CN110078615B - Chiral resolution method of naproxen - Google Patents
Chiral resolution method of naproxen Download PDFInfo
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- CN110078615B CN110078615B CN201910346001.4A CN201910346001A CN110078615B CN 110078615 B CN110078615 B CN 110078615B CN 201910346001 A CN201910346001 A CN 201910346001A CN 110078615 B CN110078615 B CN 110078615B
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Abstract
The invention provides a chiral resolution method of naproxen, which comprises the following steps: 1) dissolving naproxen racemate in chiral ionic liquid to prepare a racemate mixed solution, and adjusting the pH value of a water phase by using a buffer solution; 2) adding an organic solvent as an organic phase; 3) and respectively placing the water phase and the organic phase in a centrifuge tube, shaking and standing, and after the two phases are balanced, taking part of the organic phase for detection and analysis. The method provided by the invention adopts the chiral ionic liquid as the extracting agent to carry out chiral resolution on naproxen, and is simple, efficient, green, environment-friendly and good in separation effect.
Description
[ technical field ] A method for producing a semiconductor device
The invention relates to a method for separating naproxen enantiomers by chiral liquid-liquid extraction, in particular to chiral resolution of naproxen by adopting chiral ionic liquid.
[ background of the invention ]
Naproxen (Naproxen) has the chemical name of 2- (6-methoxy-2-naphthyl) -2-propionic acid, also called methoxy isopropyl acid, and is a non-steroidal anti-inflammatory analgesic. It has good effects of anti-inflammatory, antipyresis and analgesia, and has less adverse reaction. Its alpha position contains a chiral carbon atom, so that it has a pair of optical isomers. Clinical studies have shown that naproxen in the (S) - (+) -configuration is 28-fold more active than naproxen in its (R) - (-) -configuration. In order to improve the efficacy, reduce the toxic and side effects of the drug, expand the safe range of drug administration, reduce complications and correctly evaluate the drug, the preparation of the optical pure drug is necessary.
At present, the main resolution methods of racemic naproxen include an induced crystallization method, a chemical resolution method, a chromatography method, an enzymatic resolution method and the like. The steps of the induced crystallization method are complicated, the operation conditions are not easy to control, the single-pass yield is low, and the phenomenon of entrainment and precipitation caused by the increase of the concentration of the enantiomer is easy to occur; the chemical resolution method has blindness in screening of resolving agents, and the adopted chiral resolving agent is expensive, high in consumption, high in production cost and capable of polluting the environment; the chromatography has high cost, is mainly used for analysis and small-scale preparation, and is difficult to realize industrialization; enzymatic resolution is affected by enzyme specificity and the resolution cost is high. The chiral liquid-liquid extraction has certain rule for the resolution of various racemes, the selection of a separation system can be circulated, and the application range is greatly widened. Chiral extraction separation of racemates has considerable potential and has received considerable attention in recent years from numerous researchers.
The traditional liquid-liquid extraction industrial application shows that the liquid-liquid extraction method has the advantages of simple equipment, easy amplification, easy realization of automation and continuity in the production process and the like, and is generally carried out at normal temperature and normal pressure with low energy consumption. The chiral liquid-liquid extraction resolution method is to apply the traditional liquid-liquid extraction technology to resolution of raceme, so that two mutually incompatible phases, namely a water phase and an organic phase, exist in the chiral liquid-liquid extraction technology. The racemate to be resolved is dissolved in one phase, and a chiral extraction agent is dissolved in the other phase; it has also been investigated to add different chiral extractants simultaneously to the two phases, one of the enantiomers being selectively extracted into the other phase by chiral recognition of the two enantiomers by the chiral extractant. Chiral recognition is the key to chiral liquid-liquid extraction techniques, and is achieved by formation of diastereomers from chiral extractants and enantiomers as a result of a series of intermolecular interactions, which may include electrostatic interactions, hydrogen bonding, van der waals forces, pi-pi interactions, steric repulsion, and the like. The process of chiral recognition is usually explained by a three-point interaction pattern. The two diastereomers have different chemical and physical characteristics and have certain free energy difference, and chiral liquid-liquid extraction realizes racemate resolution by means of the free energy difference of the two diastereomers.
The key point of chiral liquid-liquid extraction lies in finding a proper chiral resolving agent, however, at present, there is no report of broad-spectrum efficient chiral resolving extractant, the chiral extracting agents are more in variety, but the chiral resolving effect on different racemates is greatly different, and at present, most studied chiral extracting agents mainly comprise tartaric acids, cyclodextrins and crown ethers.
Cyclodextrins and tartaric acids have been reported in the literature as chiral liquid-liquid extractants, for example, CN101624339A discloses a technology for extracting and separating hydrophobic enantiomers with water-soluble β -cyclodextrin, which adopts water-soluble β -cyclodextrin derivatives as chiral extractants to perform chiral resolution on naproxen by reactive extraction; CN102001904A constructs a two-phase recognition chiral extraction separation aromatic acid drug enantiomer extraction system, which adopts an extraction system of hydroxypropyl beta-cyclodextrin and L-isobutyl tartrate, but the separation effect of the two methods is poor.
The ionic liquid is a green solvent which is liquid at room temperature, completely consists of organic cations and organic or inorganic anions, and has the unique properties of nonflammability, good thermal stability, low steam pressure, better solubility for most organic or inorganic substances and the like. Chiral ionic liquids are important in ionic liquids, and are formed by introducing chiral centers into the ionic liquids, and many chiral ionic liquids are applied to the fields of asymmetric synthesis catalysis, material preparation, spectral analysis and the like in domestic and foreign researches. The most important advantage of chiral Ionic liquids is the designability of the structure, different cations and anions can be combined according to different molecular structures to meet different requirements, and documents of 'Ionic liquids in calillary electrophoresis for anionic separation', Trends in Analytical Chemistry,100,145-154,2018 describe chiral separation of chiral Ionic liquids from rotors in capillary electrophoresis, it is mentioned that the addition of chiral ionic liquid increases the separation coefficient of cyclodextrin for naproxen and other drugs, but the chiral ionic liquid alone has no effect, and the capillary electrophoresis separation is driven by high-voltage direct current, the separation is realized according to the difference of migration rate and distribution behavior, the coated chiral material is used as a stationary phase, the capillary is used as a channel and a carrier, which is different from liquid-liquid extraction, the requirements on equipment are very strict, so that the application of the chiral ionic liquid as a chiral resolving agent in liquid-liquid extraction resolution is not much at present.
The method adopts a chiral ionic liquid chiral resolving agent and adopts a liquid-liquid extraction mode to carry out chiral resolution on naproxen.
[ summary of the invention ]
In order to solve the problems in the prior art, the invention aims to provide the chiral separation method of naproxen, which has the advantages of good separation effect, environmental protection, simple and convenient operation, simple equipment, low energy consumption, easy amplification, realization of automatic and continuous production and the like, and has good industrial application prospect.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:
1) dissolving naproxen racemate in chiral ionic liquid with certain concentration to prepare a racemate mixed solution, and adjusting the pH value of a water phase by using a buffer solution with certain concentration;
2) adding an organic solvent as an organic phase;
3) and respectively placing the water phase and the organic phase in a centrifuge tube, shaking and standing, and after the two phases are balanced, taking part of the organic phase for detection and analysis.
Preferably, the chiral ionic liquid is amino acid chiral ionic liquid;
preferably, the amino acid chiral ionic liquid is selected from one or more of [ Bmim ] [ L-pro ], [ Bmim ] [ L-Trp ], [ Bmim ] [ L-Ala ], [ Bmim ] [ L-Val ] or [ Bmim ] [ L-Ser ]; preferably [ Bmim ] [ L-pro ] or [ Bmim ] [ L-Trp ];
preferably, the concentration of the amino acid chiral ionic liquid is 0.01-0.1mol/L, and preferably 0.01-0.05 mol/L.
Preferably, the concentration of the racemic mixture solution in the step 1) is 0.5 to 2, preferably 1.0 to 1.5 mol/L.
Preferably, the buffer solution in step 1) is a phosphoric acid buffer solution, and the concentration is 0.1-1mol/L, preferably 0.3-0.5 mol/L.
Preferably, the pH value in step 1) is 1-4, preferably 1.5-2.5.
Preferably, the organic solvent in step 2) is a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, or an alcohol solvent, preferably a halogenated hydrocarbon solvent, and more preferably 1, 2-dichloroethane, chloroform, or dichloromethane.
Preferably, in the step 3), the mixture is shaken in a shaking table at room temperature for 2 hours and then kept still.
The invention has the advantages that:
the method provided by the invention adopts the chiral ionic liquid as the extracting agent to carry out chiral resolution on naproxen, has the advantages of good separation effect, environmental friendliness, simplicity and convenience in operation, simple equipment, low energy consumption, easiness in amplification, capability of realizing automatic and continuous production and the like, and has a good application prospect in industry.
[ detailed description ] embodiments
Example 1:
dissolving naproxen racemate into 0.05mol/L chiral ionic liquid [ Bmim ] [ L-pro ] solution to prepare 1.0mmol/L racemate solution, adjusting the pH value of the water phase to 2 by using 0.4mol/L phosphoric acid buffer solution, adding 1, 2-dichloroethane as an organic phase, respectively placing 3.0mL of the water phase and the organic phase into a 10mL centrifuge tube, fully shaking the mixture in a shaking table for 2 hours at 20 ℃, standing the mixture for 5 minutes, after the two phases are balanced, taking part of the organic phase to perform HPLC analysis, wherein the volume of the whole extraction process is almost unchanged, experimental errors can be ignored, and the concentration of naproxen in the water phase can be obtained by a differential subtraction method.
Partition coefficient K of S and R enantiomers after extraction separation, namely KSAnd KR0.81 and 0.46, respectively, and a separation factor α of 1.75.
Example 2:
dissolving naproxen racemate into 0.04mol/L chiral ionic liquid [ Bmim ] [ L-Trp ] solution to prepare 1.2mmol/L racemate solution, adjusting the pH value of an aqueous phase to 2.5 by using 0.5mol/L phosphoric acid buffer solution, adding 1, 2-dichloroethane as an organic phase, respectively placing 3.0mL of the aqueous phase and the organic phase into a 10mL centrifuge tube, fully shaking the aqueous phase and the organic phase in a shaking table for 2 hours at 20 ℃, standing the aqueous phase and the organic phase for 5 minutes, after the two phases are balanced, taking part of the organic phase for HPLC analysis, wherein the volume of the whole extraction process is almost unchanged, the experimental error can be ignored, and the naproxen concentration in the aqueous phase can be obtained by a subtraction method.
Partition coefficient K of S and R enantiomers after extraction separation, namely KSAnd KR0.27 and 0.16, respectively, and a separation factor α of 1.68.
Example 3:
dissolving naproxen racemate into 0.05mol/L chiral ionic liquid [ Bmim ] [ L-Ala ] solution to prepare 1.5mmol/L racemate solution, adjusting the pH value of an aqueous phase to 2.3 by using 0.3mol/L phosphoric acid buffer solution, adding 1, 2-dichloroethane as an organic phase, respectively placing 3.0mL of the aqueous phase and the organic phase into a 10mL centrifuge tube, fully shaking the aqueous phase and the organic phase in a shaking table for 2 hours at 20 ℃, standing for 5 minutes, after the two phases are balanced, taking part of the organic phase to perform HPLC analysis, and because the volume of the whole extraction process is almost unchanged, the experimental error can be ignored, and the concentration of naproxen in the aqueous phase can be obtained by a differential subtraction method.
Partition coefficient K of S and R enantiomers after extraction separation, namely KSAnd KR0.40 and 0.32, respectively, and a separation factor α of 1.25.
Example 4:
dissolving naproxen racemate into 0.04mol/L chiral ionic liquid [ Bmim ] [ L-Val ] solution to prepare 1.1mmol/L racemate solution, adjusting the pH value of an aqueous phase to 1.5 by using 0.5mol/L phosphoric acid buffer solution, adding 1, 2-dichloroethane as an organic phase, respectively placing 3.0mL of the aqueous phase and the organic phase into a 10mL centrifuge tube, fully shaking the aqueous phase and the organic phase in a shaking table for 2 hours at 20 ℃, standing for 5 minutes, after the two phases are balanced, taking part of the organic phase to perform HPLC analysis, wherein the volume of the whole extraction process is almost unchanged, experimental errors can be ignored, and the concentration of naproxen in the aqueous phase can be obtained by differential subtraction.
Partition coefficient K of S and R enantiomers after extraction separation, namely KSAnd KR0.44 and 0.35, respectively, and a separation factor α of 1.27.
Example 5:
dissolving naproxen racemate into 0.05mol/L chiral ionic liquid [ Bmim ] [ L-Ser ] solution to prepare 1.3mmol/L racemate solution, adjusting the pH value of the water phase to 2 by using 0.5mol/L phosphoric acid buffer solution, adding 1, 2-dichloroethane as an organic phase, respectively taking 3.0mL water phase and 3.0mL organic phase to be placed in 10mL centrifuge tubes, fully shaking in a shaking table for 2 hours at 20 ℃, standing for 5 minutes, after the two phases are balanced, taking part of the organic phase to perform HPLC analysis, wherein the volume of the whole extraction process is almost unchanged, the experimental error can be ignored, and the concentration of naproxen in the water phase can be obtained by a differential subtraction method.
Partition coefficient K of S and R enantiomers after extraction separation, namely KSAnd KR0.48 and 0.39, respectively, and a separation factor α of 1.23.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (13)
1. A chiral resolution method of naproxen comprises the following steps:
1) dissolving naproxen racemate in chiral ionic liquid to prepare a racemate mixed solution, and adjusting the pH value of a water phase by using a buffer solution; the chiral ionic liquid is [ Bmim ] [ L-pro ] or [ Bmim ] [ L-Trp ];
2) adding an organic solvent as an organic phase;
3) and respectively placing the water phase and the organic phase in a centrifuge tube, shaking and standing, and after the two phases are balanced, taking part of the organic phase for detection and analysis.
2. The chiral resolution method of naproxen according to claim 1, wherein the concentration of the chiral ionic liquid is 0.01-0.1 mol/L.
3. The chiral resolution method of naproxen according to claim 2, wherein the concentration of the chiral ionic liquid is 0.01-0.05 mol/L.
4. The method for chiral resolution of naproxen according to claim 1, wherein the concentration of the racemic mixture solution in the step 1) is 0.5-2 mmol/L.
5. The method for chiral resolution of naproxen according to claim 4, wherein the concentration of the racemic mixture solution in the step 1) is 1.0-1.5 mmol/L.
6. The chiral resolution method of naproxen according to claim 1, wherein the buffer solution in step 1) is phosphate buffer solution, and the concentration is 0.1-1 mol/L.
7. The method for chiral resolution of naproxen according to claim 6, wherein the buffer solution in step 1) is phosphate buffer solution with a concentration of 0.3-0.5 mol/L.
8. The method for chiral resolution of naproxen according to any one of claims 1 to 7, wherein the pH value in step 1) is 1 to 4.
9. The method for chiral resolution of naproxen according to claim 8, wherein the pH value in step 1) is 1.5-2.5.
10. The method for chiral resolution of naproxen according to any one of claims 1 to 7, wherein the organic solvent in step 2) is a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent or an alcohol solvent.
11. The method for chiral resolution of naproxen according to claim 10, wherein the organic solvent in step 2) is a halogenated hydrocarbon solvent.
12. The chiral resolution method of naproxen according to claim 11, wherein the halogenated hydrocarbon solvent is 1, 2-dichloroethane, chloroform or dichloromethane.
13. The method for chiral resolution of naproxen according to any one of claims 1 to 7, wherein in step 3), the mixture is shaken in a shaker at room temperature for 2 hours and then allowed to stand.
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