CN103787983A - Simulated moving bed chromatography method for separation of Albendazole sulfoxide enantiomer - Google Patents
Simulated moving bed chromatography method for separation of Albendazole sulfoxide enantiomer Download PDFInfo
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- CN103787983A CN103787983A CN201210428362.1A CN201210428362A CN103787983A CN 103787983 A CN103787983 A CN 103787983A CN 201210428362 A CN201210428362 A CN 201210428362A CN 103787983 A CN103787983 A CN 103787983A
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- albendazole
- sulfoxide
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- moving bed
- simulated moving
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention discloses a simulated moving bed chromatography method for separation of racemic albendazole sulfoxide enantiomer. The invention is characterized in that the simulated moving bed chromatography system is employed to carry out separation on Albendazole sulfoxide enantiomer in normal phase condition, with packing of amylase-tris(3,5-dimethyl phenyl carbamate), and a mobile phase of a mixed solution of hexane and an alcohol modifier, so as to obtain high purity R-Albendazole sulfoxide and S-Albendazole sulfoxide. The simulated moving bed chromatography system realizes continuous production, and has high degree of automation and high production efficiency.
Description
Technical field
The present invention relates to the simulated moving bed chromatographic separation process of a kind of disassemble technique of chiral drug, particularly albendazole-sulfoxide.
Background technology
Albendazole (albendazole, ABZ) is a kind of broad-spectrum de-worming medicine thing that belongs to benzimidazoles, has been proved in the time of the various common neural system parasitosis for the treatment of very effective.Albendazole enters after human body, main active metabolite albendazole-sulfoxide (the albendazole sulfoxide that is it by a large amount of metabolism of effect of liver particulate enzyme, ABZSO), the insecticidal activity of ABZ is mainly derived from ABZSO, and ABZSO is a kind of racemize enantiomorph being made up of (+) ABZSO and (-) ABZSO.Humans and animals is taken this medicine after the ABZSO of (+)/(-) and is not quite similar at each ratio in autologous, and wherein (+) ABZSO proportion in people, dog, rat body is respectively 80%, 70% and 41%.Therefore, necessary to the fractionation of ABZSO.
Fractionation for ABZSO is also reported to some extent, but have no the report of systematically selecting multiple Alcoholic modifier to split ABZSO, the at present domestic report that splits ABZSO about high performance liquid chromatography (HPLC) that also there is not yet, splits preparation by simulated moving bed chromatography blank especially.
Summary of the invention
The object of this invention is to provide the method for the simulation moving-bed fractionation of a kind of albendazole-sulfoxide enantiomorph.
The technical scheme that the present invention adopts is for achieving the above object as follows: a kind of simulation moving-bed method for splitting of albendazole-sulfoxide enantiomorph, it is characterized in that with amylose starch-tri-(3,5-3,5-dimethylphenyl carbamate) be stationary phase, with the mixing solutions of normal hexane and Alcoholic modifier be moving phase, from albendazole-sulfoxide racemoid, split out highly purified R-albendazole-sulfoxide and S-albendazole-sulfoxide by simulated moving bed system, comprise the following steps:
(1), albendazole-sulfoxide racemic modification is dissolved in moving phase, concentration is: 0 ~ 100g/L;
(2), with simulation moving-bed fractionation albendazole-sulfoxide racemic modification;
(3), concentrated, recrystallization obtains highly purified two kinds of albendazole-sulfoxide enantiomorphs.
The present invention has following technique effect: the present invention adopts simulated moving bed system, from the racemic modification of albendazole-sulfoxide, split out the albendazole-sulfoxide enantiomorph with optical purity, technique is simple, produce continuous and automatic, constant product quality, solvent adopts the mixing solutions of normal hexane and Alcoholic modifier, recoverable, pollution-free, realize cleaner production.
Embodiment
1, equipment and condition are selected
Adopt simulated moving bed chromatography system, this system comprises wash-out pump, sampling pump, extraction pump, chromatographic column, magnetic valve, check valve, thermostat and PLC central controller and computer composition.Sample solution and elutriant are respectively from sample liquid entrance and elutriant entrance injected system, two enantiomorphs of albendazole-sulfoxide flow out respectively from raffinate and two outlets of extracting solution, often sample liquid and elutriant entrance at regular intervals, extracting solution and raffinate outlet switch to next chromatographic column along the mobile direction of moving phase.
2, chromatographic column filler and moving phase (solvent) are selected
Self-made fill amylose starch-tri-(3,5-3,5-dimethylphenyl carbamate) application type chiral stationary phase, filler granularity is 1 ~ 150um, and particulate is less, and size distribution is narrower, is more conducive to separate; But more mini system pressure is larger for particle diameter, and optimum particle size range is 10 ~ 30um;
Moving phase (solvent) is the mixing solutions of normal hexane and Alcoholic modifier.
3, separating step
A, sample dissolve by moving phase, concentration is 0 ~ 100g/L, chromatographic system is made up of 4 ~ 16 preparative columns, be divided into 4 districts, the more separation of chromatographic column number are better, but complexity and the system pressure of system are higher, optimal is 8 ~ 12, by the controller of simulated moving bed chromatography system, regularly control the switching of magnetic valve, injection port, extraction liquid outlet and residual solution outlet are regularly converted along the direction of moving phase, make two enantiomorphs of albendazole-sulfoxide from extracting solution and two outlet outflow systems of raffinate;
B, the product solution obtaining, obtain the qualified product of purity more than 95% through concentrated, recrystallization;
C, inspection after construction
Moving phase: normal hexane: ethanol: methyl alcohol=70:15:15
Flow velocity: 2mL/min
Pump: Jiangsu Chinese nation science and technology is analyzed pump
Chromatographic column: Chiralcel AD-H post (4.6*250mm)
Detector: Jiangsu Chinese nation science and technology UV-detector
Detect wavelength: 219nm
Further illustrate the present invention below in conjunction with example:
Separate instance one
1, the preparation of sample: sample dissolves by moving phase, making concentration is 5g/L, for subsequent use after the organic membrane filtration of 0.45um;
2, the selection of simulation moving-bed parameter: determine that parameter is as follows: sample introduction flow velocity 0.4 mL/min, elution flow rate 2.0 mL/min, extracting solution flow velocity 1.5 mL/min, raffinate flow velocity 0.9mL/min, switching time 11min, temperature is controlled at 20-25 ℃;
3, product-collecting: after simulated moving bed system is stable, collect product from two outlets respectively, obtain the finished product after concentrating under reduced pressure, recrystallization;
4, inspection after construction: after the product obtaining dissolves by moving phase, the purity that detects two exported product R-albendazole-sulfoxides and S-albendazole-sulfoxide with analysis condition is respectively 97.8% and 98.5%;
Per kilogram stationary phase can be produced R-albendazole-sulfoxide and the each 0.23kg of S-albendazole-sulfoxide every day, and moving phase consumption is 22L/kg, and the rate of recovery is 96.2%.
Separate instance two
1, the preparation of sample: sample dissolves by moving phase, making concentration is 10g/L, for subsequent use after the organic membrane filtration of 0.45um;
2, the selection of simulation moving-bed parameter: determine that parameter is as follows: sample introduction flow velocity 1.0 mL/min, elution flow rate 3.0mL/min, extracting solution flow velocity 2.2mL/min, raffinate flow velocity 1.8mL/min, switching time 10min, temperature is controlled at 20-25 ℃;
3, product-collecting: after simulated moving bed system is stable, collect product from two outlets respectively, obtain the finished product after concentrating under reduced pressure, recrystallization;
4, inspection after construction: after the product obtaining dissolves by moving phase, the purity that detects two exported product R-albendazole-sulfoxides and S-albendazole-sulfoxide with analysis condition is respectively 97.3% and 97.8%;
Per kilogram stationary phase can be produced R-albendazole-sulfoxide and the each 1.35kg of S-albendazole-sulfoxide every day, and moving phase consumption is 42.4L/kg, and the rate of recovery is 96.5%.
Separate instance three
1, the preparation of sample: sample dissolves by moving phase, making concentration is 20g/L, for subsequent use after the organic membrane filtration of 0.45um;
2, the selection of simulation moving-bed parameter: determine that parameter is as follows: sample introduction flow velocity 2.0mL/min, elution flow rate 6.0mL/min, extracting solution flow velocity 4.5mL/min, raffinate flow velocity 3.5mL/min, switching time 8.5min, temperature is controlled at 20-25 ℃;
3, product-collecting: after simulated moving bed system is stable, collect product from two outlets respectively, obtain the finished product after concentrating under reduced pressure, recrystallization;
4, inspection after construction: after the product obtaining dissolves by moving phase, the purity that detects two exported product R-albendazole-sulfoxides and S-albendazole-sulfoxide with analysis condition is respectively 96.5% and 97.1%;
Per kilogram stationary phase can be produced R-albendazole-sulfoxide and the each 4.12kg of S-albendazole-sulfoxide every day, and moving phase consumption is 90.5L/kg, and the rate of recovery is 96.7%.
Above-mentioned embodiment is used for the present invention that explains, rather than limits the invention, and in the protection domain of spirit of the present invention and claim, any modification and change that the present invention is made, all fall into protection scope of the present invention.
Claims (5)
1. the simulated moving bed chromatography separation separating method of an albendazole-sulfoxide enantiomorph, it is characterized in that: adopt simulated moving bed chromatography (being called for short SMBC) separation system, wash-out pumping capacity 0～100mL/min in system, pressure 0～10Mpa, sampling pump flow 0～50mL/min, pressure 0～10Mpa, extraction pumping capacity 0～100mL/min, pressure 0～10Mpa, 15～30 ℃ of working temperatures, chromatographic column filler is amylose starch-tri-(3, 5-3,5-dimethylphenyl carbamate), filler granularity 10～30um, moving phase is the mixing solutions of normal hexane and Alcoholic modifier, the separating step of the method is as follows:
A, albendazole-sulfoxide racemic modification dissolve by moving phase, concentration is 0～100g/L, enter chromatographic system by sampling pump, chromatographic system is made up of 4～16 preparative columns, be divided into Si Ge district, there is 1～4 pillar in every district, and wherein I district is positioned between elutriant entrance and extracting liquid outlet, and Ci district realizes the desorb of S-albendazole-sulfoxide; II district is positioned between extracting liquid outlet and injection port, and Ci district makes S-albendazole-sulfoxide Adsorption and desorption, concentrated repeatedly; III district is positioned at Ci district between injection port and raffinate outlet and obtains R-albendazole-sulfoxide; IV district is positioned between raffinate outlet and elutriant entrance, and the elutriant in III district enters into this district's reusable edible on the one hand, and JiangIII district and I separate out on the other hand, prevent that the R-albendazole-sulfoxide in raffinate from entering into I district;
B, obtain two enantiomorph products, through concentrated recrystallization, obtaining purity is more than 95% qualified product.
2. the simulated moving bed chromatographic separation process of albendazole-sulfoxide according to claim 1, is characterized in that said moving phase is the mixing solutions of normal hexane and Alcoholic modifier.
3. the simulated moving bed chromatographic separation process of albendazole-sulfoxide according to claim 1, the concentration that it is characterized in that entering simulated moving bed system is 0～100g/L, sample introduction flow velocity is 0～50mL/min, eluent flow rate is 0～100mL/min, extraction liquid flow velocity is 0～100mL/min, and raffinate flow velocity is 0～100mL/min.
4. the simulated moving bed chromatographic separation process of albendazole-sulfoxide according to claim 1, is characterized in that the time of described regular switching solenoid valve is: 5～20min.
5. the simulated moving bed chromatographic separation process of albendazole-sulfoxide according to claim 1, is characterized in that the service temperature of described simulated moving bed chromatography system is 15～30 ℃.
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| CN201210428362.1A CN103787983A (en) | 2012-11-01 | 2012-11-01 | Simulated moving bed chromatography method for separation of Albendazole sulfoxide enantiomer |
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| CN201210428362.1A CN103787983A (en) | 2012-11-01 | 2012-11-01 | Simulated moving bed chromatography method for separation of Albendazole sulfoxide enantiomer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557682A (en) * | 2014-08-12 | 2015-04-29 | 江苏汉邦科技有限公司 | Method for splitting chlortrimeton enantiomer by using simulated moving bed chromatography |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557682A (en) * | 2014-08-12 | 2015-04-29 | 江苏汉邦科技有限公司 | Method for splitting chlortrimeton enantiomer by using simulated moving bed chromatography |
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Application publication date: 20140514 |