CN103787901A - Method for resolving metoprolol enantiomers by using simulated moving bed chromatography - Google Patents
Method for resolving metoprolol enantiomers by using simulated moving bed chromatography Download PDFInfo
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- CN103787901A CN103787901A CN201210423989.8A CN201210423989A CN103787901A CN 103787901 A CN103787901 A CN 103787901A CN 201210423989 A CN201210423989 A CN 201210423989A CN 103787901 A CN103787901 A CN 103787901A
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Abstract
The invention discloses a method for resolving metoprolol enantiomers by using simulated moving bed chromatography. The method is characterized in that the simulated moving bed chromatography is adopted, an amylose-tris(3,5-dimethylphenylcarbamate) is used as a filler and n-hexane and an alcohol organic modifier are used as a mobile phase, to resolve the metoprolol enantiomers under a positive phase condition, thus obtaining high-pure R-metoprolol and S-metoprolol. The simulated moving bed chromatography is continuous production, has high automatic degree and high production efficiency.
Description
Technical field
[0001] the present invention relates to a kind of simulated moving bed chromatographic separation process of disassemble technique, particularly metoprolol of chiral drug.
Background technology
Metoprolol is selectivity β1receptorblocker, is widely used in clinically the treatment of cardiovascular disorder.Metoprolol is optically active compounds, has a pair of enantiomer, at present clinical in raceme form administration.Research shows that the receptor affinity of S-enantiomorph is 25 times of its R-enantiomorph.In isolated heart, the adenylate cyclase activity that its S-enantiomorph blocking-up Racemic isoproterenol activates is its enantiomorph 33 times.In metabolic process, also have stereoselectivity, the first pass effect of its S-enantiomorph is lower.Because 2 kinds of enantiomorphs are in the significant difference aspect pharmacodynamics and pharmacokinetics, Chiral Separation is significant for the less new drug of its pharmacology of further research and exploitation side effect.To the fractionation of this medicine, main capillary electrophoresis, the chiral Ion Pair Chromatography of adopting, also has the report that utilizes donor-receiver post to split it at present.The analysis that current saccharan post has been widely used in multiple enantiomorph separates with preparation.
In recent years, simulated moving bed chromatography technology is obtaining fast development aspect medicine separation, but has not yet to see so far open report for the method that uses simulated moving bed chromatography to separate metoprolol enantiomorph.Present method adopts simulated moving bed chromatography separation, and to divide metoprolol enantiomorph to have efficient, cost-saving, and can realize continuous separate from etc. feature.
Summary of the invention
The object of this invention is to provide the method for the simulation moving-bed fractionation of a kind of metoprolol 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 metoprolol enantiomorph, it is characterized in that with coating-type amylose starch-tri-(3,5-3,5-dimethylphenyl carbamate) be stationary phase, with the mixing solutions of normal hexane and alcohols organic modifiers be moving phase, from metoprolol racemoid, split out highly purified R-metoprolol and S-metoprolol by simulated moving bed system, comprise the following steps:
(1), metoprolol racemic modification is dissolved in moving phase, concentration is: 0 ~ 50g/L;
(2), with simulation moving-bed fractionation metoprolol racemic modification;
(3), concentrated, recrystallization obtains highly purified two kinds of metoprolol enantiomorphs.
The present invention has following technique effect: the present invention adopts simulated moving bed system, from the racemic modification of metoprolol, split out the metoprolol enantiomorph with optical purity, technique is simple, produce continuous and automatic, constant product quality, solvent adopts the mixture of normal hexane and alcohols organic modifiers, 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 metoprolol 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
With application type amylose starch-tri-(3,5-3,5-dimethylphenyl carbamate), for 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 20 ~ 40um;
Moving phase (solvent) is the mixture of normal hexane and alcohols organic modifiers.
3, separating step
A, sample dissolve by moving phase, concentration is 0 ~ 50g/L, chromatographic system is made up of 4 ~ 12 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 metoprolol 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: Virahol: diethylamine=65:35:0.1
Flow velocity: 0.5mL/min
Pump: Jiangsu Chinese nation science and technology is analyzed pump
Chromatographic column: Chiralcel OD-H post (4.6*250mm)
Detector: Jiangsu Chinese nation science and technology UV-detector
Detect wavelength: 259nm
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 0.2mL/min, elution flow rate 2.0mL/min, extracting solution flow velocity 1.2mL/min, raffinate flow velocity 1.0mL/min, switching time 12min, temperature is controlled at 20-30 ℃;
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-metoprolols and S-metoprolol with analysis condition is respectively 98.3% and 99.2%;
Per kilogram stationary phase can be produced R-metoprolol and the each 0.52kg of S-metoprolol every day, and moving phase consumption is 23L/kg, and the rate of recovery is 96.1%.
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 0.6mL/min, elution flow rate 4.0mL/min, extracting solution flow velocity 2.4mL/min, raffinate flow velocity 2.2mL/min, switching time 10min, temperature is controlled at 20-30 ℃;
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-metoprolols and S-metoprolol with analysis condition is respectively 97.6% and 98.5%;
Per kilogram stationary phase can be produced R-metoprolol and the each 1.25kg of S-metoprolol every day, and moving phase consumption is 67.8L/kg, and the rate of recovery is 95.8%.
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 1.2mL/min, elution flow rate 6.6mL/min, extracting solution flow velocity 4.0mL/min, raffinate flow velocity 3.8mL/min, switching time 11min, temperature is controlled at 20-30 ℃;
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-metoprolols and S-metoprolol with analysis condition is respectively 97.2% and 98.1%;
Per kilogram stationary phase can be produced R-metoprolol and the each 2.12kg of S-metoprolol every day, and moving phase consumption is 952.5L/kg, and the rate of recovery is 95.9%.
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 a metoprolol 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, 20～35 ℃ of working temperatures, chromatographic column filler is amylose starch-tri-(3, 5-3,5-dimethylphenyl carbamate), filler granularity 20～40um, moving phase is the mixing solutions of normal hexane and alcohols organic modifiers, the separating step of the method is as follows:
A, metoprolol racemic modification dissolve by moving phase, concentration is 0～50g/L, enter chromatographic system by sampling pump, chromatographic system is made up of 4～12 preparative columns, be divided into Si Ge district, there is 1～6 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-metoprolol; II district is positioned between extracting liquid outlet and injection port, and Ci district makes S-metoprolol Adsorption and desorption, concentrated repeatedly; III district is positioned at Ci district between injection port and raffinate outlet and obtains R-metoprolol; 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-metoprolol 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 metoprolol according to claim 1, is characterized in that described moving phase is the mixing solutions of normal hexane and alcohols organic modifiers.
3. the simulated moving bed chromatographic separation process of metoprolol according to claim 1, the concentration that it is characterized in that entering simulated moving bed system is 0～50g/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 metoprolol according to claim 1, is characterized in that the time of described regular switching solenoid valve is: 8～20min.
5. the simulated moving bed chromatographic separation process of metoprolol according to claim 1, is characterized in that the service temperature of described simulated moving bed chromatography system is 20～30 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980134A (en) * | 2014-05-30 | 2014-08-13 | 安徽省新星药物开发有限责任公司 | Preparation method of succinic acid S-metoprolol |
| CN106349089A (en) * | 2016-07-30 | 2017-01-25 | 湖南理工学院 | Method using tartrate-polybasic acid complex to extract and separate metoprolol enantiomer |
| CN106390519A (en) * | 2016-09-12 | 2017-02-15 | 华东理工大学 | Method for continuously separating aminoglutethimide racemate through multi-column simulated moving bed chromatography technology |
-
2012
- 2012-10-31 CN CN201210423989.8A patent/CN103787901A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980134A (en) * | 2014-05-30 | 2014-08-13 | 安徽省新星药物开发有限责任公司 | Preparation method of succinic acid S-metoprolol |
| CN106349089A (en) * | 2016-07-30 | 2017-01-25 | 湖南理工学院 | Method using tartrate-polybasic acid complex to extract and separate metoprolol enantiomer |
| CN106349089B (en) * | 2016-07-30 | 2021-04-02 | 湖南理工学院 | Method for extracting and separating metoprolol enantiomer by adopting tartrate-polyacid complex |
| CN106390519A (en) * | 2016-09-12 | 2017-02-15 | 华东理工大学 | Method for continuously separating aminoglutethimide racemate through multi-column simulated moving bed chromatography technology |
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Application publication date: 20140514 |