Chiral resolution method of DL-menthyl benzoate and DL-menthol

Abstract

The invention provides a chiral resolution method of DL-menthyl benzoate and DL-menthol, which comprises the following steps: (1) adding racemic DL-menthyl benzoate raw material into a solvent under a stirring condition, and dissolving at 10-20 DEG C to form a saturated solution; (2) slowly cooling the saturated solution obtained in the step (1) to 5-10 DEG C, adding an L-menthyl benzoate seed crystal, and performing crystallization and solid-liquid separation to obtain a first solid and a first liquid; and (3) adding the saturated solution obtained in the step (1) into the liquid obtained in the step (2), heating to 10-20 DEG C, then slowly cooling to 5-10 DEG C, adding D-menthyl benzoate seed crystal, crystallizing, and carrying out solid-liquid separation to obtain a second solid and a second liquid. Based on the fact that DL-menthol is difficult to separate, the DL-menthol is firstly converted into a derivative of the DL-menthol, the derivative is split, and then conversion is performed, so that chiral resolution of the DL-menthol is realized.

Description

Technical Field

[0001] This invention belongs to the field of crystallization and relates to a chiral resolution method for DL-menthyl benzoate and DL-menthol. Background Technology

[0002] L-Menthol is a natural or synthetic monoterpene alcohol with a unique cooling sensation and various biological activities, and its applications span multiple industries including food, daily chemicals, pharmaceuticals, tobacco, and agriculture. The current mainstream production method for L-menthol is an asymmetric isomerization process using a chiral BINAP-Rh catalyst and myrcene as a raw material. This method yields L-menthol with excellent optical purity (≥99%) and yield (>90%), but the precious metal catalysts used are expensive, the reaction conditions are harsh, and there are also environmental and sustainability issues. In contrast, the crystallization method has lower equipment requirements and simpler production conditions; therefore, crystallization is considered for the resolution of L-menthol.

[0003] Therefore, it is essential to develop a simple and scalable chiral resolution method for DL-menthol. Summary of the Invention

[0004] The purpose of this invention is to provide a chiral resolution method for DL-menthyl benzoate and DL-menthol. Since DL-menthol is a racemic compound with enantiomers bound 1:1 in the crystal lattice, it is difficult to separate them using conventional solubility differences, thus hindering continuous industrial production. To overcome this problem, DL-menthol is first converted into its derivative, DL-menthyl benzoate. This DL-menthyl benzoate is then resolved, and the resulting D-menthyl benzoate or L-menthyl benzoate is hydrolyzed to convert it into D-menthol and L-menthol, thereby achieving chiral resolution of D-menthol and L-menthol within DL-menthol. The chiral resolution of the DL-menthyl benzoate derivative requires only conventional solvents and seed crystals, eliminating the need for expensive catalysts and requiring relatively low-end equipment. Furthermore, the process is simple and suitable for large-scale industrial production. Finally, the mother liquor can be recycled, reducing waste of raw materials and solvents. High yields can be obtained through cyclic crystallization, enabling large-scale industrial production.

[0005] One objective of this application is to provide a chiral resolution method for DL-menthol benzoate, characterized in that the chiral resolution method comprises: (1) Under stirring conditions, racemic DL-menthol benzoate raw material is added to the solvent and dissolved at 10-20℃ (e.g., 10℃, 12℃, 15℃, 18℃, 20℃, etc.) to form a saturated solution; (2) Slowly cool the saturated solution obtained in step (1) to 5-10℃ (e.g., 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, etc.), add L-menthol benzoate seed crystals, crystallize, separate the solid and liquid, and obtain the first solid and the first liquid; (3) Add the liquid obtained in step (2) to the saturated solution obtained in step (1), heat it to 10-20℃ (e.g., 10℃, 12℃, 15℃, 18℃, 20℃, etc.), then slowly cool it to 5-10℃ (e.g., 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, etc.), add D-menthol benzoate seed crystals, crystallize, separate the solid and liquid, and obtain the second solid and the second liquid.

[0006] This application describes the chiral resolution of DL-menthyl benzoate, which only requires conventional solvents and seed crystals, has relatively low equipment requirements, and is simple to prepare, making it suitable for large-scale production applications.

[0007] Preferably, the purity of L-menthol benzoate in the racemic DL-menthol ester raw material in step (1) is not less than 50%, for example, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc. Preferably, the preparation method of the racemic DL-menthyl benzoate raw material in step (1) includes: dissolving the DL-menthyl benzoate raw material in a solvent, heating it to 10-20℃ (e.g., 10℃, 12℃, 15℃, 17℃, 20℃, etc.) to dissolve it, adding L-menthyl benzoate seed crystals, maintaining it for 8-15 min (e.g., 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, etc.), separating the solid and liquid, and removing the solvent from the separated liquid to obtain the racemic DL-menthyl benzoate raw material; Preferably, the solvent is methanol; Preferably, based on an addition amount of 220g of DL-menthol benzoate raw material, the addition amount of solvent is 450-550g (e.g., 450 g, 480 g, 500 g, 520 g, 550 g, etc.). Preferably, the amount of L-menthol benzoate seed crystals added is 5-25 wt% of the L-menthol benzoate contained in the DL-menthol benzoate raw material, such as 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, etc. Preferably, the solvent removal method is rotary evaporation.

[0008] Preferably, the solvent in step (1) is methanol; Preferably, based on the addition amount of racemic DL-menthol benzoate raw material of 260g, the addition amount of solvent in step (1) is 450-550g, for example 450g, 480g, 500g, 520g, 550g, etc. Preferably, the cooling rate in step (2) is 0.2-0.5℃ / min, for example, 0.2℃ / min, 0.3℃ / min, 0.4℃ / min, 0.5℃ / min, etc.; Preferably, the crystallization time in step (2) is 30-60 min, for example, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, etc.; Preferably, the solid-liquid separation method in step (2) is filtration; Preferably, in step (2), the first solid is L-menthol benzoate; Preferably, the amount of saturated solution added in step (3) is the sum of the mass of the raw material and methanol, minus the mass of the first solid obtained in step (2); Preferably, the cooling rate in step (3) is 0.2-0.5℃ / min, for example, 0.2℃ / min, 0.3℃ / min, 0.4℃ / min, 0.5℃ / min, etc.; Preferably, the crystallization time in step (3) is 30-60 min, for example 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, etc.; Preferably, the solid-liquid separation method in step (3) is filtration.

[0009] Preferably, the chiral separation method further includes: adding the second liquid obtained in step (3) to the saturated solution obtained in step (1), heating it to 10-20℃ (e.g., 10℃, 12℃, 15℃, 18℃, 20℃, etc.), repeating steps (2) and (3) n times, where n is 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.), and collecting and merging the first solid and the second solid obtained.

[0010] As a preferred embodiment of this application, the first solid and the second solid obtained in steps (2) and (3) are L-menthol benzoate and D-menthol benzoate, respectively. Based on the simplicity of this preparation method, the low requirements for equipment, and the ability to recycle the mother liquor, a continuous chiral separation method is provided, namely, adding the saturated solution obtained in step (1) to the mother liquor obtained in step (3), heating it to 10-20℃ (e.g., 10℃, 12℃, 15℃, 18℃, 20℃, etc.), and then slowly cooling it to 5-10℃. (e.g., 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, etc.), add L-menthyl benzoate seed crystals, crystallize, and separate solid and liquid. The solid obtained is L-menthyl benzoate. The filtrate obtained is as in step (3). Add saturated solution, raise and lower the temperature, add D-menthyl benzoate seed crystals, crystallize, and separate solid and liquid. The solid obtained is D-menthyl benzoate. The filtrate obtained is also replenished with saturated solution. Repeat steps (2) and (3) to form a continuous crystallization process.

[0011] In this invention, considering overall economic efficiency, n is preferably 3-6, for example 3, 4, 5 or 6.

[0012] In this invention, the chiral resolution of DL-menthol benzoate only requires conventional solvents and seed crystals, without the need for expensive catalysts, and the equipment requirements are relatively low. It can be scaled up. In addition, the preparation process is simple and easy to apply to large-scale industrial production. Finally, the mother liquor can also be recycled, reducing the waste of raw materials and solvents. A high yield can be obtained through cyclic crystallization, thereby realizing large-scale industrial production applications.

[0013] The second objective of this invention is to prepare D-menthyl benzoate and / or L-menthyl benzoate according to the preparation method described in the first objective.

[0014] Preferably, the purity of the D-menthol benzoate is 93-98%. Preferably, the purity of the L-menthol benzoate is 93-98%; Preferably, the yield of the D-menthol benzoate is 8-13%; Preferably, the yield of the L-menthol benzoate is 8-13%; A third objective of this invention is to provide a method for preparing D-menthol and / or L-menthol, the method comprising: A1. D-menthyl benzoate and / or L-menthyl benzoate are prepared according to the preparation method described in one of the objectives; A2. The D-menthyl benzoate and / or L-menthyl benzoate obtained in step A1 are subjected to a hydrolysis reaction to obtain D-menthol and / or L-menthol; Preferably, the hydrolysis reaction in step A2 is carried out in the presence of methanol or sodium methoxide; Preferably, the hydrolysis temperature is 60-80℃ (e.g., 60℃, 65℃, 70℃, 75℃, 80℃, etc.), and the hydrolysis time is 6-8 h (e.g., 6 h, 7 h, 8 h, etc.).

[0015] The fourth objective of this invention is to provide a chiral resolution method for DL-menthol, the chiral resolution method comprising: B1. Add DL-menthol and methyl benzoate to a solvent and reflux under the action of a catalyst to obtain DL-menthol benzoate. B2. D-menthyl benzoate and / or L-menthyl benzoate are prepared by the preparation method described in one of the objectives. B3. The D-menthyl benzoate and / or L-menthyl benzoate obtained in step B2 are subjected to a hydrolysis reaction to obtain D-menthol and / or L-menthol.

[0016] In this invention, DL-menthol, being a racemic compound, has enantiomers bound 1:1 in the crystal lattice, making it difficult to separate them through conventional solubility differences, thus hindering continuous industrial production. To overcome this problem, DL-menthol is first converted into its derivative, DL-menthyl benzoate. DL-menthyl benzoate is then separated, and the resulting D-menthyl benzoate or L-menthyl benzoate is hydrolyzed to convert into D-menthol and L-menthol, thereby achieving chiral separation of D-menthol and L-menthol in DL-menthol.

[0017] Preferably, the solvent in step B1 is toluene containing 20-40% (e.g., 20%, 25%, 30%, 35%, 40%, etc.) sodium methoxide; Preferably, based on the addition of DL-menthol of 260g, the addition of the solvent in step B1 is 500-1000mL (e.g., 500 mL, 600 mL, 700 mL, 800 mL, 900 mL, 1000 mL, etc.). Preferably, the molar ratio of DL-menthol and methyl benzoate in step B1 is 1:1 to 1:1.5, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc. Preferably, the catalyst in step B1 is a sodium methoxide / magnesium oxide type solid base; Preferably, based on the addition amount of DL-menthol being 260g, the addition amount of the catalyst in step B1 is 5-10wt%, for example, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, etc. Preferably, the hydrolysis reaction in step B1 is carried out at a temperature of 60-80℃ (e.g., 60℃, 65℃, 70℃, 75℃, 80℃, etc.) and the hydrolysis reaction takes 2-5 hours (e.g., 2 hours, 3 hours, 4 hours, 5 hours, etc.).

[0018] The fifth objective of this invention is to provide a method for preparing D-menthol and / or L-menthol according to the method described in the third objective. Alternatively, D-menthol and / or L-menthol may be prepared according to the chiral resolution method for DL-menthol described in Objective 4.

[0019] Compared with the prior art, the present invention has the following beneficial effects: In this invention, DL-menthol, being a racemic compound, has enantiomers bound 1:1 in the crystal lattice, making it difficult to separate them through conventional solubility differences, thus hindering continuous industrial production. To overcome this problem, DL-menthol is first converted into its derivative, DL-menthyl benzoate. DL-menthyl benzoate is then separated, and the resulting D-menthyl benzoate or L-menthyl benzoate is hydrolyzed to convert into D-menthol and L-menthol, thereby achieving chiral separation of D-menthol and L-menthol in DL-menthol.

[0020] Among them, the derivative DL-menthol benzoate only requires conventional solvents and seed crystals for chiral resolution, without the need for expensive catalysts, and has relatively low equipment requirements. It can be scaled up. In addition, the preparation process is simple and easy to apply to large-scale industrial production. Finally, the mother liquor can also be recycled, reducing the waste of raw materials and solvents. High yields can be obtained through cyclic crystallization, thus realizing large-scale industrial production applications. Attached Figure Description

[0021] Figure 1 This is an apparatus diagram for the chiral resolution of DL-menthol benzoate in Example 1. Detailed Implementation

[0022] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0023] Example 1 This embodiment provides a chiral resolution method for DL-menthol benzoate, including the following: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure complete dissolution of the crystals. Then, reduce the temperature to 7℃ for 20min. When the temperature reaches 7℃, add 5wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 0.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first liquid. (2) A 7°C saturated DL-menthol ester solution was added to the first liquid by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). The obtained solution was added to a 100mL D-menthol ester crystallization vessel, the stirrer was turned on, the speed was set to 200rpm, and the temperature was heated to 20°C to ensure that no crystals were present in the solution. Then the temperature was lowered to 7°C for 20min. When the temperature reached 7°C, 5wt% of D-menthol ester seed crystals were added to the crystallization vessel (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount was 0.5g). The seed crystals were uniformly dispersed in the crystallizer and maintained for 15min. The resulting crystal slurry was then filtered to obtain the second solid and the second liquid.

[0024] The first and second solids obtained in Example 1 were tested and analyzed (testing instrument: high performance liquid chromatography), and it was found that the first solid was L-menthyl benzoate and the second solid was D-menthyl benzoate.

[0025] The purity (tested by high performance liquid chromatography) and yield of the first and second solids obtained in Example 1 were tested. The results showed that the purity of the first solid was 96.29% and the yield was 13.24%; the purity of the second solid was 96.32% and the yield was 12.86%. The formula for calculating the yield is as follows: .

[0026] Example 2 This embodiment provides a chiral resolution method for DL-menthol benzoate, including the following: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure that the crystals are completely dissolved. Then, reduce the temperature to 5℃ for 20min. When the temperature reaches 5℃, add 25wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 2.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first liquid. (2) A 5°C saturated DL-menthol ester solution was added to the first liquid by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). The resulting solution was added to a 100mL D-menthol ester crystallization vessel, the stirrer was turned on, the speed was set to 200rpm, and the temperature was heated to 20°C to ensure that no crystals were present in the solution. Then the temperature was lowered to 5°C for 20min. When the temperature reached 5°C, 25wt% of D-menthol ester seed crystals were added to the crystallization vessel (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount was 2.5g). The seed crystals were uniformly dispersed in the crystallizer and maintained for 15min. The resulting crystal slurry was then filtered to obtain the second solid and the second liquid.

[0027] The first and second solids obtained in Example 2 were subjected to the same tests as in Example 1, and it was found that the first solid was L-menthyl benzoate and the second solid was D-menthyl benzoate.

[0028] The purity and yield of the first and second solids obtained in Example 2 were tested in the same way as in Example 1. It was found that the purity of the first solid was 95.67% and the yield was 25.73%; the purity of the second solid was 96.92% and the yield was 20.33%.

[0029] Example 3 This embodiment provides a chiral resolution method for DL-menthol benzoate, including the following: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure that the crystals are completely dissolved. Then, reduce the temperature to 10℃ for 20min. When the temperature reaches 10℃, add 15wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 1.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first liquid. (2) Add 10℃ saturated DL-menthol ester solution to the first liquid by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). Add the obtained solution to a 100mL D-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, and heat to 20℃ to ensure that no crystals are present in the solution. Then, reduce the temperature to 10℃ for 20min. When the temperature reaches 10℃, add 15wt% D-menthol ester seed crystals to the crystallization vessel (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount is 1.5g), so that the seed crystals are uniformly dispersed in the crystallizer. After maintaining for 15min, filter the obtained crystal slurry to obtain the second solid and the second liquid.

[0030] The first and second solids obtained in Example 3 were subjected to the same tests as in Example 1, and it was found that the first solid was L-menthyl benzoate and the second solid was D-menthyl benzoate.

[0031] The purity and yield of the first and second solids obtained in Example 3 were tested in the same way as in Example 1. It was found that the purity of the first solid was 98.27% and the yield was 10.37%; the purity of the second solid was 97.38% and the yield was 9.85%.

[0032] Example 4 This embodiment provides a method for the sequential resolution of DL-menthyl benzoate, such as... Figure 1 As shown, it includes the following steps: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure that the crystals are completely dissolved. Then, reduce the temperature to 7℃ for 20min. When the temperature reaches 7℃, add 5wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 0.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first filtrate.

[0033] (2) Add 7°C saturated DL-menthol ester solution to the first filtrate by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). Add the obtained solution to a 100mL D-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, and heat to 20°C to ensure that no crystals are present in the solution. Then, reduce the temperature to 7°C for 20min. When the temperature reaches 7°C, add 5wt% D-menthol ester seed crystals to the crystallization vessel (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount is 0.5g), so that the seed crystals are uniformly dispersed in the crystallizer. After maintaining for 15min, filter the obtained crystal slurry to obtain the second solid and the second filtrate.

[0034] (3) Add DL-menthol ester raw material to the obtained second filtrate (additional mass = sum of the net weights of L-menthol ester and D-menthol ester crystals obtained in steps (1) and (2)). Add 7°C saturated DL-menthol ester solution to the mother liquor by mass balance (additional mass = initial raw material mass + initial methanol mass - total weight of the solution after adding raw material). The obtained solution is circulated in the L-crystallization vessel and crystallizes simultaneously with the D-crystallization vessel. After five cycles, collect all the obtained first and second solids.

[0035] The first and second solids obtained in Example 4 were subjected to the same tests as in Example 1. It was found that during the cycling process, the first solid was always L-menthyl benzoate and the second solid was always D-menthyl benzoate.

[0036] The first and second solids obtained in Example 4 were subjected to the same tests and analyses as in Example 1: (1) High performance liquid chromatography test: The purity of the product obtained in each cycle is shown in Table 1.

[0037] Table 1 Purity of products obtained from each cycle step in Example 4 Crystallization process Product purity First L-ester crystallization L-96.29% First D ester crystallization D-96.32% Second L-ester crystallization L-96.18% Second D ester crystallization D-96.31% Third L-ester crystallization L-95.67% Third D ester crystallization D-93.99% Fourth L-ester crystallization L-95.38% Fourth D ester crystallization D-96.10% Fifth L-ester crystallization L-94.59% Fifth D ester crystallization D-95.89% (2) Yield analysis: Based on Calculations of the actual yields show that the final yields of L-menthol and D-menthol products in this example are 35.15% and 32.76%, respectively.

[0038] Example 5 This embodiment provides a method for the sequential resolution of DL-menthyl benzoate, such as... Figure 1 As shown, it includes the following steps: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure complete dissolution of the crystals. Then, reduce the temperature to 5℃ for 20min. When the temperature reaches 5℃, add 25wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 2.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first filtrate.

[0039] (2) Add 5°C saturated DL-menthol ester solution to the first filtrate by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). Add the obtained solution to a 100mL D-menthol ester crystallizer, turn on the stirrer, set the speed to 200rpm, and heat to 20°C to ensure that no crystals are present in the solution. Then, reduce the temperature to 5°C for 20min. When the temperature reaches 5°C, add 25wt% D-menthol ester seed crystals to the crystallizer (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount is 2.5g), so that the seed crystals are uniformly dispersed in the crystallizer. After maintaining for 15min, filter the obtained crystal slurry to obtain the second solid and the second filtrate.

[0040] (3) Add DL-menthol ester raw material to the obtained second filtrate (additional mass = sum of the net weights of L-menthol ester and D-menthol ester crystals obtained in steps (1) and (2)). Add 5°C saturated DL-menthol ester solution to the mother liquor by mass balance (additional mass = initial raw material mass + initial methanol mass - total weight of the solution after adding raw material). The obtained solution is circulated in the L-crystallization vessel and crystallizes simultaneously with the D-crystallization vessel. After five cycles, collect all the obtained first and second solids.

[0041] The first and second solids obtained in Example 5 were subjected to the same tests as in Example 1. It was found that during the cycling process, the first solid was always L-menthyl benzoate and the second solid was always D-menthyl benzoate.

[0042] The first and second solids obtained in Example 5 were subjected to the same tests and analyses as in Example 1: (1) High performance liquid chromatography test: The purity of the product obtained in each cycle is shown in Table 1.

[0043] Table 1. Purity of products obtained from each cycle step in Example 4 Crystallization process Product purity First L-ester crystallization L-96.36% First D ester crystallization D-96.78% Second L-ester crystallization L-96.52% Second D ester crystallization D-96.58% Third L-ester crystallization L-95.81% Third D ester crystallization D-96.25% Fourth L-ester crystallization L-95.91% Fourth D ester crystallization D-96.53% Fifth L-ester crystallization L-95.68% Fifth D ester crystallization D-95.72% (2) Yield analysis: It can be seen that the final yields of L-menthol ester and D-menthol ester products in this example are 37.05% and 34.98%, respectively.

[0044] Example 6 This embodiment provides a method for the sequential resolution of DL-menthyl benzoate, such as... Figure 1 As shown, it includes the following steps: (1) Add 20g of DL-menthol ester and 50g of methanol to a 100mL L-menthol ester crystallization vessel, turn on the stirrer, set the speed to 200rpm, heat to 20℃ and maintain for 20min to ensure that the crystals are completely dissolved. Then, reduce the temperature to 10℃ for 20min. When the temperature reaches 10℃, add 15wt% of L-menthol ester seed crystals to the crystallization vessel (calculated based on 10g of L-menthol ester in the raw material, the amount of seed crystals added is 1.5g), so that the seed crystals are evenly dispersed in the crystallizer. Maintain for 15min and filter the resulting crystal slurry to obtain the first solid and the first filtrate.

[0045] (2) Add 10℃ saturated DL-menthol ester solution to the first filtrate by mass balance (additional mass = raw material mass + methanol mass - net weight of obtained L-menthol ester crystals). Add the obtained solution to a 100mL D-menthol ester crystallizer, turn on the stirrer, set the speed to 200rpm, and heat to 20℃ to ensure that no crystals are present in the solution. Then, reduce the temperature to 10℃ for 20min. When the temperature reaches 10℃, add 15wt% D-menthol ester seed crystals to the crystallizer (calculated based on the initial raw material D-menthol ester mass of 10g, the seed crystal addition amount is 1.5g), so that the seed crystals are uniformly dispersed in the crystallizer. After maintaining for 15min, filter the obtained crystal slurry to obtain the second solid and the second filtrate.

[0046] (3) Add DL-menthol ester raw material to the obtained second filtrate (additional mass = sum of the net weights of L-menthol ester and D-menthol ester crystals obtained in steps (1) and (2)). Add 10℃ saturated DL-menthol ester solution to the mother liquor by mass balance (additional mass = initial raw material mass + initial methanol mass - total weight of the solution after adding raw material). The obtained solution is circulated in the L-crystallization vessel and crystallizes simultaneously with the D-crystallization vessel. After five cycles, collect all the obtained first and second solids.

[0047] The first and second solids obtained in Example 6 were subjected to the same tests as in Example 1. It was found that during the cycling process, the first solid was always L-menthyl benzoate and the second solid was always D-menthyl benzoate.

[0048] The first and second solids obtained in Example 6 were subjected to the same tests and analyses as in Example 1: (1) High performance liquid chromatography test: The purity of the product obtained in each cycle is shown in Table 1.

[0049] Table 1. Purity of products obtained from each cycle step in Example 4 Crystallization process Product purity First L-ester crystallization L-96.28% First D ester crystallization D-96.72% Second L-ester crystallization L-96.86% Second D ester crystallization D-96.73% Third L-ester crystallization L-95.29% Third D ester crystallization D-96.19% Fourth L-ester crystallization L-95.53% Fourth D ester crystallization D-95.72% Fifth L-ester crystallization L-95.15% Fifth D ester crystallization D-96.85% (2) Yield analysis: It can be seen that the final yields of L-menthol ester and D-menthol ester products in this example are 33.55% and 31.27%, respectively.

[0050] Example 7 This embodiment provides a method for preparing D-menthol and / or L-menthol, comprising: (1) D-menthyl benzoate and L-menthyl benzoate were prepared by the method in Example 4; (2) The D-menthyl benzoate or L-menthyl benzoate obtained in step (1) is subjected to alkaline hydrolysis at 70°C for 7 h in the presence of methanol to obtain D-menthol or L-menthol.

[0051] The product obtained in this embodiment was tested and found to be D-menthol and L-menthol.

[0052] The purity of the obtained D-menthol and L-menthol was tested, and it was found that the purity of D-menthol was 99.25% and the purity of L-menthol was 99.18%.

[0053] Example 8 This embodiment provides a method for preparing D-menthol and / or L-menthol, comprising: (1) D-menthyl benzoate and L-menthyl benzoate were prepared by the method in Example 5; (2) The D-menthyl benzoate or L-menthyl benzoate obtained in step (1) is subjected to alkaline hydrolysis at 60°C for 6 h in the presence of methanol to obtain D-menthol or L-menthol.

[0054] The product obtained in this embodiment was tested and found to be D-menthol and L-menthol.

[0055] The purity of the obtained D-menthol and L-menthol was tested, and it was found that the purity of D-menthol was 98.58% and the purity of L-menthol was 98.31%.

[0056] Example 9 This embodiment provides a method for preparing D-menthol and / or L-menthol, comprising: (1) D-menthyl benzoate and L-menthyl benzoate were prepared by the method of Example 6; (2) The D-menthyl benzoate or L-menthyl benzoate obtained in step (1) is subjected to alkaline hydrolysis at 80°C for 8 h under the action of methanol to obtain D-menthol or L-menthol.

[0057] The product obtained in this embodiment was tested and found to be D-menthol and L-menthol.

[0058] The purity of the obtained D-menthol and L-menthol was tested, and it was found that the purity of D-menthol was 99.25% and the purity of L-menthol was 99.03%.

[0059] Example 10 This embodiment provides a chiral resolution method for DL-menthol, including the following steps: (1) DL-menthol and methyl benzoate were added to toluene containing 30% sodium methoxide at a molar ratio of 1:1.2 (based on 26 g of DL-menthol and 800 mL of solvent). The mixture was refluxed for 6 h under the action of sodium methoxide / magnesium oxide solid alkali catalyst (based on 26 g of DL-menthol and 2.3 g of catalyst) to obtain DL-menthol benzoate. (2) D-menthol and L-menthol were prepared by repeating the preparation method of Example 7.

[0060] The D-menthol and L-menthol obtained in Example 10 were tested and found that the purity of D-menthol was 99.21% and the purity of L-menthol was 99.13%.

[0061] Example 11 This embodiment provides a chiral resolution method for DL-menthol, including the following steps: (1) DL-menthol and methyl benzoate were added to toluene containing 20% ​​sodium methoxide (based on 26 g of DL-menthol and 500 mL of solvent) at a molar ratio of 1:1. The mixture was refluxed for 2 h under the action of sodium methoxide / magnesium oxide solid alkali catalyst (based on 26 g of DL-menthol and 2.6 g of catalyst) to obtain DL-menthol benzoate. (2) D-menthol and L-menthol were prepared by repeating the preparation method of Example 8.

[0062] The D-menthol and L-menthol obtained in Example 11 were tested and found that the purity of D-menthol was 98.53% and the purity of L-menthol was 98.15%.

[0063] Example 12 This embodiment provides a chiral resolution method for DL-menthol, including the following steps: (1) DL-menthol and methyl benzoate were added to toluene containing 40% sodium methoxide (based on 26 g of DL-menthol and 1000 mL of solvent) at a molar ratio of 1:1.5. The mixture was refluxed for 5 h under the action of sodium methoxide / magnesium oxide solid base catalyst (based on 26 g of DL-menthol and 1.3 g of solvent) to obtain DL-menthol benzoate. (2) D-menthol and L-menthol were prepared by repeating the preparation method of Example 9.

[0064] The D-menthol and L-menthol obtained in Example 12 were tested and found that the purity of D-menthol was 99.21% and the purity of L-menthol was 99.20%.

[0065] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A chiral resolution method for DL-menthol benzoate, characterized in that, The chiral decomposition method includes: (1) Under stirring conditions, racemic DL-menthol benzoate raw material is added to the solvent and dissolved at 10-20℃ to form a saturated solution; (2) Slowly cool the saturated solution obtained in step (1) to 5-10℃, add L-menthol benzoate seed crystals, crystallize, and separate the solid and liquid to obtain the first solid and the first liquid; (3) Add the liquid obtained in step (2) to the saturated solution obtained in step (1), heat to 10-20℃, then slowly cool to 5-10℃, add D-menthol benzoate seed crystals, crystallize, separate solid and liquid to obtain the second solid and the second liquid.

2. The chiral decomposition method according to claim 1, characterized in that, In step (1), the composition of L-menthyl benzoate in the racemic DL-menthyl benzoate raw material is not less than 50%; Preferably, the preparation method of the racemic DL-menthyl benzoate raw material in step (1) includes: under stirring conditions, dissolving the DL-menthyl benzoate raw material in a solvent, heating to 10-20℃ to dissolve, slowly cooling to 5-10℃, adding L-menthyl benzoate seed crystals, maintaining for 8-15 min, separating the solid and liquid, removing the solvent from the separated liquid, and obtaining the racemic DL-menthyl benzoate raw material; Preferably, the solvent is methanol; Preferably, based on an addition amount of 220g of DL-menthol benzoate raw material, the addition amount of solvent is 450-550g; Preferably, the amount of L-menthyl benzoate seed crystals added is 5-25 wt% of the L-menthyl benzoate contained in the DL-menthyl benzoate raw material; Preferably, the solvent removal method is rotary evaporation.

3. The chiral decomposition method according to claim 1, characterized in that, The solvent in step (1) is methanol; Preferably, based on the addition amount of racemic DL-menthol benzoate raw material of 260g, the addition amount of solvent in step (1) is 450-550g; Preferably, the cooling rate in step (2) is 0.2-0.5℃ / min; Preferably, the crystallization time in step (2) is 30-60 min; Preferably, the solid-liquid separation method in step (2) is filtration; Preferably, in step (2), the first solid is L-menthol benzoate; Preferably, the amount of saturated solution added in step (3) is the sum of the mass of the raw material and methanol, minus the mass of the first solid obtained in step (2); Preferably, the cooling rate in step (3) is 0.2-0.5℃ / min; Preferably, the crystallization time in step (3) is 30-60 min; Preferably, the solid-liquid separation method in step (3) is filtration.

4. The chiral separation method according to claim 1, characterized in that, The chiral separation method further includes: adding the second liquid obtained in step (3) to the saturated solution obtained in step (1), heating to 10-20℃, repeating steps (2) and (3) n times, where n is 0-10, and collecting and merging the first solid and the second solid.

5. D-menthyl benzoate and / or L-menthyl benzoate are prepared by the preparation method according to any one of claims 1-4.

6. The menthyl D-benzoate and / or menthyl L-benzoate according to claim 5, characterized in that, The purity of the D-menthol benzoate is 93-98%; Preferably, the purity of the L-menthol benzoate is 93-98%; Preferably, the yield of the D-menthol benzoate is 8-36%; Preferably, the yield of the L-menthol benzoate is 8-33%.

7. A method for preparing D-menthol and / or L-menthol, characterized in that, The preparation method includes: A1. D-menthyl benzoate and / or L-menthyl benzoate are prepared by the preparation method according to any one of claims 1-4; A2. The D-menthyl benzoate and / or L-menthyl benzoate obtained in step A1 are subjected to a hydrolysis reaction to obtain D-menthol and / or L-menthol; Preferably, the hydrolysis reaction in step A2 is carried out in the presence of methanol or sodium methoxide; Preferably, the hydrolysis temperature is 60-80℃ and the hydrolysis time is 6-8 h.

8. A chiral resolution method for DL-menthol, characterized in that, The chiral decomposition method includes: B1. Add DL-menthol and methyl benzoate to a solvent and reflux under the action of a catalyst to obtain DL-menthol benzoate. B2. D-menthyl benzoate and / or L-menthyl benzoate are prepared by the preparation method described in any one of claims 1-4; B3. The D-menthyl benzoate and / or L-menthyl benzoate obtained in step B2 are subjected to a hydrolysis reaction to obtain D-menthol and / or L-menthol.

9. The chiral separation method according to claim 8, characterized in that, The solvent mentioned in step B1 is toluene containing 20-40% sodium methoxide; Preferably, based on an addition amount of DL-menthol of 260g, the addition amount of solvent in step B1 is 500-1000mL; Preferably, the molar ratio of DL-menthol and methyl benzoate in step B1 is 1:1 to 1:1.5; Preferably, the catalyst in step B1 is a sodium methoxide / magnesium oxide type solid base; Preferably, based on an addition amount of 260g of DL-menthol, the addition amount of the catalyst in step B1 is 5-10wt%; Preferably, the reaction temperature in step B1 is 60-80°C, and the reaction time is 2-5 hours.

10. The method for preparing D-menthol and / or L-menthol according to claim 7 yields D-menthol and / or L-menthol; Alternatively, D-menthol and / or L-menthol can be prepared by the chiral resolution method of DL-menthol according to claim 8 or 9.

Images