CS240345B1 - Tylosine antibiotic insulation method - Google Patents
Tylosine antibiotic insulation method Download PDFInfo
- Publication number
- CS240345B1 CS240345B1 CS847473A CS747384A CS240345B1 CS 240345 B1 CS240345 B1 CS 240345B1 CS 847473 A CS847473 A CS 847473A CS 747384 A CS747384 A CS 747384A CS 240345 B1 CS240345 B1 CS 240345B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- tylosin
- filtrate
- antibiotic
- fermentation
- solution
- Prior art date
Links
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 12
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 5
- 238000009413 insulation Methods 0.000 title 1
- 229930194936 Tylosin Natural products 0.000 claims abstract description 40
- 239000004182 Tylosin Substances 0.000 claims abstract description 40
- 229960004059 tylosin Drugs 0.000 claims abstract description 40
- 235000019375 tylosin Nutrition 0.000 claims abstract description 40
- 238000000855 fermentation Methods 0.000 claims abstract description 18
- 230000004151 fermentation Effects 0.000 claims abstract description 18
- 239000000706 filtrate Substances 0.000 claims abstract description 17
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 241000187438 Streptomyces fradiae Species 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims abstract 2
- 239000002244 precipitate Substances 0.000 claims abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940126601 medicinal product Drugs 0.000 abstract description 2
- ILSYTMBVJDPAKS-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;propan-2-one Chemical compound CC(C)=O.OC(=O)C(O)C(O)C(O)=O ILSYTMBVJDPAKS-UHFFFAOYSA-N 0.000 abstract 1
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- 238000000605 extraction Methods 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229960001717 tylosin tartrate Drugs 0.000 description 4
- ICVKYYINQHWDLM-KBEWXLTPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 ICVKYYINQHWDLM-KBEWXLTPSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- NBOODGNJLRRJNA-IAGPQMRQSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl Chemical compound OP(O)(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 NBOODGNJLRRJNA-IAGPQMRQSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940031989 tylosin phosphate Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Vynález rieši sposob izolácie antibiotika tylozínu z filtrátu fermentačnej pódy po skončení kultivácie produkčného kmeňa Streptomyces fradiae, alebo z iných vodných roztokov tylozínu, ktorý sa vyznačuje tým, že sa filtrát fermentačnej pódy, alebo iný vodný roztok tylozínu extrahuje butylacetátom, ktorý obsahuje 1 až 30 % obj. vo· vodě obmedzene rozpustného iného organického rozpúšťadla, s výhodou butanolu, z ktorého sa tylozín vyzráža ako sol', napr. acetonovým roztokom kyseliny vínnej. Získaný tylozín-tertarát sa priamo móže použit na přípravu liečebných prípravkov, alebo sa prevedie známými postupmi na tylozín-bázu, ktorá sa používá na přípravu injekci!.The invention provides a method of isolating an antibiotic tylosin from the filtrate of the fermentation post after end of cultivation of the production strain Streptomyces fradiae, or other aqueous ones tylosin solutions that are characterized by the filtrate of the fermentation process, or another aqueous solution of tylosin extracted with butyl acetate, which contains 1 to 30 vol. water-soluble other organic solvent, preferably butanol, from which the tylosin precipitates as a salt, e.g. tartaric acid acetone solution. acquired Tylosin tertarate is directly used for the preparation of medicinal products, or. \ t is carried out by known procedures on tylosin base, which is used to prepare the injection !.
Description
Vynález rieši sposob izolácie antibiotika tylozínu z filtrátu fermentačnej půdy, po skončení kultivácie produkčného kmeňa Streptomyces fradiae, alebo z iných vodných roztokov tylozínu.The invention provides a method for isolating the antibiotic tylosin from the filtrate of the fermentation broth, after cultivation of the production strain Streptomyces fradiae, or from other aqueous tylosin solutions.
Tylozín je makrolidové antibiotikum, sumárneho vzorca C45H77NO17. Má slabo bázický charakter, vo vodě je málo rozpustný, dobré rozpustný jie v polárných a semipolárnych organických rozpúšťadlách a nerozpustný v nepolárných rozpúšťadlách, a ko je hexán, či petroléter. Vodné roztoky tylozínu sú stále v rozmedzí pH 5,5 a 8,5. Kyslou hydrolýzou sa tylozín rozkládá na biologicky obdobné účinný dezmykozín.Tylosin is a macrolide antibiotic of the general formula C45H77NO17. It is poorly basic in nature, poorly soluble in water, well soluble in polar and semi-polar organic solvents, and insoluble in non-polar solvents such as hexane or petroleum ether. Aqueous tylosin solutions are still between pH 5.5 and 8.5. By acid hydrolysis, tylosin breaks down into biologically similar active desmycosine.
S kyselinami tvoří tylozín soli dobré rozpustné vo vodě a v polárných organických rozpúšťadlách.With acids tylosin forms salts soluble in water and in polar organic solvents.
Tylozín je antibiotikum používané vo veterinárnej praxi, najma na potlačenie infekcií vyvolaných gram-pozitívnymi baktériami a mykoplazmózami (Ose E. E.: J. Am. Vet. A. 137, 421—423, 1980). Samotný tylozín sa využívá obzvlášť pri liečbe dyzentérií a pneumónií hospodářských zvierat (Curtíns R, A.: Canad. Vet. J. 3, 285—288, 1962; Doornebal H.: Canad. J. Comp. Med. Sci. 29, 179—182, 1965; Schovánek V.: Veterinářství 25, 505—507, 1975). Široko sú využívané aj kombinácie tylozínu s inými antibakteriálne posobiacimi látkami, ako sú sulfonamidy (Ose E. E.: Vet. Med. Smáli Anim. Clin. 68, 539—543, 1975; Reichel, F.: Biol. Chem. Výž. Zvířat 10, 343—350, 1974), furazolidínom (US 3, 690, 869), colistinom (Ger. offen 2, 327, 392), ako aj s inertnými přísadami ako síranom sodným (US 3, 932, 995 j, polyoxyetylénestermi (Brit. 1, 219, 785), alebo s močovinou (Ger. offen 1, 812, 471). Na přípravu liečebných prípravkov sa využívá buď tylozín vo formě bázy, alebo vo formě solí, ako je tartarát, chlorid, fosfát alebo síran (Bruszewski W.: Now. Wet. 6, 349—352, 1972). V krmných zmesiach sa tiež využívá technický tylozín, připravený vysušením fermentačnej pody (Dvořák, J., Straková, J^, Ševčík, B.: Biol. Chem. Vet. 18, 77—78, 1982).Tylosin is an antibiotic used in veterinary practice, particularly to suppress infections caused by gram-positive bacteria and mycoplasmosis (Ose E. E., J. Am. Vet. A. 137, 421-423, 1980). Tylosine alone is particularly useful in the treatment of dysentery and pneumonia in farm animals (Curtins R, A .: Canad. Vet. J. 3, 285-288, 1962; Doornebal, H .: Canad. J. Comp. Med. Sci. 29, 179). —182, 1965; Schovánek V .: Veterinary 25, 505-507, 1975). Combinations of tylosin with other antibacterial scavengers such as sulfonamides have also been widely used (Ose EE: Vet. Med. Smal. Anim. Clin. 68, 539-543, 1975; Reichel, F .: Biol. Chem. Animal Nutrition 10, 343-350, 1974), furazolidine (US 3, 690, 869), colistin (Ger. Offen 2, 327, 392), as well as inert additives such as sodium sulfate (US 3, 932, 995, polyoxyethylene esters (Brit. 1, 219, 785) or with urea (Ger. Offen 1, 812, 471.) For the preparation of medicinal products either tylosin in the form of a base or in the form of salts such as tartrate, chloride, phosphate or sulphate is used (Bruszewski W Wet., 6, 349-352 (1972) .Technical tylosin prepared by drying a fermentation pod (Dvořák, J., Straková, J., Ševčík, B .: Biol. Chem. Vet. 18, 77-78 (1982).
Doposíal' sa tylozín izoloval z fermentačnej pody tak, že sa odfiltrovalo mycélium, filtrát sa extrahoval chloroformem a po oddestilovaní chloroformu za zníženého tlaku sa z olejovitého zvyšku tylozín vyzrážal hexánom, alebo petroléterom (US 3, 178, 341). Takto připravený tylozín bolo nutné před dalším použitím rekryštalizovať, alebo previesť na sol’, ako například tartarát, z ktorého sa připravila báza čistého tylozínu (Hamill R. L.: Antib. and Chemother. 11, 328—334, 1961). Preparát tylozínu o obsahu 40 % účinnej látky je možné připravit vysolením tylozínu z deproteinizovaného filtrátu fermentačnej pody, alebo extrakciou tylozínu alkoholmi z vysprayovanej fermentačnej půdy, napr. 90 % propanolom (Aut. osv. č. 197 600). Tylozín podobnej čistoty je možné získat tiež azeotropickým oddestilovaním vody z filtrátu fermentačnej pody například s n-hexylaíkoholom (Ger. offen 2, 054, 085). Tylozín vo formě tylozín tartarátu je možné připravit o vysokej čistotě extrakciou tylozínu z filtrátu fermentačnej pody extrakciou do butylacetátu (AO č. 231 279). Nevýhodou tohoto postupu je nutnost volit viacnásobnú extrakciu filtrátu, nakolko pri jednostupňovej extrakci! butylacetátom sa tylozín vyextrahuje s malým výťažkom. Pri extrakcii Ί 000 ml filtrátu fermentačnej pody 200 ml butylacetátu pri pH 9,0 a teplote 25 °C sa vyextrahuje do organické] fázy len cca 53 % tylozínu. S vyšším výťažkom možno tylozín vyextrahovat zmesou chloroform-etylacetát, ale vzhíadom na toxicitu chloroformu je využitelnost tejto metody v priemyselnom meradle značné obmedzená.Up to now, tylosin was isolated from the fermentation pod by filtering off the mycelium, extracting the filtrate with chloroform and, after distilling off the chloroform under reduced pressure, from the oily residue of tylosin precipitated with hexane or petroleum ether (US 3,178,341). The tylosin thus prepared had to be recrystallized or converted to a salt prior to further use, such as the tartrate from which pure tylosin base was prepared (Hamill R.L .: Antib. And Chemother. 11, 328-334, 1961). A 40% tylosin preparation can be prepared by salting tylosin from a deproteinized fermentation pod filtrate, or by extracting tylosin with alcohols from a sprayed fermentation broth, e.g. 90% propanol (Aut. Certificate 197 600). Tylosin of similar purity can also be obtained by azeotropically distilling water from the filtrate of a fermentation pod with, for example, n-hexyl alcohol (Ger. Offen 2,054,085). Tylosin in the form of tylosin tartrate can be prepared of high purity by extracting tylosin from the filtrate of the fermentation pod by extraction into butyl acetate (AO No. 231 279). The disadvantage of this procedure is the necessity to choose multiple extraction of the filtrate, as in the single-stage extraction! Butyl acetate extracts tylosin in a small yield. With extraction of Ί000 ml of fermentation tray filtrate with 200 ml of butyl acetate at pH 9.0 and 25 ° C, only about 53% tylosin is extracted into the organic phase. With higher yield, tylosin can be extracted with chloroform-ethyl acetate, but due to the toxicity of chloroform, the utility of this method on an industrial scale is very limited.
Bolo zistené, že tylozín je možné získat vo vysokej čistotě a výtažku z filtrátu fermentačnej pody, alebo z iných vodných roztokov, ako je napr. vodný roztok technického tylozín-fosfátu, sposobom podía vynálezu, ktorého podstata spočívá v tom, že sa filtrát fermentačnej pody, alebo iný vodný roztok tylozínu extrahuje butylacetátom, ktorý obsahuje 1 až 30% obj. vo vodě obmedzene rozpustného alkoholu, akým je například amylalkohol, izoamylalkohol, izobutylalkohol, benzylalkohol (s výhodou 10 % obj. butanolu) alebo ketonu, ako je napr. metylizobutylkeíón, metyletylketón a pod. Výhodou tohto postupu je, že stačí jednostupňová extrakcia tylozínu týmto postupom, aby sa tylozín vyextrahoval vo vysokom výtažku. Pri extrakcii 1 000 ml filtrátu fermentačnej pody 180 ml butylacetátu a 20 ml benzylalkoholu pri pH — 9,0 a teplota 20 °C sa vyextrahuje do organické} fázy 91 % tylozínu.It has been found that tylosin can be obtained in high purity and extract from the fermentation pod filtrate, or from other aqueous solutions such as e.g. An aqueous solution of technical tylosin phosphate according to the invention, characterized in that the filtrate of the fermentation pod or another aqueous solution of tylosin is extracted with butyl acetate containing 1 to 30% by volume of ethyl acetate. a water-soluble alcohol such as amyl alcohol, isoamyl alcohol, isobutyl alcohol, benzyl alcohol (preferably 10% v / v butanol) or ketone such as e.g. methylisobutyl ketone, methyl ethyl ketone and the like. The advantage of this process is that a single-stage extraction of tylosin by this process is sufficient to extract tylosin in a high yield. Extraction with 1000 ml of fermentation tray filtrate with 180 ml of butyl acetate and 20 ml of benzyl alcohol at pH 9.0 and at a temperature of 20 ° C is extracted into the organic phase of 91% tylosin.
Takto získané extrakty tylozínu na rozdiel od chloroformových extraktov možno priamo zrážať acetonovým roztokom kyseliny, napr. 1 % hmot. obj. roztokom kyseliny vínnej, čím sa získá dobré kryštalizujúca sol — tylozín tartarát. Tento sa može buď priamo využit na přípravu liečebných prípravkov, alebo sa prevedie běžnými postupmi na tylozín — bázu. Výhodou tohto postupu je, že tylozín sa získá vo vysokom výtažku a čistotě z filtrátu fermentačnej pody za použitia netoxických a fahko sa regenerujúcich rozpúšťadiel.Unlike chloroform extracts, the tylosin extracts thus obtained can be directly precipitated with an acetonic acid solution, e.g. 1 wt. vol. with a tartaric acid solution to obtain a good crystallizing sol-tylosin tartrate. This can either be used directly for the preparation of medicaments, or converted to tylosin base by conventional procedures. The advantage of this process is that tylosin is obtained in high yield and purity from the fermentation pod filtrate using nontoxic and readily regenerating solvents.
Nasledujúci příklad prevedenia spĎsob podía vynálezu len dokládá, ale nijako neobmedzuje.The following example illustrates the process according to the invention but does not limit it in any way.
K 500 ml filtrátu fermentačnej pody o účinnosti 7 630 jug/ml sa přidá 100 ml butylacetátu a 25 ml butanolu. Zmes sa za intenzívneho miešania upraví roztokom hydroxidu sodného na pH — 9,0 a nechá sa 15 minút miešať. Po tomto čase sa organická vrstva oddělí, čím sa získá 125 ml organickej fázy s účinnosťou 27 750 ,ug/ml čo je 91 pere. výťažnosť extrakcie. Získaný organický extrakt potom po kvapkách přidáváme do 300 ml acetonu, v ktorom bolo rozpuštěné 3,5 g kyseliny vínnej. Po hodině intenzívneho miešania po přidaní celého množstva organického extraktu sa vylúčený tylozín tartarát odfiltruje, premyje 30 ml acetonu a vysuší volné na vzduchu pri laboratórnej teplote, čím sa získá 4,1 g tylozín tartarátu o účinnosti 850 m. j./mg, čo je 86% výťažnosť, počítané na filtrát fermentačnej půdy.To 500 ml of the fermentation plate filtrate with an efficiency of 7,630 µg / ml was added 100 ml of butyl acetate and 25 ml of butanol. The mixture was adjusted to pH 9.0 with vigorous stirring with stirring and allowed to stir for 15 minutes. After this time, the organic layer was separated to give 125 ml of an organic phase with an efficiency of 27,750 µg / ml which was 91 pens. extraction yield. The organic extract obtained is then added dropwise to 300 ml of acetone, in which 3.5 g of tartaric acid is dissolved. After one hour of vigorous stirring after addition of all the organic extract, the precipitated tylosin tartrate is filtered off, washed with 30 ml of acetone and air-dried at room temperature to give 4.1 g of tylosin tartrate having an efficiency of 850 m. U./mg, which is 86% recovery calculated on the fermentation broth filtrate.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CS847473A CS240345B1 (en) | 1984-10-03 | 1984-10-03 | Tylosine antibiotic insulation method |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CS847473A CS240345B1 (en) | 1984-10-03 | 1984-10-03 | Tylosine antibiotic insulation method |
Publications (2)
Publication Number | Publication Date |
---|---|
CS747384A1 CS747384A1 (en) | 1985-06-13 |
CS240345B1 true CS240345B1 (en) | 1986-02-13 |
Family
ID=5423935
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CS847473A CS240345B1 (en) | 1984-10-03 | 1984-10-03 | Tylosine antibiotic insulation method |
Country Status (1)
Country | Link |
---|---|
CS (1) | CS240345B1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110407893B (en) * | 2019-08-14 | 2023-01-03 | 齐鲁制药(内蒙古)有限公司 | Method for removing D component and improving quality of tylosin tartrate |
-
1984
- 1984-10-03 CS CS847473A patent/CS240345B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
CS747384A1 (en) | 1985-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2126416C1 (en) | Erythromycin derivatives, pharmaceutical composition on their basis, method of their preparation and intermediates | |
KR100486053B1 (en) | Novel Erythromycin Derivatives, Method for Preparing Same, and Use Thereof as Drugs | |
KR930002509B1 (en) | Process for preparation of crystalline calcium pseudomonate | |
US10414746B2 (en) | Method and intermediate for preparing tulathromycin | |
EP0677530B1 (en) | Process for the preparation of azithromycin dihydrochloride | |
DE1166199B (en) | Process for the preparation of 7-aminocephalosporaneane derivatives | |
DD210283A5 (en) | PROCESS FOR THE PREPARATION OF 20-AMINOTYLOSINE DERIVATIVES | |
CN102643295A (en) | Preparation method of cefminox sodium | |
CS240345B1 (en) | Tylosine antibiotic insulation method | |
DE69709732T2 (en) | AROMATIC RIBOSE-SUBSTITUTED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT | |
CN113173956A (en) | Preparation method of clarithromycin lactobionate | |
CS221510B2 (en) | Method of making the anorganic salts of trimethylamonium derivatives of the polyenmarolide | |
RU2110578C1 (en) | Strain amycolatopsis orientalis subspecies eremomycini vkpm-s892 - a producer of antibiotic eremomycin and a method of antibiotic eremomycin producing | |
US3946013A (en) | 1,3-BIS(Beta-ethylhexyl)-5-amino-5-methylhexahydropyrimidine-pyridine-3-carboxylate, process for its preparation and pharmaceutical compositions containing this compound | |
DE2244915B2 (en) | Methoxymethyl ester of hetacillin and process for its preparation | |
WO2016189549A1 (en) | A novel process for the preparation of ethacrynate sodium | |
CN105461770A (en) | Synthesis method of 9-desoxy-9-homoerythromycin A(Z) oxime | |
US4482545A (en) | Isoefrotomycin, process of preparation, pharmaceutical composition and method of using same | |
US2438209A (en) | Reaction product of gramicidin and formaldehyde and method of production | |
DE2754323C2 (en) | ||
US5091411A (en) | Pseudo-primycin complexes, components and acid addition salts thereof as well as a process for the preparation of same | |
RU2235723C1 (en) | Method for preparing n-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinsulfon)-n'-isonicotino yl hydrazide | |
CS231279B1 (en) | Isolation method of thylosine antibioticum | |
DE1795290C3 (en) | hydroxyphenyl) acetamido] peniciUanoic acid and 6- [D-0-2,2-dimethyl-4- (3-chloro-4-hydroxyphenyl) -5oxo2H-1-imidazolidinyl] peniciUanoic acid, processes for the preparation of these compounds and pharmaceuticals prepared therefrom | |
BG61266B1 (en) | Method for the preparation of20-dehydro-20-deoxy-20-=(cis-3,5-dimethylpiperidine-1-il)-desmycosin |