A continuous flow synthesis method for ketoesters
By using a continuous flow synthesis method under acidic conditions, ethyl (R)-3 hydroxybutyrate and (R)-1,3-butanediol are converted into ketone esters, the existing ketone ester preparation methods are solved, and efficient and low-cost ketone ester synthesis is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411953227.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-27
- Publication Date
- 2025-04-04
AI Technical Summary
The existing preparation methods for ketone esters are cumbersome, time-consuming and cost-effective, and difficult to use in industrial production.
The continuous flow synthesis method was used to esterify Fischer-Speier under acidic conditions using (R)-3 hydroxybutyrate and (R)-1,3-butylene glycol as raw materials to obtain (R)-3 hydroxybutyrate (R)-3-hydroxybutyrate.
It effectively reduces synthesis costs, simplifies the process flow, reduces the generation of industrial waste, improves yield and purity, and is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a continuous flow synthesis method of ketoester. Background Art
[0002] Ketone bodies are compounds produced by the liver from fatty acids released from adipose tissue. Ketone bodies themselves can serve as a source of energy for most tissues in the body. Ingestion of compounds that increase blood levels of ketone bodies can provide a variety of clinical benefits, including enhanced physical and cognitive performance, treatment of cardiovascular disease, diabetes, neurodegenerative diseases and epilepsy. Ketone bodies include (R)-3-hydroxybutyrate and acetoacetate, and these compounds could theoretically be administered directly to achieve elevated ketone body levels in a subject. As well as serving as a nutritional supplement to improve physical performance.
[0003] (R)-3-Hydroxybutyl 3-hydroxybutyrate is a widely used ketone body. CN114957004A discloses a synthesis method and application of (R)-3-hydroxybutyl 3-hydroxybutyrate and its intermediates, but the synthesis method is complicated, time-consuming and costly. The preparation process based on lipase catalysis is difficult to use in industrial production due to the uniqueness of the enzyme and the characteristics of high temperature inactivation. The existing traditional ketoester preparation methods also generally have obvious shortcomings and / or industrial limitations.
[0004] Therefore, it is of great significance to develop a process for synthesizing and purifying (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Summary of the invention
[0005] The technical problem to be solved by the present invention is to provide a continuous flow synthesis method of ketoesters in view of the deficiencies in the above-mentioned prior art.
[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows: the present invention provides a continuous flow synthesis method of ketoesters, using inexpensive and readily available (R)-3-hydroxybutyric acid ethyl ester and (R)-1,3-butanediol as raw materials, and performing Fischer-Speier esterification under acidic conditions to obtain the final product (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in one step.
[0007] The reaction route is as follows:
[0008]
[0009] The specific method includes the following steps:
[0010] S1, using (R)-3-hydroxybutyric acid ethyl ester as raw material 1 and a mixture of (R)-1,3-butanediol and an acid as raw material 2, mixing raw material 1 and raw material 2 for continuous flow reaction, and after the reaction, extracting the product with ethyl acetate and deionized water to obtain a crude ketoester;
[0011] S2. Extracting the crude ketoester prepared in step S1 with methanol and petroleum ether to obtain a pure ketoester, namely (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
[0012] Preferably, the acid in step S1 is at least one of trifluoroacetic acid (TFA), methanesulfonic acid, and p-toluenesulfonic acid (TsOH), and more preferably p-toluenesulfonic acid.
[0013] When the acid in step S1 is p-toluenesulfonic acid, the reaction mechanism of the preparation method of the present invention is as follows:
[0014]
[0015] Preferably, the flow rate of raw material 1 is 0.5-2 mL / min, and the flow rate of raw material 2 is 2.5-10 mL / min. Most preferably, the flow rate of raw material 1 is 0.5 ml / min, and the flow rate of raw material 2 is 2.5 ml / min.
[0016] Preferably, the reaction temperature of the continuous flow reaction in step S1 is 40-100°C, for example, 40°C, 60°C, 80°C, 100°C or any value therebetween, and most preferably 60°C.
[0017] Preferably, the molar ratio of (R)-3-hydroxybutyric acid ethyl ester and (R)-1,3-butanediol in step S1 is 1:5 to 1:10, for example, 1:5, 1:7, 1:9, 1:10 or any value between them, and most preferably 1:7.
[0018] Preferably, the acid in step S1 is p-toluenesulfonic acid, and the molar ratio of (R)-3-hydroxybutyric acid ethyl ester to p-toluenesulfonic acid is 1:0.1 to 1:0.4, for example, it can be 1:0.1, 1:0.2, 1:0.3, 1:0.4 or any value between them, and most preferably is 1:0.1.
[0019] Preferably, step S1 specifically comprises:
[0020] (R)-3-hydroxybutyric acid ethyl ester is used as raw material 1, and a mixture of (R)-1,3-butanediol and acid is used as raw material 2. Raw material 1 and raw material 2 are added into the reactor at flow rates of 0.5-2 mL / min and 2.5-10 mL / min, respectively, and a continuous flow reaction is carried out at 40-100° C. After the reaction is completed, the temperature is cooled to room temperature, ethyl acetate (EA) and deionized water are added to the product, and then a saturated sodium bicarbonate solution is added. The mixture is stirred at room temperature for 0.5-2 h, the pH is adjusted to 7-7.5, the organic phase is washed with deionized water, and then dried with anhydrous sodium sulfate to obtain a crude ketoester.
[0021] Preferably, in step S1, the volume of ethyl acetate added to the product is 8 to 15 times the weight of (R)-3-hydroxybutyric acid ethyl ester, measured in mL by volume and g by weight, for example, 8, 10, 12, 13, 15 times or any value between them, most preferably 10 times.
[0022] Preferably, in step S1, the volume of deionized water added to the product is 10 to 20 times the weight of (R)-3-hydroxybutyric acid ethyl ester, measured in mL by volume and g by weight, for example, 12, 14, 16, 18, 20 times or any value between them, most preferably 18 times.
[0023] Preferably, step S2 specifically comprises:
[0024] Methanol (MeOH) and petroleum ether (PE) are added to the crude ketoester obtained in step S1, the methanol phase is separated, washed with petroleum ether, and concentrated to obtain a pure ketoester, i.e., (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
[0025] Preferably, in step S2, the volume of methanol added to the crude ketoester is 5 to 10 times the weight of (R)-3-hydroxybutyric acid ethyl ester, measured in mL by volume and g by weight, for example, 5, 6, 8, 10 times or any value between them, most preferably 5 times.
[0026] Preferably, in step S2, the volume of petroleum ether added to the crude ketoester is 4 to 8 times the weight of (R)-3-hydroxybutyric acid ethyl ester, measured in mL by volume and g by weight, for example, 4, 6, 8 or any value between them, most preferably 4 times.
[0027] The beneficial effects of the present invention are:
[0028] The present invention provides a continuous flow synthesis method for ketoesters, which effectively reduces the synthesis cost, avoids the use of dangerous and toxic reagents, effectively reduces the generation of industrial wastes, and has simple process, convenient operation, controllable reaction conditions, extremely low time cost, cheap and easily available raw materials, high yield, and is conducive to large-scale industrial production. DETAILED DESCRIPTION
[0029] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.
[0030] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.
[0031] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.
[0032] Example 1
[0033] A continuous flow synthesis method for ketoesters comprises the following steps:
[0034] Step S1. Preparation of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
[0035]
[0036] (R)-3-hydroxybutyric acid ethyl ester (20g, 0.15mol) was put into bottle 1, (R)-1,3-butanediol (95.47g, 1.06mol) and TsOH (3.44g, 0.02mol) were added into bottle 2 and stirred well, and raw materials 1 and 2 in bottles 1 and 2 were added into the reactor for continuous flow reaction; the flow rate of bottle 1 was 0.5mL / min, the flow rate of bottle 2 was 2.5mL / min, the residence time was 4.5min, and the reaction system was heated to 60°C; after 40min, the temperature was lowered to about 25°C, 200ml EA and 300mL H2O were added, and a saturated sodium bicarbonate solution was slowly added, and the temperature was kept at 25°C and stirred for 1h, and the pH was adjusted to 7. The organic phase was washed with water (360mL*2), and dried over anhydrous sodium sulfate to obtain a crude ketoester, a colorless oil, 21.92g.
[0037] Step S2. Purification of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
[0038] The crude ketone ester, 100 mL MeOH (methanol) and 80 mL PE (petroleum ether) were added to a 1 L separatory funnel, the MeOH phase was separated and washed twice with PE (40 mL*2), and concentrated (the methanol phase was concentrated by rotary evaporation) to obtain 17.33 g of a colorless oil, i.e. (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, with a yield of 64.98% and a purity of 99.12% as measured by quantitative NMR.
[0039] Example 2
[0040] A continuous flow synthesis method for ketoesters comprises the following steps:
[0041] Step S1. Preparation of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
[0042]
[0043] (R)-3-hydroxybutyric acid ethyl ester (20g, 0.15mol) was put into bottle 1, (R)-1,3-butanediol (95.47g, 1.06mol) and TFA (i.e. p-toluenesulfonic acid, 2.28g, 0.02mol) were added into bottle 2 and stirred well, and raw materials 1 and 2 in bottles 1 and 2 were added into the reactor for continuous flow reaction; the flow rate of bottle 1 was 0.5ml / min, the flow rate of bottle 2 was 2.5ml / min, the retention time was 4.5min, and the reaction system was heated to 60℃. After 40min, the temperature was lowered to about 25℃, 200ml EA and 300ml H2O were added, and a saturated sodium bicarbonate solution was slowly added, and the mixture was stirred at 25℃ for 1h, and the pH was adjusted to 7. The organic phase was washed with water (360ml*2), and dried over anhydrous sodium sulfate to obtain a crude ketoester, a colorless oil, 19.72g.
[0044] Step S2. Purification of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
[0045] The crude ketoester, 100 ml MeOH and 80 ml PE were added to a 1 L separatory funnel. The MeOH phase was separated and washed twice with PE (40 ml * 2). The methanol phase was concentrated (the methanol phase was concentrated by rotary evaporation) to obtain 15.33 g of a colorless oil, i.e. (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, with a yield of 57.48% and a purity of 98.54% as measured by quantitative NMR.
[0046] The NMR data of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate prepared in this example are as follows: 1H NMR (CD3OD-d4): δ4.209-4.126 (m, H), 3.856 (m, 1H), 2.435 (m, 2H), 1.767-1.705 (m, 2H), 1.206 (d, 3H), 1.189 (d, 3H) ppm.
[0047] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.
Claims
1. A continuous flow synthesis method for ketoesters, characterized in that: The following steps are involved: S1, using (R)-3-hydroxybutyric acid ethyl ester as raw material 1 and a mixture of (R)-1,3-butanediol and an acid as raw material 2, mixing raw material 1 and raw material 2 for continuous flow reaction, and after the reaction, extracting the product with ethyl acetate and deionized water to obtain a crude ketoester; S2. Extracting the crude ketoester prepared in step S1 with methanol and petroleum ether to obtain a pure ketoester, namely (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
2. The continuous flow synthesis method of ketoester according to claim 1, characterized in that: The acid in step S1 is at least one of trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.
3. The continuous flow synthesis method of ketoester according to claim 2, characterized in that: The flow rate of feedstock 1 was 0.5-2 mL / min, and the flow rate of feedstock 2 was 2.5-10 mL / min.
4. The continuous flow synthesis method of ketoester according to claim 3, characterized in that: The reaction temperature of the continuous flow reaction in step S1 is 40-100°C.
5. The continuous flow synthesis method of ketoester according to claim 1, characterized in that: In step S1, the molar ratio of (R)-3-hydroxybutyric acid ethyl ester to (R)-1,3-butanediol is 1:5 to 1:
10.
6. The continuous flow synthesis method of ketoester according to claim 1, characterized in that: The acid in step S1 is p-toluenesulfonic acid, and the molar ratio of (R)-ethyl 3-hydroxybutyrate to p-toluenesulfonic acid is 1:0.1 to 1:0.
4.
7. The continuous flow synthesis method of ketoester according to claim 1, characterized in that: Step S1 is specifically as follows: (R)-3-hydroxybutyric acid ethyl ester is used as raw material 1, and a mixture of (R)-1,3-butanediol and acid is used as raw material 2. Raw material 1 and raw material 2 are added into the reactor at flow rates of 0.5-2 mL / min and 2.5-10 mL / min, respectively, and a continuous flow reaction is carried out at 40-100°C. After the reaction is completed, the temperature is cooled to room temperature, ethyl acetate and deionized water are added to the product, and then a saturated sodium bicarbonate solution is added. The mixture is stirred at room temperature for 0.5-2 h, the pH is adjusted to 7-7.5, the organic phase is washed with deionized water, and then dried with anhydrous sodium sulfate to obtain a crude ketoester.
8. The continuous flow synthesis method of ketoester according to claim 7, characterized in that: In terms of volume in mL and weight in g, in step S1, the volume of ethyl acetate added to the product is 8 to 15 times the weight of (R)-3-hydroxybutyric acid ethyl ester, and the volume of deionized water added to the product is 10 to 20 times the weight of (R)-3-hydroxybutyric acid ethyl ester.
9. The continuous flow synthesis method of ketoester according to claim 1, characterized in that: Step S2 is specifically as follows: Methanol and petroleum ether are added to the crude ketoester obtained in step S1, and the methanol phase is separated and washed with petroleum ether and concentrated to obtain a pure ketoester, namely (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
10. The continuous flow synthesis method of ketoester according to claim 9, characterized in that: In terms of volume in mL and weight in g, in step S2, the volume of methanol added to the crude ketone ester is 5 to 10 times the weight of (R)-3-hydroxybutyric acid ethyl ester, and the volume of petroleum ether added to the crude ketone ester is 4 to 8 times the weight of (R)-3-hydroxybutyric acid ethyl ester.