A method for resolving racemic bodies based on dynamic dynamics

Abstract

This invention discloses a method for resolving racemic mixtures based on dynamic kinetics, belonging to the field of catalysis technology. The method includes the following steps: taking a proton-selective permeable membrane and pretreating it; using the pretreated proton-selective permeable membrane to separate the aqueous phase and organic phase for reaction, thereby resolving the racemic mixture; wherein the aqueous phase is an acid solution, and the organic phase contains at least the racemic mixture, an acyl donor, an enzyme, and an organic solvent, and the racemic mixture is a racemic mixture of a chiral secondary alcohol or its derivative. This invention utilizes a proton-selective permeable membrane as a racemic catalyst applied to the dynamic kinetic resolution process, solving the problem of incompatibility between racemic catalysts and enzyme catalysts in conventional dynamic kinetic resolution techniques. This method has advantages such as a simple reaction system, easy process control, environmental friendliness, simple post-processing, and low cost.

Description

Technical Field

[0001] This invention relates to the field of catalysis technology, specifically a method for resolving racemic mixtures based on dynamic kinetics. Background Technology

[0002] Optically pure 1-phenylethanol and its derivatives are a very important class of chiral synthons, indispensable intermediates in the synthesis of pharmaceuticals, pesticides, consumer goods, high-quality liquid crystals, and pheromones, and also important chiral auxiliaries in asymmetric synthesis. Therefore, the preparation of optically pure 1-phenylethanol is of great significance. Currently, the main methods for preparing optically pure compounds are asymmetric synthesis and racemic resolution. Asymmetric synthesis is difficult to widely apply due to problems such as high catalyst cost, narrow applicability, low optical purity of products, and time-consuming and labor-intensive process development. Compared with asymmetric synthesis, enzymatic kinetic resolution is one of the most common methods for preparing optically pure compounds in industry. This method utilizes the selective catalysis of biological enzymes to convert one enantiomer in a racemic mixture while the other enantiomer is little or not converted, thereby obtaining optically pure products and / or substrates. It has advantages such as high selectivity, mild reaction conditions, low pollution, and ease of industrialization, and has a promising future.

[0003] However, current enzymatic kinetic resolution methods still have significant drawbacks. They use racemic mixtures as raw materials to obtain the target enantiomers through the resolution process, resulting in a theoretical maximum yield of only 50%, which leads to a huge waste of resources. Summary of the Invention

[0004] The purpose of this invention is to provide a method for resolving racemic bodies based on dynamic dynamics, so as to solve the problems mentioned in the background art.

[0005] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0006] A method for resolving racemic bodies based on dynamic dynamics includes the following steps:

[0007] Take a proton-selective permeable membrane and pretreat it;

[0008] The aqueous and organic phases are separated by a pretreated proton-selective permeable membrane to separate the racemic mixture; wherein the aqueous phase is an acid solution, and the organic phase contains at least the racemic mixture, an acyl donor, an enzyme, and an organic solvent, and the racemic mixture is a racemic mixture of a chiral secondary alcohol or its derivative.

[0009] As a preferred embodiment of the present invention, the method specifically includes the following steps:

[0010] The pretreated proton-selective permeable membrane is installed between the two chambers of the dual-chamber reactor, and the solution in both chambers is able to contact the pretreated proton-selective permeable membrane.

[0011] An aqueous phase and an organic phase are added to the two chambers of a dual-chamber reactor, respectively, so that one side of the pretreated proton selectively permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase.

[0012] The reaction was started by placing the two-chamber reactor in a water bath at a constant temperature to break down the racemic mixture.

[0013] As a preferred embodiment of the present invention, the racemic mixture is a racemic mixture of 1-phenylethanol or its derivative.

[0014] As a preferred embodiment of the present invention, the pretreatment step of the proton-selective permeable membrane specifically includes:

[0015] The proton-selective permeable membrane is first treated with hydrogen peroxide at 75-85℃, then soaked in deionized water, then treated with dilute acid at 75-85℃, and then soaked in deionized water again to obtain the pretreated proton-selective permeable membrane.

[0016] As a preferred embodiment of the present invention, the proton selective permeation membrane is at least one of perfluorosulfonic acid proton exchange membrane, fluorine-free proton exchange membrane, non-perfluorinated proton exchange membrane, and composite proton exchange membrane.

[0017] As a preferred embodiment of the present invention, the acid in the aqueous phase is at least one of sulfuric acid, nitric acid, hydrochloric acid, perchloric acid, hydrobromic acid, hydroiodic acid, chloric acid, phosphoric acid, oxalic acid, formic acid, and acetic acid, and the concentration of the acid is 0.1%-98% by mass fraction.

[0018] In a preferred embodiment of the present invention, the enzyme in the organic phase is a lipase; the acyl donor is at least one selected from vinyl acetate, vinyl propionate, isopropylene acetate, and vinyl butyrate; and the organic solvent is at least one selected from n-hexane, n-heptane, n-octane, methyl tert-butyl ether, isopropyl ether, isooctane, n-pentane, cyclohexane, toluene, and tetrahydrofuran.

[0019] As a preferred embodiment of the present invention, the organic solvent is at least one selected from n-hexane, isooctane, and cyclohexane.

[0020] In a preferred embodiment of the present invention, the concentration of the racemic mixture in the organic phase is 0.1-100 mmol / L, the concentration of the acyl donor is 1-300 mmol / L, and the amount of enzyme is 0.1-100 mg / mL.

[0021] In a preferred embodiment of the present invention, the reaction temperature in the step is 20℃-80℃.

[0022] Compared with existing technologies, the embodiments of the present invention utilize proton-selective permeable membranes as racemic catalysts in dynamic kinetic resolution processes, solving the problem of incompatibility between racemic catalysts and enzyme catalysts in conventional dynamic kinetic resolution techniques. This method has advantages such as simple reaction system, easy process control, environmental friendliness, simple post-processing, and low cost. Its specific beneficial effects are as follows:

[0023] (1) The present invention uses a proton-selective permeable membrane as a racemic catalyst. The enzyme catalytic reaction occurs in the organic phase, and the racemization reaction occurs at the interface between the membrane and the organic phase. The two are physically isolated, which can effectively solve the problem of mutual interference between the two catalytic processes.

[0024] (2) The enzyme does not come into direct contact with the racemic catalyst, so the enzyme's activity and selectivity are well maintained. There is no problem of separating the enzyme from the racemic catalyst, and the enzyme recovery and recycling are very convenient.

[0025] (3) By adjusting the concentration of acid in the aqueous phase, the present invention can effectively control the activity of protons at the interface with the organic phase, thereby making it easier to control the reaction;

[0026] (4) It reduces the restrictions on acyl donors. Since water participates in the intermediate process of racemization, an aqueous environment is conducive to racemization. However, hydrolysis and transesterification are in competition, so an aqueous environment cannot be used in enzyme catalysis. To solve the above contradiction, some existing technologies have constructed a water / organic phase two-phase system, which not only increases the difficulty of operation, but also requires the use of long carbon chain acyl donors. However, this invention does not have special requirements for the carbon chain length of the acyl donor.

[0027] (5) It reduces the occurrence of side reactions. Since racemic catalysts do not require a support, the interaction between the support and the substrate is weakened, thus reducing the occurrence of side reactions.

[0028] (6) The method provided by the present invention is simple to implement. By adding a feed liquid inlet and a product outlet at the organic phase end, it is easy to achieve continuous process. Moreover, the enzyme catalyst and proton selective permeable membrane have good reusability, and the process is green and environmentally friendly. Attached Figure Description

[0029] Figure 1 The diagram below illustrates the principle of a method for resolving racemic mixtures based on dynamic kinetics, as provided in Example 1, and the structural diagram of a two-chamber reactor. Detailed Implementation

[0030] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In addition, unless otherwise specified, the equipment and reagents involved in the following embodiments can be commercially available equipment and reagents.

[0031] Existing enzymatic kinetic resolution methods still have significant drawbacks. Using racemic mixtures as raw materials, the target enantiomer is obtained through the resolution process, resulting in a theoretical maximum yield of only 50%, leading to substantial resource waste. To address this deficiency, a dynamic kinetic resolution (DKR) method was developed. This method incorporates a one-step in-situ racemization process into the traditional kinetic resolution system, allowing enantiomers not selectively catalyzed by the enzyme to continuously enter the kinetic resolution system after racemization, thus theoretically achieving a maximum yield of 100%. However, the preparation of optically pure compounds by dynamic kinetic resolution currently faces several bottlenecks, the most critical being the incompatibility between the racemic catalyst and the enzyme catalyst. Racemic catalysts are primarily chemical catalysts, whose applicable conditions differ significantly from those of enzymes. Chemical catalysts themselves or their catalytic products can easily lead to enzyme inactivation, making it difficult to reconcile the two within a single system. The primary objective of this invention is to solve these existing technical problems and provide a novel dynamic kinetic resolution technology.

[0032] In addition, there are various racemic catalysts for chiral secondary alcohols or their derivatives. While noble metal catalysts, represented by ruthenium, exhibit good performance, they are costly and pose a risk of heavy metal contamination. Protonic acid catalysts, including supported acid catalysts (such as titanium dioxide supported on sulfuric acid), acidic zeolites, and strong acid resins, are inexpensive and offer good catalytic performance. Their catalytic principle involves the combination of protons with the hydroxyl groups of the secondary alcohol, leading to dehydration and hydroxylation reactions that release protons, thus achieving racemization of the secondary alcohol. Currently used supported acid catalysts suffer from problems such as easy loss of catalytic centers. While acidic zeolites and strong acid resins have stable catalytic centers, their catalytic activity is difficult to control, easily leading to side reactions. In the "one-step" process, existing protonic acid catalysts inevitably come into contact with enzyme catalysts, easily causing enzyme deactivation and making separation from enzyme catalysts difficult, posing significant challenges to subsequent catalyst recovery and recycling. This invention, based on the principle of proton acid catalysis, proposes a technical approach using proton-selective permeable membranes as catalysts. It particularly recommends using Nafion series proton exchange membranes, manufactured by DuPont, a cation-exchange type of selectively permeable membrane. The functional groups responsible for proton exchange are sulfonic acid groups (-SO3H) fixed on the fluorocarbon polymer backbone. Nafion membranes are commonly used in fuel cells, relying on water in the membrane phase to complete proton exchange and transfer. They possess advantages such as good thermal stability, high-temperature resistance, chemical stability, and good mechanical properties. The proton-selective permeable membrane provides the necessary hydrogen ions for the racemization process, and combined with enzyme-catalyzed kinetic resolution, it enables the dynamic kinetic resolution of chiral compounds.

[0033] Specifically, in one embodiment of the present invention, a method for resolving racemic bodies based on dynamic dynamics is provided, which includes the following steps:

[0034] Take a proton-selective permeable membrane and pretreat it;

[0035] The aqueous and organic phases are separated by a pretreated proton-selective permeable membrane to separate the racemic mixture; wherein the aqueous phase is an acid solution, and the organic phase contains at least the racemic mixture, an acyl donor, an enzyme, and an organic solvent, and the racemic mixture is a racemic mixture of a chiral secondary alcohol or its derivative.

[0036] In practical applications, the above method can be implemented using a dual-chamber reactor from existing technology, specifically including the following steps:

[0037] S1. Pretreatment of the proton-selective permeable membrane.

[0038] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0039] S3. Install a ring-shaped polytetrafluoroethylene soft pad on each side of the pretreated proton selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and use clamps to bring the left and right side branch tubes close together and clamp them to isolate the solution inside the double chamber reactor from the constant temperature water outside the double chamber reactor. Then place the double chamber reactor in a water bath constant temperature shaker. Then, add the aqueous phase and the organic phase to the left and right chambers of the double chamber reactor respectively, so that one side of the pretreated proton selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase.

[0040] S4. Place the dual-chamber reactor in a water bath constant temperature environment, adjust the appropriate temperature and oscillation frequency, and start the reaction to separate the racemic mixture.

[0041] It should be noted that in actual operation, process continuity can be easily achieved by adding a feed liquid inlet and a product outlet at the organic phase end.

[0042] In a preferred embodiment of the present invention, the racemic mixture is a racemic mixture of 1-phenylethanol or a derivative thereof. Of course, the above method can be applied to the resolution of other chiral secondary alcohols or their derivatives.

[0043] In a preferred embodiment of the present invention, the step of pretreating the proton-selective permeable membrane specifically includes:

[0044] The proton-selective permeable membrane is first treated with hydrogen peroxide at 75-85℃, then soaked in deionized water, then treated with dilute acid at 75-85℃, and then soaked in deionized water again to obtain the pretreated proton-selective permeable membrane.

[0045] The hydrogen peroxide has a mass concentration of 3%-7%; the dilute acid can be dilute sulfuric acid or dilute hydrochloric acid, but is not limited to these, and its mass concentration is 3%-7%.

[0046] In a preferred embodiment of the present invention, the proton-selective permeable membrane is at least one of a perfluorosulfonic acid proton exchange membrane, a fluorine-free proton exchange membrane, a non-perfluorosulfonic acid proton exchange membrane, and a composite proton exchange membrane, but is not limited thereto. Preferably, the proton-selective permeable membrane can be a Nafion series proton exchange membrane manufactured by DuPont, such as the Nafion 117 or Nafion 212 perfluorosulfonic acid proton exchange membrane, but is not limited thereto.

[0047] In a preferred embodiment of the present invention, the acid in the aqueous phase is at least one selected from sulfuric acid, nitric acid, hydrochloric acid, perchloric acid, hydrobromic acid, hydroiodic acid, chloric acid, phosphoric acid, oxalic acid, formic acid, and acetic acid, but is not limited thereto; wherein the concentration of the acid, by mass fraction, is 0.1%-98%. Preferably, the concentration of the acid in the organic phase is 1-5 mol / L.

[0048] In a preferred embodiment of the present invention, the enzyme in the organic phase is a lipase, specifically Novozyme 40086 or Novozyme 435 lipase, but not limited thereto. The appropriate enzyme catalyst can be selected according to the chiral molecule to be separated. The acyl donor is at least one of vinyl acetate, vinyl propionate, isopropylene acetate, and vinyl butyrate, but not limited thereto. The organic solvent is at least one of n-hexane, n-heptane, n-octane, methyl tert-butyl ether, isopropyl ether, isooctane, n-pentane, cyclohexane, toluene, and tetrahydrofuran, but not limited thereto.

[0049] Preferably, the organic solvent is at least one selected from n-hexane, isooctane, and cyclohexane.

[0050] In a preferred embodiment of the present invention, the concentration of the racemic mixture in the organic phase is 0.1-100 mmol / L, the concentration of the acyl donor is 1-300 mmol / L, and the amount of enzyme is 0.1-100 mg / mL. Preferably, the concentration of the racemic mixture is 1-5 mmol / L, the concentration of the acyl donor is 2-15 mmol / L, and the amount of enzyme is 3-5 mg / mL.

[0051] In a preferred embodiment of the present invention, the reaction temperature in the step is 20°C-80°C.

[0052] The principle of the method provided in this embodiment of the invention is as follows:

[0053] In the organic phase, the racemic 1-phenylethanol and the acyl donor undergo a stereoselective transesterification reaction catalyzed by an enzyme to produce (R)-1-phenylethanol ethyl ester, leaving unreacted (S)-1-phenylethanol. Protons in the aqueous phase pass through a proton-selective permeation membrane to contact the organic phase, where (S)-1-phenylethanol is catalytically racemized at the membrane-organic phase interface. The racemic 1-phenylethanol then undergoes a further stereoselective transesterification reaction in the organic phase to produce (R)-1-phenylethanol ethyl ester. This process continues until all the racemic 1-phenylethanol is converted to (R)-1-phenylethanol ethyl ester.

[0054] The following embodiments are some specific implementation examples of the present invention in practical applications, but are not limited thereto.

[0055] Example 1

[0056] As attached Figure 1 As shown, this embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0057] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0058] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0059] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 1 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 1 mmol / L racemic 1-phenylethanol and 2 mmol / L vinyl acetate, and 300 mg of Novozyme 40086 is added as an enzyme catalyst.

[0060] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started at 45°C. Samples were taken for analysis at regular intervals. The results showed that after 24 hours of reaction, the conversion rate of 1-phenylethanol exceeded 50%; after 36 hours of reaction, the conversion rate of 1-phenylethanol was 93.1%, the yield of (R)-1-phenylethanol ethyl ester was 92.2%, the enantiomeric excess of the product was 98.2%, and no styrene, a byproduct easily caused by acidic catalysts, was detected.

[0061] Example 2

[0062] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0063] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0064] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0065] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 5 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 1 mmol / L racemic 1-phenylethanol and 2 mmol / L vinyl acetate, and 300 mg of Novozyme 435 is added as an enzyme catalyst.

[0066] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started at 45°C. Samples were taken for analysis at regular intervals. The results showed that after 36 hours of reaction, the conversion rate of 1-phenylethanol was 96.3%, the yield of (R)-1-phenylethanol ethyl ester was 93.7%, and the enantiomeric excess of the product was 98.1%.

[0067] Example 3

[0068] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0069] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0070] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0071] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 5 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 5 mmol / L racemic 1-phenylethanol and 15 mmol / L vinyl acetate, and 150 mg of Novozyme 40086 is added as an enzyme catalyst.

[0072] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started by heating at 45°C. Samples were taken for analysis at regular intervals. The results showed that after 36 hours of reaction, the conversion rate of 1-phenylethanol was 94.7%, the yield of (R)-1-phenylethanol ethyl ester was 93.5%, and the enantiomeric excess of the product was 98.7%.

[0073] Example 4

[0074] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0075] S1. A DuPont Nafion 212 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0076] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0077] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 3 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 1 mmol / L racemic 1-phenylethanol and 4 mmol / L vinyl acetate, and 300 mg of Novozyme 40086 is added as an enzyme catalyst.

[0078] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started by heating at 45°C. Samples were taken for analysis at regular intervals. The results showed that after 30 hours of reaction, the conversion rate of 1-phenylethanol was 94.7%, the yield of (R)-1-phenylethanol ethyl ester was 95.5%, and the enantiomeric excess of the product was 97.7%.

[0079] Example 5

[0080] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0081] S1. A DuPont Nafion 212 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0082] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0083] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 5 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 1 mmol / L racemic 1-phenylethanol and 6 mmol / L vinyl acetate, and 300 mg of Novozyme 40086 is added as an enzyme catalyst.

[0084] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started by heating at 45°C. Samples were taken for analysis at regular intervals. The results showed that after 24 hours of reaction, the conversion rate of 1-phenylethanol was 94.7%, the yield of (R)-1-phenylethanol ethyl ester was 97.5%, and the enantiomeric excess of the product was 98.9%.

[0085] Example 6

[0086] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0087] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 3% hydrogen peroxide at 75°C for 1.5 h, then soaked in deionized water for 40 min, then boiled in 3% dilute sulfuric acid at 75°C for 1.5 h, and finally soaked in deionized water for 40 min to obtain the pretreated proton selective permeation membrane.

[0088] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0089] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 0.1% nitric acid aqueous solution; the organic phase is 60 mL of a solution containing 0.1 mmol / L of racemic 1-phenylethanol and 1 mmol / L of vinyl propionate. The organic solvent is a mixture of n-hexane, isooctane and cyclohexane in equal volume ratios, and 6 mg of Novozyme 435 is added as an enzyme catalyst.

[0090] S4. Place the dual-chamber reactor in a water bath constant temperature environment, adjust the appropriate temperature and oscillation frequency, and heat at 80°C to start the reaction.

[0091] Example 7

[0092] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0093] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 7% hydrogen peroxide at 85°C for 0.5 h, then soaked in deionized water for 20 min, then boiled in 7% dilute hydrochloric acid at 85°C for 0.5 h, and finally soaked in deionized water for 20 min to obtain the pretreated proton selective permeation membrane.

[0094] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0095] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 98% acetic acid aqueous solution. The organic phase is 60 mL of a solution containing 100 mmol / L racemic 1-phenylethanol, 100 mmol / L vinyl acetate, 100 mmol / L isopropylene acetate and 100 mmol / L vinyl butyrate. The organic solvent is a mixture of n-hexane and methyl tert-butyl ether in equal volume ratio, and 6000 mg of Novozyme 435 is added as an enzyme catalyst.

[0096] S4. Place the dual-chamber reactor in a water bath constant temperature environment, adjust the appropriate temperature and oscillation frequency, and heat at 20°C to start the reaction.

[0097] Example 8

[0098] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0099] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute hydrochloric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0100] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0101] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) pad on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 50% formic acid aqueous solution; the organic phase is 60 mL of a solution containing 3 mmol / L of racemic 1-phenylethanol, 5 mmol / L of vinyl acetate and 3 mmol / L of vinyl butyrate. The organic solvent is a mixture of n-hexane and isooctane in equal volume ratio, and 240 mg of Novozyme 435 is added as an enzyme catalyst.

[0102] S4. Place the dual-chamber reactor in a water bath constant temperature environment, adjust the appropriate temperature and oscillation frequency, and heat at 60°C to start the reaction.

[0103] Comparative Example 1

[0104] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0105] S1. A DuPont Nafion 212 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0106] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0107] S3. Install a ring-shaped polytetrafluoroethylene (PTFE) gasket on each side of the pretreated proton-selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and clamp the left and right side branch tubes close together to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 5 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of n-hexane solution containing 1 mmol / L racemic 1-phenylethanol and 6 mmol / L vinyl acetate.

[0108] S4. The dual-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was started at 45°C. Samples were taken for analysis at regular intervals. The results showed that the conversion rate was 37.2% after 6 hours, 65.8% after 12 hours, and 85.8% after 24 hours. The target product (R)-1-phenylethanol ethyl ester was not detected in any of the samples.

[0109] Comparative Example 2

[0110] This embodiment provides a method for resolving racemic bodies based on dynamic dynamics, which includes the following steps:

[0111] In a single-chamber reactor, an aqueous phase and an organic phase were mixed at a 1:1 volume ratio. The aqueous phase consisted of 60 mL of a 5 mol / L dilute sulfuric acid solution, while the organic phase consisted of 60 mL of a hexane solution containing 1 mmol / L of racemic 1-phenylethanol and 6 mmol / L of vinyl acetate, with 300 mg of Novozyme 40086 added as an enzyme catalyst. The reaction was then heated at 45 °C, and samples were taken for analysis at regular intervals. The results showed that 1-phenylethanol gradually entered the aqueous phase from the organic phase, thus gradually decreasing the 1-phenylethanol content in the organic phase. However, the target product (R)-1-phenylethanol ethyl ester was not detected. After 24 h of reaction, the remaining 1-phenylethanol in the organic phase was 41.4% of the initial value. Furthermore, vinyl acetate in the organic phase was rapidly hydrolyzed due to contact with the acid in the aqueous phase, and was undetectable in the organic phase after 4 h.

[0112] A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used. The pretreated proton-selective permeable membrane was placed between the left and right sidewalls of a two-chamber reactor and clamped. The reaction conditions were: temperature 55℃, aqueous phase 60 mL of 1 mol / L dilute sulfuric acid solution, and organic phase 60 mL of a solution containing 1 mmol / L (S)-1-phenylethanol. Intermittent sampling and analysis were performed. After 24 h of reaction, the ee values ​​for different solvents were: n-hexane (15%), cyclohexane (29%), isooctane (36%), methyl tert-butyl ether (81%), and isopropyl ether (90%). The results showed that the racemic reactions were faster with n-hexane, isooctane, and cyclohexane, while the racemic reactions were slower with methyl tert-butyl ether and isopropyl ether (Note: In racemic reactions, a smaller ee value indicates more complete racemization). When n-hexane was used as the solvent, the ee value dropped to 15% after 24 hours, and racemization was basically completed after 36 hours. Therefore, it can be preliminarily determined that n-hexane is a better solvent, and a solvent with strong hydrophobicity is conducive to the racemization reaction.

[0113] Experimental Example

[0114] This experimental example is designed to compare the racemic reaction rates in different solvents, and it includes the following steps:

[0115] S1. A DuPont Nafion 117 perfluorosulfonic acid polymer proton exchange membrane was used as the proton selective permeation membrane. It was first treated with 5% hydrogen peroxide at 80°C for 1 hour, then soaked in deionized water for 30 minutes, then boiled in 5% dilute sulfuric acid at 80°C for 1 hour, and finally soaked in deionized water for 30 minutes to obtain the pretreated proton selective permeation membrane.

[0116] S2. Install the pretreated proton-selective permeable membrane between the left and right chambers of the dual-chamber reactor. Set a horizontal side branch in each chamber so that the solution in both chambers can contact the pretreated proton-selective permeable membrane.

[0117] S3. Install a ring-shaped polytetrafluoroethylene soft pad on each side of the pretreated proton selective permeable membrane, place it in the groove on the outer edge of the side branch tube, and use clamps to bring the left and right side branch tubes close together and clamp them to isolate the solution inside the double-chamber reactor from the constant temperature water outside the double-chamber reactor. Then, place the double-chamber reactor in a water bath constant temperature shaker. Then, add an aqueous phase and an organic phase to the left and right chambers of the double-chamber reactor respectively, so that one side of the pretreated proton selective permeable membrane is in contact with the aqueous phase and the other side is in contact with the organic phase. The aqueous phase is 60 mL of 1 mol / L dilute sulfuric acid aqueous solution; the organic phase is 60 mL of a solution containing 1 mmol / L (S)-1-phenylethanol. The solvents of the organic phase are n-hexane, cyclohexane, isooctane, methyl tert-butyl ether, and isopropyl ether, respectively.

[0118] S4. The two-chamber reactor was placed in a water bath at a constant temperature. The appropriate temperature and oscillation frequency were adjusted, and the reaction was heated at 55°C. Samples were taken for analysis at regular intervals. After 24 hours of reaction: the ee value of the hexane solvent system decreased to 15%, and racemization was basically complete after 36 hours; the ee value of the cyclohexane solvent system decreased to 29%; the ee value of the isooctane solvent system decreased to 36%; the ee value of the methyl tert-butyl ether solvent system decreased to 81%; and the ee value of the isopropyl ether solvent system decreased to 90%. The results show that the racemization reaction is faster with hexane, isooctane, and cyclohexane as solvents, and slower with methyl tert-butyl ether and isopropyl ether as solvents. Hexane is the best solvent, and solvents with strong hydrophobicity are beneficial to the racemization reaction (Note: In a racemization reaction, a smaller ee value indicates more complete racemization).

[0119] It should be noted that the optical purity and substrate conversion of the products in the above examples, comparative examples, and experimental examples can all be analyzed using a Waters e2695 high-performance liquid chromatograph (HPLC). The specific parameters are as follows: Daicel Chiralcel IG chiral column (250 mm × 4.6 mm ID); mobile phase composition: V (n-hexane):V (anhydrous ethanol) = 97:3; flow rate: 1 mL / min; UV detection wavelength: 210 nm; column temperature: 25.0 °C; injection volume: 20 μL.

[0120] Comparing the sampling and analysis results of the above embodiments and comparative examples, it is easy to see that the embodiments of the present invention utilize proton-selective permeable membranes as racemic catalysts and apply them to the dynamic kinetic resolution process, which solves the problem of incompatibility between racemic catalysts and enzyme catalysts in conventional dynamic kinetic resolution technology. In addition, this method has the advantages of simple reaction system, easy process control, green and environmentally friendly, simple post-processing, and low cost.

[0121] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for resolving racemates based on dynamic kinetic resolution, characterized in that, The method comprises the following steps: taking a proton-selective permeable membrane and pretreating the proton-selective permeable membrane; separating the aqueous phase and the organic phase by using the pretreated proton-selective permeable membrane to react and separate the racemate; wherein the aqueous phase is an acid solution, the organic phase comprises at least a racemate, an acyl donor, an enzyme and an organic solvent, the racemate is 1-phenyl ethanol racemate, the reaction temperature is 45℃, the 1-phenyl ethanol racemate and the acyl donor in the organic phase undergo a stereoselective transesterification reaction under the catalysis of the enzyme to generate (R)-1-phenyl ethanol ethyl ester and the remaining unreacted (S)-1-phenyl ethanol, the protons in the aqueous phase contact the organic phase through the proton-selective permeable membrane, and the (S)-1-phenyl ethanol is catalytically racemized at the interface between the membrane and the organic phase; the racemized 1-phenyl ethanol continues to undergo a stereoselective transesterification reaction in the organic phase to generate (R)-1-phenyl ethanol ethyl ester; the proton-selective permeable membrane is a Nafion 117 perfluorosulfonic acid polymer proton exchange membrane or a Nafion 212 perfluorosulfonic acid polymer proton exchange membrane; the aqueous phase is a dilute sulfuric acid aqueous solution with a concentration of 5 mol / L; the enzyme in the organic phase is a lipase, and specifically a commercially available Novozyme 40086 or Novozyme 435 lipase; the acyl donor is vinyl acetate; and the organic phase is a n-hexane solution of 1-phenyl ethanol racemate and vinyl acetate; in the organic phase, the concentration of the racemate is 0.1-100 mmol / L, the concentration of the acyl donor is 1-300 mmol / L, and the amount of the enzyme is 0.1-100 mg / mL.

2. A method of resolving racemates based on dynamic kinetics according to claim 1, characterized in that, The method specifically comprises the following steps: installing the pretreated proton-selective permeable membrane between the two chambers of a double-chamber reactor and enabling the solutions in the two chambers to contact the pretreated proton-selective permeable membrane; adding the aqueous phase and the organic phase into the two chambers of the double-chamber reactor respectively, so that one side of the pretreated proton-selective permeable membrane contacts the aqueous phase and the other side contacts the organic phase; placing the double-chamber reactor in a water bath constant temperature environment to start the reaction and separate the racemate.

3. A method for dynamic kinetic resolution of racemates according to claim 1 or 2, characterized in that, The step of pretreating the proton-selective permeable membrane specifically comprises: firstly treating the proton-selective permeable membrane with hydrogen peroxide at a temperature of 75-85℃, then soaking the proton-selective permeable membrane with deionized water, then treating the proton-selective permeable membrane with dilute acid at a temperature of 75-85℃, and then soaking the proton-selective permeable membrane with deionized water to obtain the pretreated proton-selective permeable membrane.

Images