DK157684B - PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC PENICILLIN ACIDS - Google Patents
PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC PENICILLIN ACIDS Download PDFInfo
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- C07D499/00—Heterocyclic 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
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Description
DK 157684BDK 157684B
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af hidtil ukendte, krystallinske penicillinsyrer, der kan anvendes som lægemidler i human-og veterinærmedicinen, som terapeutiske midler til fjerkræ, 5 pattedyr og fisk, som fodermiddeltilsætning og som vækstfremmende midler til dyr, især oral og parenteral anvendelse deraf som antibakterielle midler, først og fremmest ved behandling af infektionssygdomme forårsaget af bakterier fra gruppen omfattende enterobakterier, pseudomonas- og 10 aeromonasbakterier. De er oralt og parenteralt anvendelige. Fremgangsmåden er ejendommelig ved det i krav l's kendetegnende del angivne.The present invention relates to a particular process for the preparation of novel crystalline penicillic acids which can be used as medicaments in human and veterinary medicine, as therapeutic agents for poultry, mammals and fish, as feed additives and as growth promoters for animals, especially oral and parenteral use thereof as antibacterial agents, primarily in the treatment of infectious diseases caused by bacteria from the group comprising enterobacteria, pseudomonas and 10 aeromonas bacteria. They are orally and parenterally applicable. The process is peculiar to the characterizing part of claim 1.
Det er allerede kendt, at antibakterielle midler såsom ampicillin (jvf. USA-patentskrift nr. 2.985.648) har 15 vist sig at være meget aktive ved terapi af infektioner forårsaget af gram-positive og gram-negative bakterier. De kan dog ikke bekæmpe infektioner, der f.eks. er forårsaget af bakterier fra gruppen Klebsiella-aerobacter eller af indolpositive proteus-stammer.It is already known that antibacterial agents such as ampicillin (cf. U.S. Patent No. 2,985,648) have been found to be very active in the therapy of infections caused by gram-positive and gram-negative bacteria. However, they cannot fight infections that, e.g. is caused by bacteria from the Klebsiella aerobacter group or by indole-positive proteus strains.
20 Carbenicillin (jvf. USA-patentskrift nr. 3.142.673 og 3.282.926) er ved behandling af infektioner hos mennesker med bakterier fra gruppen Klebsiella-aerobacter kun virksomt, når det indgives i vedvarende høj dosering, således som det kun nås ved infusion.Carbenicillin (cf. U.S. Patent Nos. 3,142,673 and 3,282,926) is effective in treating infections in humans with bacteria of the Klebsiella aerobacter group when administered at sustained high dosage, as reached only by infusion. .
25 6-(α-biureido)-acetamidopenicillansyrer er beskrevet i USA-patentskrift nr. 3.483.188 og i tysk Offenlegungs-schrift nr. 1.959.920. Ingen af de i disse patentskrifter beskrevne 6-(α-biureido)-acetamidopenicillansyrer har dog en acylgruppe ved nitrogenatomet i 5-stillingen i biureido-30 gruppen.6- (α-Biureido) -acetamidopenicillanic acids are described in U.S. Patent No. 3,483,188 and in German Offenlegungschrift No. 1,959,920. However, none of the 6- (α-biureido) -acetamidopenicillanic acids described in these patents has an acyl group at the nitrogen atom at the 5-position of the biureido group.
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af methylpenicilliner, som i methylgruppen er substitueret med en gruppe B, og en acyl-biureidogruppe, hvis carbonylfunktion i acylgruppen er erstattet med en 35 -SO2-gruppe.The present invention relates to a process for the preparation of methylpenicillins which in the methyl group is substituted by a group B and an acyl biureido group whose carbonyl function in the acyl group is replaced by a 35-SO2 group.
5 4 3 2 1 acy1-N-C-N-C-NH-5 4 3 2 1 acyl-N-C-N-C-NH-
I III III III II
o oIsland Island
DK 157684 BDK 157684 B
22
Også ifølge tidligere, endnu ikke offentliggjort forslag fra ansøgerne kan der fremstilles sådanne penicilliner, som ifølge dette forslag dog ikke fås i form af de holdbare, krystallinske, fri syrer.Also, according to previous, as yet unpublished proposals from the applicants, such penicillins can be produced, which according to this proposal are not available in the form of the durable crystalline free acids.
5 Det har nu vist sig, at de nye, krystallinske penicil linsyrer med den almene formel S /S £trr A-C-NH-CH-CONH-_____X \ / 3 (j) 10 0 ^ j ^It has now been found that the new crystalline penicilic acid acids of the general formula S / S £ trr A-C-NH-CH-CONH -_____ X \ / 3 (j) 10 0 ^ j ^
C00HC00H
hvori A betyder en gruppe R^SC^ -15 R1 betyder alkyl med 1-6 carbonatomer eller alkylamino med 1-5 carbonatomer, B betyder phenyl, hydroxyphenyl eller cyclohexadien- (1,4) -1-yl, og som med hensyn til chiralitets-20 centret C* kan forekomme i de to mulige R- og S-konfigurationer og som blandinger af de deraf dannede diastereomere, har stærke antibakterielle egenskaber.wherein A represents a group R 5 the chirality center C * can occur in the two possible R and S configurations and, as mixtures of the resulting diastereomers, has strong antibacterial properties.
Det har endvidere vist sig, at de krystallinske penicillinsyrer med den almene formel I kan fremstilles, når 25 forbindelser med den almene formel b-ch-co-nh--^ \ / 3 I I K (II)Furthermore, it has been found that the crystalline penicillic acids of general formula I can be prepared when compounds of the general formula b-ch-co-nh - ^ \ / 3 I I K (II)
30 C00H30 C00H
hvori B og C* har den ovenfor anførte betydning, omsættes med forbindelser med den almene formelwherein B and C * have the meaning given above are reacted with compounds of the general formula
R1-S0o-N N-COWR1-SOO-N N-COW
35 2 (III)2 (III)
DK 157684 BDK 157684 B
3 hvori W betyder halogen, i vand ved pH 1-9 og ved en temperatur i området ca. 0°C til 50°C.3 wherein W is halogen, in water at pH 1-9 and at a temperature in the range of approx. 0 ° C to 50 ° C.
Som det er kendt fra penicillinkemien, kan a-sub-stituerede a-aminomethylpenicilliner såsom ampicillin omsæt-5 tes med acylcarbamoyleringsmidler såsom benzoylisocyanat eller N-benzoyl-N-methylcarbamoylchlorid i indifferente organiske opløsningsmidler såsom chloroform eller methylen-chlorid eller i blandinger af vand og indifferente organiske \ opløsningsmidler såsom tetrahydrofuran eller dimethylform-10 amid. Tilsætningen af organiske opløsningsmidler sker for at opnå en bedre opløselighed af carbamoyleringsmidlerne og for at tilbagetrænge den af vand forårsagede hydrolyse af disse. Før oparbejdning af reaktionsblandingen må det organiske opløsningsmiddel fjernes under skånsomme betingelser, 15 hvilket kvantitativt kun er vanskeligt gennemførligt. På grund af det store antal amidbindinger i de ved reaktionen dannede acylureido- eller acylbiureidopenicilliner fastholdes organiske opløsningsmidler såsom tetrahydrofuran, ethylace-tat, methylenchlorid eller dimethyl formamid kraftigt, hvilket 20 vanskeliggør traditionel fremstilling af sådanne opløsningsmiddelfri penicilliner. Såfremt der til oparbejdningen knyttes et yderligere tørringstrin under skærpede betingelser, stiger den følsomme penicillansyrekernes sønderdelingsgrad.As is known from the penicillin chemistry, α-substituted α-aminomethylpenicillins such as ampicillin can be reacted with acylcarbamoylating agents such as benzoyl isocyanate or N-benzoyl-N-methylcarbamoyl chloride in inert organic solvents such as chloroform or methylene chloride or inert organic solvents such as tetrahydrofuran or dimethylformamide. The addition of organic solvents is done to obtain a better solubility of the carbamoylating agents and to retard the hydrolysis thereof caused by water. Prior to reprocessing the reaction mixture, the organic solvent must be removed under gentle conditions, which is quantitatively only feasible. Owing to the large number of amide bonds in the acylureido or acylbiureidopenicillins formed by the reaction, organic solvents such as tetrahydrofuran, ethyl acetate, methylene chloride or dimethyl formamide are strongly retained, making traditional production of such solvent-free penicillins difficult. If a further drying step is attached to the work-up under aggravated conditions, the degree of decay of the sensitive penicillanic acid increases.
Det er endvidere kendt, at de ved carbamoyleringen dannede 25 penicilliner kan isoleres ved syrning af opløsningerne og ekstraktion af de fri penicillinsyrer med organiske opløsningsmidler såsom ethylacetat. Den opløste penicillinsyre skal hurtigst muligt udfældes af det organiske opløsningsmiddel med fældningsmidler såsom natrium-2-ethylhexanoat 30 som natriumsalt for at undgå den i opløsning forekommende sønderdeling af penicillinsyrerne.It is further known that the penicillins formed by the carbamoylation can be isolated by acidification of the solutions and extraction of the free penicillic acids with organic solvents such as ethyl acetate. The dissolved penicillic acid must be precipitated as quickly as possible by the organic solvent with precipitating agents such as sodium 2-ethylhexanoate 30 as sodium salt to avoid the dissolution of the penicillic acids in solution.
Det har nu overraskende vist sig, at de her omhandlede penicillinsyrer kan fremstilles i stort udbytte, når forbindelser med den almene formel II omsættes med forbindelser 35 med den almene formel III i vand uden tilsætning af et organisk opløsningsmiddel, og der indstilles en sur pH-værdiIt has now surprisingly been found that the penicillic acids of this invention can be prepared in high yield when compounds of general formula II are reacted with compounds of general formula III in water without the addition of an organic solvent and an acidic pH is adjusted. value
DK 157684BDK 157684B
4 på ca. 1-5, hvorved de her omhandlede penicillinsyrer kan isoleres uden indhold af organiske opløsningsmidler og i stabil krystallinsk form. Overraskende fås der ved den her omhandlede reaktion også høje udbytter af penicillinsyrer, 5 når der anvendes i vand tungtopløselige eller uopløselige forbindelser med den almene formel III. De her omhandlede penicilliner og den her omhandlede fremgangsmåde udgør således en berigelse af teknikken.4 in approx. 1-5, whereby the penicillic acids in question can be isolated without organic solvents content and in stable crystalline form. Surprisingly, in this reaction, high yields of penicillic acids are also obtained, when water-insoluble or insoluble compounds of general formula III are used in water. Thus, the penicillins of the present invention and the process of the present invention constitute an enrichment of the technique.
Hvis der som udgangsstoffer anvendes 1-chlorcarbonyl-10 -2-oxo-3-mesyl-imidazolin og ampicillin, kan reaktionsforløbet f.eks. illustreres ved nedenstående reaktionsskema:If 1-chlorocarbonyl-10-2-oxo-3-mesyl-imidazoline and ampicillin are used as starting materials, is illustrated by the following reaction scheme:
OISLAND
^A-coa + f~S -ch-conht—^v/CHs X5 W W »2 0£Υ<0Η3^ A-coa + f ~ S -ch-conht— ^ v / CHs X5 W W »2 0 £ Υ <0Η3
COOHCOOH
OISLAND
20 , ' i <*) Η20 / NaQH ^ CH3S02N N-CONH-CH-CONH__rS\/CH3 20°C / pH 7 V_/ I j_li /KCg3 . (i opløsning) Γ J ° coONa 25 A (R) H~0 / HCl CH-SO-N N-CONH-CH-CONH-/CH3 20°C / pH 2** ^-/ X 0J-NACB320, 'i <*) Η20 / NaQH ^ CH3SO2N N-CONH-CH-CONH__rS \ / CH3 20 ° C / pH 7 V_ / I j_li / KCg3. (in solution) Γ J ° coONa 25 A (R) H ~ O / HCl CH-SO-N N-CONH-CH-CONH- / CH3 20 ° C / pH 2 ** ^ - / X OJ-NACB3
30 (krystallinsk) COOH(Crystalline) COOH
De ifølge opfindelsen som udgangsmaterialer anvendte forbindelser med den almene formel II er allerede kendte.The compounds of the general formula II used as starting materials according to the invention are already known.
De kan - med hensyn til konfigurationen ved det asymmetriske 35 centrum i sidekæden (=C*) - forekomme i D=R-form eller L=S--form. De er beskrevet i tysk patentskrift nr. 1.156.078, i 5They may - with respect to the configuration at the asymmetric center of the side chain (= C *) - appear in D = R form or L = S form. They are described in German Patent No. 1,156,078, in 5
DK 157684BDK 157684B
USA-patent skrift nr. 3.342.677, 3.157.640, 2.985.648, 3.140.282 og 3.144.445, i sydafrikansk patentskrift nr. 68/P290, i belgisk patentskrift nr. 737.451 samt i "J. Chem.United States Patent Nos. 3,342,677, 3,157,640, 2,985,648, 3,140,282 and 3,144,445, in South African Patent No. 68 / P290, in Belgian Patent No. 737,451, and in "J. Chem.
Soc." (C) 1971, 1920 og i "J. med. Chem.” 14, 117 (1971).Soc. "(C) 1971, 1920, and in" J. with. Chem. " 14, 117 (1971).
5 Alle krystalformer og salte af forbindelserne med den almene formel II er egnede som udgangsmateriale til den her omhandlede reaktion.All crystal forms and salts of the compounds of general formula II are suitable as starting materials for the present reaction.
De ifølge opfindelsen som udgangsstoffer anvendte forbindelser med den almene formel III er hidtil ukendte, 10 men kan imidlertid fremstilles, når - i det tilfælde, hvor W betyder halogen- forbindelser med den almene formel A-H, hvori A har den ovenfor anførte betydning, omsættes med carbonsyredihalogenider W-CO-W, eventuelt i nærværelse af en base i et indifferent organisk opløsningsmiddel såsom 15 chloroform eller tetrahydrofuran eller i blandinger af vand og et organisk opløsningsmiddel såsom chloroform ved en temperatur i området 0-100°c, og de derved fremkomne forbindelser med formlen III isoleres ved frafiltrering, ekstraktion eller afdampning af opløsningsmidlet. I stedet for 20 forbindelserne med den almene formel A-H kan der ved reaktionen også anvendes de ved silylering af forbindelserne med den almene formel A-H med silyleringsmidler såsom tri-methylchlorsilan eller hexamethyldisilazan fremkomne forbindelser med den almene formel A-Si(R)3, hvor R er en ligekædet 25 eller forgrenet alkylgruppe med 1-5 carbonatomer. Forbindelserne med den almene formel A-H kan fremstilles ved omsætning af forbindelser med den almene formel 0The compounds of the general formula III according to the invention used as starting materials are novel, but can, however, be prepared when - in the case where W means halogen compounds of the general formula AH in which A has the meaning given above are reacted with carboxylic acid dihalides W-CO-W, optionally in the presence of a base in an inert organic solvent such as chloroform or tetrahydrofuran or in mixtures of water and an organic solvent such as chloroform at a temperature in the range of 0-100 ° C, and the resulting compounds of formula III is isolated by filtration, extraction or evaporation of the solvent. Instead of the compounds of general formula AH, the reaction may also be used in silylating the compounds of general formula AH with silylating agents such as trimethyl chlorosilane or hexamethyldisilazane, compounds of general formula A-Si (R) 3, wherein R is a straight chain or branched alkyl group having 1-5 carbon atoms. The compounds of general formula A-H can be prepared by reacting compounds of general formula 0
HN NHHN NH
30 \_/ med forbindelser med den almene formel R-L-SC^-W eller R1-S02“0“S02“R1, hvor R1 og W har den ovenfor anførte betydning, i indifferente organiske opløsningsmidler, eventuelt i nærværelse af en base ved temperaturer i området ca. 0-35 -100°C. I stedet for forbindelserne med den almene formel 6With compounds of the general formula RL-SC2 -W or R1-SO2 "0" SO2 "R1, wherein R1 and W have the meaning given above, in inert organic solvents, optionally in the presence of a base at temperatures in the area approx. 0-35 -100 ° C. Instead of the compounds of general formula 6
DK 157684BDK 157684B
ΛΛ
HN NHHN NH
WW
55
kan der i reaktionen også anvendes forbindelser med den almene formel QFor example, compounds of the general formula Q may be used in the reaction
ellSr N li 10 \_J \-/ hvori R har den ovenfor anførte betydning, og som kan fremstilles med silyleringsmidler såsom trimethylchlorsilan eller hexamethyldisilazan ud fra forbindelser med den almene formel 0 » Λor wherein R has the meaning given above and which can be prepared with silylating agents such as trimethylchlorosilane or hexamethyldisilazane from compounds of the general formula 0
HN NHHN NH
WW
Konfigurationen af 6-aminopenicillansyrekernens asymmetriske centre i forbindelserne med den almene formel II skal være 20 identisk med konfigurationen af de tilsvarende asymmetriske centre i 6-aminopenicillansyren, der f.eks. er udvundet af penicillin G ved fermentative processer.The configuration of the asymmetric centers of the 6-aminopenicillanic acid nucleus in the compounds of general formula II must be identical to the configuration of the corresponding asymmetric centers of the 6-aminopenicillanic acid, e.g. is extracted by penicillin G by fermentative processes.
Som eksempler på ifølge opfindelsen anvendelige forbindelser med den almene formel II skal nævnes 25 D-a-aminobenzylpenicillin, D-a-amino-p-hydroxybenzylpenicillin og D-a-amino-a- (1,4-cyclohexadien-l-yl) -methylpenicillin.Examples of compounds of the formula useful in the invention are 25 D-α-aminobenzylpenicillin, D-α-amino-β-hydroxybenzylpenicillin and D-α-amino-α- (1,4-cyclohexadien-1-yl) methylpenicillin.
Som eksempel på en ifølge opfindelsen anvendelige forbindelse med den almene formel III skal nævnes 30 l-chlorcarbonyl-2-oxo-3-mesyl-imidazolidin.As an example of a compound of the general formula III useful according to the invention, mention should be made of 30 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine.
Den her omhandlede reaktion gennemføres i vand som eneste opløsnings- eller suspenderingsmiddel.This reaction is carried out in water as the sole solvent or suspending agent.
Omsætningen kan gennemføres ved en pH-værdi i området 1-9, fortrinsvis 5-8 eller 1,5-3,0.The reaction may be carried out at a pH in the range of 1-9, preferably 5-8 or 1.5-3.0.
35 De til overholdelse af en bestemt pH-værdi, f.eks.Those for adhering to a particular pH, e.g.
5-8, anvendte baser og syrebindende midler er uorganiske5-8, bases used and acid binding agents are inorganic
DK 157684 BDK 157684 B
7 baser såsom alkali- eller jordalkalimetalhydroxider eller uorganiske syrebindende midler såsom jordalkalimetaloxider, jordalkalimetalcarbonater eller pufferblandinger eller organiske baser såsom triethylamin, N-methylpiperidin eller 5 sterisk hindrede sekundære aminer såsom diisopropylamin. Mængden af de anvendte baser bestemmes ved overholdelse af en ønsket pH-værdi.7 bases such as alkali or alkaline earth metal hydroxides or inorganic acid binding agents such as alkaline earth metal oxides, alkaline earth metal carbonates or buffer mixtures or organic bases such as triethylamine, N-methylpiperidine or 5 sterically hindered secondary amines such as diisopropylamine. The amount of bases used is determined by adhering to a desired pH value.
Reaktionstemperaturerne kan varieres inden for et større område. Der arbejdes almindeligvis ved en temperatur 10 i området 0-50°C, fortrinsvis 0-20°C. Omsætningen kan gennemføres ved normaltryk, men også ved forhøjet eller formindsket tryk. Der arbejdes almindeligvis ved normaltryk.The reaction temperatures can be varied within a larger range. It is generally operated at a temperature 10 in the range of 0-50 ° C, preferably 0-20 ° C. The reaction can be carried out under normal pressure, but also at elevated or reduced pressure. Work is usually done under normal pressure.
Ved gennemførelsen af den her omhandlede fremgangsmåde kan reaktanterne omsættes med hinanden i ækvimolære mængder.In carrying out the process of this invention, the reactants can be reacted with each other in equimolar amounts.
15 Det kan dog være hensigtsmæssigt at anvende den ene af de to reaktanter i overskud for at forhøje udbyttet. Eksempelvis kan reaktenten med den almene formel II anvendes med et overskud på 0,1-0,3 molækvivalent, hvorved sønderdelingen af reaktanten med den almene formel III i vand mindskes.However, it may be appropriate to use one of the two reactants in excess to increase the yield. For example, the reactant of the general formula II may be used with an excess of 0.1-0.3 molar equivalent, thereby reducing the decomposition of the reactant of the general formula III in water.
20 Overskuddet af reaktanten med den almene formel II kan - som følge af den gode opløselighed i vandige syrer - let fjernes ved oparbejdningen af reaktionsblandingen. Reaktanten med den almene formel III kan imidlertid også med fordel anvendes med et overskud på f.eks. 0,1-1,0 molækvivalent. Derved 25 udnyttes reaktanten med den almene formel II bedre, og der kompenseres for den som sidereaktion i vand forekommende hydrolyse af reaktanten med den almene formel III. Da de i overskud anvendte forbindelser med den almene formel III i vand hurtigt omdannes til neutrale acylurinstoffer eller 30 acylthiourinstoffer, som let kan fjernes, nedsættes penicillinernes renhed næppe derved.The excess of the reactant of the general formula II can - easily due to the good solubility in aqueous acids - be easily removed by the reprocessing of the reaction mixture. However, the reactant of the general formula III can also advantageously be used with an excess of e.g. 0.1-1.0 molar equivalent. Thereby, the reactant of the general formula II is better utilized and the hydrolysis occurring as a side reaction in water is compensated for by the reactant of the general formula III. Since the compounds of general formula III in excess used in water are rapidly converted into neutral acylureas or easily removable acylthioureas, the purity of penicillins is hardly reduced.
Ved oparbejdningen af reaktionsblandingeme indstilles en sur pH-værdi på 1-4 med uorganiske syrer såsom saltsyre, svovlsyre eller phosphorsyre eller med i vand let opløselige 35 orgainske syrer såsom oxalsyre eller citronsyre, hvorved de her omhandlede penicilliner med den almene formel I udkry-In the work-up of the reaction mixtures, an acidic pH of 1-4 is adjusted with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with water-easily soluble organic acids such as oxalic acid or citric acid, whereby the penicillins of the general formula I
DK 157684 BDK 157684 B
8 stalliserer af den vandige fase og derpå frasuges og tørres.8 stalls of the aqueous phase and is then aspirated and dried.
De her omhandlede penicillinsyrer kan ved de inden for penicillinkemien gængse metoder omdannes til ikke-tok-siske, farmaceutisk acceptable salte.The penicillic acids of this invention can be converted into non-toxic, pharmaceutically acceptable salts by the methods common to the penicillin chemistry.
5 Til de ikke-toksiske, farmaceutisk acceptable salte hører salte af den sure carboxylgruppe såsom natrium-, kalium-, magnesium-, calcium-, aluminium- og ammoniumsalte og ikke-toksiske, substituerede ammoniumsalte med aminer såsom di- og tri-lavere alkylaminer, procain, dibenzylamin, N,N'- 10 -dibenzylethylendiamin, N-benzyl-/3-phenylethylamin, N-methyl-og N-ethylmorpholin, 1-ephenamin, dihydroabiethylamin, N,N'--bis-dehydroabietylethylendiamin, N-lavere alkylpiperidin og andre aminer, der anvendes til saltdannelse af penicilliner.The nontoxic, pharmaceutically acceptable salts include salts of the acidic carboxyl group such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts and nontoxic substituted ammonium salts with amines such as di- and tri-lower alkyl amines , procaine, dibenzylamine, N, N'-10-dibenzylethylenediamine, N-benzyl- / 3-phenylethylamine, N-methyl and N-ethylmorpholine, 1-ephenamine, dihydroabiethylamine, N, N '- bis-dehydroabietylethylenediamine, N- lower alkylpiperidine and other amines used to salt penicillins.
15 Som eksempler på de her omhandlede, aktive stoffer skal enkelt nævnes:15 As examples of the active substances in question here are simply mentioned:
Krystallinsk D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)--carbonylaminoj-benzylpenicillinsyre 0Crystalline D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino-benzylpenicillic acid 0
20 /\ (R) CH20 / \ (R) CH
CH^SOgN N-C0HH-CH-C0NH---/ 3 i-M oh H j 0^ V 3CH2 SO3N N-COHH-CH-COHH --- / 3 i-M oh H j 0 ^ V 3
OOOHOOOH
25 Krystallinsk monohydrat af D-a-[(2-oxo-3-mesyl-imid- azolidin-l-yl)-carbonylamino]-benzylpenicillinsyre 0Crystalline monohydrate of D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -benzylpenicillic acid 0
(R) CH(R) CH
30 3 \ / Λ 1 X30 3 \ / Λ 1 X
I Ύ 3 ' h2°At Ύ 3 'h2 °
^ CO OH^ CO OH
99
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Krystallinsk D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)- -ca rbonylamino]-p-hydroxy-benzylpenicil1insyre 0 1 <R) g CH3S02N N-CONH-CH-CONH-j-f^\/CE3 υ ΛCrystalline Da - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -p-hydroxy-benzylpenicillinic acid (R) g CH3SO2N N-CONH-CH-CONH-jf υ Λ
P I COOHP I COOH
OHOH
Krystallinsk D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)-10 -carbonyl amino] -or- (1,4-cyclohexadien-l-yl) -methylpenicillin-syre Λ ,R! CH^SO-N N-CONH-CH-CONH—-Crystalline D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -10-carbonyl amino] -or- (1,4-cyclohexadien-1-yl) -methylpenicillic acid Λ, R CH 2 SO-N N-CONH-CH-CONH
15 \-/ JL15 \ - / JL
f \ COOHf \ COOH
De her omhandlede, aktive stoffer har kraftig anti-bakteriel virkning. De kan anvendes i human- og veterinær-20 medicinen til behandling og forebyggelse af alle sygdomme forårsaget af bakterier, der hæmmes af de her omhandlede penicilliner ved passende dosering. Som eksempler på bakterier, der hæmmes særdeles godt af de her omhandlede aktive stoffer, skal enkelt nævnes: 25 Escherichia coli 14, Escherichia coli C 165, Proteus vulgaris 1017, Klebsiella K 10, Klebsiella 63, Salmonella sp., Shigella sp., Enterobacter sp., Serratia sp., Proteus, indolnegativ, sp., Proteus, indolpositiv sp., Pasteurella pseudoturberculosis, Brucella sp., Haemophilus influenzae, 30 Bordetella bronchiseptica, Bacteroides sp., Staphylococcus aureus 133, Neisseria catarrhalis sp., Diplococcus pneumoniae sp., Streptococcus pyogenes W, Enterococcus sp., Lactobacillus sp., Corynebacterium diphteriae gravis, Corynebacterium pyogenes M, Clostridium botulinium, Clostridium tetani, 35 Borellia sp., Pseudomonas aeruginosa sp., Aeromonas hydro-phila sp.The active substances in question have a strong anti-bacterial effect. They can be used in the human and veterinary medicine to treat and prevent all diseases caused by bacteria that are inhibited by the penicillins of this invention at appropriate dosage. Examples of bacteria that are particularly well inhibited by the active substances in question should be mentioned simply: 25 Escherichia coli 14, Escherichia coli C 165, Proteus vulgaris 1017, Klebsiella K 10, Klebsiella 63, Salmonella sp., Shigella sp., Enterobacter sp., Serratia sp., Proteus, indole negative, sp., Proteus, indole positive sp., Pasteurella pseudoturberculosis, Brucella sp., Haemophilus influenzae, 30 Bordetella bronchiseptica, Bacteroides sp., Staphylococcus aureus 133, Neisseria catarrhalis ., Streptococcus pyogenes W, Enterococcus sp., Lactobacillus sp., Corynebacterium diphteriae gravis, Corynebacterium pyogenes M, Clostridium botulinium, Clostridium tetani, Borellia sp., Pseudomonas aeruginosa sp., Aeromonas hydrophila sp.
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De her omhandlede, aktive stoffer kan på kendt måde overføres i de gængse præparater og anvendes på sædvanlig måde. De kan formuleres og indgives alene eller i kombination med et farmaceutisk uskadeligt bærerstof ved en gængs far-5 maceutisk fremgangsmåde.The active substances of this invention can be known in the conventional manner in conventional compositions and used in the usual manner. They can be formulated and administered alone or in combination with a pharmaceutically harmless carrier by a conventional pharmaceutical method.
Oralt kan de indgives i form af tabletter, der tillige kan indeholde f.eks. stivelse, mælkesukker, visse lerjordarter osv. eller i form af kapsler, dråber eller granulater, alene eller sammen med de samme eller ækvivalente tilsæt-10 ningsstoffer. De kan endvidere indgives oralt i form af saft eller suspensioner, der kan indeholde til sådanne formål gængse smagskorrigerende stoffer eller farvestoffer.Orally, they may be administered in the form of tablets which may also contain e.g. starch, milk sugar, certain clay soils, etc. or in the form of capsules, drops or granules, alone or together with the same or equivalent additives. They may also be administered orally in the form of juices or suspensions which may contain, for such purposes, conventional flavoring agents or colorants.
Endvidere kan de her omhandlede aktive stoffer indgives parenteralt, f.eks. intramuskulært eller subcutant.Furthermore, the active substances herein can be administered parenterally, e.g. intramuscularly or subcutaneously.
15 De her omhandlede, aktive stoffer kan anvendes på sædvanlig måde. Ved oral eller parenteral indgift er en dosis på 25.000 - 1 mill E/kg legemsvægt/dag hensigtsmæssig (1 mol penicillin svarer som bekendt til 5,9514 x 108E). De kan indgives som enkeltdosis eller opdelt i flere doser.The active substances in question can be used in the usual manner. For oral or parenteral administration, a dose of 25,000 - 1 million E / kg body weight / day is appropriate (1 mole penicillin corresponds to 5.9514 x 108E). They can be administered as a single dose or divided into several doses.
20 Til lokal behandling kan de her omhandlede, aktive stoffer fremstilles og anvendes i form af salve eller pudder.For local treatment, the active substances of this invention may be prepared and used in the form of ointment or powder.
I veterinærmedicinen kan de her omhandlede penicilliner indgives sammen med foderet eller foderpræparater eller med drikkevandet.In the veterinary medicine, the penicillins referred to herein may be administered with the feed or feed preparations or with the drinking water.
2525
Eksempel 1 A (R) CH,S0oN N-C0NH-CH-C0NH— A\/CH3 30 \—/ X AA-3 I \ C00H - H20 204 Vægtdele ampicillin-trihydrat suspenderes i 3000 rumfangsdele vand og bringes på pH 8,5 med 2 N NaOH under 35 ydre afkøling og tilsætning af isstykker, hvorved ampicil-linet i stor udstrækning går i opløsning. Der tilsættesExample 1 A (R) CH, SON N-COHH-CH-CONH - A \ / CH3 30 \ - / X AA-3 I \ C00H - H20 204 Weight parts of ampicillin trihydrate are suspended in 3000 volumes of water and brought to pH 8, 5 with 2 N NaOH under 35 external cooling and adding pieces of ice, whereby the ampicillin dissolves to a large extent. There is added
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11 portionsvis under omrøring i løbet af 15 minutter 123 vægtdele l-chlorcarbonyl-2-oxo-3-mesyl-imidazolidin i substans, pH-værdien holdes på 7-8 ved tilsætning af yderligere natriumhydroxidopløsning, og der røres i endnu ca. 3 timer, 5 indtil NaOH-tilsætning ikke mere er nødvendig til at opretholde en pH-værdi på 7-8, og der er dannet en klar opløsning.11 portionwise with stirring over 15 minutes 123 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine in substance, the pH is kept at 7-8 by the addition of additional sodium hydroxide solution and stirring for a further ca. 3 hours, 5 until NaOH addition is no longer necessary to maintain a pH of 7-8 and a clear solution is formed.
Ved tildrypning af l N saltsyre indstilles pH-værdien i løbet af 1 time under kraftig omrøring på 2,0, hvorved penicillinsyren udkrystalliserer. Der røres i endnu 30 minutter 10 under isafkøling, suges fra, opslæmmes påny i 6000 rumfangsdele vand, gennemrøres kraftigt i 15 minutter og suges fra igen, hvorpå processen gentages én gang. Den derved fremkomne, endnu meget vandige krystalkage fordeles på en metalplade og tørres i luften i 24 timer ved hjælp af en ven-15 tilator og under lejlighedsvis omrøring og behandling i morter. Efter 12 timers eftertørring over P205 i vakuumtør-reskab viser produktet intet nævneværdigt vægttab.By adding 1 N hydrochloric acid, the pH is adjusted over 1 hour with vigorous stirring to 2.0, whereby the penicillic acid crystallizes. Stir for another 30 minutes 10 while ice-cooling, suck off, slurry again in 6000 volumes of water, stir vigorously for 15 minutes and suck off again and then repeat the process once. The resulting still very aqueous crystal cake is distributed on a metal plate and dried in the air for 24 hours by means of a ventilator and with occasional stirring and treatment in mortars. After 12 hours of post-drying over P205 in a vacuum-drying cabinet, the product shows no significant weight loss.
Udbytte: 254 vægtdele = 90,5% af det teoretiske, krystallinsk monohydrat (under mikroskop synlige nåle) af 20 D-α-[ (2-oxo-3-mesyl-imidazolidin-l-yl)-carbonylamino]-benzyl-penicillinsyre.Yield: 254 parts by weight = 90.5% of theoretical crystalline monohydrate (visible under microscope needles) of 20 D-α- [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -benzyl-penicillic acid .
/J-lactamindhold (iodometrisk) : 94% (beregnet på monohydrat) jø-lactamindhold (enzymatisk) : 100% " /?-Lactamindholdet ændrer sig ikke efter 2 måneders 25 lagring af produktet ved stuetemperatur./ L-lactam content (iodometric): 94% (based on monohydrate) lactam content (enzymatic): 100% / l - The lactam content does not change after 2 months of storage of the product at room temperature.
Vandindhold ifølge Fischer: 3,6% =1,1 mol. Penicillinindhold (ensartet hovedprodukt) i tørsubstans 97,5% efter analytisk Craig-fordeling.Water content according to Fischer: 3.6% = 1.1 mol. Penicillin content (uniform major product) in dry matter 97.5% after analytical Craig distribution.
Analyse: 30 C% H% N% S%Analysis: 30 C% H% N% S%
Beregnet med 1,1 mol H20: 45,1 4,9 12,5 11,5Calculated with 1.1 mol H2 O: 45.1 4.9 12.5 11.5
Fundet: 44,3 4,4 12,1 11,5 IR-bånd ved 3700-2800, 3355, 3320, 3063, 3025, 2978, 2930, 1770, 1720, 1668, 1517, 1389, 1354, 1253, 1210, 35 1168, 1130, 973 og 764 cm”1 (i KBr) 12Found: 44.3 4.4 12.1 11.5 IR bands at 3700-2800, 3355, 3320, 3063, 3025, 2978, 2930, 1770, 1720, 1668, 1517, 1389, 1354, 1253, 1210, 35 1168, 1130, 973 and 764 cm ”1 (in KBr) 12
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NMR-signaler ved r - 2,4-2,8 (5H), 4,4 (IH), 4,5 (2H) , 5,7 (IH), (i CD3OD) 6,0-6,4 (4H) , 6,7 (3H) , 8,5 (3H) og 8,6 ppm (3H).NMR signals at r - 2.4-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.7 (1H), (in CD3OD) 6.0-6.4 ( 4H), 6.7 (3H), 8.5 (3H) and 8.6 ppm (3H).
55
Eksempel 2 Å " CH-jSO^N N-CONH-CH-CONH-t-,Α /CH3 u Λ .Αχ“» N C00H · H20Example 2 Å "CH-CHSO ^ N N-CONH-CH-CONH-t-, Α / CH3 u Λ .Αχ" »N C00H · H2 O
2,5 Vægtdele D-a-amino-1,4-cyclohexadienyl (1) -methyl-penicillin suspenderes i 50 rumfangsdele vand, opløses i 15 netop den nødvendige mængde 2 N natriumhydroxidopløsning under omrøring, hvorpå der under afkøling med is/vand tilsættes 1,6 vægtdele l-chlorcarbonyl-2-oxo-3-methylsulfonyl--imidazolidin, og blandingens pH-værdi holdes på 7 ved passende tilsætning af 2 N natriumhydroxidopløsning. Når reak-20 tionsblandingen ikke forbruger mere natriumhydroxidopløsning, syrnes der langsomt (30 minutter) ved 1 N saltsyre til pH2.5 parts by weight of Da-amino-1,4-cyclohexadienyl (1) -methyl-penicillin is suspended in 50 parts by volume of water, dissolved in just the required amount of 2 N sodium hydroxide solution with stirring, and, while cooling with ice / water, 1 is added. 6 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylsulfonyl-imidazolidine, and the pH of the mixture is maintained at 7 by appropriate addition of 2N sodium hydroxide solution. When the reaction mixture no longer consumes sodium hydroxide solution, slowly acidify (pH 30) at 1N hydrochloric acid to pH
2. Det derved som fri syre udfældede D-a-[(2-oxo-3-methyl-sulfonyl-imidazolidin-l-yl) -carbonylamino]-l,4-cyclohexa-dienyl-l-methylpenicillin suges fra, vaskes med vand og 25 tørres i luft (luftstrøm) eller i ekssikator. Under mikroskop konstateres, at penicillinet foreligger i krystalform (nåle). Udbytte: 2,5 vægtdele (65% af det teoretiske) β-Laetamindhold: 92,3%.2. The Da - [(2-oxo-3-methylsulfonyl-imidazolidin-1-yl) -carbonylamino] -1, 4-cyclohexa-dienyl-1-methylpenicillin which is precipitated as free acid is suctioned off, washed with water and 25 is dried in air (air flow) or in desiccator. Under the microscope, the penicillin is found to be in crystal form (needles). Yield: 2.5 parts by weight (65% of theory) β-Laetam content: 92.3%.
Penicillinet foreligger som monohydrat.The penicillin is available as a monohydrate.
30 Analyse: C% H% N% S%Analysis: C% H% N% S%
Beregnet (som monohydrat): 45,0 5,2 12,5 11,4Calcd. (As monohydrate): 45.0 5.2 12.5 11.4
Fundet: 44,9 5,3 12,4 11,2 NMR-signaler ved r = 4,05 (IH), 4,25 (2H) , 4,4 (2H), 4,95 35 (IH), 5,6 (IH), 6,05 (4H), 6,65 (3H), 7,25 (4H) og 8,2-8,5 ppm (6H) .Found: 44.9 5.3 12.4 11.2 NMR signals at r = 4.05 (1H), 4.25 (2H), 4.4 (2H), 4.95 (1H), δ , 6 (1H), 6.05 (4H), 6.65 (3H), 7.25 (4H) and 8.2-8.5 ppm (6H).
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IR-bånd (carbonylområde) ved 1780, 1735, 1670 og 1530 cm”1 (i nujol).IR band (carbonyl region) at 1780, 1735, 1670 and 1530 cm ”1 (in nujol).
Eksempel 3 ’ Å " CH3S02N N-CONH-CH-CONH—- ^ Λ oAXcH3Example 3 'Z "CH 3 SO 2 N N-CONH-CH-CONH - + Λ oAXcH 3
[1 I C00H[1 In C00H
10 OH10 OH
Ved omsætning af 2,5 vægtdele D-a-amino-p-hydroxyben- zylpenicillin-trihydrat med 1,3 vægtdele l-chlorcarbonyl-2--oxo-3-methylsulfonyl-imidazolidin på den i eksempel 2 beskrevne måde fås D-a-[ (2s-oxo-3-methylsulfonylimidazolidin-15 -1-yl)-carbonylamino]-p-hydroxybenzylpenicillin i et udbytte på 60%. Under mikroskop konstateres, at penicillinet foreligger i krystallinsk form (nåle).By reacting 2.5 parts by weight of Da-amino-p-hydroxybenzylpenicillin trihydrate with 1.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylsulfonyl-imidazolidine in the manner described in Example 2, Da- [(2s -oxo-3-methylsulfonylimidazolidin-15-yl) -carbonylamino] -p-hydroxybenzylpenicillin in 60% yield. Under the microscope it is found that the penicillin is in crystalline form (needles).
/3-Lactamindhold: 94%./ 3-Lactam content: 94%.
Penicillinet foreligger som dihydrat.The penicillin is available as a dihydrate.
20 Analyse: C% H% N% S%Analysis: C% H% N% S%
Beregnet (som monohydrat): 42,6 4,9 11,8 10,8Calculated (as monohydrate): 42.6 4.9 11.8 10.8
Pundet: 42,9 4,5 11,9 11,0 røR-signaler ved r = 2,5-2,8 (2H), 3,0-3,3 (2H), 4,3-4,6 25 (3H) 5,35 (IH), 5,9-6,3 (4H) , 6,65 (3H) og 8,3-8,6 ppm (6H) (i CD30D) IR-bånd (carbonylområde) ved 1780, 1735, 1670 og 1525 cm-1 (i nujol).Pound: 42.9 4.5 11.9 11.0 tube R signals at r = 2.5-2.8 (2H), 3.0-3.3 (2H), 4.3-4.6 (3H) 5.35 (1H), 5.9-6.3 (4H), 6.65 (3H) and 8.3-8.6 ppm (6H) (in CD30D) IR bands (carbonyl region) at 1780, 1735, 1670 and 1525 cm -1 (in nujol).
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Eksempel 4 1 <R> CHoS0oN N-CONH-CH-CONH—-,A /CH3 ^ X ' 2Example 4 1 <R> CH 2 SO 4 N-CONH-CH-CONH -, A / CH 3
ί"] COOHί "] COOH
204 Vægtdele ampicillin-trihydrat suspenderes i 2400 rumfangsdele isvand. Under ydre afkøling og god omrøring 10 ved en temperatur i området 0-5°C fås ved tilsætning af 51 vægtdele triethylamin det godt vandopløselige ampicillin-triethylaminsalt. Opløsningens pH-værdi ligger på 8,5.204 parts by weight of ampicillin trihydrate are suspended in 2400 parts by volume of ice water. Under external cooling and good stirring 10 at a temperature in the range of 0-5 ° C, the well water-soluble ampicillin-triethylamine salt is obtained by adding 51 parts by weight of triethylamine. The pH of the solution is 8.5.
I løbet af 30 minutter tilsættes portionsvis ved en temperatur i området 0-5°C 116 vægtdele l-chlorcarbonyl-2-15 oxo-3-mesyl-imidazolidin. pH-værdien holdes konstant på 7-8 ved tilsætning af triethylamin. Blandingen røres i endnu 5 timer ved 0-5° C og pH 7-9. Med fortyndet saltsyre (1:1) indstilles blandingens pH-værdi på 2 under isafkøling. Der omrøres i 30 minutter. Den udkrystalliserede penicillinsyre 20 isoleres på centrifuge. Det centrifugerede fugtige produkt opslæmmes i 5000 rumfangsdele destilleret vand, og der røres i 30 minutter ved stuetemperatur. Penicillinsyren centrifugeres igen. Opslæmningen gentages, indtil den fracentrifugerede moderlud er chloridfri. Produktet tørres ved 20-25 25°C i luftstrøm, indtil vægten er konstant.Over 30 minutes, 116 parts by weight of 1-chlorocarbonyl-2-15 oxo-3-mesyl-imidazolidine are added portionwise at a temperature in the range 0-5 ° C. The pH is kept constant at 7-8 by the addition of triethylamine. The mixture is stirred for another 5 hours at 0-5 ° C and pH 7-9. With dilute hydrochloric acid (1: 1), the pH of the mixture is adjusted to 2 under ice-cooling. Stir for 30 minutes. The crystallized penicillic acid 20 is isolated on centrifuge. The centrifuged moist product is slurried in 5000 volumes of distilled water and stirred for 30 minutes at room temperature. The penicillic acid is centrifuged again. The slurry is repeated until the centrifuged mother liquor is chloride free. The product is dried at 20-25 25 ° C in air flow until the weight is constant.
Udbytte af D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)--carbonylamino] -benzyl penicillinsyre-monohydrat: 245-255 vægtdele = 87,5-91% af det teoretiske.Yield of D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -benzyl penicillic acid monohydrate: 245-255 parts by weight = 87.5-91% of theory.
jS-Lactamindhold (iodometrisk): 91% 30 /J-Lactamindhold (enzymatisk): 90%.β-Lactam content (iodometric): 91% 30 / J-Lactam content (enzymatic): 90%.
1515
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Eksempel 5 0 1 (E) CHoS0„N N-CONH-CH-CONH— fA /CH3 rT Λ 5 3 2 VJ Γ ' 2Example 5 0 1 (E) CH 2 SO 4 N N-CONH-CH-CONH-fA / CH 3 rT Λ 5 3 2 VJ Γ '2
[t Ί COOH[t Ί COOH
204 Vægtdele ampicillin-trihydrat suspenderes i 2400 rumfangsdele isvand. Under ydre afkøling og under god om-10 røring fremstilles den ved en temperatur i området 0-5°C ved tilsætning af 10%'s natriumhydroxidopløsning, der indeholder 20 vægtdele natriumhydroxid, en natriumsaltopløsning, hvis pH-værdi indstilles på 8,5. I løbet af 30 minutter tilsættes portionsvis 116 vægtdele l-chlorcarbonyl-2-oxo-3-mesyl-imid-15 azolidin ved en temperatur i området 0-5°C. pH-værdien holdes konstant på 7-8 ved tilsætning af triethylamin. Blandingen omrøres i endnu 5 timer ved 0-5°C og pH 7-8. Med fortyndet saltsyre (1:1) indstilles under isafkøling på pH 2. Der røres i 30 minutter. Den udkrystalliserede penicillinsyre 20 isoleres på centrifuge. Det centrifugerede fugtige produkt opslæmmes i 5000 rumfangsdele destilleret vand, og der røres i 30 minutter ved stuetemperatur. Penicillinsyren centrifugeres atter. Opslæmningen gentages, indtil den fracentrifugerede moderlud er chloridfri. Produktet tørres ved 20-25 25*C i luftstrøm, indtil vægten er konstant.204 parts by weight of ampicillin trihydrate are suspended in 2400 parts by volume of ice water. Under external cooling and with good stirring, it is prepared at a temperature in the range of 0-5 ° C by the addition of 10% sodium hydroxide solution containing 20 parts by weight of sodium hydroxide, a sodium salt solution whose pH is adjusted to 8.5. Over 30 minutes, 116 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine are added portionwise at a temperature in the range of 0-5 ° C. The pH is kept constant at 7-8 by the addition of triethylamine. The mixture is stirred for another 5 hours at 0-5 ° C and pH 7-8. With dilute hydrochloric acid (1: 1), adjust to pH 2 under ice-cooling. Stir for 30 minutes. The crystallized penicillic acid 20 is isolated on centrifuge. The centrifuged moist product is slurried in 5000 volumes of distilled water and stirred for 30 minutes at room temperature. The penicillic acid is centrifuged again. The slurry is repeated until the centrifuged mother liquor is chloride free. The product is dried at 20-25 25 * C in air flow until the weight is constant.
Udbytte af D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)--carbonylamino]-benzyl-penicillinsyre-monohydrat: 235-250 vægtdele = 84-89,5% af det teoretiske.Yield of D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -benzyl-penicillic acid monohydrate: 235-250 parts by weight = 84-89.5% of theory.
Eksempel 6 16Example 6 16
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* 1 <R> CH,S0oN N-CONH-CH-CONH—.-/CH3 ^ Λ οΑΧ-3 ' H2°* 1 <R> CH, SOON N-CONH-CH-CONH -.- / CH3 ^ ΑΧ ΑΧΑΧ-3 'H2 °
COOHCOOH
204 Vægtdele ampicillin-trihydrat suspenderes i 2400 rumfangsdele isvand. Under ydre afkøling og god omrøring 10 fremstilles ved en temperatur i området 0-5* C ved tilsætning af 51 vægtdele triethylamin det godt vandopløselige ampicil-lin-triethylaminsalt. Opløsningens pH-værdi ligger på 8,5.204 parts by weight of ampicillin trihydrate are suspended in 2400 parts by volume of ice water. Under external cooling and good stirring 10, at a temperature in the range of 0-5 ° C, by adding 51 parts by weight of triethylamine, the well water-soluble ampicillin-triethylamine salt is prepared. The pH of the solution is 8.5.
I løbet af 30 minutter tilsættes portionsvis 116 vægtdele l-chlorcarbonyl-2-oxo-3-mesyl-imidazolidin ved en temperatur 15 i området 0-5°C. pH-værdien holdes konstant på 7-8 ved tilsætning af 10%'s natriumhydroxidopløsning. Blandingen røres i endnu 5 timer ved 0-5°C og pH 7-8. Med fortyndet saltsyre (1:1) indstilles på pH 2 under isafkøling. Der røres i 30 minutter. Den udkrystalliserede penicillinsyre isoleres på 20 centrifuge. Det centrifugerede fugtige produkt opslæmmes i 5000 rumfangsdele destilleret vand, og der røres i 30 minutter ved stuetemperatur. Penicillinsyren centrifugeres igen. Opslæmningen gentages, indtil den fracentrifugerede moder lud er chloridfri. Produktet tørres ved 20-25°C i luftstrøm, 25 indtil vægten er konstant.Over 30 minutes, 116 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine are added portionwise at a temperature in the range of 0-5 ° C. The pH is kept constant at 7-8 by the addition of 10% sodium hydroxide solution. The mixture is stirred for another 5 hours at 0-5 ° C and pH 7-8. With dilute hydrochloric acid (1: 1), adjust to pH 2 under ice-cooling. Stir for 30 minutes. The crystallized penicillic acid is isolated on 20 centrifuges. The centrifuged moist product is slurried in 5000 volumes of distilled water and stirred for 30 minutes at room temperature. The penicillic acid is centrifuged again. The slurry is repeated until the centrifuged mother liquor is chloride free. The product is dried at 20-25 ° C in air flow, 25 until the weight is constant.
Udbytte af D-a-[(2-oxo-3-mesyl-imidazolidin-l-yl)--carbonylamino] -benzyl-penicillinsyre-monohydrat: 230-240 vægtdele = 82-85,5% af det teoretiske.Yield of D-α - [(2-oxo-3-mesyl-imidazolidin-1-yl) -carbonylamino] -benzyl-penicillic acid monohydrate: 230-240 parts by weight = 82-85.5% of theory.
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Eksempel 7 17 Λ Ά CH--NH-SO-N N-CONH-CH-CONH—_/CH3Example 7 17 Λ Ά CH - NH-SO-N N-CONH-CH-CONH -_ / CH3
- 3 2\ / (R) <K- 3 2 \ / (R) <K
5 UJ5 UJ
COOHCOOH
Ved omsætning af 4,03 vægtdele ampicillin-trihydrat med 2,42 vægtdele l-chlorcarbonyl-2-oxo-3-methylaminosul-10 fonyl-imidazolidin på den i eksempel 1 beskrevne måde fås D-α- [ (2-oxo-3-methylaminosulfonyl-imidazolidin-l-yl)-car-bonylamino]-benzylpenicillin som fri syre i 65%'s udbytte. NMR-signaler ved r = 2,3-2,8 (5H), 4,4 (IH), 4,55 (2H) , 5,85 (IH), 6,15 (4H), 7,25 (3H), 8,45 15 (3H) og 8,5 ppm (3H) (i CD3OD).By reacting 4.03 parts by weight of ampicillin trihydrate with 2.42 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylaminosulphonyl-imidazolidine in the manner described in Example 1, D-α- [(2-oxo-3) is obtained. -methylaminosulfonyl-imidazolidin-1-yl) -carbonylamino] -benzylpenicillin as free acid in 65% yield. NMR signals at r = 2.3-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.85 (1H), 6.15 (4H), 7.25 (3H) ), 8.55 (3H) and 8.5 ppm (3H) (in CD3OD).
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2318955 | 1973-04-14 | ||
| DE2318955A DE2318955C2 (en) | 1973-04-14 | 1973-04-14 | Process for the preparation of acylureidopenicillins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK437579A DK437579A (en) | 1979-10-17 |
| DK157684B true DK157684B (en) | 1990-02-05 |
Family
ID=5878127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK437579A DK157684B (en) | 1973-04-14 | 1979-10-17 | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC PENICILLIN ACIDS |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS606956B2 (en) |
| AR (1) | AR200919A1 (en) |
| AT (1) | AT331973B (en) |
| BE (1) | BE813647A (en) |
| BG (1) | BG25095A3 (en) |
| CA (1) | CA1032159A (en) |
| CH (1) | CH592672A5 (en) |
| CS (1) | CS188919B2 (en) |
| DD (1) | DD111080A5 (en) |
| DE (1) | DE2318955C2 (en) |
| DK (1) | DK157684B (en) |
| EG (1) | EG11471A (en) |
| ES (1) | ES425197A1 (en) |
| FI (1) | FI63412C (en) |
| FR (1) | FR2225151B1 (en) |
| GB (1) | GB1465355A (en) |
| HU (1) | HU168589B (en) |
| IE (1) | IE39363B1 (en) |
| IL (1) | IL44605A (en) |
| LU (1) | LU69852A1 (en) |
| NL (1) | NL7405027A (en) |
| PL (1) | PL90407B1 (en) |
| RO (1) | RO67263A (en) |
| SE (1) | SE416052B (en) |
| SU (1) | SU568368A3 (en) |
| YU (1) | YU36030B (en) |
| ZA (1) | ZA742334B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585845B (en) * | 2009-05-08 | 2011-06-22 | 浙江金华康恩贝生物制药有限公司 | Preparation process of Mezlocillin |
| CN111471057A (en) * | 2020-04-28 | 2020-07-31 | 江苏海宏制药有限公司 | Process for preparing mezlocillin sodium by solvent crystallization |
-
1973
- 1973-04-14 DE DE2318955A patent/DE2318955C2/en not_active Expired
-
1974
- 1974-03-29 FR FR7411451A patent/FR2225151B1/fr not_active Expired
- 1974-04-08 HU HUBA3057A patent/HU168589B/hu not_active IP Right Cessation
- 1974-04-08 CS CS742519A patent/CS188919B2/en unknown
- 1974-04-08 YU YU970/74A patent/YU36030B/en unknown
- 1974-04-09 RO RO7478361A patent/RO67263A/en unknown
- 1974-04-10 AR AR253239A patent/AR200919A1/en active
- 1974-04-10 SE SE7404889A patent/SE416052B/en not_active IP Right Cessation
- 1974-04-10 JP JP49040042A patent/JPS606956B2/en not_active Expired
- 1974-04-10 BG BG026358A patent/BG25095A3/en unknown
- 1974-04-10 FI FI1090/74A patent/FI63412C/en active
- 1974-04-10 ES ES425197A patent/ES425197A1/en not_active Expired
- 1974-04-11 CH CH510374A patent/CH592672A5/xx not_active IP Right Cessation
- 1974-04-11 IL IL7444605A patent/IL44605A/en unknown
- 1974-04-11 NL NL7405027A patent/NL7405027A/xx not_active Application Discontinuation
- 1974-04-11 SU SU7402013854A patent/SU568368A3/en active
- 1974-04-11 ZA ZA00742334A patent/ZA742334B/en unknown
- 1974-04-11 DD DD177841A patent/DD111080A5/xx unknown
- 1974-04-11 CA CA197,469A patent/CA1032159A/en not_active Expired
- 1974-04-11 GB GB1612374A patent/GB1465355A/en not_active Expired
- 1974-04-11 IE IE777/74A patent/IE39363B1/en unknown
- 1974-04-12 BE BE143137A patent/BE813647A/en unknown
- 1974-04-12 LU LU69852A patent/LU69852A1/xx unknown
- 1974-04-12 AT AT309774A patent/AT331973B/en not_active IP Right Cessation
- 1974-04-13 PL PL1974170376A patent/PL90407B1/pl unknown
- 1974-04-13 EG EG74114A patent/EG11471A/en active
-
1979
- 1979-10-17 DK DK437579A patent/DK157684B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU36030B (en) | 1981-11-13 |
| ZA742334B (en) | 1975-04-30 |
| SE416052B (en) | 1980-11-24 |
| DE2318955C2 (en) | 1982-12-23 |
| AR200919A1 (en) | 1974-12-27 |
| CH592672A5 (en) | 1977-10-31 |
| IL44605A (en) | 1977-06-30 |
| HU168589B (en) | 1976-06-28 |
| RO67263A (en) | 1980-03-15 |
| FR2225151B1 (en) | 1978-02-03 |
| CS188919B2 (en) | 1979-03-30 |
| DE2318955A1 (en) | 1974-10-24 |
| BE813647A (en) | 1974-10-14 |
| AU6784874A (en) | 1975-10-16 |
| FI63412B (en) | 1983-02-28 |
| FI63412C (en) | 1983-06-10 |
| AT331973B (en) | 1976-09-10 |
| JPS49135990A (en) | 1974-12-27 |
| CA1032159A (en) | 1978-05-30 |
| GB1465355A (en) | 1977-02-23 |
| JPS606956B2 (en) | 1985-02-21 |
| ATA309774A (en) | 1975-12-15 |
| EG11471A (en) | 1978-12-31 |
| BG25095A3 (en) | 1978-07-12 |
| IL44605A0 (en) | 1974-06-30 |
| NL7405027A (en) | 1974-10-16 |
| IE39363L (en) | 1974-10-14 |
| LU69852A1 (en) | 1974-11-21 |
| FR2225151A1 (en) | 1974-11-08 |
| IE39363B1 (en) | 1978-09-27 |
| SU568368A3 (en) | 1977-08-05 |
| YU97074A (en) | 1981-04-30 |
| DK437579A (en) | 1979-10-17 |
| ES425197A1 (en) | 1976-07-01 |
| PL90407B1 (en) | 1977-01-31 |
| DD111080A5 (en) | 1975-01-20 |
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