CN102924572B - Method for preparing high-purity daptomycin - Google Patents
Method for preparing high-purity daptomycin Download PDFInfo
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- CN102924572B CN102924572B CN201210447657.3A CN201210447657A CN102924572B CN 102924572 B CN102924572 B CN 102924572B CN 201210447657 A CN201210447657 A CN 201210447657A CN 102924572 B CN102924572 B CN 102924572B
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Abstract
The invention discloses a method for preparing high-purity daptomycin. The method includes steps of crude extraction and fine extraction on filtrate of daptomycin fermentation liquor, wherein the crude extraction includes guiding the daptomycin filtrate into large-pore adsorption resins for adsorbing, desorbing the resins which are saturated in adsorbing through strippant in gradient mode, then performing decompressed concentration, crystallization and drying on the stripping liquid to obtain crude daptomycin; and the fine extraction includes dissolving the crude daptomycin through polar solvents, filling the obtained dissolving solution into a polymer nanometer microsphere pillar for chromatographic separation, performing gradient eluting on the polymer nanometer microshpere pillar through elution agents, collecting the elution solution with the high performance liquid chromatography (HPLC) content larger than or equal to 98.5%, and performing decompressed concentration, crystallization and drying on the eluting solution to obtain daptomycin products with the preparation purity higher than 98.5%. The method for preparing high-purity daptomycin is easy and convenient to operate, stable in yield, low in cost and suitable for producing the daptomycin products in industrial scale production mode.
Description
Technical field
The present invention relates to industrial microbial technology field, specifically a kind of preparation method of high purity daptomycin.
Background technology
Daptomycin is a member of lipopeptid class family, belongs to ring ten lipopeptid structure groups, obtained by Streptomyces roseosporus (Streptomyces roseosporus) fermentation, and be the cyclic lipopeptide microbiotic that the first success in the whole world is at present developed.Daptomycin novel structure, bactericidal mechanism uniqueness, can destroy bacterial cell membrane function in many aspects, and kill gram-positive microorganism, it is low that characteristic shows as the concentration that restraining effect is rapid, body interior and extracorporeal disinfecting effect is required, and the validity time of microbiotic effect is long.The chemical formula of daptomycin is C
72h
101n
17o
26, molecular weight is 1620.67, its structural formula is as follows:
Daptomycin found in late 1980s by Lilly Co., Eli., and the whole world that Cubist company in 1997 has obtained daptomycin is exclusively developed, production and the selling right.Cubist company confirms that through reaching the in vitro tests of 6 years daptomycin has concentration dependent germicidal action fast and effectively to multidrug resistant gram-positive microorganism.Show clinically the advantages such as has a broad antifungal spectrum, drug effect is fast, dosage is few, toxic side effects is light compared with vancomycin, be at present in the world generally acknowledged vancomycin etc. now use antibiotic best substitute.In addition the more important thing is, daptomycin in vitro to the isolated strains that presents the resistance character such as X-1497, vancomycin and linwzolid as the golden Portugal bacterium of Methicillin-resistant Staphylococcus aureus, glycopeptide class sensitivity, penicillin resistant parapneumonia suis) etc. all have a sterilization effect of high-efficiency low-toxicity, and medication number of times is few, and treatment cost is low.
FDA in 2003 has ratified daptomycin injection and has been used for the treatment of by the complicated Skin and soft tissue infection due to gram-positive microorganism, and the microbial microbemia in golden Portugal and right side endocarditis, its security and better tolerance are the microbiotic that a kind of application is had a bright future.
At present, few about high purity daptomycin preparation method's report.The Chinese patent CN1404487 of Cubist Pharmaceuticals, Inc. of U.S. application discloses a kind ofly purifies the method for daptomycin with resin anion(R.A), the method is used alternatingly resin anion(R.A) FP-DA13, macroporous resin HP-20SS, resin anion(R.A) PorosD50 or Poros 150 daptomycin is carried out to separating-purifying, can obtain the daptomycin product of purity 98%, but this technique is loaded down with trivial details, and cost is high, be difficult to realize commercial scale production.Chinese patent CN101830970A and CN102276696A have carried out process modification on CN1404487 basis, CN101830970A adopts buffered soln that daptomycin crude product is made into sample solution, then go up the absorption of compound YT-01 reverse phase silica gel column of material, then carry out gradient elution or constant density wash-out as strippant with the aqueous solution of intensive polar solvent; CN102276696A carries out wash-out after semipurified daptomycin loading is attached to gel-type weakly anionic resin.Although these two patented technologies have been simplified flow process, have been reduced cost, but still are difficult to realize suitability for industrialized production.Daptomycin is difficult to accomplish scale production, and the one, because the suitability for industrialized production bacterial classification that not have, the 2nd, because of there is no extractive technique after suitable industrialization.
Summary of the invention
The technical issues that need to address of the present invention are to provide a kind of easy and simple to handle, with low cost, are suitable for the preparation method of the high purity daptomycin of commercial scale production.
For solving the problems of the technologies described above, the technical solution adopted in the present invention is: a kind of preparation method of high purity daptomycin, comprise the step that the filtrate of daptomycin fermented liquid is slightly put forward, the step that essence is put forward, described slightly carrying is the filtrate of daptomycin fermented liquid to be imported to macroporous adsorbent resin adsorb, macroporous adsorbent resin is carried out to gradient desorption with strippant, then stripping liquid is carried out to concentrating under reduced pressure, crystallization, dry, obtain daptomycin crude product, the HPLC content of crude product is 90% left and right; It is that daptomycin crude product polar solvent is dissolved that described essence is carried, then the lysate injection of polymer Nano microsphere post of gained is carried out to chromatographic separation, with eluent, polymer nano-microspheres post is carried out to gradient elution again, and collect HPLC content and be more than or equal to 98.5% elutriant, by this elutriant concentrating under reduced pressure, crystallization, dry, obtain HPLC content and be more than or equal to 98.5% daptomycin again.
Further improvement of the present invention is: the preparation of the filtrate of described daptomycin fermented liquid is to add flocculating aids in daptomycin fermented liquid, after being uniformly mixed, daptomycin fermented liquid is filtered, and makes the filtrate of daptomycin fermented liquid.
Further improvement of the present invention is: the consumption of above-mentioned flocculating aids is to add 0.5kg ~ 5kg flocculating aids in every 100L daptomycin fermented liquid.Be preferably 1 kg ~ 3 kg.
Further improvement of the present invention is: above-mentioned flocculating aids is perlite or diatomaceous wherein a kind of or its mixture.
Further improvement of the present invention is: described macroporous adsorbent resin is the wherein a kind of of LX-50, D113 or D312 resin.Be preferably D312 resin.
Further improvement of the present invention is: the concentration expressed in percentage by volume of macroporous adsorbent resin being carried out to the strippant of gradient desorption is respectively 30%～40% and 70%～75%.
Further improvement of the present invention is: described polymer nano-microspheres is UNIPS30RPC.
Further improvement of the present invention is: the described concentration expressed in percentage by volume that polymer nano-microspheres is carried out to the eluent of gradient elution is respectively 30%～40% and 55%～60%; Described polar solvent is methyl alcohol or the aqueous ethanolic solution of 70% concentration expressed in percentage by volume.
Further improvement of the present invention is: described strippant or eluent are aqueous ethanolic solution or methanol aqueous solution.
Further improvement of the present invention is: described slightly carry and essence to carry in step be by the concentration simmer down to 100～120g/L of daptomycin in stripping liquid or elutriant to the concentrated of stripping liquid or elutriant; Described crystallization is in concentrated solution, to add the acetone of 6～8 times of amounts or Virahol to carry out recrystallization, the crystal powder of gained vacuum-drying 24h under 40 DEG C～50 DEG C conditions after crystallization.
Owing to having adopted technique scheme, the technical progress that the present invention obtains is: method of the present invention is a kind of method of preparing high purity daptomycin, and it is easy and simple to handle, with low cost, is suitable for commercial scale production.
The present invention adds flocculating aids in solid-liquid separation process, in improving filtration velocity, shortening process cycle, has improved filtrate quality.The present invention adopts macroporous adsorbent resin to carry out enrichment and purifying to object product, has removed the interference of fermentation secondary metabolite, has improved the quality of object product.The present invention adopts novel chromatography media-polymer nano-microspheres, stablizes and has improved chromatography effect, and a step chromatographic separation just can obtain the daptomycin product that purity is greater than 98.5%.
The present invention is simple for process, sample stable yield, and yield is high, and process total recovery reaches more than 50%.Solvent for use is conventional solvent, and toxicity is little, is suitable for suitability for industrialized production.
Brief description of the drawings
The liquid chromatogram of the prepared daptomycin fine powder of Fig. 1 embodiment of the present invention 1.
Embodiment
Below in conjunction with embodiment, the present invention is described in further details:
Daptomycin fermented liquid used in the present invention is the daptomycin fermented liquid that North China research and development centre of stock company of pharmacy group microorganism culturing means obtain.Macroporous resin LX-50 is the product of Xi'an Lan Xiao company; Macroporous resin D113, D312 are the product of Anhui Samsung resin Science and Technology Ltd.; Polymer nano-microspheres UNIPS30RPC is that Suzhou Na Wei scientific & technical corporation produces; The reagent such as ethanol, methyl alcohol, acetone, Virahol are commercially available.It is 996 type detectors that the present invention carries out the high performance liquid chromatograph that HPLC detection uses, 515 pumps (Waters company).
Embodiment 1
Getting fermentation unit is the daptomycin fermented liquid 100L of 1960 μ g/mL, adds 3000g perlite as flocculating aids in above-mentioned fermented liquid, and Plate Filtration after stirring 1h, obtains daptomycin filtrate.Daptomycin filtrate is imported to macroporous resin D312 post (loading amount is as 20L) taking the flow velocity of 40L/h and carry out adsorption and enrichment, adsorb complete first with the washing of 35% aqueous ethanolic solution, use again 72% aqueous ethanolic solution desorb, desorb flow rate control is at 10L/h, in the time that in HPLC detection stripping liquid, daptomycin concentration is higher than 200 μ g/mL, start to collect, when concentration is during lower than 200 μ g/mL, stop collecting.Stripping liquid to the daptomycin concentration that concentrating under reduced pressure is collected is 120g/L, obtains daptomycin concentrated solution.Then slowly add the acetone of 7 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, dryly at 45 DEG C obtained 195g daptomycin crude product, the HPLC content of this crude product is 89.1%, and slightly carrying yield in process is 88.6%.
Taking above-mentioned gained daptomycin crude product 10g(HPLC content is 89.1%), with the aqueous ethanolic solution dissolving of 20mL 70%, injection of polymer Nano microsphere UNIPS30RPC post (loading amount is 1L) carries out chromatographic separation, then be respectively 35%, 55% methanol aqueous solution by concentration successively, as eluent, UNIPS30RPC post carried out to gradient elution, and analyze the HPLC content of elutriant.According to HPLC detected result, collect HPLC purity and be more than or equal to 98.5% elutriant, the elutriant that concentrating under reduced pressure is collected to daptomycin concentration is 120g/L, slowly add again the propyl alcohol of 8 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, be greater than at 0.08Mpa, 40 DEG C dryly in vacuum tightness, obtain HPLC purity and be 98.6% daptomycin fine powder 6.0g, UNIPS30RPC column chromatography yield is 66.4%.
Embodiment 2
Be the daptomycin fermented liquid 10L of 2060 μ g/mL with fermentation unit, in fermented liquid, add 100g perlite as flocculating aids, stir 30 minutes final vacuum suction filtrations, obtain daptomycin filtrate.This daptomycin filtrate is imported to loading amount taking the flow velocity of 4L/h and carry out adsorption and enrichment as the macroporous resin LX-50 post of 2000mL, adsorb the complete methanol aqueous solution washing that is first 30% by volumetric concentration, the methanol aqueous solution desorb that is 70% by volumetric concentration again, desorb flow rate control is at 1L/h, in the time that daptomycin concentration is higher than 200 μ g/mL in HPLC detection stripping liquid, start to collect stripping liquid, when concentration is during lower than 200 μ g/mL, stop collecting.Above-mentioned stripping liquid being evaporated at 50 DEG C to daptomycin concentration is 100g/L, then slowly add the acetone of 8 times of amounts of concentrated solution volume to carry out crystallization, obtain crystal solution, by crystal solution filtration, the dry 20.1g daptomycin crude product that obtains, the HPLC content of this crude product is 89.6%, and slightly carrying yield in process is 87.4%.
Taking above-mentioned gained daptomycin crude product 1.0g(HPLC content is 89.6%), with the methanol aqueous solution dissolving of 2mL70%, injection of polymer Nano microsphere UNIPS30RPC post (loading amount is 100mL) carries out chromatographic separation, then uses successively 40%, 60% methanol aqueous solution gradient elution.According to HPLC detected result, collect HPLC content and be more than or equal to 98.5% elutriant, the elutriant that concentrating under reduced pressure is collected to daptomycin concentration is 100g/L, slowly add again the Virahol of 6 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, is dried (temperature 45 C, vacuum tightness is greater than 0.08Mpa), obtains daptomycin fine powder 0.6g, HPLC content is 98.6%, and chromatography yield is 66.0%.
Embodiment 3
Getting fermentation unit is the daptomycin fermented liquid 10L of 2300 μ g/mL, adds 200g diatomite as flocculating aids in fermented liquid, stirs 30 minutes final vacuum suction filtrations, obtains daptomycin filtrate.Filtrate is imported to loading amount taking the flow velocity of 4L/h and carry out adsorption and enrichment as the macroporous resin D113 post of 2000mL, adsorb complete first with the washing of 40% aqueous ethanolic solution, use again 75% aqueous ethanolic solution desorb, desorb flow rate control is at 1L/h, in the time that in HPLC detection stripping liquid, daptomycin concentration is higher than 200 μ g/mL, start to collect, when concentration is during lower than 200 μ g/mL, stop collecting.Desorb is complete, it is 110g/L that the stripping liquid of collection is evaporated to daptomycin concentration, then slowly add the isopropyl acetone of 6 times of amounts of concentrated solution volume to carry out crystallization, by crystal solution filtration, 40 DEG C of dry daptomycin crude product 22.5g that obtain, the HPLC content of daptomycin crude product is 90.2%, and slightly carrying yield is 88.2%.
Taking above-mentioned gained daptomycin crude product 10g(HPLC content is 90.2%), with the methanol aqueous solution dissolving of 20mL 70%, injection of polymer Nano microsphere UNIPS30RPC post (loading amount is 1L) carries out chromatographic separation, then uses successively 30%, 58% methanol aqueous solution gradient elution.According to HPLC detected result, collect HPLC purity and be more than or equal to 98.5% elutriant, 50 DEG C of concentrating under reduced pressure elutriant to daptomycin concentration are 110g/L, slowly add again the Virahol of 7 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, and vacuum tightness is greater than 0.08Mpa, dry at 40 DEG C, obtain purity and be 98.7% daptomycin fine powder 5.9g, chromatography yield is 64.5%.
Embodiment 4
The difference of the present embodiment and embodiment 1 is:
The flocculating aids adding while slightly carrying the filtrate of preparing daptomycin fermented liquid in process is perlite or diatomaceous mixture, wherein perlite 1kg, diatomite 3kg.
Essence is put forward process and is carried out in accordance with the following methods: taking embodiment 1, slightly to carry gained daptomycin crude product 10g(HPLC content be 89.1%), methanol aqueous solution with 70% dissolves, the polymer nano-microspheres UNIPS30RPC post that injection loading amount is 1000mL carries out chromatographic separation, then be respectively 30%, 60% methanol aqueous solution by concentration successively, as eluent, UNIPS30RPC post carried out to gradient elution, and analyze the HPLC content of elutriant.According to HPLC detected result, collect HPLC purity and be 98.5% and above elutriant, at the temperature of 50 DEG C, concentrating under reduced pressure elutriant to daptomycin concentration is 110g/L, slowly add again the Virahol of 6 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, be greater than at 0.08Mpa, 45 DEG C dryly in vacuum tightness, obtain HPLC purity and be 98.7% daptomycin fine powder 5.9g, UNIPS30RPC column chromatography yield is 65.3%.
Embodiment 5
The difference of the present embodiment and embodiment 1 is following smart extracting method:
Taking above-mentioned gained daptomycin crude product 10g(HPLC content is 89.1%), aqueous ethanolic solution with 70% dissolves, the polymer nano-microspheres UNIPS30RPC post that injection loading amount is 1000mL carries out chromatographic separation, then be respectively 30%, 55% aqueous ethanolic solution by concentration successively, as eluent, UNIPS30RPC post carried out to gradient elution, and analyze the HPLC content of elutriant.According to HPLC detected result, collect HPLC purity and equal to be greater than 98.5% elutriant, at the temperature of 50 DEG C, concentrating under reduced pressure elutriant to daptomycin concentration is 120g/L, slowly add again the Virahol of 8 times of amounts of concentrated solution volume to carry out crystallization, crystal solution is filtered, be greater than at 0.08Mpa, 50 DEG C dryly in vacuum tightness, obtain HPLC purity and be 98.6% daptomycin fine powder 6.0g, UNIPS30RPC column chromatography yield is 66.4%.
Claims (4)
1. the preparation method of a high purity daptomycin, comprise the step that the filtrate of daptomycin fermented liquid is slightly put forward, the process that essence is put forward, it is characterized in that: the preparation of the filtrate of described daptomycin fermented liquid is to add flocculating aids in daptomycin fermented liquid, after being uniformly mixed, daptomycin fermented liquid is filtered, and make the filtrate of daptomycin fermented liquid; Described slightly carrying is the filtrate of daptomycin fermented liquid to be imported to macroporous adsorbent resin adsorb, and macroporous adsorbent resin carried out to gradient desorption with strippant, then stripping liquid carried out to concentrating under reduced pressure, crystallization, dry, obtains daptomycin crude product; It is that daptomycin crude product polar solvent is dissolved that described essence is carried, then the lysate injection of polymer microballoon post of gained is carried out to chromatographic separation, with eluent, micro polymer goalpost is carried out to gradient elution again, and collect HPLC content and be more than or equal to 98.5% elutriant, by this elutriant concentrating under reduced pressure, crystallization, dry, obtain HPLC content and be more than or equal to 98.5% daptomycin again;
The consumption of described flocculating aids is to add 0.5kg～5kg flocculating aids in every 100L daptomycin fermented liquid;
Described macroporous adsorbent resin is the wherein a kind of of LX-50, D113 or D312 resin; The described concentration expressed in percentage by volume that macroporous adsorbent resin is carried out to the strippant of gradient desorption is respectively 30%～40% and 70%～75%;
Described polymer microballoon is UNIPS30RPC; The described concentration expressed in percentage by volume that polymer microballoon is carried out to the eluent of gradient elution is respectively 30%～40% and 55%～60%; Described polar solvent is methyl alcohol or the aqueous ethanolic solution of 70% concentration expressed in percentage by volume.
2. the preparation method of high purity daptomycin according to claim 1, is characterized in that: described flocculating aids is perlite or diatomaceous wherein a kind of or its mixture.
3. the preparation method of high purity daptomycin according to claim 1, is characterized in that: described strippant or eluent are aqueous ethanolic solution or methanol aqueous solution.
4. the preparation method of high purity daptomycin according to claim 1, is characterized in that: described slightly carry and essence to carry in step be by the concentration simmer down to 100～120g/L of daptomycin in stripping liquid or elutriant to the concentrated of stripping liquid or elutriant; Described crystallization is in concentrated solution, to add the acetone of 6～8 times of amounts or Virahol to carry out recrystallization, the crystal powder of gained vacuum-drying 24h under 40 DEG C～50 DEG C conditions after crystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106866791A (en) * | 2015-12-11 | 2017-06-20 | 北大方正集团有限公司 | A kind of preparation method of high-purity daptomycin lactone hydrolysate |
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| CN103224547B (en) * | 2013-04-28 | 2015-05-20 | 华北制药集团新药研究开发有限责任公司 | Daptomycin separation and purification method |
| CN104387444B (en) * | 2014-11-13 | 2017-12-08 | 北大医药重庆大新药业股份有限公司 | A kind of preparation method of the high-purity samples of Daptomycin impurity RS 2 |
| CN105001305A (en) * | 2015-04-29 | 2015-10-28 | 利穗科技(苏州)有限公司 | Method for extracting high-purity daptomycin by utilizing chromatographic technique |
| CN108250270A (en) * | 2016-12-29 | 2018-07-06 | 天津领世生物科技开发有限公司 | A kind of method of the enrichment extraction Daptomycin from zymotic fluid |
| CN114344447B (en) * | 2021-12-16 | 2023-08-25 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
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Inventor after: Duan Baoling Inventor after: Lin Yi Inventor after: Wang Haiyan Inventor after: Li Lihong Inventor after: Zhang Yanli Inventor after: Dong Aihua Inventor after: Zhang Xuexia Inventor after: Ren Fengzhi Inventor after: Li Xiaolu Inventor after: Gao Renlong Inventor after: Zhu Xiuliang Inventor after: Li Ning Inventor after: Chen Shuhong Inventor after: Cheng Xiaoxun Inventor before: Duan Baoling Inventor before: Wang Haiyan Inventor before: Li Lihong Inventor before: Zhang Yanli Inventor before: Dong Aihua Inventor before: Zhang Xuexia Inventor before: Ren Fengzhi Inventor before: Li Xiaolu Inventor before: Zhu Xiuliang Inventor before: Li Ning Inventor before: Chen Shuhong Inventor before: Cheng Xiaoxun Inventor before: Lin Yi |
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Free format text: CORRECT: INVENTOR; FROM: DUAN BAOLING ZHANG XUEXIA REN FENGZHI LI XIAOLU ZHU XIULIANG LI NING CHEN SHUHONG CHENG XIAOXUN LIN YI WANG HAIYAN LI LIHONG ZHANG YANLI DONG AIHUA TO: DUAN BAOLING ZHANG XUEXIA REN FENGZHI LI XIAOLU GAO RENLONG ZHU XIULIANG LI NING CHEN SHUHONG CHENG XIAOXUN LIN YI WANG HAIYAN LI LIHONG ZHANG YANLI DONG AIHUA |