Chiral ionic liquid, preparation method thereof and application of chiral ionic liquid as chiral resolution extraction agent

Abstract

The invention discloses a chiral ionic liquid and a preparation method thereof and application of the chiral ionic liquid as a chiral resolution extraction agent, the chiral ionic liquid is cis-[C12H19O2mim] [Cl] with a cis-structure as shown in a formula A or trans-[C12H19O2mim] [Cl] with a trans-structure as shown in a formula B, and the specific structural formulas are as follows: # imgabs 0 # and # imgabs 1 #. Experiments prove that the chiral ionic liquid provided by the invention can be used as a chiral resolution extraction agent, and has the advantages of high separation factor, high enantiomer purity, low cost, simplicity and convenience in operation, mild conditions, support of continuous operation, environment friendliness and the like when being used for resolution of DL-phenyllactic acid by a multistage chiral liquid-liquid extraction method; and the method has a remarkable value for realizing the industrial production of the chiral L-phenyllactic acid.

Description

Technical Field

[0001] The invention relates to a chiral ionic liquid and a preparation method thereof and application of the chiral ionic liquid as a chiral separation extractant, belonging to the technical field of organic chemistry. Background Art

[0002] Phenyllactic acid (PLA), also known as 2-hydroxy-3-phenylpropionic acid, 3-phenyllactic acid or β-phenyllactic acid, is a small molecule natural organic acid widely present in nature. Phenyllactic acid has a broad spectrum of antibacterial activity, inhibiting Gram-positive bacteria, Gram-negative bacteria and eukaryotic microorganisms. Phenyllactic acid has good solubility, can diffuse in various food systems, and has high stability, a wide pH range and thermal stability. Therefore, phenyllactic acid has potential application value in the food industry as an antimicrobial agent. In addition, phenyllactic acid is also an important chemical synthesis precursor and has a wide range of applications in the fields of medicine, chemical industry, biosynthesis, etc. Since the second carbon atom of phenyllactic acid is a chiral carbon atom, phenyllactic acid has two enantiomers, L-phenyllactic acid and D-phenyllactic acid. Although the physical properties of these two enantiomers are the same, their corresponding optical activities are different, so there are great differences in their effects on organisms and applications in various fields. For example, studies have shown that L-phenyllactic acid can be used to synthesize antiviral and antitumor compounds, and D-phenyllactic acid can be used to synthesize hypoglycemic drugs and protein inhibitors. The current method for industrial production of phenyllactic acid is mainly chemical synthesis, and the product of chemical synthesis is DL-phenyllactic acid. It is difficult to obtain a single chiral phenyllactic acid product, and there is a bottleneck problem of difficult separation. Therefore, it is necessary to study the technology that can industrially and efficiently separate the enantiomers in DL-phenyllactic acid.

[0003] The liquid-liquid extraction method has the advantages of simple equipment, easy scale-up, easy automation and continuity of the production process, and is generally carried out at room temperature and pressure with low energy consumption. The chiral liquid-liquid extraction separation method applies the traditional liquid-liquid extraction technology to the separation of racemates. Unlike traditional liquid-liquid extraction, chiral liquid-liquid extraction achieves the separation of enantiomers by stereoselective coordination of chiral reagents with isomers, so that the isomers are unevenly distributed in the two phases. This method has many advantages such as mild operating conditions, continuous operation, easy industrial production, relatively low production cost and green environmental protection. It has been applied to the separation of racemic compounds in the fields of pharmaceuticals, chemistry, food, etc. However, the key to chiral liquid-liquid extraction is to find a suitable chiral resolution extractant. Currently, there is no broad-spectrum and efficient chiral resolution extractant. Different chiral resolution extractants have great differences in the chiral resolution extraction effects on different racemic compounds. Therefore, it is necessary to find a chiral resolution extractant that is suitable for the chiral resolution of DL-phenyllactic acid, so as to facilitate the industrial and efficient resolution of the enantiomers in DL-phenyllactic acid using chiral liquid-liquid extraction resolution. Summary of the invention

[0004] In view of the above problems and needs existing in the prior art, the object of the present invention is to provide a chiral ionic liquid and a preparation method thereof and use thereof as a chiral separation extractant.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] A chiral ionic liquid is a cis-[C 12 H 19 O 2 mim][Cl] or the trans-[C 12 H 19 O 2 mim][Cl], the specific structural formula is as follows:

[0007] , .

[0008] A method for preparing the chiral ionic liquid comprises the following steps:

[0009] a) subjecting a cis-chiral precursor represented by formula C: (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol or a trans-chiral precursor represented by formula D: (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol to an esterification reaction to obtain a chiral chloroester of the corresponding configuration; wherein the structural formulas of formula C and formula D are as follows:

[0010] , ;

[0011] b) subjecting the chiral chloroester of cis-configuration or trans-configuration obtained in step a) to an imidazole alkylation reaction with 1-methylimidazole to obtain a chiral ionic liquid of corresponding configuration.

[0012] In one embodiment, the cis-chiral precursor represented by formula C and the trans-chiral precursor represented by formula D are both prepared by a hydroboration reaction of (1S)-(-)-β-pinene.

[0013] In one embodiment, the preparation of the cis-chiral precursor shown in formula C comprises the following steps:

[0014] ① In an ice bath, slowly add the tetrahydrofuran borane solution to the tetrahydrofuran solution of (1S)-(-)-β-pinene. After the addition is completed, slowly return the temperature in the reaction system to room temperature, and then stir the reaction at room temperature for 18 to 30 hours;

[0015] ② Again in an ice bath, slowly dropwise add the protic solvent, alkaline solution and hydrogen peroxide solution to the reaction system. After the addition is complete, slowly return the temperature in the reaction system to room temperature, and then stir the reaction at room temperature for another 18 to 30 hours;

[0016] ③ Raise the temperature in the reaction system to 70-90°C and keep it warm for 1-3 hours, then terminate the reaction and proceed with post-treatment.

[0017] In a preferred embodiment, the molar concentrations of the tetrahydrofuran borane solution and the tetrahydrofuran solution of (1S)-(-)-β-pinene are both 1 mol / L.

[0018] In a preferred embodiment, the protic solvent is ethanol, the alkaline solution is a 2-4 mol / L sodium hydroxide aqueous solution, and the hydrogen peroxide solution is a hydrogen peroxide aqueous solution with a mass percentage concentration of 30%.

[0019] In one embodiment, the preparation of the trans-chiral precursor represented by formula D comprises the following steps:

[0020] S1) in an ice bath, slowly adding dimethyl sulfate to a tetrahydrofuran solution containing (1S)-(-)-β-pinene and sodium borohydride, after the addition, slowly returning the temperature in the reaction system to room temperature, and then stirring the reaction at room temperature for 18 to 30 hours;

[0021] S2) removing tetrahydrofuran from the reaction system under reduced pressure, and then adding a xylene isomer mixture to the reaction system. After the addition is completed, the temperature in the reaction system is raised to reflux and the reflux reaction is carried out for 18 to 24 hours;

[0022] S3) cooling the temperature in the reaction system to room temperature, removing xylene and re-adding tetrahydrofuran, and then slowly dropping the protonic solvent, alkaline solution and hydrogen peroxide solution into the reaction system again under an ice bath, and after the addition, slowly returning the temperature in the reaction system to room temperature, and then stirring the reaction at room temperature for another 12 to 20 hours;

[0023] S4) End the reaction and perform post-treatment.

[0024] In a preferred embodiment, the molar ratio of dimethyl sulfate to sodium borohydride is 1:1, and the molar ratio of sodium borohydride to (1S)-(-)-β-pinene is 1:(1.5-2.0).

[0025] In a preferred embodiment, the protic solvent is water, the alkaline solution is a 2-4 mol / L sodium hydroxide aqueous solution, and the hydrogen peroxide solution is a hydrogen peroxide aqueous solution with a mass percentage concentration of 30%.

[0026] In one embodiment, the esterification reaction in step a) comprises the following operations:

[0027] a1) dissolving the cis-chiral precursor represented by formula C: (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol or the trans-chiral precursor represented by formula D: (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol in tetrahydrofuran, and then slowly adding chloroacetyl chloride dropwise thereto in an ice bath;

[0028] a2) After the addition is completed, the temperature in the reaction system is slowly restored to room temperature, and then the reaction is stirred at room temperature for 8 to 16 hours;

[0029] a3) The reaction is terminated and post-processed to obtain a chiral chloroester of the corresponding configuration.

[0030] In a preferred embodiment, the molar ratio of chloroacetyl chloride to the chiral precursor is 1:(1.0-1.1).

[0031] In one embodiment, the post-treatment comprises extraction with ethyl acetate, washing with saturated brine, eluting with column chromatography and removing the solvent.

[0032] In a preferred embodiment, the elution solvent for column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:2.

[0033] In one embodiment, the imidazole alkylation reaction in step b) comprises the following operations:

[0034] b1) dissolving the chiral chloroester of cis or trans configuration in anhydrous ethanol, then adding 1-methylimidazole and reacting at 70-75°C for 4-6 days;

[0035] b2) The reaction is terminated, and the ethanol is removed by concentration, and the mixture is washed with cyclohexane and dried to obtain a chiral ionic liquid of corresponding configuration.

[0036] In a preferred embodiment, the molar ratio of the chiral chloroester to 1-methylimidazole is 1:(1.1-1.3).

[0037] One application of the chiral ionic liquid of the present invention is to use the chiral ionic liquid as a chiral separation extractant for chiral liquid-liquid extraction and separation of enantiomers.

[0038] In one embodiment, the chiral ionic liquid of the present invention is used as a chiral separation extractant for multi-stage chiral liquid-liquid extraction separation of DL-phenyllactic acid to obtain L-phenyllactic acid.

[0039] In one embodiment, the multi-stage chiral liquid-liquid extraction and separation operation comprises the following steps:

[0040] A) making the chiral ionic liquid cis-[C 12 H19 O 2 mim][Cl] or trans-[C 12 H 19 O 2 mim][Cl] is dissolved in an organic solvent to obtain an organic phase for later use; DL-phenyllactic acid is dissolved in water to obtain an aqueous phase for later use;

[0041] B) mixing equal volumes of the aqueous phase prepared in step A) and the organic phase, shaking, standing, and layering to obtain a primary extract;

[0042] C) the aqueous phase in the primary extract is mixed with an equal volume of the organic phase prepared in step A), shaken, allowed to stand, and separated into layers to obtain a secondary extract; the aqueous phase in the secondary extract is mixed with an equal volume of the organic phase prepared in step A), shaken, allowed to stand, and separated into layers to obtain a tertiary extract; this cycle is repeated N times to obtain an N-stage extract, the aqueous phase in the N-stage extract is collected and heated to evaporate water, and L-phenyllactic acid solid is obtained.

[0043] In a preferred embodiment, the organic solvent in step A) is selected from any one of n-octanol, n-heptanol, n-hexanol and dichloromethane, with n-octanol being the best.

[0044] In a preferred embodiment, in the organic phase of step A), the concentration of the chiral ionic liquid is 0.02 to 0.25 mol / L, with 0.05 to 0.15 mol / L being the best.

[0045] In a preferred embodiment, in the aqueous phase of step A), the concentration of DL-phenyllactic acid is 0.02 to 0.25 mol / L, with 0.10 to 0.20 mol / L being the best.

[0046] In a preferred embodiment, the pH of the aqueous phase in step A) is 4.0 to 6.8, with pH 6.8 being optimal.

[0047] In a preferred embodiment, each oscillation is carried out in a constant temperature oscillator at 10-50°C (10-30°C is optimal).

[0048] In a preferred embodiment, the mixture is shaken for 2 to 4 hours and allowed to stand for 2 to 4 hours each time.

[0049] In a preferred embodiment, N is a natural number between 3 and 10, and N is best between 5 and 8.

[0050] Compared with the prior art, the present invention has the following significant beneficial effects:

[0051] Experiments have shown that the chiral ionic liquid provided by the present invention can be used as a chiral separation extractant. When it is used for the multi-stage chiral liquid-liquid extraction method to separate DL-phenyllactic acid, it has many advantages such as high separation factor, high enantiomeric purity, low cost, simple operation, mild conditions, support for continuous operation, and green environmental protection. It has important application value for realizing the industrial preparation of chiral L-phenyllactic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The NMR spectrum of (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol prepared in Example 1;

[0053] Figure 2 The NMR spectrum of (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol prepared in Example 2;

[0054] Figure 3 The chiral ionic liquid cis-[C 12 H 19 O 2 mim][Cl]NMR spectrum;

[0055] Figure 4 The chiral ionic liquid cis-[C 12 H 19 O 2 Thermogravimetric analysis of mim][Cl];

[0056] Figure 5 The chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl]NMR spectrum;

[0057] Figure 6 The chiral ionic liquid trans-[C 12 H 19 O 2 Thermogravimetric analysis of mim][Cl];

[0058] Figure 7 is the HPLC spectrum of the racemic phenyllactic acid standard in Example 5;

[0059] Figure 8 is the phenyllactic acid standard curve diagram described in Example 5;

[0060] Fig. 9 It reflects the effect of different concentrations of chiral ionic liquid on the partition coefficient in Example 7;

[0061] Fig.10It reflects the effect of different concentrations of chiral ionic liquid on the separation factor in Example 7;

[0062] Fig.11 It reflects the effect of different concentrations of racemic phenyllactic acid on the partition coefficient in Example 8;

[0063] Fig.12 It reflects the effect of different concentrations of racemic phenyllactic acid on the separation factor in Example 8;

[0064] Fig.13 It reflects the effect of different pH values ​​on the partition coefficient in Example 9;

[0065] Fig.14 It reflects the effect of different pH values ​​on the separation factor in Example 9;

[0066] Fig.15 It reflects the effect of different oscillation temperatures on the partition coefficient in Example 10;

[0067] Fig.16 It reflects the effect of different oscillation temperatures on the separation factor in Example 10;

[0068] Fig.17 This is the HPLC spectrum of the primary extraction product in Example 11;

[0069] Fig.18 This is the HPLC spectrum of the secondary extraction product in Example 11;

[0070] Fig.19 This is the HPLC spectrum of the tertiary extraction product in Example 11;

[0071] Fig. 20 This is the HPLC spectrum of the four-stage extraction product in Example 11;

[0072] Fig.21 This is the HPLC spectrum of the five-stage extraction product in Example 11. DETAILED DESCRIPTION

[0073] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0074] Example 1: Preparation of (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol

[0075] In an ice bath, add 2.72 g (0.02 mol) of (1S)-(-)-β-pinene to 20 mL of tetrahydrofuran, and then slowly add 15 mL of 1 M tetrahydrofuran borane solution thereto. After the addition is complete, slowly return the temperature in the reaction system to room temperature, and then stir the reaction at room temperature for 24 hours.

[0076] Again in an ice bath, 20 mL of ethanol, 10 mL of a 3 M NaOH aqueous solution, and 15 mL of a 30% by mass hydrogen peroxide aqueous solution were sequentially added dropwise to the reaction system. After the addition was completed, the temperature in the reaction system was slowly restored to room temperature, and then the reaction was stirred at room temperature for another 24 hours.

[0077] The temperature in the reaction system was raised to 80°C and placed at 80°C for 2 hours, then the reaction was terminated, the aqueous layer was extracted with 30 mL of ethyl acetate, washed with saturated brine, eluted by column chromatography (petroleum ether / ethyl acetate = 10 / 2, volume ratio), and the product (1S, 2R, 5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol was obtained after evaporating the solvent.

[0078] The prepared product was sampled and analyzed by NMR. Figure 1 As shown: 1 H NMR (400 MHz, DMSO) δ 4.37 (t, 1H), 3.37-3.24 (m, 2H), 2.37-2.03 (m, 2H), 2.02-1.31 (m, 7H), 1.15 (s, 3H), 0.93 (s, 3H), by Figure 1 It can be proved that (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol has been successfully prepared in this example.

[0079] Example 2: Preparation of (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol

[0080] In an ice bath, first add 18.2 g (0.134 mol) (1S)-(-)-β-pinene and 3.15 g (0.083 mol) sodium borohydride to 60 mL tetrahydrofuran, and then slowly add 10.41 g (0.083 mol) dimethyl sulfate. After the addition is complete, the temperature in the reaction system is slowly restored to room temperature, and then stirred at room temperature for 24 hours.

[0081] The tetrahydrofuran in the reaction system was removed under reduced pressure, and then 30 mL of the xylene isomer mixture was added to the reaction system. After the addition was completed, the temperature in the reaction system was raised to reflux (140° C.) and refluxed for 20 hours;

[0082] The temperature in the reaction system was cooled to room temperature, and 30 mL of tetrahydrofuran was added again after removing xylene. Then, 20 mL of water, 20 mL of 3M NaOH aqueous solution, and 15 mL of 30% by mass hydrogen peroxide aqueous solution were added dropwise to the reaction system again under an ice bath. After the addition was completed, the temperature in the reaction system was slowly restored to room temperature, and then the reaction was stirred at room temperature for another 16 hours;

[0083] The reaction was terminated, and the product was extracted with 40 mL of ethyl acetate, washed with saturated brine, and eluted by column chromatography (petroleum ether / ethyl acetate = 10 / 2, volume ratio). The solvent was evaporated to obtain the product (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol.

[0084] The prepared product was sampled and analyzed by NMR. Figure 2 As shown: 1 H NMR (400 MHz, DMSO)δ 4.35 (t, 1H), 3.15 (qd, 2H), 2.08-1.92 (m, 2H), 1.91-1.22 (m, 7H), 1.18 (s,3H), 0.81 (s, 3H), from Figure 2 It can be proved that (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol has been successfully prepared in this example.

[0085] Example 3: Preparation of chiral ionic liquid cis-[C 12 H 19 O 2 mim][Cl]

[0086] 3.08 g (0.02 mol) of (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol prepared in Example 1 was dissolved in 40 mL of tetrahydrofuran, and then 2.15 g (0.019 mol) of chloroacetyl chloride was slowly added dropwise thereto in an ice bath;

[0087] After the addition, the temperature in the reaction system was slowly restored to room temperature, and then the reaction was stirred at room temperature for 12 hours to terminate the reaction, and then extracted with ethyl acetate, washed with saturated brine, eluted by column chromatography (petroleum ether / ethyl acetate = 10 / 2, volume ratio), and dried to obtain 4.23 g (0.0184 mol) of cis-configuration chiral chloroester;

[0088] The obtained 4.23 g (0.0184 mol) of the cis-configuration chiral chloroester was dissolved in anhydrous ethanol, and then 1.81 g (0.022 mol) of 1-methylimidazole was added and reacted at 70-75°C for 5 days; the reaction was terminated, the ethanol was removed by concentration, and the mixture was washed with cyclohexane and dried to obtain the cis-configuration chiral ionic liquid cis-[C 12 H 19 O 2 mim][Cl].

[0089] The prepared chiral ionic liquid was subjected to nuclear magnetic resonance analysis, and the results were as follows: Figure 3 As shown: 1 H NMR (400 MHz, DMSO)δ 9.20 (d, 1H), 7.75 (d, 2H), 5.28(s, 2H), 4.20 (q, 2H), 3.91(s, 3H), 3.31(q, 2H), 2.41-1.21 (m, 7H), 1.14 (s, 3H), 0.92 (s, 3H), given by Figure 3 It can be proved that this embodiment has successfully prepared cis-[C 12 H 19 O 2 mim][Cl].

[0090] The chiral ionic liquid cis-[C 12 H 19 O 2 mim][Cl] was subjected to thermogravimetric analysis. Figure 4 As shown by Figure 4 Visible: Chiral ionic liquid cis-[C 12 H 19 O 2 The decomposition temperature of mim][Cl] is 393.15K, and it has good thermal stability.

[0091] Example 4: Preparation of chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl]

[0092] 3.08 g (0.02 mol) of (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol prepared in Example 2 was dissolved in 40 mL of tetrahydrofuran, and then 2.15 g (0.019 mol) of chloroacetyl chloride was slowly added dropwise thereto in an ice bath;

[0093] After the addition, the temperature in the reaction system was slowly restored to room temperature, and then the reaction was stirred at room temperature for 12 hours to terminate the reaction, and then extracted with ethyl acetate, washed with saturated brine, eluted by column chromatography (petroleum ether / ethyl acetate = 10 / 2, volume ratio), and dried to obtain 4.23 g (0.0184 mol) of trans-configuration chiral chloroester;

[0094] The obtained 4.23 g (0.0184 mol) of the trans-configuration chiral chloroester was dissolved in anhydrous ethanol, and then 1.81 g (0.022 mol) of 1-methylimidazole was added and reacted at 70-75°C for 5 days; the reaction was terminated, the ethanol was removed by concentration, and the solution was washed with cyclohexane and dried to obtain the trans-configuration chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl].

[0095] The prepared chiral ionic liquid was subjected to nuclear magnetic resonance analysis, and the results were as follows: Figure 5 As shown: 1 H NMR (400 MHz, DMSO)δ 9.18 (d, 1H), 7.70 (d,2H), 5.16(s, 2H), 4.02 (q, 2H), 3.76(s, 3H), 3.40-3.12 (m, 2H), 2.19-1.26 (m, 7H), 1.22 (s, 3H), 0.83 (s, 3H), given by Figure 5 It can be proved that this embodiment has successfully produced trans-[C 12 H 19 O 2 mim][Cl].

[0096] The chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl] was subjected to thermogravimetric analysis. Figure 6 As shown by Figure 6 Visible: Chiral ionic liquid trans-[C 12 H 19 O 2 The decomposition temperature of mim][Cl] is 395.24K, and it has good thermal stability.

[0097] Example 5: Separation of racemic phenyllactic acid using the chiral ionic liquid prepared in Example 3

[0098] A) Make the chiral ionic liquid cis-[C 12 H 19 O 2mim][Cl] was dissolved in n-octanol to prepare cis-[C 12 H 19 O 2 mim][Cl] n-octanol solution as the organic phase;

[0099] B) dissolving a DL-phenyllactic acid standard in water to prepare a racemic phenyllactic acid aqueous solution having a concentration of 0.20 mol / L and a pH of 6.8 as the aqueous phase;

[0100] C) The organic phase prepared in step A) and the aqueous phase prepared in step B) were mixed in equal volumes (2 mL each), and then placed in a constant temperature oscillator at 25°C for 3 hours, allowed to stand for 3 hours, and separated into layers. 1 mL of the separated aqueous phase was then taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by HPLC. The detection conditions of HPLC were:

[0101] Daicel AD-H chiral column, using n-hexane / isopropanol / trifluoroacetic acid = 90 / 10 / 0.001 (volume ratio) as the mobile phase, elution rate of 0.5 mL / min, elution time of 30 min, column temperature of 298.15 K, detector wavelength of 261 nm;

[0102] Figure 7 is the HPLC detection spectrum of DL-phenyllactic acid standard, Figure 7 As shown, the retention time of D-phenyllactic acid is 17.38 min, and the retention time of L-phenyllactic acid is 21.62 min;

[0103] Then, the mobile phase solution was used to prepare phenyllactic acid standard solutions with concentrations of 100 ppm, 150 ppm, 200 ppm, 250 ppm, 300 ppm, 500 ppm and 700 ppm, respectively, and the solutions were analyzed by the above HPLC method, and the peak area S was plotted into a standard curve. The obtained standard curve is as follows: Figure 8 As shown, the equation of the fitted straight line is: y=0.0148x+0.3324, R 2 =0.9969;

[0104] According to the concentration of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase determined by HPLC, the concentration of D-phenyllactic acid and L-phenyllactic acid in the organic phase can be obtained by subtraction, and thus the respective distribution coefficients K of D-phenyllactic acid and L-phenyllactic acid in the extract can be calculated. D (K D =[D] 有机相 / [D] 水相 , [D] 有机相 is the concentration of D-phenyllactic acid in the organic phase, [D] 水相 represents the concentration of D-phenyllactic acid in the aqueous phase) and KL (K L =[L] 有机相 / [L] 水相 , [L] 有机相 is the concentration of L-phenyllactic acid in the organic phase, [L] 水相 is the concentration of L-phenyllactic acid in the aqueous phase) and the separation factor α (i.e.: α=K D / K L ), the specific settlement results are shown in Table 1.

[0105] In addition, referring to the above operation, the n-octanol in step A) was replaced by n-heptanol, n-hexanol, and dichloromethane, respectively, to investigate the effect of preparing organic phases with different organic solvents on the separation and extraction effect.

[0106] Example 6: Separation of racemic phenyllactic acid using the chiral ionic liquid prepared in Example 4

[0107] The difference between this embodiment and embodiment 5 is that the chiral ionic liquid in step A) is replaced by cis-[C 12 H 19 O 2 mim][Cl] is replaced by trans-[C 12 H 19 O 2 mim][Cl], and the rest of the contents are the same as described in Example 5.

[0108] Table 1 Distribution coefficients and separation factors calculated for Examples 5 and 6

[0109]

[0110] The results shown in Table 1 show that under the same conditions, the chiral ionic liquid trans-[C 12 H 19 O 2 The separation and extraction effect of mim][Cl] on racemic phenyllactic acid is better than that of chiral ionic liquid cis-[C 12 H 19 O 2 mim][Cl]; and, the organic solvent used to prepare the organic phase has a certain influence on the splitting and extraction effect. The organic phase prepared with n-octanol can make the splitting and extraction effect relatively better than other solvents.

[0111] Example 7: Investigating the effect of chiral ionic liquid concentration on separation and extraction effect

[0112] A) Make chiral ionic liquid trans-[C 12 H 19 O 2mim][Cl] was dissolved in n-octanol and prepared into trans-[C 12 H 19 O 2 mim][Cl] n-octanol solution, respectively, as the organic phase;

[0113] B) dissolving a DL-phenyllactic acid standard in water to prepare a racemic phenyllactic acid aqueous solution having a concentration of 0.20 mol / L and a pH of 6.8 as the aqueous phase;

[0114] C) The organic phases of various concentrations prepared in step A) (2 mL each) were mixed with 2 mL of the aqueous phase prepared in step B) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated into layers. 1 mL of the separated aqueous phase was then taken out for drying, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the separated aqueous phases were determined by the HPLC determination method described in Example 5, and the respective distribution coefficients K of D-phenyllactic acid and L-phenyllactic acid in the extract were calculated by the calculation method described in Example 5. D , K L and separation factor α.

[0115] Fig. 9 It reflects the influence of different concentrations of chiral ionic liquids on the distribution coefficient. Fig.10 It reflects the influence of different concentrations of chiral ionic liquids on the separation factor. Fig. 9 and Fig.10 It can be seen that when the chiral ionic liquid trans-[C 12 H 19 O 2 When the concentration of mim][Cl] is in the range of 0.05-0.15 mol / L, good separation and extraction effects can be obtained; in particular, when the chiral ionic liquid trans-[C 12 H 19 O 2 When the concentration of mim][Cl] is 0.10 mol / L, the distribution coefficient K D =2.07, K L =1.42, separation factor α=1.46, and the splitting extraction effect is relatively better.

[0116] Example 8: Investigating the effect of the concentration of racemic phenyllactic acid in the aqueous phase on the separation and extraction effect

[0117] A) Make chiral ionic liquid trans-[C 12 H 19 O 2mim][Cl] was dissolved in n-octanol to prepare a 0.10 mol / L trans-[C 12 H 19 O 2 mim][Cl] n-octanol solution as the organic phase;

[0118] B) dissolving DL-phenyllactic acid standard in water to prepare racemic phenyllactic acid aqueous solutions with concentrations of 0.02 mol / L, 0.05 mol / L, 0.10 mol / L, 0.15 mol / L, 0.20 mol / L, and 0.25 mol / L, and with a pH value of 6.8, as the aqueous phase;

[0119] C) 2 mL of the aqueous phase of different concentrations prepared in step B) were mixed with 2 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated into layers. 1 mL of the separated aqueous phase was then taken out for drying, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the separated aqueous phase were determined by the HPLC determination method described in Example 5, and the distribution coefficients K of D-phenyllactic acid and L-phenyllactic acid in the extract were calculated by the calculation method described in Example 5. D , K L and separation factor α.

[0120] Fig.11 It reflects the effect of different concentrations of racemic phenyllactic acid on the distribution coefficient. Fig.12 The effect of different concentrations of racemic phenyllactic acid on the separation factor is shown. Fig.11 and Fig.12 It can be seen that when the concentration of racemic phenyllactic acid is in the range of 0.10-0.20 mol / L, a good separation and extraction effect can be obtained; in particular, when the concentration of racemic phenyllactic acid is 0.15 mol / L, the distribution coefficient K D =2.21, K L =1.43, separation factor α=1.55, the splitting extraction effect is relatively better.

[0121] Example 9: Investigating the effect of pH value of aqueous phase on splitting and extraction effect

[0122] A) Make chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl] was dissolved in n-octanol to prepare a 0.10 mol / L trans-[C 12 H 19 O 2 mim][Cl] n-octanol solution as the organic phase;

[0123] B) dissolving DL-phenyllactic acid standard in water to prepare a concentration of 0.20 mol / L, and adjusting the pH values ​​of racemic phenyllactic acid aqueous solutions to 4.0, 4.5, 5.0, 5.5, 6.0, and 6.8 with hydrochloric acid solution as the aqueous phase;

[0124] C) 2 mL of the aqueous phases with different pH values ​​prepared in step B) were mixed with 2 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated into layers. 1 mL of the separated aqueous phases were taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the separated aqueous phases were determined by the HPLC determination method described in Example 5, and the distribution coefficients K of D-phenyllactic acid and L-phenyllactic acid in the extract were calculated by the calculation method described in Example 5. D , K L and separation factor α.

[0125] Fig.13 It reflects the influence of different pH values ​​on the relative partition coefficient of water. Fig.14 It reflects the influence of water with different pH values ​​on the separation factor. Fig.13 and Fig.14 It can be seen that the distribution coefficient and separation factor increase with the increase of the pH value of the aqueous phase. When the pH value is 6.8, the distribution coefficient K D =2.11, K L =1.45, separation factor α=1.46, the splitting extraction effect is relatively better.

[0126] Example 10: Investigating the effect of different oscillation temperatures on the splitting and extraction effect

[0127] A) Make chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl] was dissolved in n-octanol to prepare a 0.10 mol / L trans-[C 12 H 19 O 2 mim][Cl] n-octanol solution as the organic phase;

[0128] B) dissolving a DL-phenyllactic acid standard in water to prepare a racemic phenyllactic acid aqueous solution with a concentration of 0.20 mol / L and a pH value of 6.8 as the aqueous phase;

[0129] C) In parallel, 5 portions of the aqueous phase prepared in step B) (each 2 mL) were mixed with 5 portions of the organic phase prepared in step A) (each 2 mL) in equal volumes, and then the 5 mixed solutions prepared in parallel were placed in a constant temperature oscillator at 10°C, 20°C, 30°C, 40°C, and 50°C for oscillation for 3 hours, allowed to stand for 3 hours, and layered. Then, 1 mL of the layered aqueous phase was taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the layered aqueous phase were determined by the HPLC determination method described in Example 5, and the respective distribution coefficients K of D-phenyllactic acid and L-phenyllactic acid in the extract were calculated by the calculation method described in Example 5. D , K L and separation factor α.

[0130] Fig.15 It reflects the influence of different oscillation temperatures on the distribution coefficient. Fig.16 It reflects the influence of different oscillation temperatures on the separation factor. Fig.15 and Fig.16 It can be seen that the distribution coefficient increases with the increase of temperature, and the separation factor decreases with the increase of temperature. When the oscillation temperature is in the range of 10-30℃, a good separation and extraction effect can be obtained. In particular, when the oscillation temperature is 10℃, the distribution coefficient K D =1.29, K L =0.82, separation factor α=1.57, and the splitting extraction effect is relatively better.

[0131] Example 11: Separation of DL-phenyllactic acid to obtain L-phenyllactic acid using multi-stage chiral liquid-liquid extraction

[0132] A) Make chiral ionic liquid trans-[C 12 H 19 O 2 mim][Cl] was dissolved in n-octanol to prepare a 0.10 mol / L trans-[C 12 H 19 O 2 mim][Cl] n-octanol solution as the organic phase;

[0133] B) dissolving a DL-phenyllactic acid standard in water to prepare a racemic phenyllactic acid aqueous solution with a concentration of 0.20 mol / L and a pH value of 6.8 as the aqueous phase;

[0134] C) 10 mL of the aqueous phase prepared in step B) and 10 mL of the organic phase prepared in step A) were mixed in equal volumes, then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated to obtain a primary extract. 1 mL of the aqueous phase of the primary extract was taken and dried. The concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by the HPLC determination method described in Example 5. The HPLC determination spectrum is shown in FIG. Fig.17As shown: the peak area of ​​D-phenyllactic acid is 1.21, the peak area of ​​L-phenyllactic acid is 1.66, and the enantiomeric excess is 15.68%;

[0135] D) The remaining 9 mL of the aqueous phase of the primary extract was mixed with 9 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated to obtain a secondary extract. 1 mL of the aqueous phase of the secondary extract was taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by the HPLC determination method described in Example 5. The HPLC determination spectrum is shown in FIG. Fig.18 As shown: the peak area of ​​D-phenyllactic acid is 0.66, the peak area of ​​L-phenyllactic acid is 1.53, and the enantiomeric excess percentage is 39.73%;

[0136] E) The remaining 8 mL of the aqueous phase of the secondary extract was mixed with 8 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated to obtain a tertiary extract. 1 mL of the aqueous phase of the tertiary extract was taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by the HPLC determination method described in Example 5. The HPLC determination spectrum is shown in FIG. Fig.19 As shown: the peak area of ​​D-phenyllactic acid is 0.39, the peak area of ​​L-phenyllactic acid is 1.66, and the enantiomeric excess percentage is 61.95%;

[0137] F) The remaining 7 mL of the aqueous phase of the tertiary extract was mixed with 7 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated to obtain a quaternary extract. 1 mL of the aqueous phase of the quaternary extract was taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by the HPLC determination method described in Example 5. The HPLC determination spectrum is shown in FIG. Fig. 20 As shown: the peak area of ​​D-phenyllactic acid is 0.25, the peak area of ​​L-phenyllactic acid is 2.12, and the enantiomeric excess percentage is 78.90%;

[0138] G) The remaining 6 mL of the aqueous phase of the fourth-stage extract was mixed with 6 mL of the organic phase prepared in step A) in equal volumes, and then placed in a constant temperature oscillator at 25° C. for 3 h, allowed to stand for 3 h, and separated to obtain a fifth-stage extract. 1 mL of the aqueous phase of the fifth-stage extract was taken and dried, and the concentrations of D-phenyllactic acid and L-phenyllactic acid in the aqueous phase were determined by the HPLC determination method described in Example 5. The HPLC determination spectrum is shown in FIG. Fig.21 As shown: the peak area of ​​D-phenyllactic acid is 0.02, the peak area of ​​L-phenyllactic acid is 0.81, and the enantiomeric excess percentage is 95.18%.

[0139] It can be seen from the experimental results of this embodiment that the chiral ionic liquid provided by the present invention can be used as a chiral separation extractant to enable DL-phenyllactic acid to be separated by a multi-stage chiral liquid-liquid extraction method to obtain L-phenyllactic acid, which has many advantages such as high separation factor, high enantiomeric purity, low cost, simple operation, mild conditions, support for continuous operation, and green environmental protection, and has important application value for realizing the industrial preparation of chiral L-phenyllactic acid.

[0140] Finally, it should be pointed out that the above are only some preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above contents of the present invention all fall within the scope of protection of the present invention.

Claims

1. A chiral ionic liquid, characterized in that: The cis-[C 12 H 19 O2mim][Cl] or the trans-[C 12 H 19 O2mim][Cl], the specific structural formula is as follows: 、 。 2. A method for preparing the chiral ionic liquid according to claim 1, characterized in that: The steps include: a) subjecting a cis-chiral precursor represented by formula C: (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol or a trans-chiral precursor represented by formula D: (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol to an esterification reaction to obtain a chiral chloroester of the corresponding configuration; wherein the structural formulas of formula C and formula D are as follows: 、 ； b) subjecting the chiral chloroester of cis-configuration or trans-configuration obtained in step a) to an imidazole alkylation reaction with 1-methylimidazole to obtain a chiral ionic liquid of corresponding configuration.

3. The preparation method according to claim 2, characterized in that: The cis-chiral precursor shown in formula C and the trans-chiral precursor shown in formula D are both prepared from (1S)-(-)-β-pinene through a hydroboration oxidation reaction.

4. The preparation method according to claim 3, characterized in that: The preparation of the cis-chiral precursor shown in formula C comprises the following steps: ① In an ice bath, slowly add the tetrahydrofuran borane solution to the tetrahydrofuran solution of (1S)-(-)-β-pinene. After the addition is completed, slowly return the temperature in the reaction system to room temperature, and then stir the reaction at room temperature for 18 to 30 hours; ② Again in an ice bath, slowly dropwise add the protic solvent, alkaline solution and hydrogen peroxide solution to the reaction system. After the addition is complete, slowly return the temperature in the reaction system to room temperature, and then stir the reaction at room temperature for another 18 to 30 hours; ③ Raise the temperature in the reaction system to 70-90°C and keep it warm for 1-3 hours, then terminate the reaction and proceed with post-treatment.

5. The preparation method according to claim 3, characterized in that: The preparation of the trans-chiral precursor shown in formula D comprises the following steps: S1) in an ice bath, slowly adding dimethyl sulfate to a tetrahydrofuran solution containing (1S)-(-)-β-pinene and sodium borohydride, after the addition, slowly returning the temperature in the reaction system to room temperature, and then stirring the reaction at room temperature for 18 to 30 hours; S2) removing tetrahydrofuran from the reaction system under reduced pressure, and then adding a xylene isomer mixture to the reaction system. After the addition is completed, the temperature in the reaction system is raised to reflux and the reflux reaction is carried out for 18 to 24 hours; S3) cooling the temperature in the reaction system to room temperature, removing xylene and re-adding tetrahydrofuran, and then slowly dropping the protonic solvent, alkaline solution and hydrogen peroxide solution into the reaction system again under an ice bath, and after the addition, slowly returning the temperature in the reaction system to room temperature, and then stirring the reaction at room temperature for another 12 to 20 hours; S4) End the reaction and perform post-treatment.

6. The preparation method according to claim 2, characterized in that: The esterification reaction described in step a) comprises the following operations: a1) dissolving the cis-chiral precursor represented by formula C: (1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol or the trans-chiral precursor represented by formula D: (1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptane-2-methanol in tetrahydrofuran, and then slowly adding chloroacetyl chloride dropwise thereto in an ice bath; a2) After the addition is completed, the temperature in the reaction system is slowly restored to room temperature, and then the reaction is stirred at room temperature for 8 to 16 hours; a3) The reaction is terminated and post-processed to obtain a chiral chloroester of the corresponding configuration.

7. The preparation method according to claim 2, characterized in that: The imidazole alkylation reaction in step b) comprises the following steps: b1) dissolving the chiral chloroester of cis or trans configuration in anhydrous ethanol, then adding 1-methylimidazole and reacting at 70-75°C for 4-6 days; b2) The reaction is terminated, and the ethanol is removed by concentration, and the mixture is washed with cyclohexane and dried to obtain a chiral ionic liquid of corresponding configuration.

8. An application of the chiral ionic liquid according to claim 1, characterized in that: The chiral ionic liquid is used as a chiral separation extractant for chiral liquid-liquid extraction separation of enantiomers.

9. The use according to claim 8, characterized in that: The chiral ionic liquid is used as a chiral separation extractant for multi-stage chiral liquid-liquid extraction and separation of DL-phenyllactic acid to obtain L-phenyllactic acid.

10. The use according to claim 9, characterized in that: The operation of the multi-stage chiral liquid-liquid extraction and separation comprises the following steps: A) making the chiral ionic liquid cis-[C 12 H 19 O2mim][Cl] or trans-[C 12 H 19 O2mim][Cl] is dissolved in an organic solvent to obtain an organic phase for later use; DL-phenyllactic acid is dissolved in water to obtain an aqueous phase for later use; B) mixing equal volumes of the aqueous phase prepared in step A) and the organic phase, shaking, standing, and layering to obtain a primary extract; C) the aqueous phase in the primary extract is mixed with an equal volume of the organic phase prepared in step A), shaken, allowed to stand, and separated into layers to obtain a secondary extract; the aqueous phase in the secondary extract is mixed with an equal volume of the organic phase prepared in step A), shaken, allowed to stand, and separated into layers to obtain a tertiary extract; this cycle is repeated N times to obtain an N-stage extract, the aqueous phase in the N-stage extract is collected and heated to evaporate water, and L-phenyllactic acid solid is obtained.

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