CN111187339B - Method for extracting FR901379 from fermentation broth - Google Patents
Method for extracting FR901379 from fermentation broth Download PDFInfo
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- CN111187339B CN111187339B CN201911121036.4A CN201911121036A CN111187339B CN 111187339 B CN111187339 B CN 111187339B CN 201911121036 A CN201911121036 A CN 201911121036A CN 111187339 B CN111187339 B CN 111187339B
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- diatomite
- micafungin
- extracting
- precursor compound
- fermentation
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- 238000000855 fermentation Methods 0.000 title claims abstract description 45
- 230000004151 fermentation Effects 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 108010021062 Micafungin Proteins 0.000 claims abstract description 40
- 229960002159 micafungin Drugs 0.000 claims abstract description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000002243 precursor Substances 0.000 claims abstract description 29
- 238000000605 extraction Methods 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 23
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 238000000926 separation method Methods 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 238000005185 salting out Methods 0.000 claims abstract description 6
- 238000001179 sorption measurement Methods 0.000 claims abstract description 6
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 claims abstract 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 21
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 241001052560 Thallis Species 0.000 claims description 11
- 239000012141 concentrate Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 8
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 108010049047 Echinocandins Proteins 0.000 description 37
- KOOAFHGJVIVFMZ-WZPXRXMFSA-M micafungin sodium Chemical compound [Na+].C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS([O-])(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 KOOAFHGJVIVFMZ-WZPXRXMFSA-M 0.000 description 28
- 239000002904 solvent Substances 0.000 description 26
- 238000011084 recovery Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 12
- 238000000622 liquid--liquid extraction Methods 0.000 description 11
- 238000000638 solvent extraction Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 241001587826 Coleophoma empetri Species 0.000 description 5
- 239000003463 adsorbent Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910017053 inorganic salt Inorganic materials 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 229920000742 Cotton Polymers 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000001965 potato dextrose agar Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 4
- 235000013619 trace mineral Nutrition 0.000 description 4
- 239000011573 trace mineral Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- 229930182821 L-proline Natural products 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000011218 seed culture Methods 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010020326 Caspofungin Proteins 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 2
- 229960003034 caspofungin Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 239000013530 defoamer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- FDOMEEULKNYULF-UHFFFAOYSA-N heptane;methanol Chemical compound OC.CCCCCCC FDOMEEULKNYULF-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000013028 medium composition Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000345998 Calamus manan Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010030154 Oesophageal candidiasis Diseases 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 239000012501 chromatography medium Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- RLYFASGHALMQDC-UHFFFAOYSA-N heptane;2-methylpropan-1-ol Chemical compound CC(C)CO.CCCCCCC RLYFASGHALMQDC-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000401 methanolic extract Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000010451 perlite Substances 0.000 description 1
- 235000019362 perlite Nutrition 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- -1 salt compounds Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000035924 thermogenesis Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention provides a method for extracting FR901379 from fermentation liquor, which comprises the steps of carrying out solid-liquid separation on fermentation liquor of a micafungin precursor compound FR901379, and obtaining a micafungin precursor compound FR901379 and diatomite mixture through extraction, concentration, salting out, diatomite adsorption and filtration. The method avoids column chromatography purification in the purification step of the micafungin precursor compound FR901379, reduces the use amount of an organic solvent, simplifies the preparation process, and is suitable for large-scale industrial production of the micafungin precursor compound FR 901379.
Description
Technical Field
The invention relates to the field of biological pharmacy, in particular to an industrialized preparation method for extracting micafungin precursor from fermentation broth.
Background
Micafungin (Micafungin) is a novel echinocandin antifungal drug obtained by modifying a Coleophoma empetri natural product and chemically synthesizing the Micafungin; it has good inhibitory activity against candida such as candida albicans, candida glabrata, candida thermogenesis, candida krusei and candida parapsilosis, and also has good in vitro inhibitory activity against aspergillus. Micafungin (Micafungin) was developed by japan rattan corporation, marketed in japan in 12 th 2002 under the trade name Fungusrd, and approved by the FDA in the united states in 3 rd 2005, and is currently only approved for the treatment of esophageal candida infection, bone marrow transplantation, and prevention and treatment of neutropenia in ADS patients. The micafungin is a second echinocandin antifungal drug obtained after caspofungin, and can specifically inhibit the synthesis of beta (1, 3) -D-glucan which is a component of fungal cell walls, and damage the fungal cell structure to enable the fungal cell structure to be dissolved.
In recent years, the incidence of deep fungal infection starts to show a remarkable market trend, and with the application of antifungal drugs, the drug resistance of fungi is also stronger, so that the drugs for resisting deep fungal infection have become one of research hotspots of anti-infective drugs. To date, there are mainly three classes of drugs available for systemic antifungal therapy: polyenes, such as amphotericin B and liposomes thereof; azoles, such as voriconazole; echinocandins, such as caspofungin, micafungin. Amphotericin B has limited its wide clinical use since 1958 due to serious adverse reactions such as infusion reactions, nephrotoxicity and anemia. Diazoles are also limited in use due to side effects on the kidneys and retina and interactions with other drugs. Echinocandins, particularly micafungin, are of increasing interest due to their low side effects and high safety.
Micafungin (FK 463) is a semisynthetic echinocandin class of compounds against deep fungal infections. Synthesis of micafungin first, the cyclic lipopeptide compound FR901379 is produced by fermentation of fungus Coleophoma empetri, then the side chain of FR901379 is hydrolyzed and cut off by an acylase to obtain FR179642, and finally the micafungin is prepared by chemical modification.
At present, the technology for extracting echinocandin compounds from fermentation liquor is almost not reported in China, and related researches are mainly carried out by large pharmaceutical companies abroad, but the related researches are mainly concentrated on small-scale extraction in a laboratory, the extraction process route is longer, the yield of the product is very low, the used solvent species are relatively more, and the influence of some solvents on human bodies and the environment is relatively larger, so that the method is not suitable for large-scale industrial production.
The process for extracting echinocandin compounds from fermentation broth by using WO2011/121599A1 mainly comprises the following steps: extracting echinocandins compounds from fermentation liquor by using a solvent; then liquid-liquid extraction is carried out to remove part of impurities; and (3) after the activated carbon is decolorized, adsorbing by using an adsorbent, and finally resolving, concentrating and precipitating to obtain the echinocandin compound. The main problem of the process is that the solvent is used in a relatively large amount in the extraction process; in the processes of liquid-liquid extraction of fermentation liquor and liquid-liquid extraction of extraction liquor containing target components, mixed solvent layers are produced, organic phases are dissolved in different degrees in an aqueous phase, pollution is caused by direct discharge, and the recovery cost is increased; the used adsorbent is expensive, difficult to regenerate thoroughly and has a limited service life.
The process for extracting echinocandin compounds from fermentation liquor by using US5194377 and US5202309 mainly comprises the following steps: extracting echinocandins from the mycelium with a first solvent; then carrying out liquid-liquid extraction for multiple times to transfer the echinocandin compound in two phases to remove part of impurities; the extract containing the echinocandin compounds is subjected to chromatography through a plurality of different chromatographic columns, and finally the echinocandin compounds are obtained through resolution, concentration and solvent precipitation. The main problem of the process is that the solvent is used in a relatively large amount in the extraction process; in the processes of liquid-liquid extraction of fermentation liquor and liquid-liquid extraction of extraction liquor containing target components, mixed solvent layers are produced, organic phases are dissolved in different degrees in an aqueous phase, pollution is caused by direct discharge, and the recovery cost is increased; meanwhile, the used adsorbents are various, expensive, not easy to regenerate thoroughly and limited in service life; the process route is long, and the final total yield is lower.
The process for extracting echinocandin compounds from fermentation liquor by using US661082282 and US2008/0108806A1 mainly comprises the following steps: firstly, extracting echinocandin compounds from mycelium by using isobutanol; concentrating isobutanol containing echinocandin compounds, washing with water, and adding methanol-n-heptane for liquid-liquid extraction to form two phases: an organic phase (isobutanol-n-heptane) and an aqueous phase (methanol-water), the echinocandin compound being transferred into the aqueous phase; concentrating the water phase to remove methanol, adding isobutanol for liquid-liquid extraction, and transferring echinocandin compounds into the isobutanol; concentrating to remove isobutanol, adding acetonitrile, and precipitating to obtain echinocandin compounds. The main problem of the process is that the solvent is used in a relatively large amount in the extraction process; washing the isobutanol extract containing the target component with water, and adding methanol-n-heptane to perform liquid-liquid extraction, wherein a mixed solvent layer is generated, organic phases are dissolved in the water phase to different degrees, pollution is caused by direct discharge, and the recovery cost is increased; the organic phase used in the liquid-liquid extraction in the extraction process is a mixed solvent, and the recovery difficulty is relatively high.
The process for extracting echinocandin compounds from fermentation liquor in US 2010/0249271A 1 mainly comprises the following steps: extracting echinocandins from the mycelium with a first solvent; then, after vacuum concentration to remove part of the solvent, adding a metal salt adsorbent (such as calcium phosphate) to obtain an echinocandin compound-calcium phosphate compound; and dissolving the echinocandin compound from the compound by using a second solvent, concentrating to remove the second solvent, and adding a third solvent to precipitate to obtain the echinocandin compound. The main problem of the process is that the solvent is used in a relatively large amount in the extraction process; during the extraction process, metal salt compounds are added, and residues are inevitably left in the product, so that further purification is needed to remove metal ions.
The process for extracting echinocandin compounds from fermentation liquor in CN101659693 and CN101659692A mainly comprises the following steps: extracting echinocandins from the mycelium with a first solvent; concentrating to remove the first solvent, and extracting again with the second solvent; concentrating to remove the second solvent, dissolving echinocandin compounds with the first solvent again, and sequentially carrying out chromatographic operations with an acidic alumina column, an adsorption resin column and a reverse phase resin column; concentrating the resolved solution, adding solvent, and precipitating to obtain echinocandin compounds. The main problem of the process is that the use amount of the solvent is relatively large; the extraction route is longer, and the total yield is lower after multiple times of chromatography; the adsorbent has multiple types, different types of solvents can be used in the regeneration process, the recovery difficulty is increased, and the extraction cost is increased.
The process for extracting echinocandin compounds from fermentation broth in WO9611210 mainly comprises the following steps: extracting echinocandins compounds from mycelium by using acetone; concentrating to remove acetone, extracting with ethyl acetate, and extracting with n-butanol; concentrating to remove part of n-butanol, sequentially subjecting to silica gel column chromatography and centrifugal chromatography twice, subjecting to silica gel column chromatography twice, concentrating the analytical solution to dryness, adding small amount of water for dissolving, adjusting pH to 7.0, and lyophilizing to obtain echinocandin compounds. The main problem of the process is that the solvent is used in a relatively large amount in the extraction process; in the process of extracting liquid by using ethyl acetate and n-butyl alcohol, a mixed solvent layer can be generated, and the recovery difficulty is relatively high; the method has the advantages of multiple chromatography steps, low final yield and one-step centrifugal chromatography in the middle, and is not suitable for industrial production; the chromatographic medium has various types, different solvents can be used in the regeneration process, the recovery difficulty is increased, and the extraction cost is further increased.
The process for extracting echinocandin compounds from fermentation broth in US4024245, US4024246 and US4288549 mainly comprises the following steps: firstly, extracting a fermentation liquor by using methanol, then, carrying out liquid-liquid extraction on a methanol extract by using chloroform, concentrating to remove the chloroform, and then, adding diethyl ether to enable an echinocandin compound to generate a precipitate; and (3) after redissolving the precipitate, performing reversed-phase resin column chromatography, extracting the analysis solution with chloroform, concentrating again to remove chloroform, adding tertiary butanol for dissolving, and freeze-drying to obtain the echinocandin compound. The main problem of the process is that the extraction steps are more, and the final yield is lower; the extraction process uses dangerous chemical solvents such as chloroform, which is not suitable for mass production.
Disclosure of Invention
The invention aims to develop a method which is simple and convenient to operate, low in toxicity of the used solvent and suitable for industrialized production of the micafungin precursor compound FR901379, realizes large-scale production of the micafungin precursor compound FR901379, reduces production cost and reduces preparation difficulty.
The invention discloses a method for extracting micafungin precursor compound FR901379 from fermentation broth, which comprises the steps of carrying out solid-liquid separation on the fermentation broth of micafungin precursor compound FR901379, extracting, concentrating, salting out, adsorbing by diatomite and filtering.
Preferably, the extraction step extractant is selected from an organic solvent or an aqueous organic solvent solution, preferably an aqueous organic solvent solution.
In a preferred embodiment, the method comprises the steps of:
1) Carrying out solid-liquid separation on the fermentation liquor of the micafungin precursor compound FR901379 to obtain fermentation thalli;
2) Adding a polar solvent aqueous solution into the fermentation thalli for extraction to obtain an extract liquid of a micafungin precursor compound FR 901379;
3) Concentrating the extract to obtain a micafungin precursor concentrate, adding inorganic salt, stirring for salting out, adding diatomite for adsorption, and filtering to obtain a mixture of micafungin precursor compound FR901379 and diatomite.
Preferably, in the step 1), a filter aid may be added to perform solid-liquid separation, and the filter aid is preferably perlite or diatomaceous earth, and more preferably diatomaceous earth.
In a preferred embodiment, the method comprises the steps of:
1) Adding diatomite into the fermentation liquor of the micafungin precursor compound FR901379 for solid-liquid separation to obtain fermentation thalli;
2) Adding a polar solvent aqueous solution into the fermentation thalli for extraction to obtain an extract liquid of a micafungin precursor compound FR 901379;
3) Concentrating the extract to obtain a micafungin precursor concentrate, adding inorganic salt, stirring for salting out, adding diatomite for adsorption, and filtering to obtain a mixture of micafungin precursor compound FR901379 and diatomite.
Wherein, the adding amount of the diatomite in the step 1 is 8-12kg, preferably 10kg, of the fermentation broth per cubic meter.
In a preferred embodiment, the extraction time in step 2 is from 6 to 15 hours, preferably from 10 to 12 hours; the polar solvent aqueous solution used in the step 2 has a volume ratio of polar solvent to water selected from 60-80%, preferably 70%; the polar solvent is selected from one or more of C1-C4 alcohol or C1-C4 ketone, preferably one or more of acetone, methanol, ethanol, n-propanol, isopropanol or n-butanol, preferably one or more of acetone, isopropanol or ethanol, more preferably acetone or isopropanol.
In a preferred scheme, after the inorganic salt is added into the step 3 micafungin precursor concentrate, the concentration of the inorganic salt in the concentrate is 3-8mol/L, and can be 4mol/L; the inorganic salt is selected from sodium chloride, potassium chloride or (NH) 4 ) 2 SO 4 Preferably sodium chloride.
In a preferred embodiment, the diatomite is added in step 3 in an amount of 80-120kg, preferably 100kg, per cubic meter of micafungin precursor concentrate.
Compared with the prior art, the invention has the beneficial effects that: the method for creatively using salting out and diatomite adsorption avoids using complicated purification processes such as chromatography columns, simplifies the purification and separation process of the precursor compound FR901379, has the recovery rate of the compound FR901379 up to more than 95%, greatly reduces the use amount of an organic solvent, and is suitable for large-scale production of the micafungin precursor compound FR 901379.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are only illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
Preparation of fermentation broth Coleophoma empetri F-11899 (FERM BP 2635)
Seed liquid Coleophoma empetri F-11899 (FERM BP 2635) was prepared by the method of culturing seeds in the reference Scale-up fermentation of echinocandin type antibiotic FR901379 (Journal of Bioscience and Bioengineering, VOL 109No.2, 138-144, 2010) for fermentation of FR 901379.
The slant culture medium adopts Potato Dextrose Agar (PDA) culture medium, and comprises the following components: 30% of potato, 2% of glucose and 1.5% of agar.
Seed medium composition: sucrose 1%, cotton seed cake powder 2%, dry yeast 1% peptone 1%, KH 2 PO 4 0.2％，CaCO 3 0.2% of defoamer and 0.05%.
The strain Coleophoma empetri F-11899 (FERM BP 2635) is mature after 6-10 days of culture on a 25 deg.C slant, mature mycelium or spores are picked up and inoculated into seed culture medium, and then cultured on a shaker at a rotation speed of 280RPM for 2-4 days at 25 deg.C.
Example two
Fermentation broth (mutagenesis strain CGMCC 4129)
The seed culture method of seeds in reference Scale-up fermentation of echinocandin type antibiotic FR901379 (Journal of Bioscience and Bioengineering, VOL 109no.2, 138-144, 2010) prepares seed liquid of the mutagenesis strain CGMCC 4129 for fermentation of FR 901379.
The slant culture medium adopts Potato Dextrose Agar (PDA) culture medium, and comprises the following components: 30% of potato, 2% of glucose and 1.5% of agar.
Seed medium composition: sucrose 1%, cotton seed cake powder 2%, dry yeast 1% peptone 1%, KH 2 PO 4 0.2％，CaCO 3 0.2% of defoamer and 0.05%.
The strain CGMCC 4129 is mature after being cultured on a 25 ℃ inclined plane for 6-10 days, mature mycelium or spores are picked up and inoculated into a seed culture medium, and then the strain is cultured on a shaking table at the speed of 280RPM for 2-4 days at the 25 ℃.
Example III
Preparation of FR901379 fermentation broth
In a 250ml shaking flask, 50ml of a medium containing 5% mannitol, 0.5% yeast extract, 1% L-proline, 1% cotton seed cake powder, 0.1% ammonium sulfate, 0.06% magnesium sulfate, 0.1% trace element solution, and 2% MES was added, pH was adjusted to 5.5.+ -. 0.5, sterilization was performed at 121℃for 30 minutes, 1ml (2%) of the seed obtained in example 1 was inoculated into the culture, cultivation was completed at 25℃for 280r/m for 240 hours, and the sample analysis was performed, and the viscosity of the final culture was 2200cp, wherein the FR901379 content was 0.5g/L.
Trace elements: feSO 4 ·7H 2 O 10g/L，MnSO 4 ·H 2 O 10g/L，ZnSO 4 ·7H 2 O 2g/L，CaCl 2 0.7g/L，H 3 BO 3 0.56g/L，CuCl 2 ·2H 2 O 0.25g/L，(NH 4 ) 6 Mo 7 O 24 ·7H 2 O0.19 g/L, concentrated hydrochloric acid 500ml/L.
Example IV
Taking 1 cubic meter of fermentation liquor obtained by amplifying FR901379 according to the third ratio of the embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of acetone-water mixed solution with the volume ratio of 70%, stirring and extracting for 10-12 hours, filtering, concentrating filtrate under reduced pressure to remove acetone to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 4mol/L, stirring for 3-6 hours, standing for crystallization, adding 5kg of diatomite after crystallization, and filtering to obtain the mixture of FR901379 and diatomite. Sampling and detecting, wherein the recovery rate of FR901379 is 96.8%, and the purity is 93.0%.
Example five
Into a 50L fermenter, 29L of tap water, 600g of cotton seed cake powder (concentration: 2%), 1800g of mannitol (concentration: 6%), 600g of g L-proline (concentration: 2%), 240g of yeast extract (concentration: 0.8%), 30g of ammonia sulfate (concentration: 0.1%), 12g of magnesium sulfate (concentration: 0.04%), 30ml of a trace element solution (concentration: 0.1%), pH was adjusted to 5.5.+ -. 0.5 with sodium hydroxide or hydrochloric acid, sterilized at 121℃for 30 minutes, and inoculated into the culture in an amount of 0.9L (3%) to give a 30L culture. Controlling ventilation rate to 1-2vvm, dissolved oxygen to above 80%, pH 6.0+ -0.5, and culture temperature to 25+ -2deg.C, culturing for 50 hr, and adding mannitol 1% and L-proline 0.5% (based on initial culture solution volume of 30L) every day. After 240 hours of cultivation, the cultivation was ended and the sample was analyzed, and the viscosity of the final culture broth was 2300cp, wherein the content of FR901379 was 2.5g/L.
Trace elements: feSO 4 ·7H 2 O 10g/L，MnSO 4 ·H2O 10g/L，ZnSO 4 ·7H 2 O 2g/L，CaCl 2 0.7g/L，H 3 BO 3 0.56g/L，CuCl 2 ·2H 2 O 0.25g/L，(NH 4 ) 6 Mo 7 O 24 ·7H 2 O0.19 g/L, concentrated hydrochloric acid 500ml/L.
Example six
Taking 1 cubic meter of fermentation liquor of FR901379 obtained in the fifth embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of acetone-water mixed solution with the volume ratio of 70%, stirring and extracting for 10-12 hours, filtering, concentrating filtrate under reduced pressure to remove acetone to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 4mol/L, standing and crystallizing after stirring for 3-6 hours, adding 5kg of diatomite after crystallization, and filtering to obtain a mixture of FR901379 and diatomite. The recovery rate of FR901379 was 97.0% and 94.2% by sampling and detection.
Example seven
Taking 1 cubic meter of fermentation liquor of FR901379 obtained in the fifth embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of ethanol solution, stirring and extracting for 10-12 hours, filtering, adding 100L of purified water into filtrate, concentrating under reduced pressure to remove ethanol to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 4mol/L, stirring for 3-6 hours, standing for crystallization, adding 5kg of diatomite after crystallization, and filtering to obtain a mixture of FR901379 and diatomite. Sampling and detecting, wherein the recovery rate of FR901379 is 82.0%, and the purity is 78.0%.
Example eight
Taking 1 cubic meter of fermentation liquor of FR901379 obtained in the fifth embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of isopropanol water mixed solution with the volume ratio of 60%, stirring and extracting for 10-12 hours, filtering, concentrating filtrate under reduced pressure to remove isopropanol to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 4mol/L, stirring for 3-6 hours, standing for crystallization, adding 5kg of diatomite after crystallization, and filtering to obtain the mixture of FR901379 and diatomite. Sampling and detecting, wherein the recovery rate of FR901379 is 95.0% and the purity is 91.8%.
Example nine
Taking 1 cubic meter of fermentation liquor of FR901379 obtained in the fifth embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of acetone-water mixed solution with the volume ratio of 70%, stirring and extracting for 10-12 hours, filtering, concentrating filtrate under reduced pressure to remove acetone to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 3mol/L, standing and crystallizing after stirring for 3-6 hours, adding 5kg of diatomite after crystallization, and filtering to obtain a mixture of FR901379 and diatomite. Sampling and detecting, wherein the recovery rate of FR901379 is 96.0%, and the purity is 93.2%.
Examples ten
Taking 1 cubic meter of fermentation liquor of FR901379 obtained in the fifth embodiment, adding 10kg of diatomite, stirring for 30 minutes, filtering to obtain about 100kg of thalli, adding 400 liters of acetone-water mixed solution with the volume ratio of 70%, stirring and extracting for 10-12 hours, filtering, concentrating filtrate under reduced pressure to remove acetone to obtain 50 liters of FR901379 concentrated liquor, adding sodium chloride according to the amount of 8mol/L, standing and crystallizing after stirring for 3-6 hours, adding 5kg of diatomite after crystallization, and filtering to obtain a mixture of FR901379 and diatomite. Sampling and detecting, wherein the recovery rate of FR901379 is 95.0% and the purity is 92.5%.
Claims (9)
1. A process for the preparation of micafungin precursor compound FR901379, comprising the steps of:
1) Adding diatomite into the fermentation liquor of the micafungin precursor compound FR901379 for solid-liquid separation to obtain fermentation thalli;
2) Adding 60-80% acetone or isopropanol water solution into the fermentation liquor for extraction to obtain micafungin precursor compound FR901379 extract;
3) Concentrating the extract to obtain a micafungin precursor concentrate, adding sodium chloride, stirring and salting out, wherein the concentration of sodium chloride in the concentrate is 3-4mol/L, adding diatomite for adsorption, and filtering to obtain a mixture of micafungin precursor compound FR901379 and diatomite.
2. The process according to claim 1, wherein the extraction time in step 2) is from 6 to 15 hours.
3. The process according to claim 2, wherein the extraction time in step 2) is 10-12 hours.
4. The method according to claim 1, wherein the volume ratio of acetone or isopropanol to water is 70%.
5. The process of claim 1 wherein the concentration of sodium chloride in the concentrate after adding sodium chloride to the micafungin precursor concentrate of step 3) is 4mol/L.
6. The method of claim 1, wherein the diatomite is added in an amount of 80-120kg per cubic meter of micafungin precursor concentrate in step 3).
7. The method of claim 6, wherein the diatomite is added in an amount of 100kg per cubic meter of micafungin precursor concentrate in step 3).
8. The method according to claim 1, wherein the diatomite is added in an amount of 8-12kg per cubic meter of fermentation broth in step 1).
9. The method according to claim 8, wherein the diatomite is added in an amount of 10kg per cubic meter of fermentation broth in step 1).
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