A preparation method of L-carnitine

Abstract

The invention discloses a kind of preparation method of L-carnitine, comprise the steps:Trimethylamine is added in the mixed solution of NaOH, water and organic solvent, R-4-chloro-3-hydroxybutyric acid ethyl ester is slowly dripped under cryogenic conditions, stirring reaction under identical temperature conditions after dropping and finishing;Raise temperature, continue reaction;Hydrochloric acid is dripped into reaction solution and adjusted pH value until reaction solution pH value is neutral, obtain the reaction solution containing L-carnitine;Desalt the reaction solution containing L-carnitine by electrodialysis, distillation and water removal, obtain L-carnitine. The scheme provided by the application is simple to operate, mild condition, and greatly reduces the reaction time simultaneously, is suitable for industrialized production, and by screening appropriate organic solvent and mixing with water to reduce freezing point to lower reaction temperature, suppresses the generation of impurities, thus improves product yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for preparing L-carnitine. Background Art

[0002] L-carnitine, whose chemical name is (R)-3-carboxy-2-hydroxy-N,N,N-trimethylpropylamine hydroxide (inner salt), also known as L-carnitine, is currently used in the fields of medicine, health care and food, and has been stipulated as a legal multi-purpose nutrient by Switzerland, France, the United States and the World Health Organization.

[0003] Methods for synthesizing L-carnitine have been widely reported. Patents CN108863827, CN106866440, and CN204752571 disclose methods for preparing L-carnitine using epichlorohydrin as a raw material through chiral resolution, amination, cyanidation, and hydrolysis reactions. These methods require a chiral separation reactor, a thin-film evaporator, a condenser, a liquid-liquid separation structure, an amination and cyanidation reactor, a concentration reactor, a crystallization reactor, an electrodialysis structure, and a triple-effect concentrator. While these methods are currently widely used in industry, they are complex, require complex equipment, and involve the use of the highly toxic cyanide, making them unsuitable for large-scale industrial production. Patents WO2007 / 139238, US4895979, and EP0339764 disclose the preparation of L-carnitine by amination of ethyl R-4-halo-3-hydroxybutyrate with a 27-30% trimethylammonium solution in water, followed by hydrolysis with hydrochloric acid. Although the reaction time is short, the yield is less than 50%. Patent WO00 / 29370 also uses the above method, increasing the concentration of the trimethylamine solution to 45%, which increases the yield to 75%, but the reaction time is as long as 60 hours.

[0004] Given the excellent use value and market prospects of L-carnitine, how to design a process route for synthesizing L-carnitine that can simultaneously meet the comprehensive requirements of simple operation, mild conditions, short reaction time and high yield is currently an urgent problem to be solved. Summary of the Invention

[0005] In order to solve the problems in the background technology, the present application provides a method for preparing L-carnitine with a simple process and mild conditions, which is specifically achieved by the following scheme:

[0006] A method for preparing L-carnitine comprises the following steps:

[0007] 1) adding trimethylamine to a mixed solution of NaOH, water, and an organic solvent, slowly adding R-4-chloro-3-hydroxybutyric acid ethyl ester dropwise at low temperature, and stirring the mixture at the same temperature after the addition is completed;

[0008] 2) Raise the temperature and continue the reaction;

[0009] 3) adding hydrochloric acid dropwise to the reaction solution to adjust the pH until the pH of the reaction solution is neutral, thereby obtaining a reaction solution containing L-carnitine;

[0010] 4) Desalting the reaction solution containing L-carnitine by electrodialysis and removing water by distillation to obtain L-carnitine.

[0011] Furthermore, the melting point of the organic solvent is lower than -20°C and the polarity is greater than 4.2.

[0012] Furthermore, the organic solvent is methanol, ethanol or N,N-dimethylformamide.

[0013] Furthermore, the molar ratio of the R-4-chloro-3-hydroxybutyric acid ethyl ester, trimethylamine and NaOH is 1:1-2:1-2.

[0014] Furthermore, the volume ratio of the organic solvent to water is 1:3-10.

[0015] Furthermore, the slowly adding dropwise R-4-chloro-3-hydroxybutyric acid ethyl ester under low temperature conditions has a dropping temperature of -20 to -10°C.

[0016] Furthermore, the slowly adding of ethyl R-4-chloro-3-hydroxybutyrate under low temperature conditions is performed for 1 to 3 hours.

[0017] Furthermore, the temperature of the reaction is raised and the reaction is continued at 20° C., and the reaction time is 1 to 3 hours.

[0018] In the solution of the present application, L-carnitine is prepared by reacting ethyl R-4-chloro-3-hydroxybutyrate and trimethylamine in a sodium hydroxide aqueous solution. The operation is simple, the conditions are mild, and the reaction time is greatly shortened, making it suitable for industrial production.

[0019] When using this process to prepare L-carnitine, the impurity 4-hydroxycrotonic acid is easily produced. The present application uses an organic solvent mixed with water to lower the solvent's freezing point, allowing the reaction to proceed at conditions below 0°C, thereby inhibiting the production of 4-hydroxycrotonic acid. Furthermore, it is preferred to use an organic solvent with a low melting point, strong polarity, and good water solubility to mix with water to increase the product yield. The L-carnitine yield using the present solution can reach over 90%. DETAILED DESCRIPTION

[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0021] Example 1

[0022] 7.2g NaOH (1.5eq), 35.5g trimethylamine (40%) (2eq), 140ml water and 18ml methanol were added to a reaction flask. 20g (1eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at -10°C. The addition lasted for 3 hours. After the addition was complete, the mixture was stirred and the reaction continued for 2 hours. The temperature was subsequently raised to 20°C and the reaction continued for 2 hours. After the reaction was complete, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 86.1% 4-hydroxycrotonic acid, 10.2% L-carnitine and a 92.3% L-carnitine nominal yield.

[0023] The L-carnitine in this example was separated and purified by an electrodialysis device available in the art to obtain pure L-carnitine.

[0024] Example 2

[0025] 7.2g NaOH (1.5eq), 35.5g trimethylamine (40%) (2eq), 122ml water and 36ml methanol were added to a reaction flask. 20g (1eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at -15°C. The addition lasted for 3 hours. After the addition was complete, the mixture was stirred and the reaction continued for 2 hours. The temperature was subsequently raised to 20°C and the reaction continued for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to neutral with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 88.1% 4-hydroxycrotonic acid, 9.2% L-carnitine and a 90.4% L-carnitine nominal yield.

[0026] Example 3

[0027] 7.2g NaOH (1.5eq), 47.3g trimethylamine (30%) (2eq), 129ml water and 18ml ethanol were added to the reaction flask. 20g (1eq) of R-4-chloro-3-hydroxybutyric acid ethyl ester was added dropwise at -10°C. The addition lasted for 3h. After the addition was complete, the mixture was stirred and the reaction was continued for 2h. The temperature was subsequently raised to 20°C and the reaction was continued for 2h. After the reaction was completed, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing levocarnitine. The reaction solution was subjected to HPLC analysis, which revealed 86.4% 4-hydroxycrotonic acid, 10.4% levocarnitine and a 93.1% nominal yield of levocarnitine.

[0028] Example 4

[0029] 7.2g NaOH (1.5eq), 35.5g trimethylamine (30%) (1.5eq), 137ml water and 18ml methanol were added to the reaction flask. 20g (1eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at -10°C. The addition lasted for 3 hours. After the addition was complete, the mixture was stirred and the reaction continued for 2 hours. The temperature was subsequently raised to 20°C and the reaction continued for 2 hours. After the reaction was complete, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 86.6% 4-hydroxycrotonic acid, 10.2% L-carnitine and a 92.9% L-carnitine nominal yield.

[0030] Example 5

[0031] 7.2g NaOH (1.5eq), 35.5g trimethylamine (30%) (1.5eq), 137ml water and 18ml methanol were added to the reaction flask. 20g (1eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at -10°C. The addition lasted for 1.5h. After the addition was complete, the mixture was stirred and the reaction continued for 2h. The temperature was subsequently raised to 20°C and the reaction continued for 2h. After the reaction was complete, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 87.5% 4-hydroxycrotonic acid, 9.8% L-carnitine and a 92.1% L-carnitine nominal yield.

[0032] Example 6

[0033] 28.8g NaOH (1.5eq), 142g trimethylamine (30%) (1.5eq), 548ml water and 72ml methanol were added to the reaction flask. 20g (1eq) of R-4-chloro-3-hydroxybutyric acid ethyl ester was added dropwise under a temperature of -10°C. The addition lasted for 1.5 hours. After the addition was complete, the reaction was stirred for 2 hours. The temperature was subsequently raised to 20°C and the reaction was continued for 2 hours. After the reaction was complete, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. The reaction solution was subjected to HPLC analysis, which revealed 87.2% 4-hydroxycrotonic acid, 9.9% L-carnitine and a 92.5% L-carnitine nominal yield.

[0034] Example 7

[0035] 0.72 kg NaOH (1.5 eq), 3.55 kg trimethylamine (30%) (1.5 eq), 13.65 L water, and 1.8 L methanol were added to a reactor. 80 g (1 eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at -10°C for 2 hours. After the addition was complete, the reaction was stirred and continued for 2 hours. The temperature was then raised to 20°C and the reaction continued for another 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 86.2% 4-hydroxycrotonic acid, 10.6% L-carnitine, and a nominal yield of 93.5% for L-carnitine.

[0036] Comparative Example 1

[0037] 7.2g NaOH (1.5eq), 35.5g trimethylamine (40%) (2eq), and 158ml water were added to a reaction flask. 20g (1eq) of ethyl R-4-chloro-3-hydroxybutyrate was added dropwise at 0°C for 3 hours. After the addition was complete, the reaction was stirred and continued for 2 hours. The temperature was then raised to 20°C and the reaction continued for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with hydrochloric acid to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 90.3% 4-hydroxycrotonic acid, 7.1% L-carnitine, and a standardized yield of 81.3% L-carnitine.

[0038] Comparative Example 2

[0039] 7.2g NaOH (1.5eq), 35.5g trimethylamine (40%) (2eq), 140ml water and 18ml tetrahydrofuran (THF) were added to the reaction flask. 20g (1eq) of R-4-chloro-3-hydroxybutyric acid ethyl ester was added dropwise at -10°C. The addition lasted for 3 hours. After the addition was complete, the mixture was stirred and the reaction was continued for 2 hours. The temperature was subsequently raised to 20°C and the reaction was continued for 2 hours. After the reaction was completed, the reaction solution was adjusted to a neutral pH with hydrochloric acid solution to obtain a reaction solution containing L-carnitine. HPLC analysis of the reaction solution revealed 88.1% 4-hydroxycrotonic acid, 7.8% L-carnitine and a nominal yield of 85.7% for L-carnitine.

[0040] It can be seen from the reaction results of the above examples and comparative examples that, compared with the synthesis of L-carnitine by reaction in aqueous solution, the reaction in a mixed solvent prepared from water and an organic solvent can effectively reduce by-products and improve the yield; and the preference for the organic solvent can further improve the purity and yield of the product.

[0041] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for preparing L-carnitine, characterized in that: The steps include: 1) adding trimethylamine to a mixed solution of NaOH, water, and an organic solvent, slowly adding R-4-chloro-3-hydroxybutyric acid ethyl ester dropwise at low temperature, and stirring the mixture at the same temperature after the addition is completed; the melting point of the organic solvent is lower than -20°C and the polarity is greater than 4.2; the volume ratio of the organic solvent to water is 1:3 to 10; and the temperature for slowly adding R-4-chloro-3-hydroxybutyric acid ethyl ester dropwise at low temperature is -20 to -10°C; 2) Raise the temperature to 20°C and continue the reaction for 1 to 3 hours; 3) adding hydrochloric acid dropwise to the reaction solution to adjust the pH until the pH of the reaction solution is neutral, thereby obtaining a reaction solution containing L-carnitine; 4) Desalting the reaction solution containing L-carnitine by electrodialysis and removing water by distillation to obtain L-carnitine.

2. The method for preparing L-carnitine according to claim 1, wherein The organic solvent is methanol, ethanol or N,N-dimethylformamide.

3. The method for preparing L-carnitine according to claim 1, wherein The molar ratio of the R-4-chloro-3-hydroxybutyric acid ethyl ester, trimethylamine and NaOH is 1:1-2:1-2.

4. The method for preparing L-carnitine according to claim 1, wherein The slowly adding of ethyl R-4-chloro-3-hydroxybutyrate under low temperature conditions takes place over a period of 1 to 3 hours.