CN112480028B - Method for chiral resolution of promethazine - Google Patents
Method for chiral resolution of promethazine Download PDFInfo
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- CN112480028B CN112480028B CN202011387808.1A CN202011387808A CN112480028B CN 112480028 B CN112480028 B CN 112480028B CN 202011387808 A CN202011387808 A CN 202011387808A CN 112480028 B CN112480028 B CN 112480028B
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- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/26—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom without other substituents attached to the ring system
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3833—Chiral chromatography
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
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Abstract
The invention provides a method for chiral resolution of promethazine, which comprises the following steps: (1) preparing a test solution: weighing a certain amount of promethazine reference substance, and dissolving the promethazine reference substance by adopting an organic solution to prepare a promethazine test sample solution; and (2) chiral resolution using supercritical chromatography: separating promethazine enantiomer in the promethazine test sample solution by supercritical chromatography, wherein the stationary phase is polysaccharide derivative chiral chromatographic column, the mobile phase A is supercritical fluid, the mobile phase B is organic solvent, the column temperature is 30-45 deg.C, the column pressure is 10-20MPa, the column pressure is constant pressure, the flow rate is 1-3ml/min, and the ultraviolet wavelength is 254nm. The method overcomes the defects of the prior art, and has the characteristics of mild and simple operation conditions, low cost, high sensitivity, high separation speed, environmental protection and the like.
Description
Technical Field
The invention relates to a method for chiral resolution of promethazine.
Background
Promethazine is an inorganic substance, also known as finasteride, of formula C 17 H 20 N 2 S, structural formula shown below, is a common antitussive drug, an antihistamine, that competitively blocks histamine H1 receptors, antagonizes histamine-induced telangiectasia, and reduces its permeability. Therefore, the cough caused by the stimulation of the trachea can be smoothed. Because promethazine has a chiral center, it has a dextrorotatory form of R-and a levorotatory form of S-. At present, no literature report is found on the research on the drug effects and toxicology of different R and S configuration enantiomers of promethazine, so that the establishment of a chiral resolution method of the promethazine enantiomer is particularly important for further research.
The chiral resolution of promethazine usually adopts high performance liquid chromatography and capillary electrophoresis, and the liquid chromatography mainly adopts ovomucoid chiral stationary phase or cellulose chiral stationary phase for resolution, but the requirements on mobile phase are higher (in the aspects of mobile phase reagent purity and the like), the experimental cost is higher, and the column efficiency is low. The capillary electrophoresis mainly adopts cyclodextrin substances as an electrophoresis medium to realize the separation and detection of the promethazine enantiomer, and has the advantages of low experimental cost, wide application range, long analysis time, low separation degree and no prospect of amplification to preparation scale.
In summary, the methods for chiral separation of promethazine in the prior art have the following disadvantages: higher requirement on the mobile phase, higher experimental cost, long analysis time and lower separation degree.
Disclosure of Invention
In order to overcome the technical defects of high requirement on a mobile phase, high experimental cost, long analysis time and low separation degree of the method for chiral separation of promethazine in the prior art, the invention aims to provide a method for chiral separation of promethazine, which comprises the following steps:
(1) Preparing a test solution: weighing a certain amount of promethazine reference substance, and dissolving the reference substance by adopting an organic solution to prepare a promethazine test sample solution; and
(2) Chiral resolution was performed using supercritical chromatography: separating promethazine enantiomer in the promethazine sample test solution by supercritical chromatography, wherein the stationary phase is polysaccharide derivative chiral chromatographic column, the mobile phase A is supercritical fluid, the mobile phase B is organic solvent, the column temperature is 30-45 deg.C, the column pressure is 10-20MPa, the column pressure is constant pressure, and the flow rate is 1-3ml/min. SupercriticaL Fluid Chromatography (SFC) is performed using SupercriticaL fluid CO 2 The technology of separating and analyzing by depending on the solvation capacity of the mobile phase as the mobile phase has the characteristics of simple and convenient operation conditions, quick separation, high sensitivity, environmental protection and the like.
Further, the organic solvent in steps (1) and (2) is selected from one or more of methanol, ethanol, acetonitrile and isopropanol. Methanol is preferred.
Further, the organic solvent in the step (2) accounts for 10 to 20% of the volume of the mobile phase A and the mobile phase B.
Further, the volume ratio of the organic solvent in the step (2) in the mobile phase a and the mobile phase B is 15%, the organic solvent comprises methanol and isopropanol, and the volume ratio is methanol: isopropanol = 9.
Further, the polysaccharide derivative in step (2) is amylose-tris (3, 5-dimethylphenylcarbamate).
Further, the supercritical fluid in step (2) is supercritical carbon dioxide. Because the supercritical fluid CO2 has the characteristics of low viscosity, high diffusion rate and high mass transfer capacity, the method has unique advantages in the field of separation of chiral compounds and analogues, and has the advantages of low requirement on a mobile phase, low experimental cost, short analysis time, greenness, environmental protection and high separation degree.
Further, the flow rate in step (2) is 2ml/min.
Further, the column pressure in step (2) is 10MPa.
Further, the column temperature in step (2) was 35 ℃.
All reagents in this application are commercially available.
Compared with the prior art, the technical scheme of the application has the following beneficial effects:
according to the technical scheme, the promethazine is directly subjected to chiral resolution by using a supercritical fluid chromatography, and a mobile phase of the promethazine consists of supercritical carbon dioxide and an organic solvent, so that the emission of organic waste liquid can be reduced, and the method is green and environment-friendly; because the supercritical fluid CO2 has the characteristics of low viscosity, high diffusion rate and high mass transfer capacity, the method has unique advantages in the field of separation of chiral compounds and analogues, overcomes the defects of the prior art, and has the characteristics of mild and simple operation conditions, low cost, high sensitivity, high separation speed and the like.
Drawings
FIG. 1 is a chromatographic separation profile of example 1;
FIG. 2 is a chromatographic separation profile of example 2;
FIG. 3 is a chromatographic separation profile of example 3;
FIG. 4 is a chromatographic separation profile of example 4;
FIG. 5 is a chromatographic separation profile of example 5;
FIG. 6 is a chromatographic separation profile of example 6;
FIG. 7 is a chromatographic separation profile of example 7;
FIG. 8 is a chromatogram of the comparative example.
Detailed Description
The advantages of the invention are further illustrated by the following detailed description of the preferred embodiments in conjunction with the drawings.
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The implementations described in the exemplary embodiments below do not represent all implementations consistent with the present disclosure. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present disclosure, as detailed in the appended claims.
The terminology used in the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used in this disclosure and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.
Example 1:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. The method adopts a supercritical fluid chromatograph (SHIMADZU) Nexera UC SFC system, uses a (Daicel) CHIRALPAK AD-H chiral chromatographic column, is a chiral chromatographic column of polysaccharide derivatives of which the silica gel surface is coated with amylose-tri (3, 5-dimethylphenylcarbamate), and has the specification of 250mm multiplied by 4.6mm, the particle size of 5 mu m and the mobile phase A of supercritical CO 2 The mobile phase B is two organic solvents of methanol-isopropanol (90,v/v), and the B phase accounts for 15 percent. The column temperature of the polysaccharide derivative chiral chromatographic column is 35 ℃; the column pressure is 10MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See FIG. 1 for results. As can be seen from FIG. 1, the two enantiomeric chromatographic peaks of promethazine can be effectively separated, and simultaneously, the elution order of the enantiomers of promethazine is studied by using a Chiralyser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the corresponding relationship between the isomers, the first peak is the dextroisomer of promethazine R-, the second peak is the levoisomer of promethazine S-, and the chromatographic instrument shows that the separation degree is 2.618.
Example 2:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. The method adopts supercritical fluid chromatography as (SHIMADZU) Nexera UC SFC system, uses (Daicel) CHIRALPAK AD-H chiral chromatographic column, is a chiral chromatographic column of polysaccharide derivatives with silica gel surface coated with amylose-tris (3, 5-dimethylphenylcarbamate), and has the specification of 250mm × 4.6mm, the particle size of 5 μm, and the mobile phase A is supercritical CO 2 The mobile phase B is two organic solvents of methanol-isopropanol (90,v/v), and the B phase accounts for 15 percent. The column temperature of the polysaccharide derivative chiral chromatographic column is 40 ℃; the column pressure is 10MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See FIG. 2 for results. As can be seen from FIG. 2, two enantiomeric chromatographic peaks of promethazine were separated effectively, and the elution order of the enantiomers of promethazine was investigated by a chiral laser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the correspondence between the isomers, the first peak was the dextroisomer of promethazine R-, the second peak was the levoisomer of promethazine S-, and the chromatographic instrument showed a resolution of 2.169.
Example 3:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. A supercritical fluid chromatograph is adopted as a (SHIMADZU) Nexera UC SFC system, a (Daicel) CHIRALPAK AD-H chiral chromatographic column is adopted, the silica gel surface is coated with amylose-tri (3, 5-dimethylphenyl carbamate) polysaccharide derivative chiral chromatographic column, the specification is 250mm multiplied by 4.6mm, the particle size is 5 mu m, a mobile phase A is supercritical CO2, a mobile phase B is methanol, and a phase B accounts for 15%. The column temperature of the polysaccharide derivative chiral chromatographic column is 40 ℃; the column pressure is 10MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See FIG. 3 for results. As can be seen from FIG. 3, the chromatographic peaks of two promethazine enantiomers can be effectively separated, and simultaneously, the elution order of the promethazine enantiomers is studied by using a Chiralyser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the corresponding relationship between the isomers, the first peak is the dextroisomer of promethazine R-, the second peak is the levoisomer of promethazine S-, and the chromatographic instrument shows that the separation degree is 1.163.
Example 4:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. A supercritical fluid chromatograph is adopted as a (SHIMADZU) Nexera UC SFC system, a (Daicel) CHIRALPAK AD-H chiral chromatographic column is used, the chiral chromatographic column is a polysaccharide derivative type chiral chromatographic column of which the silica gel surface is coated with amylose-tris (3, 5-dimethylphenyl carbamate), the specification is 250mm multiplied by 4.6mm, the particle size is 5 mu m, a mobile phase A is supercritical CO2, a mobile phase B is two organic solvents (95, 5 v/v) of methanol and ethanol, and a phase B accounts for 20 percent. The column temperature of the polysaccharide derivative chiral chromatographic column is 40 ℃; the column pressure is 10MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See FIG. 4 for results. As can be seen from FIG. 4, the two enantiomeric chromatographic peaks of promethazine were separated effectively, and the elution order of the enantiomers of promethazine was investigated by a chiral laser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the correspondence between the isomers, the first peak was the dextroisomer of promethazine R-, the second peak was the levoisomer of promethazine S-, and the chromatographic instrument showed a resolution of 1.089.
Example 5:
weighing a certain amount of promethazine reference substance, dissolving with methanol, diluting to constant volume, and preparing promethazine test solution. The method adopts a supercritical fluid chromatograph (SHIMADZU) Nexera UC SFC system, uses a (Daicel) CHIRALPAK AD-H chiral chromatographic column, is a chiral chromatographic column of polysaccharide derivatives of which the silica gel surface is coated with amylose-tri (3, 5-dimethylphenylcarbamate), and has the specification of 250mm multiplied by 4.6mm, the particle size of 5 mu m and the mobile phase A of supercritical CO 2 And the mobile phase B is methanol-acetonitrile two organic solvents (95, v/v), and the B phase accounts for 20 percent. The column temperature of the polysaccharide derivative chiral chromatographic column is 40 ℃; the column pressure is 16MPa; the detection wavelength is 254nm; the flow rate is 1.5mL/min; the injection volume was 5. Mu.L.
See FIG. 5 for results. As can be seen from FIG. 5, the chromatographic peaks of two enantiomers of promethazine can be separated effectively, and the elution order of the enantiomers of promethazine is investigated by a chiral ser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the corresponding relationship between the isomers, the first peak is the dextroisomer of promethazine R-, and the second peak is the levoisomer of promethazine S-, and the chromatographic instrument shows a resolution of 1.030.
Example 6:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. A supercritical fluid chromatograph is adopted as a (SHIMADZU) Nexera UC SFC system, a (Daicel) CHIRALPAK AD-H chiral chromatographic column is used, the chiral chromatographic column is a polysaccharide derivative type chiral chromatographic column of which the silica gel surface is coated with amylose-tris (3, 5-dimethylphenyl carbamate), the specification is 250mm multiplied by 4.6mm, the particle size is 5 mu m, a mobile phase A is supercritical CO2, a mobile phase B is two organic solvents of methanol-acetonitrile (80, 20, v/v), and a phase B accounts for 13%. The column temperature of the polysaccharide derivative chiral chromatographic column is 45 ℃; the column pressure is 11MPa; the detection wavelength is 254nm; the flow rate is 2.5mL/min; the injection volume was 5. Mu.L.
See FIG. 6 for results. As can be seen from FIG. 6, the chromatographic peaks of two promethazine enantiomers can be effectively separated, and simultaneously, the elution order of the promethazine enantiomers is studied by using a Chiralyser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the corresponding relationship between the isomers, the first peak is the dextroisomer of promethazine R-, the second peak is the levoisomer of promethazine S-, and the chromatographic instrument shows that the separation degree is 0.632.
Example 7:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. A supercritical fluid chromatograph is adopted as a (SHIMADZU) Nexera UC SFC system, a (Daicel) CHIRALPAK AD-H chiral chromatographic column is used, the chiral chromatographic column is a polysaccharide derivative type chiral chromatographic column of which the silica gel surface is coated with amylose-tri (3, 5-dimethylphenyl carbamate), the specification is 250mm multiplied by 4.6mm, the particle size is 5 mu m, a mobile phase A is supercritical CO2, a mobile phase B is two organic solvents (85, 15, v/v) of methanol-isopropanol, and a phase B accounts for 25 percent. The column temperature of the polysaccharide derivative chiral chromatographic column is 31 ℃; the column pressure is 12MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See FIG. 7 for results. As can be seen from FIG. 7, the chromatographic peaks of two promethazine enantiomers can be effectively separated, and simultaneously, the elution order of the promethazine enantiomers is studied by using a Chiralyser-MP type optical rotation detector (IBZ Messtech-nik, germany) to determine the corresponding relationship between the isomers, the first peak is the dextroisomer of promethazine R-, the second peak is the levoisomer of promethazine S-, and the chromatograph shows that the separation degree is 2.097.
Comparative example:
weighing a certain amount of promethazine reference substance, dissolving with methanol and fixing volume, and preparing promethazine test sample solution. A supercritical fluid chromatograph is adopted as a (SHIMADZU) Nexera UC SFC system, a (Daicel) CHIRALPAK AD-H chiral chromatographic column is adopted, the silica gel surface is coated with amylose-tri (3, 5-dimethylphenyl carbamate) polysaccharide derivative chiral chromatographic column, the specification is 250mm multiplied by 4.6mm, the particle size is 5 mu m, a mobile phase A is supercritical CO2, a mobile phase B is methanol, and a phase B accounts for 15%. The column temperature of the polysaccharide derivative chiral chromatographic column is 50 ℃; the column pressure is 15MPa; the detection wavelength is 254nm; the flow rate is 2mL/min; the injection volume was 5. Mu.L.
See fig. 8 for results. As can be seen from fig. 8, the chromatographic peaks of the two enantiomers of promethazine were not separated efficiently, and the chromatogram showed a single peak, so the degree of separation was 0. In summary, the present application employs supercritical fluid chromatography and is effective in chiral resolution of promethazine under specific chromatographic conditions.
The separated dextro-isomer of promethazine R-and levorotatory isomer of promethazine S-can be used for subsequent practical industrial application, for example, the difference of drug effects of dextro-isomer of promethazine R-and levorotatory isomer of promethazine S-is very large: the dextro-isomer of promethazine R-has stronger anti-osteoporosis effect compared with the racemic modification and the levo-isomer of promethazine S-; the dextrorotatory form of promethazine R-is effective in inhibiting osteoclasts; the dextrorotatory form of promethazine R-significantly reduced IL-6 production by histamine-stimulated cells compared to the levorotatory form of promethazine S-. It should be noted that the embodiments of the present invention have been described in terms of preferred embodiments, and not by way of limitation, and that those skilled in the art can make modifications and variations of the embodiments described above without departing from the spirit of the invention.
Claims (1)
1. A method for chiral resolution of promethazine, comprising the steps of:
(1) Preparing a test solution: weighing a certain amount of promethazine reference substance, and dissolving the promethazine reference substance by adopting an organic solution to prepare a promethazine test sample solution, wherein the concentration is 20mg/ml; and
(2) Chiral resolution was performed using supercritical chromatography: separating promethazine enantiomer in the promethazine sample test solution by supercritical chromatography, wherein the stationary phase is polysaccharide derivative chiral chromatographic column, the ultraviolet wavelength is 254nm, the mobile phase A is supercritical carbon dioxide, the mobile phase B is methanol and isopropanol, the volume ratio is methanol: isopropanol =9, the column temperature is 35 ℃, the column pressure is 10MPa, the column pressure is constant pressure, and the flow rate is 2ml/min;
the volume ratio of the mobile phase A to the mobile phase B in the step (2) is 10-20%;
the polysaccharide derivative in step (2) is amylose-tris (3, 5-dimethylphenylcarbamate).
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