Resolution method of aryl propionic acid raceme drug

Abstract

The invention discloses an enantioselective reversed micelle extraction and resolution method of an aryl propionic acid raceme drug. According to the resolution method, a reverse micelle formed by a dipeptidyl chiral surfactant in a water-insoluble organic solvent is used as a chiral recognition extraction agent, one enantiomer in a racemate drug aqueous solution is selectively recognized and extracted to a reverse micelle phase, and the other enantiomer which is not recognized is left in the aqueous phase; and separating the reversed micelle phase from the water phase to obtain the two optical isomers of the aryl propionic acid medicine. The resolution method of the aryl propionic acid racemate drug has the characteristics of simplicity in operation, low resolution cost, reusability of the reverse micelle and the like, and is suitable for the requirements of large-scale resolution.

Description

Technical Field

[0001] The present invention belongs to the technical field of chiral resolution of drugs, and particularly relates to an enantioselective reverse micellar extraction and resolution method for arylpropionic acid racemic drugs using a dipeptide-based chiral surfactant as a chiral recognition agent. Background Art

[0002] The enantiomers of chiral drugs often have significant differences in pharmacological activity, pharmacokinetic properties, and toxicity. Therefore, obtaining optically pure enantiomeric drugs is crucial for human health. The racemic resolution method is an important way to obtain chiral drug enantiomers. Currently, a variety of racemic resolution methods have been developed, and high optical purity enantiomers can also be obtained through certain technical means. However, each resolution method also has its own limitations, such as limited applicability, high cost, poor environmental friendliness, cumbersome operation, or inapplicability to large-scale production.

[0003] Arylpropionic acid drugs are a widely used non-steroidal anti-inflammatory drug (NSAIDs). Commonly used arylpropionic acid drugs in clinical practice include naproxen, ibuprofen, ketoprofen, carprofen, suprofen, pirprofen, fenoprofen, flurbiprofen, indoprofen, loxoprofen, pranoprofen, alminoprofen, zaltoprofen, etc. There are chiral carbon atoms in the molecular structures of these drugs, and different enantiomers have differences in pharmacological activity and pharmacokinetic properties. Among them, the S-enantiomer is the main active ingredient, while the R-enantiomer has very low activity and can cause side effects.

[0004] For the resolution of arylpropionic acid drugs, Ye et al. (Enantiomeric separation of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs by HPLC with hydroxypropyl-beta-cyclodextrin as chiral mobile phase additive, Biomedical Chromatography, 2010, 24(8):799-807) used hydroxypropyl-β-cyclodextrin as a chiral mobile phase additive and employed high performance liquid chromatography to perform enantiomeric separation of 8 arylpropionic acid drugs. This method has high separation efficiency, but has high equipment costs and large solvent consumption, and is only suitable for the separation and analysis of a small amount of enantiomers, and is not suitable for large-scale resolution of enantiomers. You Pengyong et al. (Enzymatic resolution of ibuprofen drugs catalyzed by papain, Journal of East China University of Science and Technology (Natural Science Edition), 2012, 38(6):687-693) achieved chiral resolution of ibuprofen drugs using papain as a catalyst. This method has mild conditions and high selectivity, but the enzyme is easily inactivated and the cost is high. Tang et al. (Equilibrium studies on reactive extraction of naproxen enantiomers using hydrophilic β-cyclodetrin derivatives extractants, Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2010, 69(1-2):213-220) used a method combining chiral liquid-liquid extraction and complexation reaction to resolve naproxen. Among the three cyclodextrin-based chiral resolving agents used, the best enantioselectivity coefficient obtained was only 1.59, and the enantioselectivity was low.

[0005] Therefore, the resolution of arylpropionic acid drugs needs to solve problems such as cumbersome operation, low enantioselectivity, and high costs to meet the requirements of large-scale resolution. Summary of the Invention

[0006] The object of the present invention is to provide a method for enantioselective reverse micelle extraction and resolution of arylpropionic acid drugs, which has the advantages of simple operation, low cost, high enantioselectivity, continuous operation, and easy scale-up, and is suitable for the requirements of large-scale resolution of chiral arylpropionic acid drugs.

[0007] To achieve the above object, the present invention provides a method for enantioselective recognition and resolution of arylpropionic acid drugs, and the technical solution is as follows:

[0008] The enantioselective reverse micelle extraction and resolution method for arylpropionic acid racemate drugs uses a dipeptide-based chiral surfactant with the general formula (I) structure to form a reverse micelle in a non-aqueous solvent as a chiral recognition extractant, selectively recognizing one enantiomer in the aqueous solution of the arylpropionic acid racemate and extracting it into the reverse micelle phase, while the other enantiomer that is not recognized remains in the aqueous phase. The two optical enantiomers of the arylpropionic acid drug are obtained by separating the reverse micelle phase and the aqueous phase.

[0009]

[0010] The dipeptide-based chiral surfactant with the general formula (I) structure is one of the structures shown in the general formulas (II) to (V).

[0011]

[0012] Among them, R1 and R2 are each independently methyl, isopropyl, isobutyl, sec-butyl, 1,3-propylene, benzyl, p-hydroxybenzyl, indolylmethyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, methylthioethyl, imidazolylmethyl, aminobutyl, guanidinopropyl, carboxymethyl, carboxyethyl, carboxypropyl, carbamoylmethyl, carbamoylethyl.

[0013] R3 and R4 are each independently H, a straight-chain or branched-chain alkyl group with C4 - C 20 and an aryl group containing C0 - C 18 . Among them, the C4 - C 20 refers to C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 15 , C 16 , C 17 , C 18 , C 19 and C 20 ; the C0 - C 18 refers to H, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 15 , C 16 , C 17 and C 18 .

[0014] In the above-mentioned enantioselective reverse micelle extraction and resolution method for arylpropionic acid drugs, when the chiral surfactant has the general formulas (II) and (III), that is, when its dipeptide polar group is L-aminoacyl-L-aminoacyl group and L-aminoacyl-D-aminoacyl group, the formed reverse micelles selectively recognize the R-enantiomer of arylpropionic acid drugs and enter the reverse micelle phase, while the S-enantiomer remains in the aqueous phase. The reverse micelle phase and the aqueous phase are separated to obtain the R-enantiomer and S-enantiomer of arylpropionic acid drugs respectively.

[0015] In the above-mentioned enantioselective reverse micelle extraction and resolution method for arylpropionic acid drugs, when the chiral surfactant has the general formulas (IV) or (V), and its dipeptide polar group is D-aminoacyl-D-aminoacyl group and D-aminoacyl-L-aminoacyl group, the formed reverse micelles selectively recognize the S-enantiomer of arylpropionic acid drugs and enter the reverse micelle phase, while the R-enantiomer remains in the aqueous phase. The reverse micelle phase and the aqueous phase are separated to obtain the S-enantiomer and R-enantiomer of arylpropionic acid drugs respectively.

[0016] The above-mentioned racemic arylpropionic acid drugs include naproxen, ibuprofen, ketoprofen, carprofen, suprofen, pirprofen, fenoprofen, flurbiprofen, indoprofen, loxoprofen, pranoprofen, alminoprofen, zaltoprofen.

[0017] The non-aqueous solvent for the formation of reverse micelles by the above-mentioned dipeptide-based chiral surfactant is a single organic solvent that is poorly soluble in water or a mixture of two or three solvents that are poorly soluble in water, and is selected from one or a mixture of two solvents or a mixture of three solvents among organic solvents such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, etc. that are poorly soluble in water.

[0018] The above-mentioned organic solvents that are poorly soluble in water are selected from one or a mixture of two solvents or a mixture of three solvents of the following solvents: dichloromethane, chloroethane, 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, isooctanol, cyclohexanol, propyl ether, butyl ether, pentyl ether, hexyl ether, cyclohexyl ether, diphenyl 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, isooctyl acetate.

[0019] The reversed micelle phase and the aqueous phase obtained by enantioselective reversed micelle extraction can be further purified by conventional separation and purification methods to improve the optical purity, and the reversed micelles can be reused. Among them, after the reversed micelle phase is back-extracted with water, it is separated and purified by conventional methods (such as concentration, crystallization, etc.) to obtain the single enantiomer of arylpropionic acid drugs, and the reversed micelles can be reused; the aqueous phase is directly separated and purified by conventional methods (such as concentration, crystallization, etc.) to obtain another single enantiomer of arylpropionic acid drugs.

[0020] The preparation method of the dipeptide-based chiral surfactant with the general formula (Ⅰ) structure is as follows: Amino-protected chiral amino acid is activated by a condensing agent for the carboxyl group to generate an active intermediate, and then coupled with another chiral amino acid to obtain an amino-protected dipeptide; The amino-protected dipeptide is coupled with an amine by a condensing agent to prepare an amino-protected dipeptide-based amide; The amino-protecting group is removed using a deprotecting agent to obtain the dipeptide-based chiral surfactant. The preparation process is as follows:

[0021]

[0022] Wherein: The amino-protecting group PG is selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), phthaloyl (Pht), 2,4-dimethoxybenzyl (Dmb), benzyl (Bn), p-methoxybenzyl (PMB), trifluoroacetyl (Tfa).

[0023] The condensing agent is selected from EDCI / HOSu, DCC / HOSu, DIC / HOSu, EDCI / HOAt, DCC / / HOAt, DIC / HOAt, EDCI / HOBt, DCC / HOBt, DIC / HOBt, CDI, MsCl, TsCl, NsCl, Boc2O, BOP, PyBOP, HATU, HBTU, SOCl2, C2Cl2O2.

[0024] L is selected from N-hydroxysuccinimidyl (-OSu), 7-azabenzotriazol-1-yl (-OAt), 1-hydroxybenzotriazolyl (-OBt), imidazolyl, methanesulfonyloxy (-OMs), p-toluenesulfonyloxy (-OTs), p-nitrobenzenesulfonyloxy (-ONs), tert-butoxycarbonyloxy (-OBoc), benzotriazoloxy, 7-azabenzotriazoloxy or chlorine atom (-Cl).

[0025] The deprotecting agent is selected from H2 / Pd-C, HBr / HAc, HF, TFA, HCl, BF3, 2-mercaptoethanesulfonic acid, formic acid, piperidine, triethylamine, diethylamine, ammonia water, Pd(PPh3)4 / Bu3SnH.

[0026] Compared with the prior art, the beneficial technical effects achieved by the present invention are as follows:

[0027] (1) The chiral polar group in the dipeptide-based chiral surfactant has a specific chiral recognition effect on the enantiomers in the racemic drugs of arylpropionic acids. Among them, L-aminoacyl-L-amino acids and L-aminoacyl-D-amino acids can selectively recognize the R-configured arylpropionic acid drugs and selectively bring them into the reverse micelle phase, while the S-configured ones that are not chiral recognized remain in the aqueous phase; D-aminoacyl-D-amino acids and D-aminoacyl-L-amino acids can selectively recognize the S-configured arylpropionic acid drugs and selectively bring them into the reverse micelle phase, while the R-configured ones that are not chiral recognized remain in the aqueous phase. Therefore, the enantioselective reverse micelle extraction and resolution method for the racemic drugs of arylpropionic acids of the present invention has high enantioselectivity.

[0028] (2) The reverse micelle phase obtained by extraction and separation can be reused after back-extraction with water.

[0029] (3) The resolution method for the racemic drugs of arylpropionic acids provided by the present invention has the characteristics of simple operation and low resolution cost, and is suitable for the requirements of large-scale resolution. Description of the Drawings

[0030] Figure 1 Figure is the TEM image of cyclohexane solutions of dipeptide-based chiral surfactant LLPDN at different concentrations. From left to right, the concentrations are 44.5 mg / L, 89.0 mg / L, and 178.0 mg / L in sequence.

[0031] Figure 2 Figure is the TEM images of the reverse micelle phase of 89.0 mg / L chiral surfactant LLPDN in cyclohexane before and after extraction of an 89.0 mg / L aqueous solution of naproxen racemate. The left figure is the TEM image of the reverse micelle phase before extraction, and the right figure is the TEM image of the reverse micelle phase after extraction. Detailed Embodiments

[0032] The technical solutions of the present invention are further described below in conjunction with specific embodiments, but these embodiments do not limit the present invention in any form. If not otherwise specified in the embodiments, they are conventional reagents and conventional methods.

[0033] Example 1

[0034] Preparation of L-phenylalanyl-L-leucyl-N,N-didodecylamine (LPLDN)

[0035] Preparation of Fmoc-L-phenylalanine-2,5-dioxopyrrolidin-1-yl ester

[0036] Fmoc-L-phenylalanine (395.3 mg, 1 mmol) was dissolved in DMF (10 mL). After cooling and stirring in an ice-salt bath for 10 min, N-hydroxysuccinimide (HOSu, 129.2 mg, 1.1 mmol) was added. When the temperature dropped to 0 °C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 234.7 mg, 1.2 mmol) was added, and the mixture was stirred until the reaction reached room temperature and then stirred for an additional 6 h. Ethyl acetate (40 mL) was added to the reaction solution, and it was washed successively with saturated NaHCO3 solution (20 mL × 2) and saturated NaCl solution (20 mL). The organic phase was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation under vacuum to obtain the reaction product, which was directly used in the next step without further purification.

[0037] Preparation of Fmoc-L-phenylalanyl-L-leucine

[0038] The above-mentioned Fmoc-L-phenylalanine-2,5-dioxopyrrolidin-1-yl ester was dissolved in THF (10 mL). After cooling and stirring in an ice-salt bath to 0 °C, a solution of L-leucine (145.7 mg, 1.1 mmol) in 1 mol / L NaHCO3 solution (10 mL) was added dropwise. After the addition was complete, the reaction continued for 8 h. The pH of the reaction solution was adjusted to 2 - 3 with 1 mol / L HCl solution, and then it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The combined organic phase was dried over anhydrous MgSO4 and concentrated under vacuum to 5 mL. 20 mL of petroleum ether was added, and a white solid precipitated. The solid was collected to obtain 431.1 mg of the product, with a yield of 86%.

[0039] Preparation of Fmoc-L-phenylalanyl-L-leucyl-N,N-didodecylamine

[0040] Fmoc-L-phenylalanyl-L-leucine (500.6 mg, 1 mmol) was dissolved in DMF (10 mL). After cooling and stirring in an ice-salt bath for 10 min, N-hydroxysuccinimide (129.2 mg, 1.1 mmol) was added. The reaction was stirred until the temperature dropped to 0 °C, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added. After stirring at 0 °C for 1 h, didodecylamine (401.1 mg, 1.1 mmol) was added, and the reaction continued to stir at 0 °C for 10 h. The solvent was removed from the reaction solution by rotary evaporation under vacuum, and the residue was purified by column chromatography (the volume ratio of the eluent was ethyl acetate:petroleum ether = 1:14) to obtain 261.3 mg of the product, with a yield of 31%.

[0041] Preparation of L-phenylalanyl-L-leucyl-N,N-didodecylamine (LPLDN)

[0042] Fmoc-L-phenylalanyl-L-leucyl-N,N-didodecylamine (261.3 mg, 0.3109 mmol) was dissolved in DMF (5 mL). Diethylamine (5 mL) was added dropwise with stirring at room temperature. After the addition was complete, the reaction mixture was stirred for an additional 4 h. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with saturated NaCl solution (20 mL × 3). The organic phase was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (eluent volume ratio: ethyl acetate: petroleum ether: diethylamine = 10:40:0.5) to obtain 158.6 mg of the product with a yield of 83%.

[0043] Example 2

[0044] Preparation of L-leucyl-L-phenylalanyl-N,N-didodecylamine (LLPDN)

[0045] Preparation of Fmoc-L-leucine 2,5-dioxopyrrolidin-1-yl ester

[0046] Fmoc-L-leucine (360.6 mg, 1 mmol) was dissolved in anhydrous dichloromethane (10 mL). After cooling and stirring in an ice-salt bath for 10 min, 129.2 mg (1.1 mmol) of N-hydroxysuccinimide was added. When the temperature of the reaction solution dropped to 0 °C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added. The reaction mixture was stirred until it reached room temperature and then stirred for an additional 6 h. The reaction solution was washed successively with saturated NaHCO3 solution (10 mL × 2) and saturated NaCl solution (10 mL), dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under vacuum to obtain the reaction product, which was directly used in the next step without further purification.

[0047] Preparation of Fmoc-L-leucyl-L-phenylalanine

[0048] The above-mentioned Fmoc-L-leucine 2,5-dioxopyrrolidin-1-yl ester (450.2 mg, 1 mmol) was dissolved in tetrahydrofuran (5 mL). The solution was cooled and stirred in an ice-salt bath to 0 °C, and a solution of L-phenylalanine (183.6 mg) dissolved in 1 mol / L NaHCO3 solution (5 mL) was added dropwise. The reaction mixture was stirred for an additional 8 h. The pH of the reaction solution was adjusted to 2 - 3 with 1 mol / L hydrochloric acid, and the solution was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to 5 mL. 20 mL of petroleum ether was added, and a white solid precipitated. The solid was collected to obtain 457.4 mg of the product with a yield of 91%.

[0049] Preparation of Fmoc-L-leucyl-L-phenylalanyl-N,N-didodecylamine

[0050] Fmoc-L-leucyl-L-phenylalanine (500.2 mg, 1 mmol) was dissolved in anhydrous dichloromethane (10 mL). After cooling with an ice-salt bath and stirring for 10 min, N-hydroxysuccinimide (129.2 mg, 1.1 mmol) was added. The reaction mixture was stirred until the temperature dropped to 0 °C, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added. After stirring for 1 h, didodecylamine (437.5 mg, 1.2 mmol) was added, and the reaction was continued with stirring for 12 h. The solvent was removed by rotary evaporation under vacuum, and the residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:14, v / v) to obtain 361.0 mg of a pale yellow liquid product with a yield of 43%.

[0051] Preparation of L-leucyl-L-phenylalanyl-N,N-didodecylamine (LLPDN)

[0052] Fmoc-L-leucyl-L-phenylalanyl-N,N-didodecylamine (359.6 mg, 0.4317 mmol) was dissolved in N,N-dimethylformamide (5 mL). Diethylamine (5 mL) was added dropwise under stirring at room temperature. After the addition was complete, the reaction was continued with stirring for 4 h. 40 mL of ethyl acetate was added to the reaction mixture, and it was washed with saturated NaCl solution (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (eluent: ethyl acetate: petroleum ether: diethylamine = 10:40:0.5, v / v / v) to obtain 196.5 mg of a yellow oily liquid product with a yield of 74%.

[0053] Example 3

[0054] Preparation of L-valyl-L-seryl-N,N-ditetradecylamine (LVSTN)

[0055] Preparation of Fmoc-L-valine-2,5-dioxopyrrolidin-1-yl ester

[0056] Fmoc-L-valine (346.3 mg, 1 mmol) was dissolved in dichloromethane (10 mL). After cooling with an ice-salt bath and stirring for 10 min, N-hydroxysuccinimide (129.2 mg, 1.1 mmol) was added. When the temperature of the reaction mixture dropped to 0 °C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added, and the reaction mixture was stirred to room temperature and then reacted for an additional 6 h. The reaction mixture was washed successively with saturated NaHCO3 solution (20 mL × 2) and saturated NaCl solution (20 mL), dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation under vacuum to obtain the reaction product, which was directly used in the next step without further purification.

[0057] Preparation of Fmoc-L-valyl-L-serine

[0058] Dissolve the above Fmoc-L-valine-2,5-dioxopyrrolidin-1-yl ester in THF (10 mL), cool it in an ice-salt bath and stir to 0 °C, add dropwise L-serine (107.2 mg, 1.1 mmol) dissolved in 1 mol / L NaHCO3 solution (10 mL), and continue the reaction for 8 h after the addition is complete. Adjust the pH of the reaction solution to 2 - 3 with 1 mol / L HCl solution, extract the reaction solution with ethyl acetate (20 mL × 3), and combine the organic phases. Dry the organic phase with anhydrous MgSO4, concentrate it in vacuo to 5 mL, add 20 mL of petroleum ether, and a white solid precipitates. Collect 353.9 mg of the product with a yield of 83%.

[0059] Preparation of Fmoc-L-valyl-L-seryl-N,N-ditetradecylamine

[0060] Dissolve Fmoc-L-valyl-L-serine (426.5 mg, 1 mmol) in DMF (10 mL), add N-hydroxysuccinimide (129.2 mg, 1.1 mmol) under cooling and stirring in an ice-salt bath, continue stirring until the temperature of the reaction solution drops to 0 °C, and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol). After stirring for 1 h, add ditetradecylamine (474.5 mg, 1.1 mmol) and continue stirring for 10 h. Rotavapor the reaction solution to remove the solvent, purify the residue by column chromatography (the volume ratio of the eluent is ethyl acetate:petroleum ether = 1:14), and obtain 286.4 mg of the product with a yield of 35%.

[0061] Preparation of L-valyl-L-seryl-N,N-ditetradecylamine

[0062] Dissolve Fmoc-L-valyl-L-seryl-N,N-ditetradecylamine (286.4 mg, 0.3500 mmol) in DMF (5 mL), add dropwise diethylamine (5 mL) under stirring at room temperature, and continue stirring for 4 h after the addition is complete. Add ethyl acetate (20 mL) to the reaction solution, wash it with saturated NaCl solution (20 mL × 3), dry the organic phase with anhydrous MgSO4, then rotavapor to remove the solvent, purify the residue by column chromatography (the volume ratio of the eluent is ethyl acetate:petroleum ether:diethylamine = 10:40:0.5), and obtain 175.8 mg of the product with a yield of 84%.

[0063] Example 4

[0064] Preparation of D-tyrosyl-D-threonyl-N,N-dipalmitylamine (DYTHN)

[0065] Preparation of Fmoc-D-tyrosine-2,5-dioxopyrrolidin-1-yl ester

[0066] Fmoc-D-tyrosine (415.9 mg, 1 mmol) was dissolved in anhydrous DMF (10 mL). After cooling with an ice-salt bath and stirring for 10 min, N-hydroxysuccinimide (129.2 mg, 1.1 mmol) was added. When the temperature of the reaction solution dropped to 0 °C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added, and the reaction was continued with stirring for 6 h. Ethyl acetate (40 mL) was added to the reaction solution, and it was washed successively with saturated NaHCO3 solution (20 mL × 2) and saturated NaCl solution (20 mL). The organic phase was dried over anhydrous MgSO4 and then the solvent was removed by rotary evaporation under vacuum to obtain the reaction product, which was directly used in the next step without further purification.

[0067] Preparation of Fmoc-D-tyrosyl-D-threonine

[0068] The above-mentioned Fmoc-D-tyrosine-2,5-dioxopyrrolidin-1-yl ester was dissolved in THF (10 mL). After cooling with an ice-salt bath and stirring to 0 °C, a solution of L-threonine (132.4 mg, 1.1 mmol) in 1 mol / L NaHCO3 solution (10 mL) was added dropwise. After the addition was complete, the reaction was continued with stirring for 8 h. The pH of the reaction solution was adjusted to 2 - 3 with 1 mol / L HCl solution, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. After drying the organic phase over anhydrous MgSO4, it was concentrated under vacuum to 5 mL, 20 mL of petroleum ether was added, and a white solid was precipitated. The product 400.4 mg was collected, and the yield was 79%.

[0069] Preparation of Fmoc-D-tyrosyl-D-threonyl-N,N-dicetylamine

[0070] Fmoc-D-tyrosyl-D-threonine (504.5 mg, 1 mmol) was dissolved in DMF (10 mL). After cooling with an ice-salt bath and stirring for 10 min, N-hydroxysuccinimide (129.2 mg, 1.1 mmol) was added. Stirring was continued until the temperature of the reaction solution dropped to 0 °C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.7 mg, 1.2 mmol) was added, and after stirring the reaction for 1 h, dicetylamine (522.9 mg, 1.1 mmol) was added, and the reaction was continued with stirring for 10 h. After the solvent was removed by rotary evaporation under vacuum from the reaction solution, the residue was purified by column chromatography (the volume ratio of the eluent was ethyl acetate:petroleum ether = 1:14) to obtain the product 317.7 mg, and the yield was 33%.

[0071] Preparation of D-tyrosyl-D-threonyl-N,N-dicetylamine

[0072] Fmoc-D-tyrosyl-D-threonyl-N,N-dipalmitylamine (317.7 mg, 0.334 mmol) was dissolved in DMF (5 mL). Diethylamine (5 mL) was added dropwise under stirring at room temperature. After the addition, the reaction mixture was stirred for another 4 h. The reaction solution was added with ethyl acetate (20 mL) and washed with saturated NaCl solution (20 mL × 3). The organic phase was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation under vacuum. The residue was purified by column chromatography (eluent volume ratio: ethyl acetate: petroleum ether: diethylamine = 10:40:0.5) to obtain 210.2 mg of the product with a yield of 86%.

[0073] Example 5

[0074] Solutions of 10 g / L chiral surfactants L-phenylalanyl-L-leucyl-N,N-didodecylamine (LPLDN), L-leucyl-L-phenylalanyl-N,N-didodecylamine (LLPDN), L-valyl-L-seryl-N,N-ditetradecylamine (LVSTN), and D-tyrosyl-D-threonyl-N,N-dipalmitylamine (DYTHN) dissolved in different organic solvents were prepared as stock solutions. Then the stock solutions were diluted in proportion to obtain chiral surfactant solutions with different concentrations, and the ultraviolet absorption spectra of the solutions with different concentrations were measured. A double logarithmic curve of absorbance versus concentration at the maximum absorption wavelength was made, and the concentration at the inflection point was the critical micelle concentration (CMC). The CMCs of the reverse micelles formed by various chiral surfactants in different organic solvents are shown in the following table:

[0075] Chiral surfactant Organic solvent CMC / (mg / L) LPLDN n-Hexane 54.6 LPLDN Cyclohexane 86.5 LPLDN n-Heptane 133.1 LPLDN Isooctane 139.3 LPLDN n-Octane 143.0 LLPDN n-Hexane 58.9 LLPDN Cyclohexane 89.0 LLPDN n-Heptane 133.8 LLPDN Isooctane 168.7 LLPDN n-Octane 201.9 LVSTN n-Hexane 61.3 LVSTN Cyclohexane 92.5 LVSTN Dichloromethane 237.6 LVSTN n-Heptane 156.8 DYTHN Cyclohexane 126.7 DYTHN Trichloromethane 249.5 DYTHN Isoheptane 166.2

[0076] TEM images of chiral surfactant LLPDN / cyclohexane with different concentrations are shown in the appendix Figure 1 As shown, for the cyclohexane solution of LLPDN with a concentration of 44.5 mg / L, since the concentration of LLPDN was less than the CMC, the existence of reverse micelles was not observed; while for the LLPDN / cyclohexane solution with a concentration of 89.0 mg / L, since its concentration reached the CMC, reverse micelles were observed; for the LLPDN / cyclohexane solution with a concentration of 178.0 mg / L, since its concentration exceeded the CMC, the size of the reverse micelles became larger and the structure became inhomogeneous.

[0077] Example 6

[0078] Five kinds of reverse micelle solutions of chiral surfactant LLPDN dissolved in n - hexane, cyclohexane, n - heptane, isooctane and n - octane were prepared according to the critical micelle concentrations (58.9 mg / L, 89.0 mg / L, 133.8 mg / L, 168.7 mg / L and 201.9 mg / L). And five kinds of aqueous solutions of racemic naproxen with concentrations of 22.8 mg / L, 34.4 mg / L, 51.8 mg / L, 65.3 mg / L and 78.1 mg / L were prepared. The above - mentioned reverse micelle solutions were respectively taken and mixed with an equal volume of the aqueous solution of racemic naproxen. After stirring at room temperature for 10 min, the mixture was allowed to stand for stratification, and the organic phase and the aqueous phase were separated. The concentrations of naproxen enantiomers were analyzed by high - performance liquid chromatography (HPLC). The enantioselectivity coefficient (α) and enantiomeric excess value (e.e.%) were calculated according to the following formula:

[0079]

[0080] Among them, c org,R and c org,S represent the concentrations of R - naproxen and S - naproxen in the organic phase respectively, and c aqu,R and c aqu,S represent the concentrations of R - naproxen and S - naproxen in the aqueous phase respectively.

[0081] The enantioselectivity coefficient (α) and enantiomeric excess value (e.e.%) are as follows in the table:

[0082] Chiral surfactant Organic solvent α e.e.% LLPDN n-Hexane 1.28 12.2 LLPDN Cyclohexane 2.29 38.9 LLPDN n-Heptane 1.66 24.1 LLPDN Isooctane 1.48 18.9 LLPDN n-Octane 1.27 11.5

[0083] For the cyclohexane reverse micelle solution of 89.0 mg / L LLPDN, before and after the extraction of 89.0 mg / L racemic naproxen solution, the TEM images of its reverse micelle phase are as shown in the appendix Figure 2 shown.

[0084] Example 7

[0085] Three kinds of reverse micelle solutions of chiral surfactant LPLDN dissolved in cyclohexane, n - heptane and n - octane were prepared according to the critical micelle concentrations (86.5 mg / L, 133.1 mg / L and 143.0 mg / L), and three kinds of aqueous solutions of racemic naproxen with concentrations of 33.5 mg / L, 51.5 mg / L and 55.3 mg / L were prepared. The above - mentioned reverse micelle solutions were respectively taken and mixed with an equal volume of the aqueous solution of racemic naproxen. After stirring at room temperature for 10 min, the mixture was allowed to stand for stratification, and the organic phase and the aqueous phase were separated. The concentrations of naproxen enantiomers were analyzed by high - performance liquid chromatography (HPLC). The enantioselectivity coefficient (α) and enantiomeric excess value (e.e.%) were calculated, and the results are as follows in the table:

[0086] Chiral surfactant Organic solvent α e.e.% LPLDN n-Hexane 1.43 17.3 LPLDN Cyclohexane 1.92 31.1 LPLDN n-Heptane 1.57 21.8

[0087] Example 8

[0088] Four kinds of reverse micelle solutions of chiral surfactant LVSTN dissolved in n - hexane, cyclohexane, n - heptane and dichloromethane were prepared according to the critical micelle concentrations (61.3 mg / L, 92.5 mg / L, 156.8 mg / L and 237.6 mg / L), and three kinds of reverse micelle solutions of chiral surfactant DYTHN dissolved in cyclohexane, iso - heptane and chloroform were prepared according to the critical micelle concentrations (126.7 mg / L, 166.2 mg / L and 249.5 mg / L). In addition, aqueous solutions of ibuprofen at 21.7 mg / L, ketoprofen at 39.8 mg / L, carprofen at 73.5 mg / L, suprofen at 104.9 mg / L, pirprofen at 40.2 mg / L, indoprofen at 65.4 mg / L and flurbiprofen at 85.2 mg / L were prepared respectively. Then, the above - mentioned reverse micelle solutions were respectively mixed with an equal - volume racemic body aqueous solution, stirred at room temperature for 10 min, and then allowed to stand for phase separation. The organic phase and the aqueous phase were separated, and the concentrations of drug enantiomers were analyzed by high - performance liquid chromatography (HPLC), and the enantioselectivity coefficient (α) and enantiomeric excess value (e.e.%) were calculated. The results are shown in the following table:

[0089] Chiral surfactant Organic solvent Racemate α e.e.% LVSTN n-Hexane Ibuprofen 1.59 22.4 LVSTN Cyclohexane Ketoprofen 1.33 13.8 LVSTN n-Heptane Carprofen 1.81 28.3 LVSTN Dichloromethane Suprofen 1.42 17.1 DYTHN Cyclohexane Pirprofen 1.20 9.0 DYTHN Isoheptane Indoprofen 1.44 17.6 DYTHN Trichloromethane Flurbiprofen 1.69 25.2

Claims

1. A method for resolving a racemic drug of arylpropionic acid, characterized in that: Using a reversed micelle formed by a dipeptide-based chiral surfactant with the structure of general formula (Ⅰ) in an organic solvent sparingly soluble in water as a chiral recognition extractant to selectively recognize one enantiomer in the aqueous solution of a racemic arylpropionic acid drug, enabling it to enter the reversed micelle phase, while the other enantiomer remains in the aqueous phase due to non-recognition. Separating the reversed micelle phase and the aqueous phase yields the two optical isomers of the racemic arylpropionic acid drug. Wherein: R1 and R2 are each independently methyl, isopropyl, isobutyl, sec-butyl, 1,3-propylene, benzyl, p-hydroxybenzyl, indolylmethyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, methylthioethyl, imidazolylmethyl, aminobutyl, guanidinopropyl, carboxymethyl, carboxyethyl, carboxypropyl, carbamoylmethyl, carbamoylethyl; R3 and R4 are independently H, C4~C 20 Straight-chain alkyl and branched-chain alkyl, containing C0~C 18 wherein the C4~C 20 , refers to C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 15 , C 16 , C 17 , C 18 , C 19 and C 20 ; The C0~C 18 , refers to H, C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 15 , C 16 , C 17 and C 18 .

2. The resolution method of the arylpropionic acid racemic drug according to claim 1, characterized in that: The dipeptide-based chiral surfactant with the structure of general formula (Ⅰ) is one of the structures shown in general formulas (Ⅱ) to (Ⅴ); 3. The method for resolving the racemic arylpropionic acid drug according to claim 1, characterized in that: In the general formula (Ⅰ) of the chiral surfactant, when the dipeptide polar group is L-aminoacyl-L-aminoacyl and L-aminoacyl-D-aminoacyl, the reversed micelle formed in the organic solvent selectively recognizes the R-configuration optical isomer in the aqueous solution of the racemic arylpropionic acid. The recognized R-configuration enantiomer enters the reversed micelle phase, and the unrecognized S-configuration enantiomer remains in the aqueous phase. Separating the reversed micelle phase and the aqueous phase yields the R-configuration and S-configuration arylpropionic acid drugs respectively.

4. The resolution method of the arylpropionic acid racemate drug according to claim 1, characterized in that: In the general formula (Ⅰ) of the chiral surfactant, when the dipeptide polar group is D-aminoacyl-D-aminoacyl and D-aminoacyl-L-aminoacyl, the reversed micelle formed in the organic solvent selectively recognizes the S-configuration optical isomer in the aqueous solution of the racemic arylpropionic acid. The recognized S-configuration enantiomer enters the reversed micelle phase, and the unrecognized R-configuration enantiomer remains in the aqueous phase. Separating the reversed micelle phase and the aqueous phase yields the S-configuration and R-configuration arylpropionic acid drugs respectively.

5. The resolution method of the arylpropionic acid racemic drug according to claim 1, characterized in that: The water-insoluble non-aqueous solvent in which the dipeptide-based chiral surfactant forms a reversed micelle is a single water-insoluble organic solvent or a mixture of two or three water-insoluble solvents, selected from one or a mixture of two or a mixture of three of the following water-insoluble organic solvents: hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, etc.

6. The method for resolving racemic arylpropionic acid drugs according to claim 1, wherein: The water-insoluble non-aqueous solvent in which the dipeptide-based chiral surfactant forms a reversed micelle is selected from one or a mixture of two or a mixture of three of the following solvents: dichloromethane, chloroethane, 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, isooctanol, cyclohexanol, propyl ether, butyl ether, pentyl ether, hexyl ether, cyclohexyl ether, diphenyl 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, isooctyl acetate.

7. The resolution method of the arylpropionic acid racemic drug according to any one of claims 1 or 2, characterized in that: The preparation method of the dipeptide-based chiral surfactant with the general formula (Ⅰ-Ⅴ) is as follows: Amino-protected chiral amino acid is activated by a condensing agent for the carboxyl group to generate an active intermediate, and then coupled with another chiral amino acid to obtain an amino-protected dipeptide; The amino-protected dipeptide is coupled with an amine by a condensing agent to prepare an amino-protected dipeptide-based amide; The amino-protecting group is removed by a deprotecting agent to obtain the dipeptide-based chiral surfactant; The preparation process is as follows: Wherein: The amino-protecting group PG is selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), phthaloyl (Pht), 2,4-dimethoxybenzyl (Dmb), benzyl (Bn), p-methoxybenzyl (PMB), trifluoroacetyl (Tfa); The condensing agent is selected from EDCI / HOSu, DCC / HOSu, DIC / HOSu, EDCI / HOAt, DCC / / HOAt, DIC / HOAt, EDCI / HOBt, DCC / HOBt, DIC / HOBt, CDI, MsCl, TsCl, NsCl, Boc2O, BOP, PyBOP, HATU, HBTU, SOCl2, C2Cl2O2; L is selected from N-hydroxysuccinimide group (-OSu), 7-azabenzotriazol-1-yl group (-OAt), 1-hydroxybenzotriazolyl group (-OBt), imidazolyl group, methanesulfonyloxy group (-OMs), p-toluenesulfonyloxy group (-OTs), p-nitrobenzenesulfonyloxy group (-ONs), tert-butoxycarbonyloxy group (-OBoc), benzotriazoloxy group, 7-azabenzotriazoloxy group or chlorine atom (-Cl); The deprotecting agent is selected from H2 / Pd-C, HBr / HAc, HF, TFA, HCl, BF3, 2-mercaptoethanesulfonic acid, formic acid, piperidine, triethylamine, diethylamine, ammonia water, Pd(PPh3)4 / Bu3SnH.

8. The resolution method of the arylpropionic acid racemic drug according to any one of claims 1, 3-4, characterized in that: The racemic arylpropionic acid drugs described above are any one of the racemic drugs of naproxen, ibuprofen, ketoprofen, carprofen, suprofen, pirprofen, fenoprofen, flurbiprofen, indoprofen, loxoprofen, pranoprofen, alminoprofen, zaltoprofen.

9. The resolution method of the arylpropionic acid racemate drug according to any one of claims 1, 3 - 4, characterized in that: For the reverse micelle phase and the aqueous phase obtained by enantioselective reverse micelle extraction and separation, conventional separation and purification methods are used to further improve the optical purity: After the reverse micelle phase is back-extracted with water, it is separated and purified by concentration and crystallization methods to obtain a single enantiomer of arylpropionic acid drug, and the reverse micelle can be reused; The aqueous phase is directly separated and purified by concentration and crystallization methods to obtain another single enantiomer of arylpropionic acid drug.

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