DE1445446B - Benzylpenicillin acetoxymethyl ester and process for its preparation - Google Patents
Benzylpenicillin acetoxymethyl ester and process for its preparationInfo
- Publication number
- DE1445446B DE1445446B DE1445446B DE 1445446 B DE1445446 B DE 1445446B DE 1445446 B DE1445446 B DE 1445446B
- Authority
- DE
- Germany
- Prior art keywords
- benzylpenicillin
- acetoxymethyl
- preparation
- acetoxymethyl ester
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- NLOOMWLTUVBWAW-HLLBOEOZSA-N Penamecillin Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2)(C)C)C(=O)OCOC(=O)C)C(=O)CC1=CC=CC=C1 NLOOMWLTUVBWAW-HLLBOEOZSA-N 0.000 title claims description 6
- 229960000596 penamecillin Drugs 0.000 title claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- -1 acetoxymethyl halide Chemical class 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 229960000626 benzylpenicillin Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000019371 penicillin G benzathine Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229940056360 Penicillin G Drugs 0.000 description 2
- NHYXMAKLBXBVEO-UHFFFAOYSA-N bromomethyl acetate Chemical compound CC(=O)OCBr NHYXMAKLBXBVEO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O CC[NH+](CC)CC Chemical class CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 210000000936 Intestines Anatomy 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Description
1 21 2
Penicilline und ihre Salze sind im allgemeinen wegen ihrer Inaktivierung im Magen und Darm bei oraler Einnahme gegenüber parenteraler Anwendung weniger wirksam. Es sind höhere Dosen erforderlich, um gleich hohe Spiegel im Blut zu erreichen.Penicillins and their salts are generally oral because of their inactivation in the stomach and intestines Ingestion less effective than parenteral use. There are higher doses required to be equal Reach high levels in the blood.
Es wurde nun gefunden, daß sich mit dem Benzylpenicillin-acetoxymethylesterIt has now been found that with the benzylpenicillin acetoxymethyl ester
c. CH3 c. CH 3
CH,CONHCH —CH, CONHCH -
CO-N-CO-N-
C-CH3 C-CH 3
-CH-CO-O-CH2-O — OC — CH3 -CH-CO-O-CH 2 -O - OC - CH 3
der entsprechend den allgemeinen Angaben der USA.-Patentschrift 2 578 570 gewonnen werden kann, bei oraler Anwendung besonders hohe Blutspiegel erzielen lassen, die wesentlich höher liegen als der von Penicillin G oder anderen Estern dieser oder anderer Penicilline.which can be obtained according to the general information of US Pat. No. 2,578,570, in the case of oral use, particularly high blood levels can be achieved, which are significantly higher than that of penicillin G or other esters of these or other penicillins.
Der Benzylpenicillin-acetoxymethylester wird dadurch hergestellt, daß ein Acetoxymethylhalogenid mit Benzylpenicillin oder einem Salz davon in einem inerten Lösungsmittel, insbesondere Dimethylformamid, bei einer Temperatur zwischen O bis 30 C umgesetzt wird.The benzylpenicillin acetoxymethyl ester is thereby manufactured that an acetoxymethyl halide with benzylpenicillin or a salt thereof in one inert solvents, especially dimethylformamide, at a temperature between 0 and 30 ° C is implemented.
Geeignete Benzylpeniciilinsalze sind Alkalimetall- und Aminsalze, beispielsweise Natrium-. Kalium-, Diäthylamin- und Triäthylaminsalze. Das Acetoxymethylhalogenid ist vorzugsweise das Bromid, kann aber ebenso das Chlorid sein. Die Acetoxymethylhalogenide können durch Erhitzen des entsprechenden Acetylhalogenids mit Paraformaldehyd in Gegenwart von wasserfreiem Zinkchlorid und nachfolgendem Abtrennen des Acetoxymethylhalogenids durch Destillation hergestellt werden.Suitable benzylpenicilin salts are alkali metal and amine salts such as sodium. Potassium, diethylamine and triethylamine salts. The acetoxymethyl halide is preferably the bromide, but can also be the chloride. The acetoxymethyl halides can by heating the corresponding acetyl halide with paraformaldehyde in the presence of anhydrous zinc chloride and subsequent separation of the acetoxymethyl halide can be produced by distillation.
Das für die Reaktion verwendete Dimethylformamid sollte so trocken wie möglich sein, um Nebenreaktionen mit Wasser, welche die Ausbeute des Produkts verringern, zu vermeiden. Nach beendigter Reaktion wird das Produkt zweckmäßigerweise in Wasser (vorzugsweise auf pH 6 gepuffert) gegossen und der ausgefällte Benzylpenicillinester abfiltriert. Er kann dann in einem geeigneten organischen Lösungsmittel, beispielsweise Chloroform oder Isopropylalkohol. aufgenommen und in kristalliner Form abgetrennt werden. Der kristalline Benzylpenicillin-acetoxymethylester hat einen Schmelzpunkt von 106 bis 108 C und einen [u]--''-Wert von + 154°.The dimethylformamide used for the reaction should be as dry as possible to avoid side reactions with water, which will reduce the yield of the product. After finished In the reaction, the product is expediently poured into water (preferably buffered to pH 6) and the precipitated benzylpenicillin ester is filtered off. It can then be dissolved in a suitable organic solvent, for example chloroform or isopropyl alcohol. taken up and separated in crystalline form. The crystalline benzylpenicillin acetoxymethyl ester has a melting point of 106 to 108 C and a [u] - ″ value of + 154 °.
In den nachfolgenden Beispielen beziehen sich die Infrarot-Absorptionsdaten (IR) auf die Stellungen der Maxima, die in cm ' angegeben werden.In the examples below, the infrared absorption (IR) data refer to the poses the maxima, which are given in cm '.
Ein Gemisch von Benzylpenicillin-triäthylammoniumsalz (2,6 g des Triäthylammoniumsalzes von Penicillin G), Acetoxymethylbromid (4,5 ecm) und Dimethylformamid (10 ecm) werden eine Nacht lang bei Zimmertemperatur geschüttelt und dann in Wasser gegossen. Das Produkt wird in Chloroform gesammelt, das Lösungsmittel verdampft und der Rückstand wiederholt durch Dekantieren mit Wasser und dann mit Petroleum gewaschen. Man erhält ein Harz (2.05 g). welches aus einem Gemisch von Isopropanol und Äthanol in farblosen Prismen (1.82 g) kristallisiert: Schmelzpunkt 105 bis 106 C nach Trocknen im Vakuum: IR 1782 (/^-Lactam), 1760 (Ester CO).A mixture of benzylpenicillin triethylammonium salt (2.6 g of the triethylammonium salt of penicillin G), acetoxymethyl bromide (4.5 ecm) and Dimethylformamide (10 ecm) are shaken for one night at room temperature and then poured in water. The product is collected in chloroform, the solvent evaporated and the The residue was washed repeatedly by decanting with water and then with petroleum. You get a resin (2.05 g). which consists of a mixture of isopropanol and ethanol in colorless prisms (1.82 g) crystallized: Melting point 105 to 106 C after drying in vacuo: IR 1782 (/ ^ - lactam), 1760 (Ester CO).
Dimethylformamid (22 kg mit weniger als 0.05'"» Wasser) und trockenes Kaliumbenzylpenicillinat (10 kg) wurden in ein Reaktionsgefäß eingebracht und auf 10 C abgekühlt.Dimethylformamide (22 kg with less than 0.05 '"» Water) and dry potassium benzyl penicillinate (10 kg) were placed in a reaction vessel and cooled to 10 C.
Acetoxymethylbromid (4.15 kg) wurden der Lösung im Verlauf einer Stunde zugegeben. Hierbei wurde die Temperatur auf unterhalb 15 C gehalten und anschließend das Rühren weitere 6 Stunden bei 10 bis 15 C fortgesetzt.Acetoxymethyl bromide (4.15 kg) was added to the solution over the course of one hour. Here was the temperature was kept below 15 ° C. and then stirring was continued for a further 6 hours 10 to 15 C continued.
Das Reaktionsgemisch wurde dann im Verlauf einer Stunde zu einer auf pH 6 gepufferten Lösung, hergestellt aus Wasser (100 1). Kaliumdihydrogenphosphat (280 g) und Dikaliumhydrogenphosphat (720 g) zugegeben, wobei das Gemisch heftig gerührt und auf 5 C abgekühlt wurde. Nach weiterem, stundenlangem Rühren wurde der ausgefällte weiße Feststoff durch Filtrieren gesammelt und mit Wasser (5 I) gewaschen. Das gewaschene Produkt wurde in kochendem Isopropylalkohol (141) gelöst und die Lösung auf 15 C abgekühlt. Das umkristallisierte Produkt wurde gesammelt und bei 40 bis 45 C im Vakuum getrocknet. Es wurden 9,1 kg Benzylpenicillin-acetoxymethylester vom Schmelzpunkt 106 bis 108 C und einem [,<]; -Wert von + 154 (l"/o in Chloroform) in 83"/()iger theoretischer Ausbeute erhalten.The reaction mixture then became a pH 6 buffered solution made from water (100 liters) over the course of one hour. Potassium dihydrogen phosphate (280 g) and dipotassium hydrogen phosphate (720 g) were added, the mixture being stirred vigorously and cooled to 5 ° C. After stirring for an additional hour, the precipitated white solid was collected by filtration and washed with water (5 L). The washed product was dissolved in boiling isopropyl alcohol (141) and the solution cooled to 15 ° C. The recrystallized product was collected and dried at 40 to 45 ° C. in vacuo. 9.1 kg of benzylpenicillin acetoxymethyl ester with a melting point of 106 to 108 C and a [, <]; -Value of + 154 (1 "/ o in chloroform) obtained in 83" / () iger theoretical yield.
Claims (1)
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2228255A1 (en) * | 1971-06-09 | 1972-12-28 | Beecham Group Ltd., Brentford, Middlesex (Grossbritannien) | New esters of penicillins and cephalosporins and processes for their preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2228255A1 (en) * | 1971-06-09 | 1972-12-28 | Beecham Group Ltd., Brentford, Middlesex (Grossbritannien) | New esters of penicillins and cephalosporins and processes for their preparation |
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