-tetrazolyl) thiomethyl] -cephem-4-carboxylate,

Smp.: 115 - 120° C (dekomp.) EKSEMPEL 53 I 20 ml vandfrit methylenchlorid suspenderedes 1,72 g 2,3-dioxo-1-piperazinoeddikesyre, og der tilsattes 3,25 g trimethylsilyl-chlorid og derpå 2,93 g triethylamin ved 5° C, hvorefter blandingen fik lov at reagere ved stuetemperatur i en time. M.p .: 115-120 ° C (decomp.) Example 53 In 20 ml of anhydrous methylene chloride was suspended 1.72 g of 2,3-dioxo-1-piperazinoeddikesyre, to which was added 3.25 g of trimethylsilyl chloride and then 2.93 g of triethylamine at 5 ° C, after which the mixture was allowed to react at room temperature for one hour. Reaktionsopløsningen blev derefter afkølet til -50° C, der tilsattes 1,1 g trichlormethylchlorformiat, og temperaturen af den resulterende blanding blev hævet til stuetemperatur i løbet af en time, hvorefter blandingen fik lov at reagere ved denne temperatur i en time. The reaction solution was then cooled to -50 ° C, was added 1.1 g of trichloromethyl chloroformate, and the temperature of the resulting mixture was raised to room temperature over one hour after which the mixture was allowed to react at this temperature for one hour. Opløsningsmidlet blev derefter fjernet ved destillation under formindsket tryk til opnåelse af hvide krystaller. The solvent was then removed by distillation under reduced pressure to give white crystals.

På den anden side blev 3,49 g 6-[D(-)-a-aminophenylacetamido]-penicillansyre suspenderedes i 40 ml 50% vandfrit tetrahydro-furan, og der tilsattes 1,85 g natriumhydrogencarbonat til dannelse af en opløsning, som derpå blev afkølet til -5° C. Til denne opløsning sattes, langsomt en opløsning af de ovenfor opnåede krystaller i 15 ml tetrahydrofuran, og reaktionen fik lov at foregå i en time ved 5 - 7° C. Derefter blev det organiske opløsningsmiddel fjernet ved destillation under formindsket tryk, og der sattes 15 ml ethylacetat til remanensen. On the other hand, 3.49 g of 6- [D (-) - alpha-aminophenylacetamido] -penicillanic acid was suspended in 40 ml of 50% anhydrous tetrahydrofuran, to which was added 1.85 g of sodium hydrogen carbonate to form a solution, which is then was cooled to -5 ° C. to this solution was added, slowly, a solution of the above-obtained crystals in 15 ml of tetrahydrofuran, and the reaction was allowed to proceed for one hour at 5-7 ° C. Then the organic solvent was removed by distillation under reduced pressure, and there was added 15 ml of ethyl acetate to the residue. Efter henstand blev det vandige lag skilt fra, tilsat 50 ml ethylacetat, og blandingens pH-værdi blev indstillet til 2 ved 2Nsaltsyre, hvorefter det organiske lag blev skilt fra. After standing, the aqueous layer separated, added with 50 ml of ethyl acetate, and the mixture pH was adjusted to 2 by 2Nsaltsyre, then the organic layer was separated. Dette blev vasket med 10 ml mættet natriumchloridopløsning, og tørret over vandfrit magnesiumsulfat og opløsningsmidlet derpå fjernet ved destillation under formindsket tryk. This was washed with 10 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate and the solvent was then removed by distillation under reduced pressure. Remanensen blev behandlet med diethyl-ether, hvorved der blev opnået 2,74 (udbytte 50,1%) 6-[D(-)-a-(4-carboxymethyl-2,3-dioxo-l-piperazinocarbonylamino )phenylacet-amido jpenicillansyre, IR (KBr) cm"1: 1780, 1720, 1690 - 1670 177 151538 MR (dg-DMSO) ppm værdier: 1,4 (3H, s, CH3), 1,55 (3H, s, CH,,), 3,4- 4,0 (4H, m, CH2 x 2), 4,15 (IH, s, CH), 4,18 (2H, s, CH2), 5,3- 5,75 (3H, m, CH x 3), 7,32 (5H, bs, aromatisk proton), 9,22 (IH, d, NH), 9,75 (IH, d, NH). The residue was treated with diethyl ether to obtain 2.74 (yield 50.1%) of 6- [D (-) - a- (4-carboxymethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacet amido- jpenicillansyre, IR (KBr) cm "1: 1780, 1720, 1690-1670 177 151 538 MR (d₆-DMSO) ppm value: 1.4 (3H, s, CH 3), 1.55 (3H, s, CH ,, ), 3,4- 4,0 (4H, m, CH 2 x 2), 4.15 (IH, s, CH), 4.18 (2H, s, CH2), 5,3- 5.75 (3H , m, CH × 3), 7.32 (5H, bs, aromatic protons), 9.22 (IH, d, NH), 9.75 (IH, d, NH).

På samme måde som beskrevet ovenfor fremstilledes følgende forbindelser : 6-[D(-)-a-(4-carboxymethyl-2,3-dioxo-l-piperazino-carbonylamino)-p-hydroxyphenylacetamido]penicillan-syre, In the same manner as described above the following compounds: 6- [D (-) - a- (4-carboxymethyl-2,3-dioxo-l-piperazino-carbonylamino) -p-hydroxyphenylacetamido] penicillanic acid,

Smp.: 191 - 195° C (dekomp.) IR (KBr) cm"1: ^c=0 1770, 1715, 1700 - 1670; 6-[D(-)-a-(4-V- carboxy-n-propyl-2,3-dioxo-l-pipe-razinocarbonylamino )phenylac et amido ]penicillansyre, M.p .: 191 - 195 ° C (dec.) IR (KBr) cm "1: ^ c = 0 1770, 1715, 1700-1670; 6- [D (-) - a- (4-carboxy-N- n -propyl-2,3-dioxo-l-pipe razinocarbonylamino) phenylac an amido] penicillanic acid,

Smp.: 170° C (dekomp.) IR (KBr) cm"1: ^C=Q 1775, 1715, 1710 - 1670. M.p .: 170 ° C (dec.) IR (KBr) cm "1: ^ C = Q 1775, 1715, 1710-1670.

KKftttMPEL 54 KKftttMPEL 54

Forbindelserne med formlen (II) eller (IV) og reaktive derivater af forbindelser med formlen (III) eller (V) blev udvalgt og omsat på samme måde som beskrevet under (1) eller (2) i de ovenstående eksempler til opnåelse af 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino)phenylacetamido]penicillansyre med de følgende substituenter som R1 i formlen (I) 151338 178 2 Smeltepunkt The compounds of formula (II) or (IV) and reactive derivatives of compounds of formula (III) or (V) were selected and reacted in the same manner as described in (1) or (2) in the above Examples to give 6- [D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonyl-amino) phenylacetamido] penicillanic acid having the following substituents as R 1 in formula (I) 151 338 178 2 M.p.

R (Dekomp.) 0 C R (dec.) C 0

-CH20C2H5 125 - 136 -ch2oc-^o> m. uo o -CH20(CH2)2CH3 135 - 137 -CH20(CH2)5CH5 90 - 95 -CH2OCH2CH<™3 95 - 97 -CH20C2H5 125-136 -ch2oc- ^ o> m. O uo -CH20 (CH2) 2CH3 135-137 -CH20 (CH2) 5CH5 90-95 -CH2OCH2CH <3 ™ 95-97

Ull-7 Ull-7

D D

7°¾ -CH20CH2C^ CH3 108 - 112 7 ° -CH20CH2C ¾ ^ CH3 108-112

\cEL \ Cel

5 126 . 5,126. 130 nch3 -CH20CH<^3ch 80 - 83 IU- 179 151338 -CE^CR^2^ 81 - 84 _<¥*5__ /¾ ~CH2OC <-CH3 129 - 133 \ch3 -CH 0(CH2)3CH3 65 - 67 ch3 /CH3 -ch-o-ch2ch< 3 104,5 CH3 CH3 /CH, -CH-0-CH2CH 70 - 75 c2h5 3 -CH-0CH2CH3 gg 130 NCH3 -CH20CH <^ 3 CH 80-83 IU- 179 151 338 -CE ^ CR ^ 2 ^ 81-84 _ <* ¥ 5__ / ¾ ~ CH 2 OC <-CH3 129-133 \ 0 CH3 CH (CH2) 3CH3 65 - 67 CH 3 / CH 3 -CH-O-CH 2 CH <104.5 3 CH 3 CH 3 / CH, -CH-0-CH 2 CH 70-75 3 C2H5 -CH 0CH2CH3-gg

CH CH

ch3ch3 -CH-0(CH2)3CH3 CH 175 - 180 rv. ch3ch3 -CH-0 (CH2) 3CH3 CH 175-180 RV.

ch3ch3 /CH3 -CH-0CH—CH^ 175 _ 1?7 ch3ch3 / CH 3 -CH-CH-0CH ^ 175 _ 1? 7

CH CH

/\ CH,CH, 5 3 /CH, -CH9OCCH< 5 185 - 189 2 0 -ch2oc(ch2)3ch3 176 _ 1?9 0 -CHOC(CH«),CB, I j 233 105 - 110 ΓΗ / \ CH, CH, 5 3 / CH, -CH9OCCH <5185 to 189 2 0 -CH 2 OC (CH2) 3CH3 176 _ 1? 9 0 -CHOC (CH '), CB, in J. 233105-110 ΓΗ

Claims (5)

  1. 1. Analogifremgangsmåde til fremstilling af racemiske eller optisk aktive penicilliner eller cephalosporiner med den almene formel: (0)nz™ir™\ AN NC-NH-CH-CONH—j—f /-mu· JXj . 1. A process for the preparation of racemic or optically active penicillins or cephalosporins of the general formula: (0) NZ ™ IR ™ \ AN NC-NH-CH-CONH-j-f / -mu · JXj. rZ r3 R 0 COOR1 hvori R1 betyder hydrogen, en kation, som danner et ikke-toxisk salt, eller en phthalidyl-, indanyl, (C1_4)alkoxy-(C1_4)alkyl-, (C2_4) acyloXy- (ci_4)alkyl·-, piperidino-(C]L_4)alkyl- eller morpho- lino-(C1-4)alkylgruppe, n er 1 eller 2, idet oxygruppen eller -grupperne kan være vilkårligt tilknyttet 2- og 3-positionerne i 2 3 piperazinnngen, R og R kan være ens eller forskellige og hver for sig betyder hydrogen eller en (C1_g)alkylgruppe, A betyder hydrogen, en (C2_4)alkenyl-, (C5_7)cycloalkyl-, phenyl-, benzyl-, (C1_4)alkylaminocarbonyl-, (C-L_7)acyloxy-(C1_4)alkyl- eller (Ci_4)alkylsulfonylgruppe, en (C^_^g)acylgruppe, som kan være substitueret med chlor, eller en (C^^) alkyl gruppe, som kan være substitueret med chlor, hydroxy eller carboxyl,betyder ch3 V eller | rZ R 3 COOR 1 R 0 wherein R 1 is hydrogen, a cation which forms a non-toxic salt, or the phthalidyl, indanyl, (C1-4) alkoxy- (C1-4) alkyl, (C2-4) acyloxy (ci_4) alkyl · - , piperidino (C] L_4) alkyl or morpholinyl linolenic (C 1-4) alkyl group, n is 1 or 2, the oxy group or groups may be arbitrarily assigned to the 2- and 3-positions of the 2 3 piperazinnngen, and R R may be the same or different and each represents hydrogen or (C1_g) alkyl group, a is hydrogen, a (C2-4) alkenyl, (C5_7) cycloalkyl, phenyl, benzyl, (C 1-4) alkylaminocarbonyl, (C -L_7) acyloxy (C1-4) alkyl or (Ci_4) alkylsulfonyl group, a (C ^ _ ^ g) acyl group which may be substituted by chlorine, or a (C ^^) alkyl group which may be substituted by chlorine, hydroxyl or carboxyl, V is CH3 or | ch3 5=c-ch2r^ hvor R4 betyder hydrogen, en azidogruppe, en pyridinium-gruppe, en (C-L_Zf)alkoxy-, (C-L_Zf)acyloxy- eller carbamoyloxy-gruppe, en (C-L_^) alkoxythiocarbonylthiogruppe, en (C-L_^)al-kylthiogruppe, som kan være substitueret med carboxyl, eller 151338 1S1 en oxazolylthio-, thiazolylthio-, thiazolinylthio-, imidazolyl-thio-, pyridazinylthio-, pyrimidinylthio-, oxadiazolylthid-, thiadiazolylthio-, triazolylthio-, tetrazolylthio-, piperazi-nylthiocarbonylthio-, isoxazolylcarbonylthio-, (pyridyl-1-oxid)thio- eller (5-oxo-2,5-dihydro-l,2,4-triazinyl)thiogrup-pe, som kan være substitueret med (C^_^>alkyl, og R° betyder en (C5_(g)cycloalkadienyl-, thienyl-, phenyl- eller hydroxy-phenylgruppe, kendetegnet ved, (a) at en racemisk eller optisk aktiv forbindelse med den alalmene formel: R7-NH-CH-CONE-rf S ^ (χχ) i 5 R5 0 i C00Rla 5 la hvori R og Z har den ovenstående betydning, R betyder hydrogen , en saltdannende kation eller en beskyttende gruppe, som er kendt inden for penici 5 = CH 3 C-CH 2 R ^ wherein R 4 is hydrogen, an azido group, one pyridinium group, a (C-L_Zf) alkoxy, (C-L_Zf) acyloxy or carbamoyloxy group, a (C ^ L_) alkoxythiocarbonylthiogruppe, one (C-L _ ^) al-alkylthio group which may be substituted by carboxyl, or 151,338 1S1 one oxazolylthio-, thiazolylthio-, thiazolinylthio-, imidazolyl-thio, pyridazinylthio-, pyrimidinylthio-, oxadiazolylthid-, thiadiazolylthio-, triazolylthio- , tetrazolylthio-, piperazino-nylthiocarbonylthio-, isoxazolylcarbonylthio-, (pyridyl-1-oxide) thio or (5-oxo-2,5-dihydro-l, 2,4-triazinyl) thiogrup group, which may be substituted with (C ^ _ ^> alkyl and R ° means a (C5_ (g) cycloalkadienyl-, thienyl, phenyl or hydroxy-phenyl group, characterized in that (a) a racemic or optically active compound of the formula alalmene: R7 -NH-CH-CONE-rf ^ S (χχ) in 5 R 5 0 in C00Rla 5 la wherein R and Z have the above meaning, R is hydrogen, a salt forming cation or a protective group which is known in the penici llin- eller cephalosporin-området, og R betyder hydrogen eller en konventionel beskyttende silylgruppe eller phosphorholdig gruppe, som let kan fjernes ved behandling med vand eller en alkohol, omsættes med et reaktivt derivat i carboxylgruppen af en forbindelse med den almene formel: <$>n AH HC-OH (ΠΙ) w II R^R3° 2 3 hvori A, R , R og n har den ovenstående betydning, eller (b) at en forbindelse med den almene formel: (it) . llin- or cephalosporin art, and R is hydrogen or a conventional silyl protecting group or phosphorus-containing group, which are readily removable by treatment with water or an alcohol, is reacted with a reactive derivative of the carboxyl group of a compound of the general formula: <$> n AH HC-OH (ΠΙ) W II R ^ R3 ° 2 3 wherein A, R, R and n have the above meaning, or (b) reacting a compound of the general formula: (it). C00Rla 182 151338 la 7 v, hvori R , R og ✓ Z har den ovenstående betydning, omsættes med en racemisk eller optisk aktiv forbindelse med formlens „„ . C00Rla 182 151 338 7 v la, wherein R, R and ✓ Z has the above meaning, is reacted with a racemic or optically active compound of the formula is "". 0„ (V) AH SC-SH-CH-ξ-ΟΗ Jrfs0 *5° R .R px 5 hvori A, R , r, r og n har den ovenstående betydning·, eller med et reaktivt derivat deraf i carboxyl-gruppen, eller (c) at en racemisk eller optisk aktiv forbindelse med den almene formel: v£\n δ A-NIJ-C-HHtCH-CONH-γ—( Λ · (VI) w* *5 ° “ K · COOR13 hvori A, Rla, R2, R3, R5 og n har den ovenstående betydning, og B betyder en substituent, som let kan erstattes med et nucleo-filt reagens, omsættes med en forbindelse med den almene formel: R8M (VII) hvori M betyder et hydrogenatom eller et alkalimetal- eller Q jordalkalimetalatom, og R betyder en azidogruppe, en (C^_^)al-koxygruppe, en (C1_^)alkoxythiocarbonylthiogruppe, en al kyl thiogruppe , som kan være substitueret med carboxyl, eller en oxazolylthio-, thiazolylthio-, thiazolinylthio-, imidazolylthio-, pyridazinylthio-, pyrimidinylthio, oxadiazolylthio-, thiadiazo-lylthio-, triazolylthib-, tetrazolylthio-, piperazinylthiocarbo-nylthio-, isoxazolylcarbonylthio-, (pyridyl 0 "(V) AH SC-SH-CH-ξ-ΟΗ Jrfs0 * 5 ° R, R px 5 wherein A, R, R, R and n have the above meaning ·, or with a reactive derivative thereof at the carboxyl group or (c) a racemic or optically active compound of the general formula: v £ \ n δ A-NIJ-C HHtCH -CONH-γ- (Λ · (VI) W * * 5 ° "K · COOR 13 in which a, RLA, R 2, R 3, R 5 and n have the above meaning and B represents a substituent that can easily be replaced with a nucleotide reagent, is reacted with a compound of the general formula: R8M (VII) wherein M is a hydrogen atom or an alkali metal or Q alkaline earth metal atom, and R represents an azido group, a (C ^ _ ^) al-alkoxy group, a (C 1 _ ^) alkoxythiocarbonylthiogruppe, an alkyl thio group which may be substituted by carboxyl, or oxazolylthio-, thiazolylthio-, thiazolinylthio-, imidazolylthio-, pyridazinylthio-, pyrimidinylthio, oxadiazolylthio-, thiadiazol-lylthio-, triazolylthib-, tetrazolylthio-, piperazinylthiocarbo-nylthio-, isoxazolylcarbonylthio-, (pyridyl -l-oxid)thio- eller (5-oxo-2,5-dihydro-l,2,4-triazinyl)thiogruppe, som eventuelt kan være substitueret med (C^^)alkyl, eller omsættes med pyridin, 183 1 5 1 3 3 8 hvorpå om nødvendigt den beskyttende gruppe fjernes fra en under (a), (b) eller (c) dannet forbindelse, hvori R·1"3 er en beskyttende gruppe. -L-oxide) thio or (5-oxo-2,5-dihydro-l, 2,4-triazinyl) thio group which may optionally be substituted by (C ^^) alkyl, or is reacted with pyridine, 183 1 5 1 3 3 8 which, if necessary, the protective group is removed from a sub (a), (b) or (c) the resulting compound in which R 1 · "3 is a protecting group.
  2. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at piperazinoringen har oxygenatomer i positionerne 2 og 3· 2. The method of claim 1, characterized in that the piperazino ring having oxygen atoms at positions 2 and 3 ·
  3. 3. Fremgangsmåde ifølge krav 2, kendetegnet ved, at A er hydrogen, en (C2_^)alkenyl-, phenyl- eller benzylgruppe eller en (C-, Ί 5)alkylgruppe, som eventuelt er substitueret med -L-Xd 2 * chlor, hydroxy eller carboxyl, og R og hver for sig er hydrogen eller (C^g)alkyl. 3. A method according to claim 2, characterized in that A is hydrogen, a (C 2 _ ^) alkenyl, phenyl or benzyl group or a (C, Ί 5) alkyl group which is optionally substituted by -L 2 * Xd-chloro , hydroxy, or carboxyl, and R and are each independently hydrogen or (C ^ g) alkyl.
  4. 4. Fremgangsmåde ifølge krav 3, kendetegnet ved, at den fremstillede forbindelse med formlen (i) er 6— ØD(—)— a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamidoj penicillansyre eller et farmaceutisk acceptabelt salt deraf. 4. A method according to claim 3, characterized in that the prepared compound of the formula (I) is 6- ØD (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamidoj penicillanic acid or a pharmaceutically acceptable salt thereof.
  5. 5. Fremgangsmåde ifølge krav 3, kendetegnet ved, at den fremstillede forbindelse med formlen (I) er 7-{D(-)-a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenyl-acetamido] -3- [5- (l-methyl-1,2,3,4-tetrazolyl)thiomethyl3 cephem-4-carboxylsyre eller et farmaceutisk acceptabelt salt deraf. 5. A method according to claim 3, characterized in that the prepared compound of formula (I) is 7- {D (-) - a- (4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) -p-hydroxyphenyl acetamido] -3- [5- (l-methyl-1,2,3,4-tetrazolyl) thiomethyl3 cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
DK201975A 1974-05-09 1975-05-07 Analogifremgangsmaade for the preparation of racemic or optically active penicillins or cephalosporins DK151338C (en)

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FR2338046B2 (en) * 1976-01-19 1979-07-20 Toyama Chemical Co Ltd
JPS6026800B2 (en) * 1976-01-22 1985-06-25 Toyama Chemical Co Ltd
JPS52106883A (en) * 1976-02-13 1977-09-07 Toyama Chem Co Ltd Novel penicillins and cephalosporins
JPS612672B2 (en) * 1976-09-01 1986-01-27 Shionogi & Co
DE2857696C2 (en) * 1977-07-23 1984-08-30 Toyama Chemical Co. Ltd., Tokio / Tokyo, Jp
DE2810083A1 (en) * 1978-03-08 1979-09-20 Bayer Ag Beta-lactam compounds
DE2813771A1 (en) * 1978-03-30 1979-10-11 Bayer Ag Beta-lactam compounds
DE2817228A1 (en) * 1978-04-20 1979-10-31 Bayer Ag A process for the production of semisynthetic beta-lactam antibiotics
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FR2320295B1 (en) 1980-11-07 grant
NL162386B (en) 1979-12-17 application
NL162386C (en) 1980-05-16 grant
DE2519400B2 (en) 1981-05-21 application
DK151338C (en) 1988-07-18 grant
FR2269937A1 (en) 1975-12-05 application
FI751340A (en) 1975-11-10 application
FI63760B (en) 1983-04-29 application
DK201975A (en) 1975-11-10 application
BE828692A (en) 1975-11-03 grant
DE2519400C3 (en) 1982-02-11 grant
NL7505375A (en) 1975-11-11 application
GB1508064A (en) 1978-04-19 application
BE828692A1 (en) grant
GB1508062A (en) 1978-04-19 application
FR2320295A1 (en) 1977-03-04 application
DE2560239C2 (en) 1984-10-11 grant
FI63760C (en) 1983-08-10 grant
DE2519400A1 (en) 1976-03-04 application
FR2269937B1 (en) 1979-06-15 grant

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