Method for preparing N-ethyl-L-menthyl formamide by continuous flow technology
Through continuous flow technology, the method of synthesising N-ethyl-L-mint-based formamide in multiple steps has solved the problems of low total reaction yield, high reaction risk and low product quality in the prior art, and achieved an efficient and stable preparation process, with a total yield of more than 87%.
Patent Information
- Application Number
- CN202411874332.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-19
- Publication Date
- 2025-05-06
AI Technical Summary
In the prior art, the total reaction yield of N-ethyl-L-menthol-formamide is low, the reaction risk is high, and the product quality is not high.
Using continuous flow technology, L-menthol-based chloride was synthesized by chlorination of L-menthol and dimethylsulfoxide, followed by reaction with metal magnesium to form L-menthol-based magnesium chloride, and reacted with CO2 to form L-menthol-formic acid, and finally N-ethyl-L-menthol-formamide was synthesized by acid chloride and amidation reaction.
The total yield of reactions is improved, the risk of reaction is reduced, and the quality of the product is significantly improved, with the total yield reaching more than 87%.
Smart Images
Figure BDA0005196493850000021 
Figure FDA0005196493840000011
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for preparing N-ethyl-L-menthylformamide using a continuous flow technology. Background Art
[0002] Cooling agents are a general term for all chemical substances that can produce a cooling effect and are not strong in medicinal properties. Because they can give a feeling of coolness and freshness, and have a refreshing and awakening effect, they are essential additives in people's daily lives and are widely used in products in the fields of food, daily chemicals, tobacco and medicine. Compared with traditional cooling agents, N-ethyl-L-menthyl carboxamide (WS-3) cooling agents have the advantages of a stronger cooling feeling, no strong mint taste, no bitterness, almost non-toxicity and pleasant aroma, and are deeply loved by people. However, there is still a certain degree of difficulty in its synthesis, and there is no mature synthesis technology in China. At present, there is a possible route for the preparation of WS-3 reported in the literature: using L-menthol as a raw material, the product is obtained by chlorination, cyanation and Ritter reaction. Wang Yongsan, Li Chunrong and others chlorinated L-menthol with SOCl2, and then reacted with NaCN to obtain menthonitrile, and reacted with ethyl sulfate to obtain the target product.
[0003] Route 1 uses L-menthol as a raw material, undergoes chlorination, Grignard reaction, and then reacts with ethylamine to prepare the target product. The main disadvantage of this route is that menthyl chloride is not active enough, and the preparation of the corresponding Grignard reagent is difficult. The experiment requires strict anhydrous and oxygen-free reaction conditions. The total yield of the reaction is low, only about 30%.
[0004] Route 2 uses L-menthol as a raw material, and obtains the product through chlorination, cyanation and Ritter reaction. This method is simpler than the previous method, but it also has the problem of low yield, and there are selectivity problems in the cyanation reaction and Ritter reaction during the reaction process, which reduces the content of the (-)-N-ethyl-L-menthylcarboxamide with the strongest cooling feeling in the final product, and the product quality is not high. Summary of the invention
[0005] The object of the present invention is to provide a method for preparing N-ethyl-L-menthylformamide by continuous flow technology, so as to solve the problems of low total reaction yield, high reaction risk and low product quality in the prior art.
[0006] The purpose of the present invention can be achieved through the following technical solutions:
[0007] A method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology, the synthesis route of which is as follows:
[0008]
[0009] The specific preparation steps are as follows:
[0010] S1, L-menthyl alcohol and dimethyl sulfoxide are chlorinated to synthesize L-menthyl chloride;
[0011] S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran, and reacting with metal magnesium through a Grignard reagent continuous flow reactor to continuously synthesize an L-menthyl magnesium chloride reaction solution;
[0012] S3, continuously reacting the L-menthyl magnesium chloride reaction solution in step S2 with CO2 gas through a rotary cutting tubular reactor to synthesize L-menthyl formic acid;
[0013] S4, first reacting L-menthyl carboxylic acid with triphosgene through chlorination reaction, and then reacting it with ethylamine through amidation reaction to synthesize N-ethyl-L-menthyl carboxamide.
[0014] Step S1 uses thionyl chloride to chlorinate menthol, and the reaction temperature is maintained at about 20 to 40°C. During the chlorination of menthol, it is important to ensure that it is in an anhydrous state, otherwise thionyl chloride will react and decompose with water, resulting in poor chlorination effect and low yield. Step S2 also needs to ensure that it is in an anhydrous state during the reaction process. First, the reactor needs to be replaced with argon to ensure that there is no air in the reactor, and then an initiator is injected into the reactor, and the reactor is heated to about 60°C, and the feeding is stopped. The reactor is kept warm for a period of time. After that, the color of the solution in the reactor is blackened through the viewing window, and a large number of small bubbles are generated. There is a phenomenon of temperature rise, and the temperature rise is about 3 to 5°C. The temperature will drop for a period of time, and the reaction solution will turn black, indicating that the reaction is successfully initiated. After that, the raw materials are pumped into the reactor by a plunger pump for continuous reaction to synthesize L-menthyl magnesium chloride. When collecting, it is important to ensure that it is in an anhydrous state and refrigerated at low temperature. In step S3, a gas flow meter is used to measure CO2 during the reaction process, the temperature of the rotary cut tubular reactor is set, the reaction time is about 10 to 20 minutes, a back pressure valve needs to be added at the outlet of the reactor, the pressure required in the reactor is set, and the raw material feed pump is turned on to pass CO2 to react to obtain L-menthyl formic acid. In step S4, the acyl chloride reaction requires that L-menthyl formic acid be dissolved in dichloromethane, triphosgene is also dissolved in dichloromethane, the temperature of the reactor is set, the flow rate is set according to the reaction time, a plunger pump is used to feed the reaction, and the reaction solution is post-treated and then reacted with ethylamine to obtain N-ethyl L-menthyl formamide through amidation.
[0015] Furthermore, in the chlorination reaction process of step S1, the solvent is any one of dichloromethane, acetone, and acetonitrile, preferably dichloromethane.
[0016] Furthermore, in step S1, FeCl2 is used as a catalyst, and the mass fraction of the catalyst FeCl2 in the solvent is about 15%; the reaction temperature of the rotary cutting tube reactor is 5-30°C, and the rotation speed is 300-1200r / min; preferably, the temperature of the rotary cutting tube reactor is 25°C, and the rotation speed is 700r / min.
[0017] Furthermore, in the Grignard reaction process of step S2, the initiator is any one of iodine, ethyl bromide and Grignard reagent, preferably ethyl bromide; the initiator content is about 5%, and the initiation temperature is 50-85°C; further, the initiation temperature is 60°C.
[0018] Furthermore, during the CO2 reaction in step S3, the gas flow rate is 300-800 mL / min, preferably 400 mL / min, and further the reaction temperature is 10°C.
[0019] Furthermore, the solvent for dissolving L-menthyl carboxylic acid in step S4 is any one of dichloromethane, ethyl acetate and toluene.
[0020] Furthermore, in the acyl chloride reaction process of step S4, the molar ratio of L-menthyl carboxylic acid to triphosgene is 1:0.3 to 0.8, preferably 1:0.5.
[0021] Furthermore, the amount of ethylamine used in the amidation reaction of step S4 is 3 / 10 of the mass of L-menthyl carboxylic acid.
[0022] Beneficial effects of the present invention:
[0023] The present invention is a method for synthesizing N-ethyl-L-menthylformamide in multiple steps by using a continuous flow reactor. The entire process route involves two sets of equipment, a rotary cut tube reactor and a Grignard reagent continuous flow reactor. The rotary cut tube reactor has the advantages of strong mixing ability and high mass transfer coefficient. In the process of synthesizing N-ethyl-L-menthylformamide in multiple steps, it has obvious advantages in chlorination, acyl chloride and amidation reactions. With L-menthyl alcohol as the starting material, the continuous multiple-step synthesis of the target product is achieved. The Grignard reagent continuous flow reactor equipment changes the traditional reaction and feeding methods. The unique magnesium chips storage bin of this set of equipment is also the place where the Grignard reagent is produced. The pre-configured raw materials are used by a plunger pump. When the raw materials flow into the storage bin and contact with the magnesium chips, a reaction will occur. After the reaction is completed, the raw materials flow out of the reactor for collection, which shortens the reaction time and avoids side reactions in the kettle reaction process. The Grignard reagent obtained by continuous synthesis can be directly used as a raw material for continuous synthesis of downstream products for subsequent continuous reactions. In this way, the overall reaction system for the synthesis of some chemical products is connected in series, which reduces the cost while ensuring the stability of the provided Grignard reagent and reducing the fluctuation of product quality caused by different batches of Grignard reagents used. DETAILED DESCRIPTION
[0024] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0025] Embodiment 1
[0026] S1, take 100g L-menthyl alcohol and pack it into a bottle for stand-by use, 150g thionyl chloride and pack it into a bottle for stand-by use, 15g of FeCl2 is dissolved in 85g of dichloromethane, setting the reactor temperature to 25 ° C, the rotating speed is 700r / min, the flow rate of the plunger pump is set after stirring, three pumps are used to drive three raw materials into the reactor for reaction, the residence time is 5min, the reaction solution L-menthyl chloride is collected at the reaction outlet, and the post-processing is stand-by. The detection result shows that the content of menthyl chloride is 93%, and the yield is 95%.
[0027] S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran with a mass fraction of 30%, setting the reactor temperature to 60°C, starting the feed reaction after stabilization, with a residence time of 15 minutes, collecting the reaction liquid under argon protection at the outlet, and the detection result shows that there is no raw material remaining;
[0028] S3, using a pump to pump the reaction solution into the reactor, turning on the CO2 gas flowmeter, setting the gas flow rate to 400mL / min, setting the reactor temperature to 10°C, and collecting the reaction solution after the reaction is completed. After testing, no L-menthyl magnesium chloride remains, the L-menthyl formic acid content is 97%, and the yield is 88%.
[0029] S4, 100g L-menthol formic acid was dissolved in 200mL dichloromethane, 80g triphosgene was dissolved in 240mL dichloromethane, the temperature and speed in the reactor were set, the organic solution of menthyl formic acid and triphosgene was respectively pumped into the reactor for reaction for 5min, and the reaction solution was collected at the outlet; 30g ethylamine was dissolved in 150g water, 6g NaOH was added, and a solution was prepared, and a rotary cut tubular reactor was used to react for 15min to complete the amidation, the reaction solution was acidified to be neutral, and the reaction solution was extracted with ether, and the solvent was removed after drying to obtain the product N-ethyl-L-menthol formamide, the product content was 99%, the yield was 98%, and the crude product appearance was a slightly yellowish white solid. Taking L-menthol as the starting material, the total yield was 87%.
[0030] Embodiment 2
[0031] S1, take 100g L-menthol alcohol and pack it into a bottle for stand-by use, 150g thionyl chloride and pack it into a bottle for stand-by use, 15g FeCl2 is dissolved in 85g of dichloromethane, setting the reactor temperature is 20 ℃, the rotating speed is 800r / min, the flow rate of the plunger pump is set after stirring, three pumps are used to drive three raw materials into the reactor for reaction, the residence time is 7min, and the reaction solution L-menthol chloride is collected at the reaction outlet, and the aftertreatment is stand-by. The detection result shows that the content of menthyl chloride is 90%, and the yield is 93%.
[0032] S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran with a mass fraction of 35%, setting the reactor temperature to 65°C, starting the feed reaction after stabilization, with a residence time of 20 min, collecting the reaction liquid under argon protection at the outlet, and detecting that there is no raw material remaining;
[0033] S3, using a pump to pump the reaction solution into the reactor, turning on the CO2 gas flowmeter, setting the gas flow rate to 400mL / min, setting the reactor temperature to 10°C, and collecting the reaction solution after the reaction is completed. After testing, no L-menthyl magnesium chloride remains, the content of menthyl formic acid is 95%, and the yield is 80%.
[0034] S4, 100g L-menthol formic acid was dissolved in 200mL dichloromethane, 80g triphosgene was dissolved in 240mL dichloromethane, the temperature and speed in the reactor were set, the organic solution of menthyl formic acid and triphosgene was respectively pumped into the reactor for reaction for 5min, and the reaction solution was collected at the outlet; 30g ethylamine was dissolved in 150g water, 6g NaOH was added, and a solution was prepared, and a rotary cut tubular reactor was used to react for 15min to complete the amidation, the reaction solution was acidified to be neutral, and the reaction solution was extracted with ether, and the solvent was removed after drying to obtain the product N-ethyl-L-menthol formamide, the product content was 99%, the yield was 98%, and the crude product appearance was a slightly yellowish white solid. Taking L-menthol as the starting material, the total yield was 83%.
[0035] Embodiment 3
[0036] S1, take 100g L-menthyl alcohol and pack it into a bottle for stand-by use, 150g thionyl chloride and pack it into a bottle for stand-by use, 15g of FeCl2 is dissolved in 85g of dichloromethane, setting the reactor temperature to 25 ° C, the rotating speed is 700r / min, the flow rate of the plunger pump is set after stirring, three pumps are used to drive three raw materials into the reactor for reaction, the residence time is 5min, the reaction solution L-menthyl chloride is collected at the reaction outlet, and the post-processing is stand-by. The detection result shows that the content of menthyl chloride is 93%, and the yield is 95%.
[0037] S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran with a mass fraction of 30%, setting the reactor temperature to 60°C, starting the feed reaction after stabilization, with a residence time of 15 minutes, collecting the reaction liquid under argon protection at the outlet, and the detection result shows that there is no raw material remaining;
[0038] S3, using a pump to pump the reaction solution into the reactor, turning on the CO2 gas flowmeter, setting the gas flow rate to 600mL / min, setting the reactor temperature to 10°C, and collecting the reaction solution after the reaction is completed. After testing, no L-menthyl magnesium chloride remains, the content of menthyl formic acid is 95%, and the yield is 87%.
[0039] S4, 100g L-menthol formic acid was dissolved in 200mL dichloromethane, 80g triphosgene was dissolved in 240mL dichloromethane, the temperature and speed in the reactor were set, the organic solution of menthyl formic acid and triphosgene was respectively pumped into the reactor for reaction for 10min, and the reaction solution was collected at the outlet; 30g ethylamine was dissolved in 150g water, 6g NaOH was added, and a solution was prepared, and a rotary cut tubular reactor was used to react for 15min to complete the amidation, the reaction solution was acidified to be neutral, and the reaction solution was extracted with ether, and the solvent was removed after drying to obtain the product N-ethyl-L-menthol formamide, the product content was 99%, the yield was 98%, and the crude product appearance was a slightly yellowish white solid. Taking L-menthol as the starting material, the total yield was 81%.
[0040] Embodiment 4
[0041] S1, take 100g L-menthyl alcohol and pack it into a bottle for stand-by use, 150g thionyl chloride and pack it into a bottle for stand-by use, 15g of FeCl2 is dissolved in 85g of dichloromethane, setting the reactor temperature to 25 ° C, the rotating speed is 700r / min, the flow rate of the plunger pump is set after stirring, three pumps are used to drive three raw materials into the reactor for reaction, the residence time is 5min, the reaction solution L-menthyl chloride is collected at the reaction outlet, and the post-processing is stand-by. The detection result shows that the content of menthyl chloride is 93%, and the yield is 95%.
[0042] S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran with a mass fraction of 30%, setting the reactor temperature to 60°C, starting the feed reaction after stabilization, with a residence time of 15 minutes, collecting the reaction liquid under argon protection at the outlet, and the detection result shows that there is no raw material remaining;
[0043] S3, using a pump to pump the reaction solution into the reactor, turning on the CO2 gas flowmeter, setting the gas flow rate to 400mL / min, setting the reactor temperature to 20°C, and collecting the reaction solution after the reaction is completed. After testing, no L-menthyl magnesium chloride remains, the content of menthyl formic acid is 87%, and the yield is 80%.
[0044] S4, 100g L-menthol formic acid is dissolved in 200mL dichloromethane, 80g triphosgene is dissolved in 240mL dichloromethane, the temperature and speed in the reactor are set, the organic solution of menthyl formic acid and triphosgene is respectively pumped into the reactor for reaction for 10min, and the reaction solution is collected at the outlet; 30g ethylamine is dissolved in 150g water, 6g NaOH is added, and a solution is prepared, and a rotary cut tubular reactor is used to react for 15min to complete the amidation, the reaction solution is acidified to be neutral, and the reaction solution is extracted with ether, and the solvent is removed after drying to obtain the product N-ethyl-L-menthol formamide, the product content is 95%, the yield is 90%, and the crude product appearance is a slightly yellowish white solid. Taking L-menthol as the starting material, the total yield is 75%.
[0045] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the invention or exceed the scope defined by the claims, they shall all fall within the protection scope of the present invention.
Claims
1. A method for preparing N-ethyl-L-menthylcarboxamide using continuous flow technology, characterized in that: Its synthetic route is as follows: The specific preparation steps are as follows: S1, L-menthyl alcohol and dimethyl sulfoxide are chlorinated to synthesize L-menthyl chloride; S2, dissolving L-menthyl chloride in anhydrous tetrahydrofuran, and reacting with metal magnesium through a Grignard reagent continuous flow reactor to continuously synthesize an L-menthyl magnesium chloride reaction solution; S3, continuously reacting the L-menthyl magnesium chloride reaction solution in step S2 with CO2 gas through a rotary cutting tubular reactor to synthesize L-menthyl formic acid; S4, first reacting L-menthyl carboxylic acid with triphosgene through chlorination reaction, and then reacting it with ethylamine through amidation reaction to synthesize N-ethyl-L-menthyl carboxamide.
2. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: In the chlorination reaction process of step S1, the solvent is any one of dichloromethane, acetone and acetonitrile.
3. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: In step S1, FeCl2 is used as a catalyst, and the mass fraction of the catalyst FeCl2 in the solvent is 15%; the reaction temperature of the rotary cutting tubular reactor is 5-30°C, and the rotation speed is 300-1200r / min.
4. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: In the Grignard reaction process of step S2, the initiator is any one of iodine, ethyl bromide and Grignard reagent; the initiator content is 5%, and the initiation temperature is 50-85°C.
5. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: During the CO2 reaction in step S3, the gas flow rate is 300-800 mL / min and the reaction temperature is 10°C.
6. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: The solvent for dissolving L-menthyl carboxylic acid in step S4 is any one of dichloromethane, ethyl acetate and toluene.
7. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: In the acyl chloride reaction of step S4, the molar ratio of L-menthyl carboxylic acid to triphosgene is 1:0.3-0.
8.
8. The method for preparing N-ethyl-L-menthylcarboxamide by continuous flow technology according to claim 1, characterized in that: The amount of ethylamine used in the amidation reaction of step S4 is 3 / 10 of the mass of L-menthyl carboxylic acid.