A method for resolving racemic drugs of beta-blockers

Abstract

The invention discloses an enantioselective reverse micelle extraction and splitting method for a racemic drug of a beta-blocker class. The splitting method is to use a reverse micelle formed by a chiral amino acid substituted with an N-alkanoyl group in an organic solvent that is insoluble in water as a chiral recognition extractant, select and recognize one enantiomer of the beta-blocker in a racemic aqueous solution and extract it into the reverse micelle, while the other enantiomer that is not recognized remains in the aqueous phase, and separate the reverse micelle phase and the aqueous phase to obtain two optical isomers of the beta-blocker. The beta-blocker splitting method has the characteristics of high enantioselectivity, simple splitting process, simple process operation, reusable reverse micelle and low splitting cost, and is suitable for the requirements of large-scale splitting.

Description

Technical Field

[0001] The invention belongs to the technical field of chiral drug separation, and in particular relates to a method for separating a racemic drug of a beta-receptor blocker by enantioselective reverse micelle extraction. Background Art

[0002] The enantiomers of chiral drugs have the same chemical composition, but their differences in spatial stereostructure often lead to different biological activities, which in turn affect the physicochemical properties, pharmacological activity, and drug metabolism of the drugs. To date, although there are many methods for preparing chiral drugs, the separation of racemic drugs is still the main way to obtain commercial chiral drugs.

[0003] β-blockers are an important class of circulatory system drugs, widely used in the treatment of angina pectoris, myocardial infarction, hypertension, arrhythmia, etc., and also used in the treatment of migraine and glaucoma. The commonly used β-blockers in clinical practice mainly include propranolol, alprenolol, oxprenolol, pindolol, nadolol, esmolol, metoprolol, pralolol, atenolol, acebutolol, labetalol, carvedilol and other drugs. The common structural feature of these drugs is that they are aminoethanol compounds containing a secondary alcohol carbon chiral center. There are obvious differences in the pharmacological activities of their enantiomers. The separation of racemates is the main source for the preparation of such chiral aminoethanol drugs.

[0004] For the separation of aminoethanol drugs, Zou et al. (Enantioseparations of 11Amino AlcoholsUsing Di-n-amyl L-Tartrate–Boric Acid Complex as Chiral Mobile Phase Additiveby RP-HPLC, Chromatographia, 2015, 78(11-12)) disclosed a method for separating amino alcohol enantiomers by reversed-phase high performance liquid chromatography using di-n-amyl tartaric acid-boric acid complex as chiral mobile phase additive. Although this method has good separation effect, it is only applicable to the analysis of enantiomers. The separation process is complex and the separation cost is high when used for the preparation of enantiomers, and it is difficult to achieve large-scale separation. Shan Ruoni et al. (Study on the separation of metoprolol by liquid-liquid extraction with amino acid ionic liquid, Journal of Chemical Engineering of Colleges and Universities, 2019, 33(6)) disclosed a method for separating metoprolol enantiomers by chiral liquid-liquid extraction using amino acid ionic liquid as chiral recognition agent. The enantioselectivity coefficient of the separation was 1.29, which is low.

[0005] Therefore, the splitting of β-blockers urgently needs to solve problems such as complex splitting process, cumbersome process operation, low enantioselectivity and high splitting cost in order to meet the requirements of large-scale splitting. Summary of the invention

[0006] The purpose of the present invention is to provide an enantioselective reverse micelle extraction separation method for racemic drugs of beta-receptor blockers, which has the characteristics of simple separation process, simple process operation, high enantioselectivity and low separation cost, and is suitable for the large-scale separation requirements of chiral aminoethanol beta-receptor blockers.

[0007] To achieve the above object, the present invention provides a method for resolving a racemic drug of a beta-blocker by enantioselective reverse micelle extraction, and the technical scheme is as follows:

[0008] The enantioselective reverse micelle extraction and separation method of racemic drugs of beta-receptor blockers is that the reverse micelle formed by the chiral amino acid surfactant substituted with N-alkanoyl in a non-aqueous solvent is used as a chiral recognition extractant, and one enantiomer in the aqueous solution of the racemic drugs of beta-receptor blockers is molecularly recognized and combined, so that the enantiomer enters the reverse micelle, while the other enantiomer not recognized by the molecule remains in the aqueous phase, and the reverse micelle phase and the aqueous phase are separated to obtain two optical isomers of the beta-receptor blocker.

[0009] In the above-mentioned enantioselective reverse micelle extraction and separation method of beta-blocker drugs, when the N-alkanoyl-substituted chiral amino acid is an N-alkanoyl-substituted L-amino acid, the reverse micelle in the non-aqueous solvent selectively recognizes the D-configuration optical isomer in the beta-blocker and enters the reverse micelle phase, while the L-configuration optical isomer of the beta-blocker remains in the aqueous phase, and the reverse micelle phase and the aqueous phase are separated to obtain the D-configuration and L-configuration beta-blockers, respectively.

[0010] In the above-mentioned enantioselective reverse micelle extraction and separation method of beta-blocker drugs, when the N-alkanoyl-substituted chiral amino acid is an N-alkanoyl-substituted D-amino acid, the reverse micelle in the non-aqueous solvent selectively recognizes the L-configuration optical isomer in the beta-blocker and enters the reverse micelle phase, while the D-configuration optical isomer of the beta-blocker remains in the aqueous phase, and the reverse micelle phase and the aqueous phase are separated to obtain the L-configuration and D-configuration beta-blockers, respectively.

[0011] The beta-blocker racemic drugs described in the present invention are compounds with aminoethanol structural characteristics, including propranolol, alprenolol, oxprenolol, pindolol, nadolol, esmolol, metoprolol, pralolol, atenolol, acebutolol, labetalol and carvedilol.

[0012] The enantioselective reverse micelle extraction and resolution method of the racemic drug of the beta-blocker class, wherein the chiral amino acid substituted with an N-alkanoyl group that is used as a surfactant to form reverse micelles, has the following characteristics:

[0013] The amino acid is one of the following L-configuration or D-configuration amino acids: alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, histidine, lysine, arginine, aspartic acid, glutamic acid, asparagine, and glutamine.

[0014] The alkyl group is one of the following straight or branched alkyl groups: octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonadecyl, triacontyl, triacontyl, dotriacontyl, trictriacontyl and tetratriacontyl.

[0015] The non-aqueous solvent for the chiral amino acid surfactant to form reverse micelles is a single organic solvent that is insoluble in water or a mixed organic solvent that is insoluble in water, including one or a mixture of two or three organic solvents such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, etc. that are insoluble in water.

[0016] The insoluble organic solvent is selected from one or a mixture of two or three of the following solvents: dichloromethane, monochloroethane, dichloroethane, chloroform, carbon tetrachloride, n-pentane, isopentane, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane, isooctane, n-pentanol, isopentanol, n-hexanol, isohexanol, n-heptanol, isoheptanol, n-octanol, isooctane, cyclohexanol, propyl ether, butyl ether, pentyl ether, hexyl ether, cyclohexyl ether, phenyl ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, butanone, pentanone, hexanone, cyclohexanone, ethyl formate, propyl formate, butyl formate, pentyl formate, hexyl formate, isooctyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, hexyl acetate, and isooctyl acetate.

[0017] The reverse micelle phase and aqueous phase obtained by enantioselective reverse micelle extraction separation can be further improved in optical purity by conventional separation and purification methods, and the reverse micelle can be reused. Among them, after the reverse micelle phase is reversely extracted with aqueous solution, conventional methods such as concentration and crystallization are used for separation and purification to obtain a monorotatory beta-receptor blocker, and the reverse micelle can be reused; the aqueous phase is directly separated and purified by conventional methods such as concentration and crystallization to obtain another monorotatory beta-receptor blocker.

[0018] Compared with the prior art, the beneficial technical effects achieved by the present invention are as follows:

[0019] (1) The chiral polar group in the chiral amino acid surfactant has a molecular recognition effect on the enantiomers in the racemic drug of the β-blocker class, wherein: the L-amino acid can selectively recognize the D-configuration of the β-blocker and can selectively bring it into the reverse micelle phase, while the L-configuration that is not recognized by the molecule remains in the aqueous phase; the D-amino acid can selectively recognize the L-configuration of the β-blocker and can selectively bring it into the reverse micelle phase, while the D-configuration that is not recognized by the molecule remains in the aqueous phase. Therefore, the method for resolving the racemic drug of the β-blocker class of the present invention has high enantioselectivity for resolution.

[0020] (2) The reverse micelle phase obtained by extraction separation can be reused after aqueous back extraction.

[0021] (3) The method for resolving the racemic drug of the β-blocker class provided by the present invention has the characteristics of simple resolving process, simple process operation, low resolving cost, etc., and is suitable for the requirements of large-scale resolving. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 TEM images of n-hexane solutions of chiral surfactant DLV with different concentrations. From left to right, the concentrations are 0.5 g / L, 1 g / L and 2 g / L.

[0023] Figure 2 This is the TEM image of the reverse micelle phase before and after extraction of 1 g / L propranolol racemic aqueous solution in n-hexane reverse micelle solution of 1 g / L chiral surfactant DLV. The left image is the TEM image of the reverse micelle phase before extraction, and the right image is the TEM image of the reverse micelle phase after extraction.

[0024] Figure 3 It is the HPLC chromatogram of the reverse micelle phase after extraction equilibrium of equal volumes of 1 g / L aqueous solution of propranolol racemate and 1 g / L n-hexane reverse micelle solution of chiral surfactant DLV. DETAILED DESCRIPTION

[0025] The technical scheme of the present invention is further described below in conjunction with specific examples, but these examples do not limit the present invention in any form. If there is no special explanation in the examples, all conventional reagents and conventional methods are used.

[0026] Example 1

[0027] Prepare 10g / L chiral surfactants 2-decyldodecanoyl-L-valine (DLV), 2-decyldodecanoyl-L-leucine (DLL), 2-butylhexanoyl-L-phenylalanine (BHF), octadecanoyl-D-asparagine (ODN) dissolved in different organic solvents as mother liquors, then dilute the mother liquors in proportion to obtain chiral surfactant solutions of different concentrations, and measure the UV absorption spectra of solutions of different concentrations. Make a double logarithmic curve of absorbance and concentration at the maximum absorption wavelength, and the concentration at the inflection point is the CMC. The CMC of various chiral surfactants forming reverse micelles in different organic solvents is as follows:

[0028] Chiral surfactants Organic solvents CMC / (g / L) DLV n-Pentane 1.0 DLV n-Hexane 1.0 DLV Cyclohexane 2.0 DLV n-Heptane 2.5 DLV n-octane 2.5 DLL n-Pentane 1.0 DLL n-Hexane 1.0 DLL Cyclohexane 1.5 DLL n-Heptane 2.5 BHF n-Hexane 6.5 BHF Ethylene dichloride 9.0 ODN Toluene 5.5 ODN chlorobenzene 6.0

[0029] TEM images of n-hexane solutions of chiral surfactant DLV with different concentrations are shown in the attached figure. Figure 1 As shown, for the n-hexane solution with a concentration of 0.5 g / L DLV, since the concentration of DLV is less than CMC, no reverse micelles are observed; while for the n-hexane solutions with concentrations of 1 g / L and 2 g / L DLV, since the concentration of DLV reaches or exceeds CMC, DLV is observed to exist in the n-hexane solvent in the form of reverse micelles.

[0030] Example 2

[0031] Reverse micelle solutions of chiral surfactant DLV dissolved in n-pentane, n-hexane, and cyclohexane were prepared at critical micelle concentrations (1 g / L, 1 g / L, and 2 g / L), and aqueous solutions of propranolol racemate were prepared at two concentrations (1 g / L and 2 g / L). The reverse micelle solutions of the three concentrations were taken and mixed with aqueous solutions of propranolol racemate of the same concentration and volume, respectively, and magnetically stirred for 10 minutes. The layers were allowed to stand and the organic phase and the aqueous phase were separated. The concentration of propranolol enantiomers was analyzed by high performance liquid chromatography, and the enantiomeric selectivity coefficient (α) and enantiomeric excess (ee%) were calculated according to the following formula:

[0032]

[0033]

[0034] Among them, c org,D and c aqu,D represents the concentration of D-propranolol in the organic phase and the aqueous phase, respectively, c org,L and c aqu,L Represent the concentrations of L-propranolol in the organic phase and the aqueous phase, respectively.

[0035] The enantiomeric selectivity coefficient (α) and enantiomeric excess value (ee%) are shown in the following table:

[0036] Chiral surfactants Organic solvents α ee% DLV n-Pentane 1.72 25.4 DLV n-Hexane 2.75 40.6 DLV Cyclohexane 1.48 17.7

[0037] For the reverse micelle solution of 1 g / L chiral surfactant DLV in n-hexane, the TEM images of the reverse micelle phase before and after extraction of 1 g / L propranolol racemate solution are shown in the attached figure. Figure 2 The HPLC chromatogram of the extracted reverse micelle phase is shown in the attached figure. Figure 3 shown.

[0038] Example 3

[0039] Reverse micelle solutions of chiral surfactant DLL dissolved in n-hexane, cyclohexane and n-heptane were prepared according to critical micelle concentrations (1 g / L, 1.5 g / L and 2.5 g / L), and aqueous solutions of propranolol racemate were prepared according to three concentrations (1 g / L, 1.5 g / L and 2.5 g / L). The reverse micelle solutions of three concentrations were taken and mixed with aqueous solutions of propranolol racemate of the same concentration and volume, respectively, and magnetically stirred for 10 minutes. The layers were allowed to stand and the organic phase and aqueous phase were separated. The concentration of propranolol enantiomers was analyzed by high performance liquid chromatography, and the enantiomeric selectivity coefficient (α) and enantiomeric excess (ee%) were calculated. The results are shown in the following table:

[0040] Chiral surfactants Organic solvents α ee% DLL n-Hexane 1.35 13.2 DLL Cyclohexane 1.43 16.8 DLL n-Heptane 1.21 8.8

[0041] Example 4

[0042] Reverse micelle solutions of chiral surfactant BHF in n-hexane, BHF in dichloroethane, HDN in toluene and HDN in chlorobenzene were prepared according to critical micelle concentrations (6.5 g / L, 9.0 g / L, 5.5 g / L and 6.0 g / L). Aqueous solutions of five racemic forms of alprenolol, pindolol, metoprolol and atenolol were prepared at a concentration of 1 g / L. Equal volumes of the four reverse micelle solutions and the four racemic aqueous solutions were mixed and magnetically stirred for 10 minutes. The layers were allowed to stand and the organic phase and aqueous phase were separated. The concentration of the enantiomers was analyzed by high performance liquid chromatography, and the enantiomeric selectivity coefficient (α) and enantiomeric excess (ee%) were calculated. The results are shown in the following table:

[0043] Chiral surfactants Organic solvents Racemate α ee% BHF n-Hexane Alprenolol 1.82 24.8 BHF Ethylene dichloride Pindolol 1.42 15.2 ODN Toluene Metoprolol 2.20 32.7 ODN chlorobenzene Atenolol 1.35 13.6

Claims

1. A method for resolving a racemic drug of a beta-blocker, characterized in that: The reverse micelle formed by the chiral amino acid substituted with N-alkanoyl in a non-aqueous solvent which is insoluble in water is used as a chiral recognition extractant, which undergoes molecular recognition and binding to one enantiomer in an aqueous solution of a racemic drug of the beta-blocker class, so that this enantiomer enters the reverse micelle, while the other enantiomer which is not recognized by the molecule remains in the aqueous phase. The reverse micelle phase and the aqueous phase are separated to obtain two optical isomers of the beta-blocker.

2. The method for resolving a racemic drug of a beta-blocker according to claim 1, characterized in that: When the N-alkanoyl-substituted chiral amino acid is an N-alkanoyl-substituted L-amino acid, the reverse micelle formed in the non-aqueous solvent selectively recognizes the D-configuration optical isomer in the aqueous solution of the beta-receptor blocker, the recognized D-configuration beta-receptor blocker enters the reverse micelle phase, and the L-configuration beta-receptor blocker remains in the aqueous phase, and the reverse micelle phase and the aqueous phase are separated to obtain the D-configuration and L-configuration beta-receptor blockers respectively.

3. The method for resolving a racemic drug of a beta-blocker according to claim 1, characterized in that: When the N-alkanoyl-substituted chiral amino acid is an N-alkanoyl-substituted D-amino acid, the reverse micelle in the non-aqueous solvent selectively recognizes the L-configuration optical isomer in the aqueous solution of the beta-receptor blocker, the recognized L-configuration beta-receptor blocker enters the reverse micelle phase, and the D-configuration beta-receptor blocker remains in the aqueous phase, and the reverse micelle phase and the aqueous phase are separated to obtain the L-configuration and D-configuration beta-receptor blockers, respectively.

4. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The beta-blocker racemic drug is a compound with aminoethanol structural characteristics, and is any racemic form of propranolol, alprenolol, oxprenolol, pindolol, nadolol, esmolol, metoprolol, pralolol, atenolol, acebutolol, labetalol, and carvedilol.

5. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The N-alkanoyl-substituted chiral amino acid, wherein the amino acids are independently selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, histidine, lysine, arginine, aspartic acid, glutamic acid, asparagine, glutamine.

6. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The N-alkanoyl-substituted chiral amino acid, wherein the alkyl group is independently selected from a linear or branched octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, tritriacontyl, dotriacontyl, trictriacontyl, and tetratriacontyl.

7. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The non-aqueous solvent that is sparingly soluble in water is a single organic solvent that is sparingly soluble in water or a mixed organic solvent that is sparingly soluble in water, selected from one or a mixture of two or three organic solvents that are sparingly soluble in water, such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, and esters.

8. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The non-aqueous solvent that is sparingly soluble in water is selected from one or a mixture of two or three of the following: methylene chloride, ethylene monochloride, dichloroethane, chloroform, carbon tetrachloride, n-pentane, isopentane, n-hexane, cyclohexane, n-heptane, isoheptane, n-octane, isooctane, n-pentanol, isopentanol, n-hexanol, isohexanol, n-heptanol, isoheptanol, n-octanol, isooctane, cyclohexanol, propyl ether, butyl ether, pentyl ether, hexyl ether, cyclohexyl ether, phenyl ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, butanone, pentanone, hexanone, cyclohexanone, ethyl formate, propyl formate, butyl formate, pentyl formate, hexyl formate, isooctyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, hexyl acetate, and isooctyl acetate.

9. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The reverse micelle phase and aqueous phase obtained by the enantioselective reverse micelle extraction separation are further improved in optical purity by conventional separation and purification methods; wherein the reverse micelle phase is separated and purified by concentration and crystallization after aqueous reverse extraction, and the aqueous phase is directly separated and purified by concentration and crystallization.

10. The method for resolving a racemic beta-blocker drug according to any one of claims 1 to 3, characterized in that: The reverse micelle phase obtained by the enantioselective reverse micelle extraction separation can be reused after aqueous reverse extraction.

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