DE1073489B - Process for the production of pure neomycin or its salts - Google Patents
Process for the production of pure neomycin or its saltsInfo
- Publication number
- DE1073489B DE1073489B DENDAT1073489D DE1073489DA DE1073489B DE 1073489 B DE1073489 B DE 1073489B DE NDAT1073489 D DENDAT1073489 D DE NDAT1073489D DE 1073489D A DE1073489D A DE 1073489DA DE 1073489 B DE1073489 B DE 1073489B
- Authority
- DE
- Germany
- Prior art keywords
- neomycin
- pure
- salts
- base
- production
- 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
- 229960004927 neomycin Drugs 0.000 title claims description 24
- 239000011780 sodium chloride Substances 0.000 title claims description 14
- 150000003839 salts Chemical class 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 235000002639 sodium chloride Nutrition 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 239000003792 electrolyte Substances 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- -1 base precipitates Chemical class 0.000 claims 1
- 210000000056 organs Anatomy 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 4
- 235000013325 dietary fiber Nutrition 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- KJFMBFZCATUALV-UHFFFAOYSA-N Phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 1
- 241000187438 Streptomyces fradiae Species 0.000 description 1
- 240000007313 Tilia cordata Species 0.000 description 1
- 235000015450 Tilia cordata Nutrition 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- OIXVKQDWLFHVGR-WQDIDPJDSA-N neomycin B sulfate Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO OIXVKQDWLFHVGR-WQDIDPJDSA-N 0.000 description 1
- 230000002887 neurotoxic Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/228—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings
- C07H15/232—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DEUTSCHESGERMAN
Das als Neomycin bekannte Stoffwechselprodukt von Streptomyces fradiae konnte bislang in reiner Form in wirtschaftlich tragbarer Weise nicht hergestellt werden (vgl. britische Patentschrift 785 982 und USA.-Patentschrift 2 793 978). Das bislang im Handel erhältliche Neomycin in Form von löslichen Salzen enthält höchstens 65°/o reines Neomycin und besteht zu mindestens 35% aus größtenteils Undefinierten basischen Ballaststoffen. Es ist bekannt, daß das handelsübliche Neomycin bei der Injektion neurotoxische Schaden hervorrufen und insbesondere auf das Zentralnervensystem nachteilig einwirken kann. Hieraus ergab sich die Aufgabe, ein reines Neomycin herzustellen, um die Gefahr der Beeinflussung des nervus acusticus und des nervus vestibularis zu beseitigen oder doch zu vermindern. Es konnte außerdem damit gerechnet werden, daß die DL 50 nach Beseitigung der Ballaststoffe höher sein, d. h. die allgemeine toxische Wirkung des Neomycins bei gleichbleibender Dosis verringert sein würde.The metabolic product of Streptomyces fradiae known as neomycin has so far been able to be used in pure Form cannot be manufactured in an economically viable manner (see British Patent 785,982 and U.S. Patent 2,793,978). The previously commercially available neomycin in the form of soluble salts Contains no more than 65% pure neomycin and consists of at least 35% largely undefined basic fiber. It is known that the commercially available neomycin is neurotoxic when injected Can cause damage and, in particular, have a detrimental effect on the central nervous system. This gave rise to the task of producing a pure neomycin in order to avoid the risk of influencing the nervus acousticus and the nervus vestibularis to be eliminated or at least reduced. It could also the DL 50 can be expected to be higher after the fiber has been eliminated, i.e. H. the general the toxic effect of neomycin would be reduced at the same dose.
Die Aufgabe, ein reines Neomycin herzustellen, wird nach der vorliegenden Erfindung wie folgt gelöst:The object of producing a pure neomycin is achieved according to the present invention as follows:
Ein handelsübliches Neomycinsulfat mit zur Zeit maximal 65% Neomycinbase wird in konzentrierter wässeriger Lösung unterhalb 5° C langsam mit etwa 4O°/oiger Natronlauge versetzt, bis das als Indikator angewandte Phenolphthalein nach rot umschlägt. Dabei entsteht eine übersättigte Lösung der Neomycinbase bei einem pH-Wert von etwa 11. Nunmehr wird so viel reines gepulvertes Natriumchlorid hinzugegeben, bis bei weiterer Zugabe keine erkennbare Fällung der Neomycinbase mehr eintritt. Durch die Zugabe von Natriumchlorid wird die Neomycinbase als weißer Niederschlag, durchsetzt mit etwas Natriumchlorid, ausgefällt, während die Ballaststoffe sich noch in Lösung befinden. Der Niederschlag wird auf einer Glasfilternutsche abgesaugt. Im Filtrat sind neben geringen Mengen Natronlauge und Natriumsulfat die Ballaststoffe in löslicher basischer Form und daneben gelöstes Natriumchlorid enthalten. Auf der Nutsche bleibt die reine Neomycinbase, durchsetzt mit Natriumchlorid, zurück, weil sie unlöslich ist. Daneben befinden sich auf der Nutsche noch geringe Spuren von Natronlauge, Natriumsulfat und Ballaststoffen in gelöster Form.A commercially available neomycin sulphate with currently a maximum of 65% neomycin base is slowly mixed with about 40% sodium hydroxide solution in a concentrated aqueous solution below 5 ° C. until the phenolphthalein used as an indicator turns red. Here, a supersaturated solution is formed of neomycin at a pH value of about 11. It is now added as much pure powdered sodium chloride until further addition no discernible precipitation of the neomycin occurs more. By adding sodium chloride, the neomycin base is precipitated as a white precipitate, interspersed with a little sodium chloride, while the dietary fiber is still in solution. The precipitate is suctioned off on a glass suction filter. In addition to small amounts of caustic soda and sodium sulphate, the filtrate contains dietary fibers in a soluble basic form and also dissolved sodium chloride. The pure neomycin base, interspersed with sodium chloride, remains on the suction filter because it is insoluble. In addition, there are still small traces of sodium hydroxide, sodium sulfate and dietary fiber in dissolved form on the suction filter.
Zur Entfernung dieser anhaftenden Substanzen wird der Niederschlag mit geringen Mengen destilliertem Wasser einmal oder mehrmals nachgewaschen und wiederum abgesaugt, wobei auch ein Teil des noch ungelösten Natriumchlorids in Lösung geht und entfernt wird. Der dann verbleibende Niederschlag wird mit trockener Luft weitgehend trpckengesaugt und dann mit einem organischen Lösungsmittel, z. B. mit absolutem Alkohol, versetzt. Dabei geht die Verfahren zur Herstellung von reinem Neomycin bzw. seinen SalzenTo remove these adhering substances, the precipitate is distilled with small amounts Water washed once or several times and again vacuumed off, with part of the undissolved sodium chloride goes into solution and is removed. The then remaining precipitate is largely sucked dry with dry air and then with an organic solvent, e.g. B. with absolute alcohol. This is the process for the production of pure neomycin or its salts
Anmelder:Applicant:
O. W. G.-Chemie G. m. b. H.r Kiel, Kolonnenweg 4OWG-Chemie G. mb H. r Kiel, Kolonnenweg 4
Edmund Günter Linde, Hamburg, ist als Erfinder genannt wordenEdmund Günter Linde, Hamburg, has been named as the inventor
Neomycinbase in Lösung, während das Natriumchlorid ungelöst bleibt und durch Filtration abgetrennt wird.Neomycin base in solution while the sodium chloride remains undissolved and separated by filtration will.
Aus der Lösung der Neomycinbase in absolutem Alkohol kann nun ein wasserlösliches Salz der Neomycinbase wie folgt gewonnen werden:From the solution of the neomycin base in absolute alcohol, a water-soluble salt can now be obtained Neomycin base can be obtained as follows:
In die Lösung der Neomycinbase in absolutem Alkohol wird bei gleichzeitiger Eiskühlung des Reaktionsgefäßes vorgetrocknetes HCl-Gas eingeleitet. Dabei fällt das in absolutem Alkohol unlösliche Neomycinhydrochlorid aus. Die Reaktion ist beendet, wenn ein weiteres Einleiten von HCl-Gas keinen Niederschlag von Neomycinhydrochlorid mehr ergibt. Nach beendeter Reaktion wird der Inhalt des Reaktionsgefäßes wieder auf die Glasfilternutsche gegeben und abgesaugt. Anschließend werden die letzten Spuren des Lösungsmittels entweder im Kalktrockenschrank oder durch Vakuumtrocknung entfernt.In the solution of the neomycin base in absolute alcohol, the reaction vessel is cooled with ice introduced predried HCl gas. That which is insoluble in absolute alcohol falls Neomycin hydrochloride. The reaction is ended when no further introduction of HCl gas Precipitation of neomycin hydrochloride gives more. When the reaction is complete, the contents of the reaction vessel put back on the glass suction filter and sucked off. Then the last tracks the solvent is removed either in a lime drying cabinet or by vacuum drying.
Das so gewonnene Neomycinhydrochlorid ist ein rein weißes amorphes oder mikrokristallines Pulver von außerordentlich leichter Wasserlöslichkeit. Da es leicht hygroskopisch ist, muß es luftdicht verschlossen aufbewahrt werden. Wrässerige Lösungen des Neomycinhydrochlorids sind völlig klar und ohne jeden Farbstich. Seine biologische Wirksamkeit ist besonders groß und frei von schädlichen Nebenwirkungen, insbesondere auf das Zentralnervensystem.The neomycin hydrochloride obtained in this way is a pure white amorphous or microcrystalline powder that is extremely easily soluble in water. Since it is slightly hygroscopic, it must be kept airtight. W r ässerige solutions Neomycinhydrochlorids are completely clear and without any color cast. Its biological effectiveness is particularly great and free of harmful side effects, especially on the central nervous system.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1073489B true DE1073489B (en) | 1960-01-21 |
Family
ID=597743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DENDAT1073489D Pending DE1073489B (en) | Process for the production of pure neomycin or its salts |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1073489B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2793978A (en) * | 1955-06-27 | 1957-05-28 | Olin Mathieson | Ion exchange purification of neomycin |
| GB785982A (en) * | 1955-02-16 | 1957-11-06 | Boots Pure Drug Co Ltd | Improvements in or relating to the isolation of the antibiotic neomycin |
-
0
- DE DENDAT1073489D patent/DE1073489B/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB785982A (en) * | 1955-02-16 | 1957-11-06 | Boots Pure Drug Co Ltd | Improvements in or relating to the isolation of the antibiotic neomycin |
| US2793978A (en) * | 1955-06-27 | 1957-05-28 | Olin Mathieson | Ion exchange purification of neomycin |
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