Chiral surfactant for enantioselective reverse micelle extraction
By using enantioselective reverse micelles formed by N-alkanoyl-substituted chiral amino acids, the problem of resolving racemic compounds in the prior art is solved, and an efficient and low-cost resolution effect is achieved, which is suitable for large-scale production.
Patent Information
- Application Number
- CN202510578767.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-04-21
- Publication Date
- 2025-09-19
AI Technical Summary
The existing reverse micelle extraction technology cannot effectively separate racemic compounds, and the operation is complex and costly, making it difficult to meet the needs of large-scale production.
N-alkanoyl-substituted chiral amino acids are used as chiral surfactants to form enantioselective reverse micelles in non-aqueous solvents. The enantiomers in the racemic compound are identified and resolved, and the resolution is achieved by separating the reverse micelle phase and the aqueous phase.
The method achieves highly selective and efficient separation of racemic compounds, is easy to operate, low in cost, suitable for large-scale production, and the reverse micelles are reusable.
Smart Images
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Abstract
Description
Technical Field
[0001] This application is a divisional application of patent application No. 202310430190X. The original application was filed on April 21, 2023. The invention is titled "A method for resolving racemic compounds by enantioselective reverse micelle extraction." This invention belongs to the field of chiral resolution technology and specifically relates to a chiral surfactant for enantioselective reverse micelle extraction, its preparation method, and its application. Background Art
[0002] Although enantiomers of chiral drugs share the same chemical composition, differences in their stereochemical structures often lead to different biological activities, which in turn affect the drug's physicochemical properties, pharmacological activity, and drug metabolism. To date, despite numerous methods for preparing chiral drugs, resolution of racemic drugs remains the primary route for commercializing chiral drugs.
[0003] Reverse micelles are thermodynamically stable, optically transparent, nanoscale systems formed by the self-assembly of a surfactant dissolved in a non-aqueous solvent at a certain concentration. The hydrophilic "head" faces inward, contacting the water pool, while the hydrophobic "tail" contacts the surrounding hydrophobic solvent, maintaining the system's thermodynamic equilibrium. In a reverse micelle system, the internal "water pool" dissolves biomolecules and prevents their denaturation. This "water pool" property of reverse micelles has led to the development of reverse micelle extraction technology for the extraction and separation of proteins, enzymes, antibodies, and antibiotics. However, existing reverse micelle extraction techniques are only suitable for the extraction and separation of bioactive molecules and are not suitable for the resolution of racemic compounds.
[0004] The invention discloses a chiral surfactant for enantioselective reverse micelle extraction. The reverse micelle formed by the chiral surfactant can resolve racemic compounds. Summary of the Invention
[0005] The present invention aims to provide a chiral surfactant for enantioselective reverse micelle extraction. The reverse micelle formed by the chiral surfactant can resolve racemic compounds. The chiral surfactant has the characteristics of simple resolution process, simple process operation, high enantioselectivity and low resolution cost, and is suitable for the large-scale resolution requirements of preparing chiral compounds from racemates.
[0006] To achieve the above object, the technical solution of the present invention is as follows:
[0007] The chiral surfactant has the following characteristics:
[0008] The chiral surfactant is an N-alkanoyl-substituted chiral amino acid.
[0009] The N-alkanoyl-substituted chiral amino acid has an amino acid configuration of L-configuration or D-configuration.
[0010] The N-alkanoyl-substituted chiral amino acids, wherein the amino acids are independently alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, histidine, lysine, arginine, aspartic acid, glutamic acid, asparagine, and glutamine.
[0011] The N-alkanoyl-substituted chiral amino acid, wherein the alkyl group is independently a straight 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, triuncontyl, dotriacontyl, trictriacontyl, or tetratriacontyl.
[0012] The preparation method of the N-alkanoyl-substituted chiral amino acid chiral surfactant is as follows:
[0013] Malonate (S1) is used as the raw material, and undergoes a C-alkylation reaction with a halogenated hydrocarbon under base catalysis to produce an alkyl malonate (S2); S2 is hydrolyzed to produce an alkyl malonate (S3); S3 is subjected to high-temperature decarboxylation to produce an alkyl acid (S4); S4 is chlorinated and then undergoes an N-acylation reaction with a chiral amino acid to produce an N-alkanoyl-substituted chiral amino acid (S).
[0014] The present invention also provides an application of the enantioselective reverse micelle formed by the chiral surfactant in the resolution of amino alcohol racemic compounds.
[0015] The enantioselective reverse micelles formed by the chiral surfactant are used to resolve racemic compounds. The reverse micelles formed by the chiral surfactant in a non-aqueous solvent are used as chiral recognition extractants to selectively identify one enantiomer from a racemic aqueous solution. The identified enantiomer enters the reverse micelles, while the unrecognized enantiomer remains in the aqueous phase. The reverse micelle phase and the aqueous phase are separated to achieve the resolution of the racemic compound.
[0016] The enantioselective reverse micelles formed by the chiral surfactant are used to resolve racemic compounds, and the non-aqueous solvent has the following characteristics:
[0017] The non-aqueous solvent is a single organic solvent or a mixed organic solvent that is hardly soluble in water, selected from one or a mixture of two or three organic solvents such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, and esters that are hardly soluble in water.
[0018] The sparingly water-soluble organic solvent is selected from the group consisting of 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, or a mixture of two or three solvents.
[0019] The enantioselective reverse micelles formed by the chiral surfactant are used to resolve racemic compounds, and the amino alcohol racemic compounds include: propranolol, alprenolol, oxprenolol, pindolol, nadolol, esmolol, metoprolol, pralolol, atenolol, acebutolol, labetalol, and carvedilol.
[0020] The enantioselective reverse micelles formed by the chiral surfactant are used to resolve racemic compounds. The resolution of amino alcohol racemic compounds comprises the following steps:
[0021] A reverse micelle solution of a chiral surfactant in a non-aqueous solvent and an aqueous solution of a racemic compound are prepared, the reverse micelle solution and the aqueous solution of the racemic compound are mixed, stirred or shaken to allow the enantiomers in the racemic compound to reach distribution equilibrium in the reverse micelle phase and the aqueous phase, and the phases are allowed to stand or centrifuged to separate the reverse micelle phase and the aqueous phase to obtain a reverse micelle phase and an aqueous phase containing optically active enantiomers, respectively.
[0022] The reverse micelle phase and aqueous phase obtained by the above phase separation can be subjected to conventional separation and purification methods to further improve optical purity, and the reverse micelle can be reused. The reverse micelle phase, after aqueous counterextraction, can be separated and purified using conventional methods such as concentration and crystallization to obtain a monospinal amino alcohol, and the reverse micelle can be reused. The aqueous phase can be directly separated and purified using conventional methods such as concentration and crystallization to obtain another monospinal amino alcohol.
[0023] Compared with the prior art, the present invention has the following beneficial technical effects:
[0024] (1) The chiral polar group in the chiral surfactant has a molecular recognition effect on one enantiomer in the racemate, and can selectively bring this enantiomer into the reverse micelle phase, while the other enantiomer that is not recognized by the molecule remains in the aqueous phase, thus achieving high enantioselectivity in the separation.
[0025] (2) The reverse micelle phase obtained by extraction and separation can be reused after aqueous reverse extraction.
[0026] (3) The method for resolving racemic compounds by enantioselective reverse micelle extraction provided by the present invention has the advantages of large processing capacity, simple operation, simple equipment, and low resolution cost. It is suitable for the requirements of large-scale production and provides a new approach for the resolution of chiral compounds. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 TEM images of n-hexane solutions of chiral surfactant DLV with different concentrations, from left to right: 0.5 g / L, 1 g / L, and 2 g / L.
[0028] Figure 2 The left figure is the TEM image of the reverse micelle phase before and after extraction of a 1 g / L propranolol racemate aqueous solution containing a 1 g / L chiral surfactant DLV in n-hexane. The right figure is the TEM image of the reverse micelle phase before extraction, and the left figure is the TEM image of the reverse micelle phase after extraction.
[0029] Figure 3 The figure is a HPLC chromatogram of the reverse micelle phase after extraction equilibrium between 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
[0030] The technical solution of the present invention is further described below with reference to specific examples, but these examples do not limit the present invention in any form. Unless otherwise specified in the examples, conventional reagents and conventional methods are used.
[0031] Example 1
[0032] Preparation of 2-decyldodecanoyl-L-valine (DLV)
[0033] Preparation of diethyl 2,2-didecylmalonate
[0034] 1.60 g of diethyl malonate was dissolved in 8 mL of tetrahydrofuran. 0.40 g of NaH (60%) was added at 0°C and allowed to react until the solution became clear. 2.21 g of 1-bromodecane was then added, and the temperature was raised to 85°C and refluxed for 5 h. The reaction mixture was cooled to 0°C, and 0.40 g of NaH (60%) was added. After stirring for 45 min, 2.21 g of 1-bromodecane was added, and the temperature was raised to 85°C and allowed to react for 5 h. The reaction mixture was cooled to room temperature, filtered to remove the white solid, and the filtrate was purified by vacuum distillation to obtain diethyl 2,2-didecylmalonate (2.30 g, 52% yield) as a yellow oil.
[0035] Preparation of 2,2-didecylmalonic acid
[0036] 1.32 g of diethyl 2,2-didecylmalonate was dissolved in 3 mL of ethanol, followed by the addition of 7.5 mL of 4 M NaOH solution and reflux at 85°C for 10 h. The reaction mixture was evaporated to remove the solvent, and the residue was adjusted to pH 2 with 2 M HCl solution. The mixture was then extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous magnesium sulfate overnight and the solvent was removed by rotary evaporation under reduced pressure to obtain 2,2-didecylmalonic acid (0.70 g, 61% yield) as a yellow oil.
[0037] Preparation of 2-decyldodecanoic acid
[0038] 1.15 g of 2,2-didecylmalonic acid was dissolved in 3 mL of acetic acid and heated at 185°C for 8 h for decarboxylation. The solvent was removed by rotary evaporation to obtain 2-decyldodecanoic acid (0.97 g, yield 95%) as a yellow-brown oil.
[0039] Preparation of 2-decyldodecanoyl-L-valine (DLV)
[0040] 0.34g of 2-decyldodecanoic acid was added to 1mL of thionyl chloride and refluxed at 90°C for 3h. Excess thionyl chloride was removed by rotary evaporation under reduced pressure, and the resulting alkyl chloride was dissolved in 5.5mL of tetrahydrofuran. Separately, 0.13g of L-valine was dissolved in 5.5mL of 0.2M NaOH solution. The alkyl chloride solution in tetrahydrofuran was slowly added dropwise at 0°C, while 2M NaOH solution was added dropwise to maintain the pH between 8 and 9. After the addition was complete, the reaction was continued at 0°C with stirring for 3h. The reaction was extracted with 15mL of ethyl acetate to remove unreacted alkyl chloride. The aqueous phase was acidified to pH 2 with 1M hydrochloric acid and extracted with ethyl acetate (15mL x 3). The organic phases were combined and dried overnight over anhydrous magnesium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain 2-decyldodecanoyl-L-valine (0.24g, 55% yield) as a yellow-brown viscous substance. 1 H NMR (400MHz, CDCl3) δ6.02(1H,d),4.58(1H,t),2.30~2.25(1H,m),1.67~1.64(1H,m),1.39~1.25(36H,m),1.00(3H,d),0.97(3H,d),0.90(6H,t).
[0041] Example 2
[0042] Preparation of 2-decyldodecanoyl-L-leucine (DLL)
[0043] 0.14 g of L-leucine was used instead of 0.13 g of L-valine, and the steps of Example 1 were followed to obtain yellow-brown viscous 2-decyldodecanoyl-L-leucine (0.23 g, yield 51%).1 H NMR (400MHz, CDCl3) δ8.82(1H,d), 4.58~4.50(1H,m), 2.24~2.18(1H,m), 1.86~1.60(7H,m), 1.34~1.1.19(32H,m), 0.98~0.84(12H,d).
[0044] Example 3
[0045] Preparation of 2-butylhexanoyl-L-phenylalanine (BHF)
[0046] Using 2.74 g of 1-bromodecane instead of 4.42 g of 1-bromodecane and 0.18 g of L-phenylalanine instead of 0.13 g of L-valine, the steps of Example 1 were followed to obtain yellow-brown viscous 2-butylhexanoyl-L-phenylalanine (0.17 g, yield 53.1%). 1 H NMR (400MHz, CDCl3) δ7.41~7.26(5H,m),6.03(1H,d),4.71(1H,t),3.09~2.85(2H,d),2.31~2.25(1H,m),1.40~1.26(12H,m),0.90(6H,t).
[0047] Example 4
[0048] Preparation of Octadecanoyl-D-asparagine (ODN)
[0049] Using 3.05 g of 1-bromodecane instead of 4.42 g of 1-bromodecane and 0.15 g of D-asparagine instead of 0.13 g of L-valine, the steps of Example 1 were followed to obtain yellow viscous octadecanoyl-D-asparagine (0.18 g, yield 47.4%). 1 HNMR (400MHz, CDCl3) δ6.03~5.82(3H,d),4.78(1H,t),2.95~2.70(2H,d),2.12(2H,t),1.42~1.26(30H,m),0.89(3H,t).
[0050] Example 5
[0051] Determination of critical micelle concentration
[0052] Prepare 10g / L chiral surfactant solutions dissolved in different organic solvents as stock solutions. Then dilute the stock solutions proportionally to obtain chiral surfactant solutions of varying concentrations. Then measure the UV absorption spectra of these solutions. Create a double-logarithmic plot of absorbance versus concentration at the wavelength of maximum UV absorption. The concentration at the inflection point is the CMC. The CMCs for various chiral surfactants to form reverse micelles in various organic solvents are shown in the following table:
[0053]
[0054] TEM images of n-hexane solutions of chiral surfactant DLV with different concentrations are shown in the attached figure. Figure 1 As shown in the figure, 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.
[0055] Example 6
[0056] Reverse micelle solutions of the chiral surfactant DLV in n-pentane, n-hexane, and cyclohexane were prepared at critical micelle concentrations (1 g / L, 1 g / L, and 2 g / L). Aqueous solutions of the propranolol racemate were also prepared at two concentrations (1 g / L and 2 g / L). The three reverse micelle solutions were mixed with aqueous solutions of the propranolol racemate at the same concentration and volume, respectively, and magnetically stirred for 10 minutes. The layers were allowed to stand, and the organic and aqueous phases were separated. The propranolol enantiomer concentrations were analyzed by high-performance liquid chromatography. The enantioselectivity coefficient (α) and enantiomeric excess (ee%) were calculated according to the following formula:
[0057]
[0058]
[0059] Among them, c org,R and c aqu,R represents the concentration of R-propranolol in the organic phase and the aqueous phase, respectively, c org,S and c aqu,S Represent the concentrations of S-propranolol in the organic phase and the aqueous phase, respectively.
[0060] The obtained enantiomeric selectivity coefficient (α) and enantiomeric excess value (ee%) are shown in the following table:
[0061] 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
[0062] The TEM images of the reverse micelle phase of the 1 g / L chiral surfactant DLV n-hexane reverse micelle solution before and after extraction of the 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.
[0063] Example 7
[0064] Reverse micelle solutions of the chiral surfactant DLL in n-hexane, cyclohexane, and n-heptane were prepared at critical micelle concentrations (1 g / L, 1.5 g / L, and 2.5 g / L). Aqueous solutions of the propranolol racemate were also prepared at three different concentrations (1 g / L, 1.5 g / L, and 2.5 g / L). The reverse micelle solutions of each concentration were mixed with aqueous solutions of the propranolol racemate at the same concentration and volume, and magnetically stirred for 10 minutes. The layers were allowed to stand, and the organic and aqueous phases were separated. The propranolol enantiomer concentrations were analyzed by high-performance liquid chromatography, and the enantioselectivity coefficient (α) and enantiomeric excess (ee%) were calculated. The results are shown in the following table:
[0065] 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
[0066] Example 8
[0067] Reverse micelle solutions of the chiral surfactant BHF in n-hexane, BHF in dichloroethane, HDN in toluene, and HDN in chlorobenzene were prepared at critical micelle concentrations (6.5 g / L, 9.0 g / L, 5.5 g / L, and 6.0 g / L). Aqueous solutions of the five racemates of alprenolol, pindolol, metoprolol, and atenolol were also prepared at a concentration of 1 g / L. Equal volumes of the four reverse micelle solutions and the four racemate aqueous solutions were mixed and magnetically stirred for 10 minutes. The layers were allowed to stand, and the organic and aqueous phases were separated. The enantiomer concentrations were analyzed by HPLC, and the enantioselectivity coefficient (α) and enantiomeric excess (ee%) were calculated. The results are shown in the following table:
[0068] 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 chiral surfactant for enantioselective reverse micelle extraction, characterized in that: The chiral surfactant is an N-alkanoyl-substituted chiral amino acid.
2. The chiral surfactant for enantioselective reverse micelle extraction according to claim 1, characterized in that: In the N-alkanoyl-substituted chiral amino acid, the configuration of the chiral amino acid is L-configuration or D-configuration.
3. The chiral surfactant for enantioselective reverse micelle extraction according to claim 1, characterized in that: In the N-alkanoyl-substituted chiral amino acids, the amino acids are each independently selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, histidine, lysine, arginine, aspartic acid, glutamic acid, asparagine, and glutamine.
4. The chiral surfactant for enantioselective reverse micelle extraction according to claim 1, characterized in that: In the N-alkanoyl-substituted chiral amino acids, the alkyl groups are independently selected from 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.
5. A method for preparing the chiral surfactant for enantioselective reverse micelle extraction according to claim 1, characterized in that: The preparation of the chiral surfactant comprises the following steps: Malonate (S1) is used as the raw material, and undergoes a C-alkylation reaction with a halogenated hydrocarbon under base catalysis to produce an alkyl malonate (S2); S2 is hydrolyzed to produce an alkyl malonate (S3); S3 is subjected to high-temperature decarboxylation to produce an alkyl acid (S4); S4 is chlorinated and then undergoes an N-acylation reaction with a chiral amino acid to produce an N-alkanoyl-substituted chiral amino acid (S).
6. Use of the chiral surfactant for enantioselective reverse micelle extraction according to claim 1 in the resolution of amino alcohol racemate compounds.
7. Use of the chiral surfactant for enantioselective reverse micelle extraction according to claim 6 in the resolution of amino alcohol racemate compounds, characterized in that: The reverse micelle formed by the chiral surfactant in a non-aqueous solvent that is hardly soluble in water is used as a chiral recognition extractant to selectively identify one enantiomer from a racemic aqueous solution. The identified enantiomer enters the reverse micelle, while the unrecognized enantiomer remains in the aqueous phase. The reverse micelle phase and the aqueous phase are separated to achieve resolution of the racemic compound.
8. Use of the chiral surfactant for enantioselective reverse micelle extraction according to claim 7 in the resolution of amino alcohol racemate compounds, characterized in that: The non-aqueous solvent is a single organic solvent or a mixed organic solvent that is hardly soluble in water, selected from one or a mixture of two or three organic solvents such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, and esters that are hardly soluble in water.
9. Use of the chiral surfactant for enantioselective reverse micelle extraction according to claim 7 in the resolution of amino alcohol racemate compounds, characterized in that: The sparingly water-soluble organic solvent is selected from the group consisting of 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, or a mixture of two or three solvents.
10. Use of the chiral surfactant for enantioselective reverse micelle extraction according to claim 6 in the resolution of amino alcohol racemate compounds, characterized in that: The amino alcohol racemate compound is one of propranolol, alprenolol, oxprenolol, pindolol, nadolol, esmolol, metoprolol, pralol, atenolol, acebutolol, labetalol and carvedilol.