Method for resolution of D, L-menthol enantiomer

Abstract

The invention discloses a method for resolution of D, L-menthol enantiomers, which comprises the following steps: (1) adding a D, L-menthol solution into a working unit filled with a chiral resolving agent, and enabling the chiral resolving agent and D, L-menthol to be fully subjected to adsorption reaction; (2) separating reactants obtained in the step (1): collecting feed liquid containing D-menthol; (3) adding an eluent into the working unit, and enabling the chiral resolving agent and the L-menthol to be fully subjected to desorption reaction; and (4) separating a reactant obtained in the step (3), and collecting a feed liquid containing the L-menthol. The method is simple to operate, reaction steps such as esterification and hydrolysis are not needed, and enantiomer resolution of D, L-menthol can be realized at normal temperature and normal pressure.

Description

Technical Field

[0001] This invention relates to the field of chemical separation, specifically a method for the enantiomeric separation of D,L-menthol. Background Technology

[0002] Menthol is a monoterpene compound with the molecular formula C64. 10 H 20 O, scientifically known as 2-isopropyl-5-methylcyclohexanol, has three chiral carbon atoms and eight stereoisomers. The main configuration of menthol in natural products such as peppermint is L-menthol, namely (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexanol. This configuration has a strong natural peppermint aroma and can provide a strong cooling sensation to the human body. Its enantiomer, D-menthol, only provides a weak cooling sensation. This difference stems from the differential activation of the TRPM8 channel by the menthol stereoisomers in the human body (Xiaoying C, Lizhen X, Heng Z, et al. Differential Activation of TRPM8 by the Stereoisomers of Menthol[J]. Frontiers in Pharmacology, 2022, 13: 898670.).

[0003] Currently, the artificial synthesis of L-menthol mainly relies on asymmetric catalytic synthesis. As early as the 1970s, Takasago Chemical Co., Ltd. of Japan achieved the industrial synthesis of L-menthol using an asymmetric catalytic method. The company used myrcene as a raw material, telomerizing it with diethylamine under the catalysis of n-butyllithium to N,N-diethylgeraniol, which was then isomerized using a chiral organometallic rhodium BINAP catalyst to obtain a single chiral (+)-citronellol enamine. Following multiple steps of hydrolysis, cyclization, and hydrogenation, L-menthol was obtained. Currently, most major industrial asymmetric catalytic synthesis methods for L-menthol require expensive rhodium catalysts, involve cumbersome reaction steps, and face the problem of difficult catalyst recovery. There is a need to develop more economical and environmentally friendly industrial production methods for L-menthol.

[0004] Enantiomer resolution is a method that starts with the racemic form of a chiral compound, creates a chiral environment using a chiral resolving agent, and identifies enantiomers to achieve separation. This method does not require expensive and difficult-to-recover precious metal catalysts, and there are already industrial applications. The thymol route used by Symrise in Germany employs a conventional chemical synthesis coupled with recrystallization: thymol is hydrogenated in the presence of a nickel or cobalt-based catalyst to generate a mixture of four diastereomers (menthol, isomenthol, neomenthol, and neoisomenthol). D,L-menthol is separated by distillation, and then L-menthol is obtained by transesterification with methyl benzoate followed by a coupled recrystallization enantiomer separation process. In recent years, the method for producing L-menthol through enantiomer resolution has made some progress. CN 111892483 B and CN 103910607 A disclose two methods for resolving DL-menthol via esterification. Both of these patents require a hydrolysis step when recovering L-menthol products. CN103614450 A discloses a method for resolving D,L-menthol using lipase catalysis. This method suffers from the disadvantages of high cost of biological enzymes and difficulty in industrial application. CN 104531823 B discloses a method for resolving D,L-menthol using ionic liquid as a green medium for enzyme catalysis. However, the ionic liquid used in this method is expensive, and the resolving steps are relatively complicated. Summary of the Invention

[0005] In order to overcome the above-mentioned shortcomings and deficiencies of the prior art, the present invention aims to provide a method for enantiomer separation of D,L-menthol, which is simple to operate, does not require esterification and hydrolysis reaction steps, and can achieve enantiomer separation of D,L-menthol at room temperature and pressure.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] Embodiments of the present invention provide a method for enantiomer separation of D,L-menthol, comprising the following steps:

[0008] (1) Add D,L-menthol solution to the working unit containing chiral resolving agent to allow the chiral resolving agent to fully undergo an adsorption reaction with D,L-menthol;

[0009] (2) Separate the reactants obtained in step (1): Collect the liquid containing D-menthol;

[0010] (3) Add eluent to the working unit to allow the chiral resolving agent to fully desorb from L-menthol;

[0011] (4) Separate the reactants obtained in step (3) and collect the liquid containing L-menthol.

[0012] In some embodiments of the present invention, the chiral resolving agent is a chiral small molecule @Zr-BTC material; the chiral small molecule @Zr-BTC material is synthesized from achiral Zr-BTC and a chiral small molecule with a carboxyl group, wherein the chiral small molecule with a carboxyl group is at least one of L-tartaric acid and L-mandelic acid.

[0013] In some embodiments of the present invention, the chiral resolving agent is prepared by the following method:

[0014] (1) Add a methanol solution of 4-pyridinecarboxaldehyde dropwise to an aqueous solution containing sodium carbonate and L-leucine, stir at room temperature for 1 to 4 hours, add sodium borohydride aqueous solution dropwise under ice-water bath conditions, continue stirring for 0.5 to 2 hours, filter, and adjust the pH of the filtrate to 4 to 7; rotary evaporate to obtain a white solid, dissolve in methanol at 55 to 65°C, filter, and rotary evaporate to obtain a chiral ligand;

[0015] (2) Dissolve the chiral ligand obtained in step (1) in water, adjust the pH to 6-8, then mix it with an organic solvent containing zinc salt and sonicate for 2-60 min, centrifuge to collect the white solid and wash it.

[0016] In some embodiments of the present invention, the chiral resolving agent is prepared by the following method:

[0017] β-Cyclodextrin and γ-isocyanate-propyltriethoxysilane were dissolved in anhydrous pyridine and stirred under reflux at 75-85°C. Then, a phenyl isocyanate derivative was added and stirred at 95-110°C. Then, acidified silica gel was added and stirred at 95-110°C. After the reaction was completed, the mixture was filtered, washed, and dried to obtain a white powdery solid, which is the modified cyclodextrin.

[0018] In some embodiments of the present invention, the solvent of the D,L-menthol solution in step (1) is at least one of ethanol, chloroform and n-hexane; the eluent in step (3) is at least one of methanol, ethanol and acetonitrile.

[0019] In some embodiments of the present invention, the chiral resolving agent used in step (1) is in a mass ratio of (1 to 20):1 with D,L-menthol.

[0020] In some embodiments of the present invention, during the adsorption reaction in step (1), at least one of the following operations is performed: standing, stirring, and shaking; during the desorption reaction in step (3), at least one of the following operations is performed: standing, stirring, and shaking.

[0021] In some embodiments of the present invention, when the operation is stirring or shaking, the frequency condition is 120 to 300 rpm.

[0022] In some embodiments of the present invention, the reaction operation temperature in steps (1) and (3) is (15-35) °C and the reaction time is 60-1440 minutes.

[0023] In some embodiments of the present invention, the ratio of chiral resolving agent to eluent used in step (3) is 1 mg: (0.2 to 1.0) mL.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] (1) The method for the resolution of D,L-menthol enantiomers of the present invention has fewer resolution reaction steps, does not require derivatization, esterification, hydrolysis and other reaction steps, and can achieve the resolution of D,L-menthol enantiomers at room temperature and pressure, with low energy consumption.

[0026] (2) The method of the present invention for the enantiomer separation of D,L-menthol is easy to recover both the chiral resolving agent and the menthol product, and is convenient for large-scale use.

[0027] (3) The chiral resolving agent used in the method of the present invention for the enantiomer resolution of D,L-menthol is inexpensive and easy to recycle. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of the workflow of the method for enantiomer separation of D,L-menthol according to the present invention.

[0029] Figure 2 This is a performance test data graph for Embodiment 1 of the present invention.

[0030] Figure 3 This is a performance test data graph for Embodiment 2 of the present invention.

[0031] Figure 4 This is a performance test data graph for Embodiment 3 of the present invention.

[0032] Figure 5 This is a performance test data graph for Embodiment 4 of the present invention.

[0033] Figure 6 This is a graph showing the performance test data of Comparative Example 1 of the present invention. Detailed Implementation

[0034] The present invention is further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0035] Embodiments of the present invention disclose a method for enantiomer separation of D,L-menthol, such as... Figure 1 As shown, it includes the following steps:

[0036] (1) Add D,L-menthol solution to the working unit containing chiral resolving agent to allow the chiral resolving agent to fully undergo an adsorption reaction with D,L-menthol;

[0037] (2) Separate the reactants obtained in step (1): Collect the liquid containing D-menthol;

[0038] (3) Add eluent to the working unit to allow the chiral resolving agent to fully desorb from L-menthol;

[0039] (4) Separate the reactants obtained in step (3) and collect the liquid containing L-menthol.

[0040] Example 1

[0041] Add 80 mL of a 0.1–0.5 mg / mL D,L-menthol n-hexane solution to a reaction flask containing 0.2 g of the chiral MOF material L-Tar@Zr-BTC disclosed in CN 115678026 A. Allow the mixture to stand at 25°C for 1440 min to adsorb. Then, filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and allow it to stand at 25°C for 1440 min to desorb. Then, filter to separate the feed solution and chiral resolving agent from the reaction flask. Evaporate and crystallize the collected filtrate to recover the single configuration of menthol.

[0042] Example 2

[0043] Add 80 mL of a 0.2–0.5 mg / mL D,L-menthol n-hexane solution to a reaction flask containing 0.2 g of the chiral MOF material disclosed in CN 118480184 A. Allow the mixture to stand at 25 °C for 1440 min to adsorb. Then filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and allow it to stand at 25 °C for 1440 min to desorb. Then filter to separate the feed solution and chiral resolving agent from the reaction flask. Evaporate and crystallize the collected filtrate to recover the single configuration of menthol.

[0044] Example 3

[0045] Add 80 mL of a 0.05–0.5 mg / mL D,L-menthol n-hexane solution to a reaction column containing the chiral functionalized modified cyclodextrin material Sil-MPCD disclosed in CN 117050210 A, and adsorb at 25 °C for 60 min. Then separate the feed solution and chiral resolving agent in the reaction column. Next, add 80 mL of methanol to the column and desorb at 25 °C for 60 min, then separate the feed solution and chiral resolving agent in the reaction column. The collected feed solution can be evaporated and crystallized to recover the single configuration of menthol.

[0046] Example 4

[0047] Add 80 mL of a 0.1–0.5 mg / mL D,L-menthol n-hexane solution to a reaction flask containing 0.2 g of the chiral MOF material L-Man@Zr-BTC disclosed in CN 115678026 A. Stir at 300 rpm for 120 min at 25°C for adsorption reaction. Afterward, filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and stir at 300 rpm for 120 min at 25°C for desorption reaction. Filter to separate the feed solution and chiral resolving agent from the reaction flask. Evaporate and crystallize the collected filtrate to recover the single configuration of menthol.

[0048] Example 5

[0049] Add 80 mL of a 0.05–0.5 mg / mL D,L-menthol n-hexane solution to a reaction flask containing 0.2 g of the chiral MOF material disclosed in CN 118480184 A. Initiate the adsorption reaction by shaking at 120 rpm for 360 min at 25 °C. Afterward, filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and initiate the desorption reaction by shaking at 120 rpm for 360 min at 25 °C. Filter to separate the feed solution and chiral resolving agent from the reaction flask. Evaporate and crystallize the collected filtrate to recover the single configuration of menthol.

[0050] Example 6

[0051] Add 80 mL of a 0.05–0.5 mg / mL D,L-menthol n-hexane solution to a reaction flask containing 0.2 g of the chiral functionalized modified cyclodextrin material Sil-MPCD disclosed in CN 117050210 A. Initiate the adsorption reaction by shaking at 120 rpm for 360 min at 25 °C. Afterward, filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and initiate the desorption reaction by shaking at 120 rpm for 360 min at 25 °C. Filter to separate the feed solution and chiral resolving agent from the reaction flask. The collected filtrate can be evaporated and crystallized to recover the single configuration of menthol.

[0052] Comparative Example 1

[0053] Add 80 mL of D,L-menthol n-hexane solution (0–0.5 mg / mL) to a reaction flask containing 0.2 g of the achiral MOF material Zr-BTC. Allow the mixture to stand at 25 °C for 1440 min to adsorb. Then, filter to separate the feed solution and the chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of methanol and allow it to stand at 25 °C for 1440 min to desorb. Then, filter to separate the feed solution and the chiral resolving agent from the reaction flask. Samples of the feed solutions from each of the above steps are analyzed by gas chromatography.

[0054] Comparative Example 2

[0055] The only difference between this comparative example and Example 4 is the working solvent used; all other conditions are the same.

[0056] Add 80 mL of D,L-menthol methanol solution (0–0.5 mg / mL) to a reaction flask containing 0.2 g of the chiral MOF material disclosed in CN 118480184 A. Stir at 300 rpm for 120 min at 25°C using a magnetic stirrer to carry out the adsorption reaction. Then, filter to separate the feed solution and chiral resolving agent from the reaction flask. Immerse the filter residue in 80 mL of n-hexane and stir at 300 rpm for 120 min at 25°C to carry out the desorption reaction. Then, filter to separate the feed solution and chiral resolving agent from the reaction flask. Samples of the feed solutions from each of the above steps are analyzed by gas chromatography.

[0057] In Comparative Example 2, the working unit could not function properly because the corresponding working solvent was not used in accordance with the provisions of this invention, and the adsorption and desorption processes could not be carried out, thus the enantiomeric separation of D,L-menthol could not be achieved.

[0058] test:

[0059] Determination of adsorption capacity and enantiomeric purity:

[0060] Take small amounts of the feed solution before adsorption, the feed solution after adsorption reaction, and the feed solution after desorption reaction, filter them through 0.22 μm, and then detect them in a gas chromatograph.

[0061] Gas chromatography conditions: Column: Cyclosil-B chiral column or Cyclodex-B chiral column (30m × 0.25mm, 0.25μm); Injector temperature: 250℃; Injection method: split injection, split ratio (20~200):1; Carrier gas: helium; Flow rate: 1.6mL / min; Injection volume: 1μL; Detection conditions: FID, 250℃; Column oven: (85~115)℃ isothermal.

[0062] Figures 2-5These are the adsorption isotherms of D,L-menthol for the adsorbent materials in different concentrations of D,L-menthol n-hexane solutions in Examples 1-4. It can be observed that the adsorption capacity of the material for one configuration of menthol is consistently greater than that for the other configuration, indicating that the working unit in Examples 1-4 has good enantiomeric resolution capability for D,L-menthol.

[0063] Figure 6 This is a comparison of the adsorption capacity of the adsorbent material for D,L-menthol under different concentrations of D,L-menthol hexane under the operating conditions of Comparative Example 1. Because a chiral resolving agent within the preferred range of this invention was not used, almost no difference was observed in the adsorption capacity of the material for D,L-menthol, and enantiomer separation of D,L-menthol could not be achieved.

[0064] Those skilled in the art will readily understand that the above description is merely an embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for enantiomer separation of D,L-menthol, characterized in that, Includes the following steps: (1) Add D,L-menthol solution to the working unit containing chiral resolving agent to allow the chiral resolving agent to fully undergo an adsorption reaction with D,L-menthol; (2) Separate the reactants obtained in step (1): Collect the liquid containing D-menthol; (3) Add eluent to the working unit to allow the chiral resolving agent to fully desorb from L-menthol; (4) Separate the reactants obtained in step (3) and collect the liquid containing L-menthol.

2. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The chiral resolving agent is a chiral small molecule @Zr-BTC material; the chiral small molecule @Zr-BTC material is synthesized from achiral Zr-BTC and a chiral small molecule with a carboxyl group, wherein the chiral small molecule with a carboxyl group is at least one of L-tartaric acid and L-mandelic acid.

3. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The chiral resolving agent is prepared by the following method: (1) Add a methanol solution of 4-pyridinecarboxaldehyde dropwise to an aqueous solution containing sodium carbonate and L-leucine, stir at room temperature for 1 to 4 hours, add sodium borohydride aqueous solution dropwise under ice-water bath conditions, continue stirring for 0.5 to 2 hours, filter, and adjust the pH of the filtrate to 4 to 7; rotary evaporate to obtain a white solid, dissolve in methanol at 55 to 65°C, filter, and rotary evaporate to obtain a chiral ligand; (2) Dissolve the chiral ligand obtained in step (1) in water, adjust the pH to 6-8, then mix it with an organic solvent containing zinc salt and sonicate for 2-60 min, centrifuge to collect the white solid and wash it.

4. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The chiral resolving agent is prepared by the following method: β-Cyclodextrin and γ-isocyanate-propyltriethoxysilane were dissolved in anhydrous pyridine and stirred under reflux at 75-85°C. Then, a phenyl isocyanate derivative was added and stirred at 95-110°C. Then, acidified silica gel was added and stirred at 95-110°C. After the reaction was completed, the mixture was filtered, washed, and dried to obtain a white powdery solid, which is the modified cyclodextrin.

5. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The solvent of the D,L-menthol solution in step (1) is at least one of ethanol, chloroform and n-hexane; the eluent in step (3) is at least one of methanol, ethanol and acetonitrile.

6. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The mass ratio of the chiral resolving agent used in step (1) to D,L-menthol is (1-20):

1.

7. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, In the adsorption reaction process described in step (1), at least one of the following operations is performed: standing, stirring, and shaking; in the desorption reaction process described in step (3), at least one of the following operations is performed: standing, stirring, and shaking.

8. The method for enantiomer separation of D,L-menthol according to claim 7, characterized in that, When the operation is stirring or shaking, the frequency condition is 120–300 rpm.

9. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The reaction operation temperature in steps (1) and (3) is (15-35)℃, and the reaction time is 60-1440 minutes.

10. The method for enantiomer separation of D,L-menthol according to claim 1, characterized in that, The ratio of chiral resolving agent to eluent used in step (3) is 1 mg: (0.2-1.0) mL.

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