PROCEDURE FOR THE ISOLATION OF CLAVULANIC ACID AND PHARMACEUTICALLY ACCEPTABLE SALTS FROM THE STREPTOMYCES FERMENTATION BROTH SP P 6621 FERM P 2804.

摘要

A NEW AND IMPROVED PROCESS FOR THE ISOLATION OF CLAVULANIC ACID AND PHARMACEUTICALLY ACCEPTABLE SALTS HAS BEEN DISCOVERED AS POTASSIC CLAVULANATE FROM THE AQUAUS FERMENTATION CULTIVATION OF DE P421 DUR PUR FERN 280 AQUEOUS FERMENTATION OF THE MICELIUM, A LARGER PART OF THE PROTEINS AND OTHER SUSPENDED SOLID PARTICLES ARE ELIMINATED BY MICROFILTRATION AT A PH VALUE OF THE MIDDLE BETWEEN 5.8 AND 6.2 AND AT A TEMPERATURE BETWEEN APPROX. 20 ADO (THE AQUEOUS PHASE) IS OPTIONAL AND ADDITIONALLY PURIFIED BY ULTRAFILTRATION, AND THE PURIFIED CULTIVATION STOCK IN THIS WAY IS CONCENTRATED BY REVERSE OSMOSIS, THEN IS DIRECTLY REMOVED IN A COUNTER-CURRENT DISTRIBUTOR IN CENTRIFUGAL EXTRACTORS OF PH OF THE ENVIRONMENT BETWEEN 1 AND 3, WITH WHICH THE STILL REMAINING PROTEINS ARE SIMULTANEOUSLY REMOVED, FROM THE ORGANIC PHASE OBTAINED THE SOLUBLE IMPURITIES IN WATER ARE REMOVED BY WASHING THE ORGANIC PHASE WITH WATER, THE ORGANIC PHASE IS DRIED IN VACUUM FOR A CONTENT IN WATER LESS THAN 0.1% VOL. AND THEN CONCENTRATED BY EVAPORATION, DISCOLORED BY AN ACTIVE CARBON TREATMENT, AND THEN THE CLAVULANIC ACID PRESENT IN THE DRY ORGANIC PHASE, MORE CORRECTLY IN THE ETHYL ACETATE PHASE, IS ISOLATED AND PURIFIED BY A REACTION WITH N, N ' DIISOPROPILETILENDIAMINA AT A TEMPERATURE OF APPROX. ROOM TEMPERATURE FOR THE INTERMEDIARY DICLAVULANATE OF N, N''DIISOPROPYLETHYLENE DIAMONIC WHICH IS ISOLATED AND THEN REACTING WITH 2-ETHYL POTASSIUM IN ISOPROPANOL TO PRODUCE THE POTASIC SALT OF CLAVULAN ACID