NO119272B

NO119272B -

Info

Publication number: NO119272B
Application number: NO14572162A
Authority: NO
Inventors: E Testa; G Cignerella; G Pifferi
Original assignee: Lepetit Spa
Priority date: 1962-02-14
Filing date: 1962-09-14
Publication date: 1970-04-27
Also published as: ES280754A1; SE308313B; BR6243133D0; GB962943A; CH398601A; BR6241133D0

Description

Fremgangsmåte til fremstilling av farmakologisk aktive penicillinforbindelser. Process for the preparation of pharmacologically active penicillin compounds.

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av nye farmakologisk aktive halvsyntetiske penicilliner, som fremstilles ved at man går ut fra 6-amino-penicillansyre som har formelen: The present invention relates to a process for the production of new pharmacologically active semi-synthetic penicillins, which are produced by starting from 6-amino-penicillanic acid which has the formula:

respektive ikke-giftige salter av denne. respective non-toxic salts thereof.

De forbindelser som fremstilles i henhold til oppfinnelsen, representeres ved den folgende formel: The compounds produced according to the invention are represented by the following formula:

hvor X er alkylengruppe med 1-3 C-atomer, og salter derav, inkludert ikke-giftige metallsalter, som f.eks. natrium-, kalium-, aluminium-, ammonium- og substituerte ammoniumsalter, som er oppnådd ved reaksjon med slike aminer som vanlig benyttes i forbindelse med penicilliner, f.eks. prokain, dibenzylamin og N,N'-dibenzyletylenamin. where X is an alkylene group with 1-3 C atoms, and salts thereof, including non-toxic metal salts, such as e.g. sodium, potassium, aluminium, ammonium and substituted ammonium salts, which have been obtained by reaction with such amines as are usually used in connection with penicillins, e.g. procaine, dibenzylamine and N,N'-dibenzylethyleneamine.

Foreliggende fremgangsmåte, som er en i og for seg kjent standard-fremgangsmåte, er kjennetegnet ved at 6-aminopenicillansyre eller et salt derav omsettes med et a-f enyl-to-karbobenzoksyaminosyre-derivat med formelen: The present method, which is a standard method known in and of itself, is characterized by the fact that 6-aminopenicillanic acid or a salt thereof is reacted with an α-phenyl-to-carbobenzoxyamino acid derivative with the formula:

hvor X har den ovennevnte betydning, i nærvær av et tertiært amin, hvoretter, karbobenzoksygruppen avspaltes ved katalytisk hydrogenering og en erholdt fri syre omsettes eventuelt med en base til det tilsvarende salt. De dannede forbindelser inneholder et asymmetrisk karbon-atom, og de tilsvarende diastereoisomere kan fremstilles ved vanlige fremgangsmåter. Fksempelvis kan de optisk aktive former av (3-amino-ot-fenyletylpenicillin fremstilles av racemisk a-fenyl-(3-karbobenzoksy-aminopropionsyrer, som er blitt fremstilt av den racemiske blanding via dennes salt * n* 4 optisk aktive baser, som f.eks. kinin, cinkonin, stryknin og morfin. where X has the above meaning, in the presence of a tertiary amine, after which, the carbobenzoxy group is cleaved off by catalytic hydrogenation and a free acid obtained is optionally reacted with a base to the corresponding salt. The compounds formed contain an asymmetric carbon atom, and the corresponding diastereoisomers can be prepared by usual methods. For example, the optically active forms of (3-amino-o-phenylethylpenicillin can be prepared from racemic a-phenyl-(3-carbobenzoxy-aminopropionic acids), which have been prepared from the racemic mixture via its salt * n* 4 optically active bases, such as .eg quinine, cinchonine, strychnine and morphine.

Den folgende tabell angir den minste inhibitoriske konsentra-sjon i<y>/ml in vitro av noen av de nye penicilliner like overfor en del patogene mikroorganismer. The following table indicates the minimum inhibitory concentration in<y>/ml in vitro of some of the new penicillins against a number of pathogenic microorganisms.

Britisk patent nr. 873 049 beskriver penicilliner som har en kjemisk struktur som ligner forbindelsen fremstilt ifolge foreliggende oppfinnelse, men hvori aminogruppen i 6-aminopenicillansyren er bundet til et oc-aminosyreacylradikal. British Patent No. 873,049 describes penicillins having a chemical structure similar to the compound prepared according to the present invention, but in which the amino group of the 6-aminopenicillanic acid is attached to an oc-amino acid acyl radical.

Det er blitt funnet at penicillinene som fremstilles ifolge foreliggende oppfinnelse, har en overlegen virkning i forhold til slike som er beskrevet i det nevnte britiske patent, hvilket fremgår av folgende tabell. It has been found that the penicillins produced according to the present invention have a superior effect compared to those described in the aforementioned British patent, which is evident from the following table.

De nye penicilliner har stor motstandsevne både mot syrer og mot penase. Stabiliteten av noen av de nye penicilliner i saltsyre fpH = l) sammenlignet med fenoksymetylpenicillin, som er kjent som et av de penicilliner som er minst folsomt for sure media, er vist i den folgende tabell. Prosentmengden av ikke-nedbygget penicillin til for-skjellige tider er angitt i tabellen. The new penicillins have great resistance both to acids and to penase. The stability of some of the new penicillins in hydrochloric acid fpH = 1) compared to phenoxymethylpenicillin, which is known as one of the penicillins least sensitive to acidic media, is shown in the following table. The percentage amount of non-degraded penicillin at different times is indicated in the table.

De folgende eksempler belyser oppfinnelsens fremgangsmåte nærmere. The following examples illustrate the method of the invention in more detail.

Eksempel 1 Example 1

Til 82.5 g |3-amino-a-fenylpropionsyre i 200 ml 10%-ig NaOH setter man dråpevis ved 15°C<p>g under omroring 98 g benzylklorkarbo-nat. Omroringen fortsettes i 1.5 timer ved romtemperatur. Oppløs-ningen ekstraheres med dietyleter, og det vandige lag surgjores med 50%-ig svovelsyre til kongorod reaksjon. Den oljeaktige utfelling ekstraheres med dietyleter, ekstraktene vaskes med vann, torkes og inndampes, hvorved man får 140 g N-karbobenzoksy-P-amino-a-fenylpropionsyre, med smeltepunkt 124°-127°C. To 82.5 g of |3-amino-a-phenylpropionic acid in 200 ml of 10% NaOH, 98 g of benzyl chlorocarbonate are added dropwise at 15°C with stirring. Stirring is continued for 1.5 hours at room temperature. The solution is extracted with diethyl ether, and the aqueous layer is acidified with 50% sulfuric acid to a Congorod reaction. The oily precipitate is extracted with diethyl ether, the extracts are washed with water, dried and evaporated, thereby obtaining 140 g of N-carbobenzoxy-P-amino-a-phenylpropionic acid, with a melting point of 124°-127°C.

Til 155 g kinin i 700 ml 90%-ig etylalkohol settes det en varm opplosning av 140 g N-karbobenzoksy-Ø-amino-cc-fenylpropionsyre i 500 ml etylalkohol. Blandingen avkjoles og utfellingen filtreres fra. Utbyttet er 13 g og dets smeltepunkt 176°-177°C, og dets /oc/D= -125°f0.2 io i etylalkohol). Kininsaltet suspenderes i 1 liter vann, og blandingen gjores sur med 10%-ig HC1, og ekstraheres med dietyleter. De forenede ekstrakter vaskes med vann, torkes over NagSO^, og inndampes, hvorved man får 55 g (-)-N-karbobenzoksy-(3-amino-a-fenylpropionsyre, som har smeltepunkt 99°-100°C og /a/^ = -93°( 1% etylalkohol) . To 155 g of quinine in 700 ml of 90% ethyl alcohol is added a hot solution of 140 g of N-carbobenzoxy-Ø-amino-cc-phenylpropionic acid in 500 ml of ethyl alcohol. The mixture is cooled and the precipitate is filtered off. The yield is 13 g and its melting point 176°-177°C, and its /oc/D= -125°f0.2 io in ethyl alcohol). The quinine salt is suspended in 1 liter of water, and the mixture is made acidic with 10% HCl and extracted with diethyl ether. The combined extracts are washed with water, dried over Na2SO4 and evaporated, whereby 55 g of (-)-N-carbobenzoxy-(3-amino-a-phenylpropionic acid) is obtained, which has a melting point of 99°-100°C and /a/ ^ = -93° (1% ethyl alcohol) .

Til en blanding av 52 g (-)-N-karbobenzoksy-P-amino-a-fenylpropionsyre, 1300 ml vannfri aceton og 27 ml vannfritt trietylamin, som er kjolt til 0°C, tilsettes det dråpevis og under omroring 18.5 ml etylklorkarbonat. Blandingen omrores grundig i 10 minutter etter avslutningen av tilsetningsoperasjonen, hvoretter blandingen avkjoles til -5°C og behandles porsjonsvis med 37-566-aminopenicillansyre i 1000 ml 4%-ig natriumbikarbonat, mens temperaturen holdes under 0°C. To a mixture of 52 g of (-)-N-carbobenzoxy-P-amino-α-phenylpropionic acid, 1300 ml of anhydrous acetone and 27 ml of anhydrous triethylamine, which has been cooled to 0°C, 18.5 ml of ethyl chlorocarbonate is added dropwise and with stirring. The mixture is stirred thoroughly for 10 minutes after the end of the addition operation, after which the mixture is cooled to -5°C and treated in portions with 37-566-aminopenicillanic acid in 1000 ml of 4% sodium bicarbonate, while the temperature is kept below 0°C.

Omroringen fortsettes i.30 minutter ved romtemperatur. Stirring is continued for 30 minutes at room temperature.

Blandingen ekstraheres med dietyleter, deretter reguleres dens pH til 2 med fortynnet saltsyre og den ekstraheres igjen med dietyleter. Eterekstraktene vaskes med vann og pH-verdien reguleres til 6.2 ved hjelp av NaHCO^. Opplosningen av natriumsaltet av (-)-N-karbobenzoksy-P-amino-a-fenyletylpenicillin settes til en suspen-sjon av vandig Pd/CaCO^, som på forhånd er blitt mettet med hydrogen, og blandingen rystes i 1 time. Blandingen blir filtrert, regulert til pH = 2 og ekstrahert med dietyleter, det vandige lags pH reguleres til 4»6°g det inndampes i vakuum til et lite volum, og fryses. Utbyttet blir 40 g (-)-P-amino-oc-fenyletylpenicillin, som smelter ved 225°-230°C funder spaltning) og har / a/* ° =-203.° The mixture is extracted with diethyl ether, then its pH is adjusted to 2 with dilute hydrochloric acid and it is extracted again with diethyl ether. The ether extracts are washed with water and the pH value is adjusted to 6.2 using NaHCO^. The solution of the sodium salt of (-)-N-carbobenzoxy-P-amino-α-phenylethylpenicillin is added to a suspension of aqueous Pd/CaCO 3 , which has previously been saturated with hydrogen, and the mixture is shaken for 1 hour. The mixture is filtered, adjusted to pH = 2 and extracted with diethyl ether, the pH of the aqueous layer is adjusted to 4-6°g, it is evaporated in vacuum to a small volume, and frozen. The yield is 40 g of (-)-P-amino-oc-phenylethylpenicillin, which melts at 225°-230°C finds cleavage) and has / a/* ° =-203.°

Eksemgel_2_-_2_ Eczema Gel_2_-_2_

Ved samme arbeidsmåte som i eksempel 1 ble det fremstilt: a-fenyl-Y-aminopropylpenicillin, smeltepunkt 193°-195°0. a-fenyl-6-aminobutylpenicillin, smeltepunkt l80°-l85°G. Using the same working method as in example 1, the following was produced: α-phenyl-Y-aminopropylpenicillin, melting point 193°-195°0. a-phenyl-6-aminobutylpenicillin, melting point l80°-l85°G.

Claims

Process for the preparation of pharmacologically active penicillins having the formula:

where X is an alkylene group with 1-3 carbon atoms, as well as non-toxic salts thereof, characterized in that 6-aminopenicillanic acid or a salt thereof is reacted with an α-phenyl-C»-carbobenzoxyamino acid derivative with the formula:

where X has the above meaning, in the presence of a tertiary amine, after which the carbobenzoxy group is cleaved off by catalytic hydrogenation and a free acid obtained is optionally reacted with a base to the corresponding salt.