CN102952178A - Preparation method for high-purity echinocandin compound - Google Patents
Preparation method for high-purity echinocandin compound Download PDFInfo
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Abstract
The invention discloses a preparation method for an echinocandin compound by using a Coleophoma sp. fermentation culture. The method comprises the following steps: carrying out filtration, macroporous resin adsorption, desorption, condensation, crystallization and the like on the Coleophoma sp. fermentation culture so as to obtain a crude extract of the echinocandin compound FR179642; and carrying out chromatographic separation on the crude extract of the echinocandin compound FR179642 by using a reversed-phase filling material so as to obtain an echinocandin compound FR179642 product with high purity. The invention has the following advantages: a macroporous resin is used to extract and separate the echinocandin compound FR179642 in the method, and the method is simple and feasible and is suitable for industrial production; and through application of the reversed-phase filling material in chromatographic separation of the echinocandin compound FR179642, the echinocandin compound FR179642 product with high purity is prepared.
Description
Technical field
The invention belongs to the industrial microbial technology field, be specifically related to the preparation method of a kind of high purity echinocandin compounds FR179642.
Background technology
In recent years, along with spreading of extensive application, chemotherapy of tumors, organ transplantation and the acquired immune deficiency syndrome (AIDS) of extensive pedigree antibiotic and immunosuppressor etc., the crowd who causes immunity system to be suppressed is on the increase, the sickness rate of deep fungal infection begins to present obvious ascendant trend, and the utilization along with antifungal drug, the resistance of fungi is also more and more stronger, so that the application of antifungal drug has the trend of swift and violent increase.Therefore, the medicine of anti-deep fungal infection has become one of study hotspot of anti-infective, day by day causes people's concern.
Echinocandin is the novel antifungal drug of a class, and is obviously different from the mechanism of action of present clinical antifungal drug commonly used, is β-1, and the inhibitor of 3-glucan synthase acts on the cell walls of fungi.Cell walls is difference maximum between fungi and the mammalian cell, so the interference cell wall is synthetic, the integrity that affect cell walls will cause fungal cell's death and to the people without injury, so side effect is less, security is higher.
The echinocandin class medicine has had 3 kind listings, i.e. Caspofungin, MFG and anidulafungins at present.Wherein MFG Japan rattan pool company develops, and 2005 is the 2nd kind of echinocandin antifungal agent thing of FDA approval after Caspofungin by the U.S. FDA authentication.The deep fungal infection that Candida, Eurotium are caused has extensive anti-microbial effect; Candida albicans, Candida glabrata, candida krusei and other candidiasis to anti-azole drug all have good anti-microbial activity.Simultaneously, MFG is without renal toxicity, and with other drug almost without interacting, therefore good potential applicability in clinical practice is arranged.
MFG is the synthetic echinocandin antifungal agent thing of a kind of water-soluble semi, is to modify and get through natural product echinocandin compounds FR179642.Echinocandin compounds FR179642 is the fermentating metabolism product of sheath Phoma (Coleophoma sp.), is the main raw material of synthetic MFG.Its structural formula is as follows:
At present, extract the bibliographical information that separates about echinocandin compounds FR179642 less.Chinese patent 200810130526.6 has reported echinocandin derivatives, preparation method and as the purposes of anti-mycotic agent, content relates generally to the research of synthetic aspect, and final purified product seldom relates to echinocandin compounds FR179642.Chinese patent 97194475.X has reported that the cyclic lipopeptide acyl enzyme can effectively make the acyl side-chain deacylation of cyclic lipopeptide compound F 17-hydroxy-corticosterone R901739 thing and analog thereof; thereby the effect that makes FR901739 pass through the acyl group saccharase generates the method for FR179642, does not have concrete separation and purification process.Report is more on Japan's microbiotic magazine is fermentation and laboratory separation purification method about FR901379.Report in the document in addition also relevant for synthetic method (the Masaki Tomishima of (FK463) from FR179642 to the MFG, Hidenori Ohki, Akira Yamada, et al.FK463, a Novel Water-soluble Echinocandin Lipopeptide:Synthesis and Antifungal Activity[J], THEJOURNAL OF ANTIBIOTICS, 1999,52 (7): 674-676).
Summary of the invention
The object of the invention is to develop a kind of easy and simple to handle, solvent for use toxicity is low, is suitable for the method for suitability for industrialized production echinocandin compounds FR179642.The present invention adopts macroporous adsorbent resin to extract separation FR179642, and is further purified by the reversed phase chromatography medium, to prepare highly purified FR179642 product.Simple for process, be suitable for suitability for industrialized production, for MFG synthetic provides strong raw material basis.
The below specifically describes the present invention:
In the methods of the invention, by adding flocculating aids, improve the fermented liquid filtering velocity, by solid-liquid separation, obtain the filtrate of FR179642.The filtrate importing macroporous adsorbent resin of FR179642 is carried out enrichment, and the impurity that polarity is larger and small molecular protein flow out owing to not being adsorbed.After saturated resin was used the deionized water purification and washing, with the mixed solution desorb of polar solvent and water, stripping liquid was concentrated, crystallization, obtained the crude extract of FR179642.Crude extract obtains the product of highly purified FR179642 through the reverse phase filler chromatographic separation.
Particularly, the present invention relates to the preparation method of a kind of high purity echinocandin compounds FR179642, comprise the steps:
1) in the fermented liquid of echinocandin compounds FR179642, adds flocculating aids, stir;
2) fermented liquid with FR179642 carries out solid-liquid separation, obtains the filtrate of FR179642;
3) the filtrate importing macroporous adsorbent resin with FR179642 adsorbs;
4) absorption is complete, carries out first resin and purifies, and then the mixed solution with polar solvent and water carries out desorb, obtains the stripping liquid of FR179642;
5) it is concentrated behind the 4-5 adding acidic substance adjusting pH value in the stripping liquid, then uses the polar solvent crystallization, gets the FR179642 crude extract;
6) the FR179642 crude extract is carried out the reverse phase filler chromatographic separation, with the mixed solution gradient desorption of polar solvent and water;
7) it is concentrated behind the 4-5 adding acidic substance adjusting pH value in the stripping liquid that chromatographic separation obtains, and then uses the polar solvent crystallization, obtains highly purified echinocandin compounds FR179642 product.
Wherein, step 1) flocculating aids in is perlite or diatomite, is preferably perlite.The flocculating aids consumption is every liter of fermented liquid 50-100 gram, is preferably the 50-70 gram.
Step 2) the solid-liquid separation process in is the modes such as traditional centrifugal, filter press.
Step 3) macroporous adsorbent resin in is the low-pole polymeric adsorbent of LX-18 or AB-8 etc., and the consumption of polymeric adsorbent is the 1/20-1/5 of FR179642 filtrate volume, is preferably 1/12-1/8; The resin column blade diameter length ratio is 1/5-1/8, and the absorption flow velocity is 1-3BV/h, is preferably 1-2BV/h.
Step 4), 5), 6), 7) in polar solvent be a kind of in methyl alcohol, ethanol or the acetone, the desorb polar solvent is preferably methyl alcohol or ethanol, the crystallization polar solvent is preferably ethanol or acetone.
Step 4) resin in purifies as using 3 times of column volumes of deionized water wash, and desorb polar solvent ratio is 10-40%, is preferably 15%-25%; The desorb flow velocity is 1/3-1BV/h, is preferably 1/3-1/2BV/h.
Step 5), 7) described acidic substance are other organic acid or the mineral acid such as hydrochloric acid, oxalic acid, glacial acetic acid, are preferably glacial acetic acid.
Step 5), 7) in stripping liquid to be concentrated into concentrated solution concentration be 50-100mg/mL, the recrystallisation solvent add-on be the concentrated solution volume 6-10 doubly, be preferably 6-8 doubly.
Step 6) reverse phase filler in is for adopting polymer microballoon, the ODS C of the preparation of polystyrene or polyacrylic ester and derivative thereof
18Or Fraclite800, be preferably polymer microballoon or ODS C
18
After the mixed solution gradient desorption of the polar solvent step 6) and water, polar solvent gradient concentration are 1-3 times of column volume of 5% mixed solution washing, be eluted to the whole wash-outs of echinocandin compounds FR179642 with the mixed solution of 15% concentration complete.
Products obtained therefrom of the present invention can be for the synthesis material of MFG, and the weight content of FR179642 can reach more than 90%, and the area normalization percentage composition reaches more than 98%, and sample recovery rate is greater than 60%.
The present invention has the following advantages: 1. added flocculating aids in the solid-liquid separation process, improved filtration velocity, shortened process cycle, improved the quality of filtrate.2. adopt macroporous adsorbent resin that the purpose product is separated and enrichment, further abandoned the interference of fermentation secondary metabolite, improved the quality of purpose product.3. the application of reversed phase chromatography medium can obtain highly purified FR179642 product, and yield is high.4. technique is simple, and sample recovery rate is high, and omnidistance total recovery reaches on 60%.5. omnidistance solvent for use is conventional solvent, and toxicity is little, is suitable for suitability for industrialized production.
Description of drawings
Fig. 1 embodiment 1FR179642 fermented liquid HPLC collection of illustrative plates
Fig. 2 embodiment 1FR179642 crude extract HPLC collection of illustrative plates
Fig. 3 embodiment 1FR179642 fine powder HPLC collection of illustrative plates
Embodiment
Following embodiment only is used for setting forth realizing method of the present invention, should not be construed as limitation of the present invention.FR179642 fermented liquid used in the present invention is research and development centre of magnificent medicine stock company microorganism culturing means, the FR179642 fermented liquid that obtains.The LX-18 resin is that Xi'an Lanxiao Sci-Tech Co., Ltd. produces; The AB-8 resin is that Zhengjiang City Ninth Heaven chemical industry company limited produces; Polymer microballoon is that Suzhou is received little scientific ﹠ technical corporation and produced; ODS C18 resin is to look forward in length and breadth Science and Technology Ltd.'s production in Beijing; The Fraclite800 resin is that Shanghai calm moral company produces.The reagent such as methyl alcohol, ethanol, acetone are commercially available.The high performance liquid chromatograph that the present invention uses is 996 type detectors, 515 pumps (Waters company).
Embodiment 1
Get FR179642 fermented liquid 20.0L, fermentation unit 520 μ g/mL (9.67g).In fermented liquid, add the 1kg perlite, stir 30min final vacuum suction filtration, obtain 16.8L clear filtrate (seeing accompanying drawing 1).Filtrate is imported the LX-18 adsorption resin column, and (Φ 8 * 50cm), and loading amount is 1400mL, and the loading flow velocity is 1400mL/h.Then saturated resin deionized water purification and washing uses 10% acetone desorb, and the desorb flow velocity is 470mL/h.Stripping liquid concentrates after transferring PH=4.0 with glacial acetic acid, is concentrated into 193mL, slowly adds 1930mL acetone and analyses the powder crystallization, and static, filtration obtains FR179642 crude extract 12.82g (seeing accompanying drawing 2).FR179642 crude extract polymer microballoon chromatographic separation, the acetone-water gradient elution.The elutriant segmentation is concentrated, crystallization, drying (40 ℃ of temperature, vacuum tightness is greater than 0.08Mpa), obtains at last FR179642 refined powder 5.92g.Extracting total recovery is 60.1%, fine powder HPLC content 98.1% (seeing accompanying drawing 3).
Get FR179642 fermented liquid 100.0L, fermentation unit 723 μ g/mL (72.3g).In fermented liquid, add 7kg diatomite, stir 30min final vacuum suction filtration, obtain 84.3L clear filtrate (similar to accompanying drawing 1 peak shape).Filtrate is imported the AB-8 adsorption resin column, and (Φ 14 * 80cm), and loading amount is 8.5L, and the loading flow velocity is 17L/h.Then saturated resin deionized water purification and washing uses 40% methyl alcohol desorb, and the desorb flow velocity is 3.5L/h.Stripping liquid concentrates after transferring PH=4.5 with oxalic acid, is concentrated into 723mL, slowly adds 5784mL methyl alcohol and analyses the powder crystallization, and static, filtration obtains FR179642 crude extract 105.7g (similar to accompanying drawing 2 peak shapes).FR179642 crude extract ODS C
18Chromatographic separation, the methanol-water gradient elution.The elutriant segmentation is concentrated, crystallization, drying (40 ℃ of temperature, vacuum tightness is greater than 0.08Mpa), obtains at last FR179642 refined powder 45.1g.Extracting total recovery is 61.5%, fine powder HPLC content 98.6% (similar to accompanying drawing 3 peak shapes).
Embodiment 3
Get FR179642 fermented liquid 500.0L, fermentation unit 643 μ g/mL (321.5g).In fermented liquid, add the 50kg perlite, stir 30min final vacuum suction filtration, obtain 427L clear filtrate (similar to accompanying drawing 1 peak shape).Filtrate is imported the LX-18 adsorption resin column, and (Φ 24 * 140cm), and loading amount is 50L, and the loading flow velocity is 75L/h.Then saturated resin deionized water purification and washing uses 25% ethanol desorb, and the desorb flow velocity is 25L/h.Stripping liquid concentrates after transferring PH=5.0 with hydrochloric acid, is concentrated into 4.0L, slowly adds the 24L dehydrated alcohol and analyses the powder crystallization, and static, filtration obtains FR179642 crude extract 460g (similar to accompanying drawing 2 peak shapes).FR179642 crude extract polymer microballoon chromatographic separation, the alcohol-water gradient elution.The elutriant segmentation is concentrated, crystallization, drying (40 ℃ of temperature, vacuum tightness is greater than 0.08Mpa), obtains at last FR179642 refined powder 208g.Extracting total recovery is 63.5%, fine powder HPLC content 98.3% (similar to accompanying drawing 3 peak shapes).
Claims (10)
1. the preparation method of a high purity echinocandin compounds FR179642 comprises the steps:
1) in the fermented liquid of echinocandin compounds FR179642, adds flocculating aids, stir;
2) fermented liquid is carried out solid-liquid separation, obtain the filtrate of echinocandin compounds FR179642;
3) the filtrate importing macroporous adsorbent resin with echinocandin compounds FR179642 adsorbs;
4) absorption is complete, carries out resin and purifies, and the stripping liquid that then mixes with polar solvent and water carries out desorb, obtains the stripping liquid of echinocandin compounds FR179642;
5) it is concentrated behind the 4-5 adding acidic substance adjusting pH value in the stripping liquid, then uses the polar solvent crystallization, gets echinocandin compounds FR179642 crude extract;
6) echinocandin compounds FR179642 crude extract is carried out the reverse phase filler chromatographic separation, with the mixed solution gradient concentration desorb of polar solvent and water;
7) it is concentrated behind the 4-5 adding acidic substance adjusting pH value in the stripping liquid that chromatographic separation obtains, and then uses the polar solvent crystallization, obtains highly purified echinocandin compounds FR179642 product.
2. method according to claim 1, wherein step 1) in flocculating aids be perlite or diatomite, its consumption is every liter of fermented liquid 50-100 gram.
3. method according to claim 1, wherein step 2) in the solid-liquid separation process be centrifugal, filter press mode.
4. method according to claim 1, wherein step 3) in macroporous adsorbent resin be the low-pole polymeric adsorbent, be preferably AB-8 or LX-18 low-pole polymeric adsorbent, its consumption is the 1/20-1/5 of echinocandin compounds FR179642 filtrate volume.
5. method according to claim 1, wherein step 4), 5), 6), 7) in polar solvent be a kind of in methyl alcohol, ethanol or the acetone.
6. method according to claim 1, wherein step 4) described in resin purify as with 3 times of column volumes of deionized water wash, the concentration of stripping liquid Semi-polarity solvent is 10-40%.
7. method according to claim 1, wherein step 5), 7) described acidic substance are a kind of in organic acid or the mineral acid, are preferably hydrochloric acid, oxalic acid or glacial acetic acid.
8. method according to claim 1, wherein step 5), 7) in stripping liquid to be concentrated into concentration be 50-100mg/mL, the recrystallisation solvent add-on be the concentrated solution volume 6-10 doubly.
9. method according to claim 1, wherein step 6) described in reverse phase filler for adopting polymer microballoon, the ODS C of the preparation of polystyrene or polyacrylic ester and derivative thereof
18Or Fraclite800.
10. method according to claim 1, step 6 wherein) polar solvent described in and the mixed solution gradient concentration desorb of water, desorption process is after polar solvent concentration is 1-3 times of column volume of 5% mixed solution washing, is drawn to the whole desorbs of echinocandin compounds FR179642 with the mixed solution solution of 15% concentration complete.
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| CN102627688A (en) * | 2012-03-30 | 2012-08-08 | 上海天伟生物制药有限公司 | High purity cyclic peptide compound and preparation method and application thereof |
| CN102659930A (en) * | 2012-03-30 | 2012-09-12 | 上海天伟生物制药有限公司 | High-purity cyclopeptide crystal and its preparation method and use |
| CN104418940A (en) * | 2013-08-28 | 2015-03-18 | 重庆乾泰生物医药有限公司 | Preparation method of high-purity cyclohexyl peptide type compound |
| CN104877010A (en) * | 2015-06-15 | 2015-09-02 | 华北制药集团新药研究开发有限责任公司 | Preparation method of pristinamycin IA mono-component |
| CN105254721A (en) * | 2014-05-13 | 2016-01-20 | 江苏豪森药业股份有限公司 | Purification salt conversion method of micafungin |
| CN106755221A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of preparation method of MFG parent nucleus FR179642 |
| CN106928323A (en) * | 2017-03-02 | 2017-07-07 | 重庆乾泰生物医药有限公司 | A kind of preparation method of high-purity oritavancin key intermediate A82846B |
| CN110876800A (en) * | 2019-11-18 | 2020-03-13 | 中南大学 | Application of micafungin in preparation of antitumor drugs and antitumor drugs |
| CN111187339A (en) * | 2018-11-15 | 2020-05-22 | 江苏豪森药业集团有限公司 | Method for extracting FR901379 from fermentation liquor |
| CN111434675A (en) * | 2019-01-11 | 2020-07-21 | 苏州纳微科技股份有限公司 | Separation and purification method of micafungin mother ring |
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| CN102627688A (en) * | 2012-03-30 | 2012-08-08 | 上海天伟生物制药有限公司 | High purity cyclic peptide compound and preparation method and application thereof |
| CN102659930A (en) * | 2012-03-30 | 2012-09-12 | 上海天伟生物制药有限公司 | High-purity cyclopeptide crystal and its preparation method and use |
| CN104418940A (en) * | 2013-08-28 | 2015-03-18 | 重庆乾泰生物医药有限公司 | Preparation method of high-purity cyclohexyl peptide type compound |
| CN106518980B (en) * | 2013-08-28 | 2019-04-09 | 重庆乾泰生物医药有限公司 | A kind of preparation method of high-purity cyclohexyl peptide compounds |
| CN106518980A (en) * | 2013-08-28 | 2017-03-22 | 重庆乾泰生物医药有限公司 | Preparing method of high-purity cyclic hexapeptide compound |
| CN105254721A (en) * | 2014-05-13 | 2016-01-20 | 江苏豪森药业股份有限公司 | Purification salt conversion method of micafungin |
| CN104877010B (en) * | 2015-06-15 | 2018-05-29 | 华北制药集团新药研究开发有限责任公司 | A kind of preparation method of pristinamycin I A one pack systems |
| CN104877010A (en) * | 2015-06-15 | 2015-09-02 | 华北制药集团新药研究开发有限责任公司 | Preparation method of pristinamycin IA mono-component |
| CN106755221A (en) * | 2016-11-28 | 2017-05-31 | 无锡福祈制药有限公司 | A kind of preparation method of MFG parent nucleus FR179642 |
| CN106928323A (en) * | 2017-03-02 | 2017-07-07 | 重庆乾泰生物医药有限公司 | A kind of preparation method of high-purity oritavancin key intermediate A82846B |
| CN106928323B (en) * | 2017-03-02 | 2021-08-20 | 重庆乾泰生物医药有限公司 | Preparation method of high-purity oritavancin key intermediate A82846B |
| CN111187339A (en) * | 2018-11-15 | 2020-05-22 | 江苏豪森药业集团有限公司 | Method for extracting FR901379 from fermentation liquor |
| CN111187339B (en) * | 2018-11-15 | 2023-12-01 | 江苏豪森药业集团有限公司 | Method for extracting FR901379 from fermentation broth |
| CN111434675A (en) * | 2019-01-11 | 2020-07-21 | 苏州纳微科技股份有限公司 | Separation and purification method of micafungin mother ring |
| CN110876800A (en) * | 2019-11-18 | 2020-03-13 | 中南大学 | Application of micafungin in preparation of antitumor drugs and antitumor drugs |
| CN110876800B (en) * | 2019-11-18 | 2023-06-27 | 中南大学 | Application of micafungin in preparation of antitumor drugs and antitumor drugs |
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