Purification method of chlorinated menthol
Through a multi-step purification method, including alkaline alcoholylation, sulfuric acid washing, sodium bicarbonate washing and distillation, the purity of L-chloromint was successfully improved, and the problem of insufficient purity in the prior art was solved, so as to achieve the realization of the problem of insufficient purity in the prior art. The acquisition of high content products.
Patent Information
- Application Number
- CN202411669295.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-21
- Publication Date
- 2025-02-25
AI Technical Summary
The existing L-chloromentum synthesis methods cannot effectively improve the purity of the product, resulting in the inability to meet the purity requirements in subsequent reactions.
A purification method including multiple steps is adopted: first obtaining the primary purification solution by alkaline alcoholylation and distillation, then obtaining the intermediate purification solution by multiple sulfuric acid washing, then washing with sodium bicarbonate water to neutral and drying, and finally Distillation results in high content of L-chloromint.
The purity of L-chloromint is effectively improved. The content of L-chloromint in the product is greater than 95%, avoiding the impact of impurities on subsequent reactions, and the purification steps are simple and efficient.
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Figure CN119504347A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical purification, and in particular to a method for purifying chloromenthol. Background Art
[0002] L-Chloromenthol CAS: 16052-42-9, also known as L-chloromenthol or L-chloromenthane, is a chlorinated product of L-menthol. It is mainly used to prepare food additives such as synthetic cooling agent WS-3 (N-ethyl-2-isopropyl-5-methylcyclohexaneamide) / WS-5 (N-(ethoxycarbonylmethyl)-p-menthyl-3-carboxamide) / WS-12 (N-(4-methoxyphenyl)-p-menthyl-3-carboxamide), and is an important intermediate. At the same time, this product is also a precursor for the preparation of tocopherol and anti-AIDS drugs.
[0003] The synthesis method of L-chloromenthol is disclosed in the prior art. For example, Zheng Wei et al.'s "Study on a New Method for Synthesizing Chloromenthane" proposed a new method for converting menthol into chloromenthane using selenium dioxide as a catalyst and trimethylsilyl chloride; Zhang Hongzhe's "Study on the Synthesis of Chloromenthol from L-menthol" used L-menthol as a raw material and synthesized chloromenthol through a chlorination reaction. The experiment compared the yields of the products in different chlorination reagents, catalysts and reaction media. The results showed that the reaction system had a great influence on the chlorination reaction. Under the conditions investigated, when phosphorus pentachloride was used as a chlorination reagent, aluminum chloride hexahydrate was used as a catalyst, and tetrahydrofuran was used as a solvent, the separation yield of the product was the highest, reaching 90%. Furthermore, the separated product was tested and characterized by infrared spectroscopy and refractive index, indicating that a high-purity product can be obtained through a simple distillation process.
[0004] L-chloromenthol is a precursor for preparing menthyl formic acid, and its purity directly affects the purity of menthyl formic acid. However, the product content formed by the existing synthesis method is not high, and it cannot be further purified by the existing synthesis method, and high-purity chloromenthol cannot be obtained.
[0005] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention
[0006] In order to solve the above technical defects, the technical solution adopted by the present invention is to provide a method for purifying chloromenthol, comprising the steps of:
[0007] S1, heating and stirring the crude L-chloromenthol and the alcoholysis liquid to perform alkaline alcoholysis, distilling off the solvent and then washing with water, allowing to stand for stratification to form an alcoholysis aqueous phase liquid at a lower layer and an alcoholysis oil phase liquid at an upper layer, wherein the alcoholysis oil phase liquid is a primary purified liquid;
[0008] S2, adding concentrated sulfuric acid to the preliminary oil liquid, stirring, performing multiple sulfuric acid washings and standing for stratification to obtain an intermediate purified liquid located in an upper layer;
[0009] S3, washing the intermediate purified liquid with sodium bicarbonate water until it becomes neutral, drying, filtering, and obtaining a final purified liquid;
[0010] S4, the final purified liquid is distilled to obtain L-chloromenthol finished product.
[0011] The content of L-chloromenthol in the crude L-chloromenthol product is 70% to 90%, and the content of L-chloromenthol in the finished L-chloromenthol product is greater than 95%.
[0012] Preferably, in said step S2, the steps are included:
[0013] S21, adding concentrated sulfuric acid to the preliminary purified solution, stirring for 30 minutes and then standing to separate layers;
[0014] S22, extracting the pickling oil phase liquid located at the upper layer after standing and stratifying in the previous step, adding concentrated sulfuric acid to the pickling oil phase liquid, stirring for 30 minutes, and then standing and stratifying;
[0015] S23, repeating step S22 for 3 to 5 times to obtain the intermediate purified liquid located in the upper layer of the static stratification.
[0016] Preferably, in step S1, the alcoholysis solution is obtained by mixing an alkali agent, an alcohol agent and water, wherein the alkali agent is one of sodium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide, and the alcohol agent is one of ethanol, methanol, isopropanol, propylene glycol and ethylene glycol.
[0017] Preferably, in the step S1, the mass ratio of the alkali agent to the crude L-chloromenthol is: alkali agent: L-chloromenthol = (0.01-0.1):1.
[0018] Preferably, when the alkaline agent is potassium hydroxide or sodium hydroxide, the concentration of potassium hydroxide or sodium hydroxide in the alcoholysis solution is 0.1% to 10%.
[0019] Preferably, the mass ratio of the concentrated sulfuric acid and the crude L-chloromenthol in step S2 is: concentrated sulfuric acid: crude L-chloromenthol = (0.1-1):1.
[0020] Preferably, the mass ratio of the concentrated sulfuric acid and the crude L-chloromenthol in step S2 is: concentrated sulfuric acid: crude L-chloromenthol = (0.2-1): 1
[0021] Preferably, in step S3, the desiccant used in the drying process is one or more of anhydrous calcium chloride, anhydrous magnesium sulfate, and anhydrous sodium sulfate.
[0022] Preferably, in step S4, reduced pressure distillation is used during the distillation process.
[0023] Preferably, in step S4, reduced pressure molecular distillation is used during the distillation process.
[0024] Compared with the prior art, the beneficial effect of the present invention is that the present invention removes impurities in the crude product, increases the product content to more than 95%, avoids the influence of impurities on subsequent reactions, and has the advantages of simple purification steps and high efficiency. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 is the chromatogram of crude L-chloromenthol before purification;
[0026] Figure 2 The figure is a chromatogram of the L-chloromenthol product after purification by the present invention. DETAILED DESCRIPTION
[0027] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.
[0028] like Figure 1 and Figure 2 As shown, Figure 1 is the chromatogram of crude L-chloromenthol before purification. Figure 2 The figure is a chromatogram of the L-chloromenthol product after purification by the present invention.
[0029] The purification method of chloromenthol of the present invention comprises the steps of:
[0030] S1, heating and stirring the crude L-chloromenthol product (content 70% to 90%) and the alcoholysis liquid to perform alkaline alcoholysis, distilling off the solvent and then washing with water, allowing to stand and separate to form an alcoholysis aqueous phase liquid at a lower layer and an alcoholysis oil phase liquid at an upper layer, wherein the alcoholysis oil phase liquid is the primary purified liquid;
[0031] S2, adding concentrated sulfuric acid to the preliminary oil liquid and stirring to perform sulfuric acid washing, and allowing to stand for stratification to obtain an intermediate purified liquid located in an upper layer;
[0032] S3, washing the intermediate purified liquid with sodium bicarbonate water until it becomes neutral, drying, filtering, and obtaining a final purified liquid;
[0033] S4, the final purified liquid is distilled to obtain a high-content (>95%) L-chloromenthol finished product.
[0034] Preferably, in said step S2, the steps are included:
[0035] S21, adding concentrated sulfuric acid to the preliminary purified solution, stirring for 30 minutes and then standing to separate layers;
[0036] S22, extracting the pickling oil phase liquid located at the upper layer after standing and stratifying in the previous step, adding concentrated sulfuric acid to the pickling oil phase liquid, stirring for 30 minutes, and then standing and stratifying;
[0037] S23, repeating step S22 for 3 to 5 times to obtain the intermediate purified liquid located in the upper layer of the static stratification.
[0038] Preferably, in step S1, the alcoholysis solution is obtained by mixing an alkali agent, an alcohol agent and water, wherein the alkali agent is one of sodium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide, and the alcohol agent is one of ethanol, methanol, isopropanol, propylene glycol and ethylene glycol.
[0039] Specifically, the alcohol agent and water are first mixed, heated and stirred, and then the crude L-chloromenthol product is added. After the crude L-chloromenthol product is added, the alkali agent is added in stages, the amount of the alkali agent added in the latter time is less than the amount of the alkali agent added in the previous time, and the interval between two adjacent additions of the alkali agent is 2h to 8h.
[0040] Preferably, in the step S1, the mass ratio of the alkali agent to the crude L-chloromenthol is: alkali agent: L-chloromenthol = (0.01-0.1):1.
[0041] Preferably, when the alkaline agent is potassium hydroxide or sodium hydroxide, the concentration of potassium hydroxide or sodium hydroxide in the alcoholysis solution is 0.1% to 10%.
[0042] Preferably, the mass ratio of the concentrated sulfuric acid and the crude L-chloromenthol in step S2 is: concentrated sulfuric acid: crude L-chloromenthol = (0.1-1):1.
[0043] Preferably, the mass ratio of the concentrated sulfuric acid and the crude L-chloromenthol in step S2 is: concentrated sulfuric acid: crude L-chloromenthol = (0.2-1): 1
[0044] Preferably, in step S3, the desiccant used in the drying process is one or more of anhydrous calcium chloride, anhydrous magnesium sulfate, and anhydrous sodium sulfate.
[0045] Preferably, in step S4, vacuum distillation is used during the distillation process, preferably vacuum molecular distillation.
[0046] The invention is simple to operate, has significant effects, does not require chromatography purification, and is easy to industrialize; and can increase the low content of L-chloromenthol to more than 95%, thereby ensuring the normal development of subsequent reactions and providing a guarantee for the subsequent production of cooling agent series products.
[0047] Embodiment 1
[0048] Methanol (250 g) and water (50 g) were added to a 1L round-bottom flask equipped with a condenser and stirred at 90°C. 200 g of crude menthyl chloride mixture (purity 79.4%) was added to the above mixture. 30 drops of phenolphthalein indicator solution (ethanol solution containing 1% phenolphthalein) were added, and then 8.0 g of KOH was added, which dissolved and showed violet color, indicating the alkalinity of the culture medium, and stirred for 8 hours. Another 4.0 g of KOH was added, and after 2 hours, another portion of 2.0 g of KOH was added, and the mixture was stirred for 3 hours. Most of the methanol was recovered by vacuum decompression, and the organic phase was washed once with water (100 mL) and n-hexane (200 mL).
[0049] The organic phase was washed with concentrated sulfuric acid 3 times, 40 ml each time, and then washed with 100 ml of distilled water and 40 ml of saturated sodium bicarbonate aqueous solution. The oil phase was dried with anhydrous magnesium sulfate, filtered and molecularly distilled. The total mass of the main components collected was 155.40 g (content 95.2%). Calculated yield: 93.16% (calculated as chloromenthol).
[0050] Embodiment 2
[0051] In a 1L round-bottom flask equipped with a condenser, add anhydrous ethanol (270 g) and water (30 g) and stir at 90°C. Add 200 g of crude menthyl chloride mixture (purity 79.4%) to the above mixture, add 30 drops of phenolphthalein indicator solution (ethanol solution containing 1% phenolphthalein), then add 9.40 g of NaOH, dissolve and show violet color, indicating the alkalinity of the culture medium, and stir for 8 hours. Add another 7.0 g of NaOH, and after 2 hours, add another portion of 2.45 g of NaOH, and stir the mixture for 3 hours. After vacuum decompression to recover most of the ethanol, wash the organic phase once with water (100 mL) and n-hexane (200 ml).
[0052] The organic phase was washed with concentrated sulfuric acid 5 times, 36 ml each time, and then washed with 100 ml of distilled water and 40 ml of saturated sodium bicarbonate aqueous solution. The oil phase was dried with anhydrous sodium sulfate, filtered and molecularly distilled. The total mass of the main components collected was 148.18 g (content 96.2%). Calculated yield: 89.76% (calculated as chloromenthol).
[0053] Embodiment 3
[0054] Add isopropanol (240 g) and water (60 g) to a 1L round-bottom flask equipped with a condenser and stir at 90°C. Add 200 g of crude menthyl chloride mixture (purity 79.4%) to the above mixture, add 30 drops of phenolphthalein indicator solution (ethanol solution containing 1% phenolphthalein), then add 4.0 g of sodium ethoxide, dissolve and show violet color, indicating the alkalinity of the culture medium, and stir for 8 hours. Add 2.0 g of sodium ethoxide, and after 2 hours, add a portion of 1.0 g of sodium ethoxide, and stir the mixture for 3 hours. After vacuum decompression to recover most of the isopropanol, wash the organic phase once with water (100 mL) and n-hexane (200 mL).
[0055] The organic phase was washed once with concentrated sulfuric acid, 40 ml each time, and then washed with 100 ml of distilled water and 40 ml of saturated sodium bicarbonate aqueous solution. The oil phase was dried over anhydrous magnesium sulfate, filtered and molecularly distilled. The total mass of the main components collected was 160.5 g (content 95.0%). Calculated yield: 96.2% (calculated as chloromenthol).
[0056] Embodiment 4
[0057] Add propylene glycol (260 g) and water (40 g) to a 1L round-bottom flask equipped with a condenser and stir at 95°C. Add 200 g of crude menthyl chloride mixture (purity 79.4%) to the above mixture, add 30 drops of phenolphthalein indicator solution (ethanol solution containing 1% phenolphthalein), then add 8.0 g of sodium methoxide, dissolve and show violet color, indicating the alkalinity of the culture medium, and stir for 8 hours. Add 4.0 g of sodium methoxide, and after 2 hours, add a portion of 1.0 g of sodium methoxide, and stir the mixture for 3 hours. After vacuum decompression to recover most of the isopropanol, wash the organic phase once with water (100 mL) and n-hexane (200 mL).
[0058] The organic phase was washed twice with concentrated sulfuric acid, 40 ml each time, and then washed with 100 ml of distilled water and 40 ml of saturated sodium bicarbonate aqueous solution. The oil phase was dried over anhydrous magnesium sulfate, filtered and molecularly distilled. The total mass of the main components collected was 155.0 g (content 95.5%). Calculated yield: 93.2% (calculated as chloromenthol).
[0059] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.
Claims
1. A method for purifying chloromenthol, characterized in that: Includes steps: S1, heating and stirring the crude chloromenthol and the alcoholysis liquid to perform alkaline alcoholysis, distilling off the solvent and then washing with water, allowing to stand for stratification to form an alcoholysis aqueous phase liquid at a lower layer and an alcoholysis oil phase liquid at an upper layer, wherein the alcoholysis oil phase liquid is a primary purified liquid; S2, adding concentrated sulfuric acid to the preliminary oil liquid, stirring, performing multiple sulfuric acid washings and standing for stratification to obtain an intermediate purified liquid located in an upper layer; S3, washing the intermediate purified liquid with water until it is neutral, drying, and filtering to obtain a final purified liquid; S4, the final purified liquid is distilled to obtain a chloromenthol product.
2. The method for purifying chloromenthol as claimed in claim 1, characterized in that: In the step S2, the steps are included: S21, adding concentrated sulfuric acid to the preliminary purified solution, stirring for 30 minutes and then standing to separate layers; S22, extracting the pickling oil phase liquid located at the upper layer after standing and stratifying in the previous step, adding concentrated sulfuric acid to the pickling oil phase liquid, stirring for 30 minutes, and then standing and stratifying; S23, repeating step S22 for 3 to 5 times to obtain the intermediate purified liquid located in the upper layer of the static stratification.
3. The method for purifying chloromenthol as claimed in claim 2, characterized in that: In the step S1, the alcoholysis solution is obtained by mixing an alkali agent, an alcohol agent and water, wherein the alkali agent is one of sodium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide, and the alcohol agent is one of ethanol, methanol, isopropanol, propylene glycol and ethylene glycol.
4. The method for purifying chloromenthol as claimed in claim 3, characterized in that: In the step S1, the mass ratio of the alkali agent to the crude chloromenthol is: alkali agent: chloromenthol = (0.01-0.1):
1.
5. The method for purifying chloromenthol as claimed in claim 3, characterized in that: When the alkaline agent is potassium hydroxide or sodium hydroxide, the concentration of potassium hydroxide or sodium hydroxide in the alcoholysis solution is 0.1% to 10%.
6. The method for purifying chloromenthol as claimed in claim 2, characterized in that: The mass ratio of the concentrated sulfuric acid to the crude chloromenthol in step S2 is: concentrated sulfuric acid: crude chloromenthol = (0.1-1):
1.
7. The method for purifying chloromenthol as claimed in claim 2, characterized in that: The mass ratio of the concentrated sulfuric acid to the crude chloromenthol in step S2 is: concentrated sulfuric acid: crude chloromenthol = (0.2-1):
1.
8. The method for purifying chloromenthol as claimed in claim 1, characterized in that: In step S3, the desiccant used in the drying process is one or more of anhydrous calcium chloride, anhydrous magnesium sulfate, and anhydrous sodium sulfate.
9. The method for purifying chloromenthol as claimed in claim 1, characterized in that: In the step S4, reduced pressure distillation is used in the distillation process.
10. The method for purifying chloromenthol according to claim 1, characterized in that: In the step S4, reduced pressure molecular distillation is used in the distillation process.