A kind of synthesis process of L-carnitine

Abstract

The present invention belongs to the technical field of organic synthesis of pharmaceutical compounds, and in particular to a synthesis process of L-carnitine. The following steps are included: 4-chloroacetoacetic acid ethyl ester is dissolved in acetone, and then an acid reagent is added to adjust the pH to 4-5, and a mixed solution containing 4-chloroacetoacetic acid is obtained by vacuum distillation; the mixed solution containing 4-chloroacetoacetic acid is mixed and stirred with a trimethylamine aqueous solution to form a reaction solution, and the reaction solution and an alkali reagent are mixed to obtain a mixed solution containing trimethylammonium sodium acetoacetate; the mixed solution containing trimethylammonium sodium acetoacetate is adjusted to pH 6.4-6.8 with a potassium phosphate buffer, and then ketoreductase, coenzyme and cosolvent are added to the mixed reaction to obtain L-carnitine. The present invention uses 4-chloroacetoacetic acid ethyl ester as the starting synthetic material, first acidifies it, and then reacts with trimethylamine in the trimethylamine aqueous solution to form trimethylammonium sodium acetoacetate, and trimethylammonium sodium acetoacetate is subjected to the reduction hydrogenation of ketoreductase and coenzyme to obtain L-carnitine.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis of pharmaceutical compounds, and particularly relates to a synthesis process of L-carnitine. Background Art

[0002] L-carnitine, also known as L-carnitine, has the chemical name (R)-3-carboxy-2-hydroxy-N,N,N-trimethyl-1-propylamine hydroxide inner salt. It is a non-protein amino acid derivative and an essential substance in mammalian energy metabolism. It is also a substance necessary for the human body to metabolize long-chain fatty acids to produce energy.

[0003] L-Carnitine's primary function is to facilitate the transport of fatty acids into mitochondria for energy production. Mitochondria are the energy production centers within cells, producing ATP by oxidizing fatty acids, thereby providing the energy needed for cellular activity. L-Carnitine acts as a fatty acid carrier, helping fatty acids cross the mitochondrial membrane and enter the mitochondria for β-oxidation, ultimately producing ATP. In the human body, L-Carnitine synthesis occurs primarily in the liver and kidneys. It can also be consumed through the diet, primarily from animal foods such as meat and dairy products, or through supplements. L-Carnitine has a wide range of applications in the pharmaceutical and health product industries. Medically, it is used to treat conditions related to fatty acid metabolism, such as hyperlipidemia, cardiovascular disease, and certain metabolic disorders. L-Carnitine is also widely added to sports nutrition supplements to enhance athletic performance and promote body fat metabolism.

[0004] The document "Gu Songlin, Rui Liqin, Zhou Bin, et al. Synthesis of L-(-)-Carnitine" describes a synthesis method for L-carnitine. The method involves using (S)-epichlorohydrin and trimethylamine as starting materials. The epoxy ring on the (S)-epichlorohydrin is cleaved in a weakly acidic, near-neutral environment, leading to ring-opening and condensation with trimethylamine. The chlorine atom is then replaced with a cyano group via cyanidation with sodium cyanide, which is then hydrolyzed to yield L-carnitine. This method was widely used in the past, but due to the high toxicity of sodium cyanide, new, safer synthetic routes have been developed.

[0005] Patent CN103044278A discloses a method for synthesizing L-carnitine using D-(-)-tartaric acid as a raw material. The invention uses D-(-)-tartaric acid as a raw material, boric acid as a catalyst, and esterifies benzyl alcohol to synthesize D-(-)-dibenzyl tartrate; then, under the catalysis of sodium borohydride, D-(-)-dibenzyl tartrate is reduced to obtain D-(-)-2,3,4-trihydroxybenzyl ester; D-(-)-2,3,4- Trihydroxybenzyl ester is brominated in a hydrogen bromide and acetic acid solution to produce D-(-)-3-hydroxy-2,4-dibromobenzyl ester. D-(-)-3-hydroxy-2,4-dibromobenzyl ester is then selectively debrominated and hydrogenated using a Pd / C catalyst and hydrogen to produce D-(-)-3-hydroxy-4-bromobenzyl ester. Finally, D-(-)-3-hydroxy-4-bromobenzyl ester is aminated with trimethylamine, hydrolyzed, and ion-exchanged to produce L-carnitine. This process involves numerous steps and is not suitable for industrial scale-up.

[0006] Patent CN103709058A discloses a method for synthesizing L-carnitine. The invention first reduces the substrate ethyl 4-chloroacetoacetate with ketoreductase to produce (R)-4-chloro-3-hydroxybutyrate; then, in an alkaline environment, the (R)-4-chloro-3-hydroxybutyrate and an aqueous solution of trimethylamine are caused to react for a period of time in an environment with water as a solvent. After adjusting the pH value and post-processing, L-carnitine is obtained, with a maximum yield of 79.8%.

[0007] Patent CN104030934A discloses a method for preparing a L-carnitine compound. This invention uses ethyl 4-chloroacetoacetate as the starting material and uses an asymmetric catalyst, a phosphine ligand ruthenium complex, for hydrogenation reduction to obtain (R)-4-chloro-3-hydroxybutyric acid ethyl ester. (R)-4-chloro-3-hydroxybutyric acid ethyl ester and an aqueous solution of trimethylamine are reacted in a water-based solvent environment under the catalysis of an inorganic base for a period of time. After that, the pH is adjusted with concentrated hydrochloric acid, and the L-carnitine compound is purified on a resin column, with a maximum yield of 88.4%.

[0008] The difference between the preparation of L-carnitine using ethyl 4-chloroacetoacetate lies in the different catalysts used to catalyze the reduction of the ketone group. The similarity lies in the fact that both utilize nucleophilic substitution between (R)-ethyl 4-chloro-3-hydroxybutyrate and trimethylamine. However, this reaction route has the following problems: (1) As an oily substance with poor hydrophilicity, (R)-ethyl 4-chloro-3-hydroxybutyrate does not mix evenly with the solvent water and trimethylamine aqueous solution, resulting in a long reaction time and poor efficiency; (2) Since (R)-ethyl 4-chloro-3-hydroxybutyrate has a hydroxyl group and an adjacent chlorine atom, it is easy to form an intramolecular cyclization in an alkaline environment to generate an alkylene oxide byproduct.

[0009] Therefore, developing a new synthesis process for L-carnitine to avoid the problem of poor compatibility between reactants and reduce the synthesis of by-products is of great significance for further improving the synthesis efficiency of L-carnitine. Summary of the Invention

[0010] In response to the shortcomings of the prior art, the present invention uses ethyl 4-chloroacetoacetate as the starting synthetic material, first acidifies it, then reacts it with trimethylamine in a trimethylamine aqueous solution to form sodium trimethylammonium acetoacetate or potassium trimethylammonium acetoacetate. The sodium trimethylammonium acetoacetate or potassium trimethylammonium acetoacetate is then subjected to the reductive hydrogenation of ketoreductase and a coenzyme to produce L-carnitine, thereby solving the problems raised in the background art. Specifically, the technical solution of the present invention includes the following:

[0011] A synthesis process of L-carnitine, comprising the following steps:

[0012] Ethyl 4-chloroacetoacetate is dissolved in acetone, an acid reagent is added to adjust the pH to 4-5, and a mixed solution containing 4-chloroacetoacetic acid is obtained by vacuum distillation;

[0013] The mixed solution containing 4-chloroacetoacetic acid is mixed with a trimethylamine aqueous solution and stirred to form a reaction solution, and the reaction solution is mixed with an alkaline reagent to react to obtain a mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate;

[0014] The mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate is adjusted to pH 6.4-6.8 with potassium phosphate buffer, and then ketoreductase, coenzyme and cosolvent are added for mixed reaction to obtain the L-carnitine.

[0015] Furthermore, the function of the acetone is to dissolve and disperse ethyl 4-chloroacetoacetate, so the amount of acetone used can be controlled to be 1 to 2 times the amount of ethyl 4-chloroacetoacetate.

[0016] Furthermore, the acid reagent includes hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

[0017] Furthermore, the mass concentration of the trimethylamine aqueous solution is 30% or 50%.

[0018] Furthermore, the alkaline reagent includes sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0019] Furthermore, the mass ratio of ethyl 4-chloroacetoacetate: aqueous trimethylamine solution: alkaline reagent is 1:1~2:1~1.5.

[0020] Furthermore, the reaction conditions for the mixed reaction of the reaction solution and the alkaline reagent include a reaction temperature of 20° C. to 25° C. and a reaction time of 8 h to 10 h.

[0021] Furthermore, the molar concentration of the potassium phosphate buffer is 0.1 mol / L, and the buffering range is 6.4-6.8.

[0022] Furthermore, the ketoreductase is KRED reductase.

[0023] Furthermore, the coenzyme includes NAD+ or NADP+.

[0024] Furthermore, the co-solvent includes ethanol or propanol.

[0025] Furthermore, the mass percentage of the mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate: ketoreductase, coenzyme: cosolvent is 100%: 0.1%~0.5%: 0.002%~0.01%: 10%~20%.

[0026] Furthermore, the reaction conditions for the mixed reaction of adding ketoreductase, coenzyme and cosolvent include a reaction temperature of 25° C. to 30° C. and a reaction time of 18 h to 30 h.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The present invention creatively develops a new synthesis route for L-carnitine. Most of the existing technologies use the reaction of (R)-4-chloro-3-hydroxybutyric acid ethyl ester with trimethylamine aqueous solution. However, (R)-4-chloro-3-hydroxybutyric acid ethyl ester is an oily substance with poor hydrophilicity. When mixed with trimethylamine aqueous solution, stratification may occur, resulting in less contact between the reactant (R)-4-chloro-3-hydroxybutyric acid ethyl ester and trimethylamine, and the reaction is not thorough. In addition, (R)-4-chloro-3-hydroxybutyric acid ethyl ester has a hydroxyl group and an adjacent chlorine atom. Under base catalysis, it is easy to undergo intramolecular cyclization to produce an alkylene oxide by-product, which consumes (R)-4-chloro-3-hydroxybutyric acid ethyl ester and trimethylamine, resulting in the most The final yield cannot be further improved. In the present invention, ethyl 4-chloroacetoacetate is used as a starting material. Since ethyl 4-chloroacetoacetate has poor hydrophilicity, it is first acidified and hydrolyzed to remove the ester group to obtain 4-chloroacetoacetic acid having a carboxyl group, thereby enhancing its water solubility. Then, 4-chloroacetoacetic acid and an aqueous solution of trimethylamine are reacted under the catalysis of an alkaline reagent. Trimethylamine acts as a nucleophilic reagent to attack (R)-4-chloro-3-hydroxybutyric acid ethyl ester, generating trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate through a nucleophilic substitution reaction. The keto group on the trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate is hydrogenated and reduced to a hydroxyl group under the combined action of ketoreductase and a coenzyme, thereby finally obtaining L-carnitine.

[0029] (2) The synthetic route designed by the present invention not only avoids the problem of incomplete reaction caused by poor compatibility between reactants, but also avoids the formation of alkylene oxide by-products, so that the final yield of L-carnitine can reach about 90%, further improving the reaction efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The synthetic route of the present invention is shown in FIG. DETAILED DESCRIPTION

[0031] The following will clearly and completely describe the technical solutions of the present invention through the embodiments of the present invention. Obviously, the embodiments described 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 those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0032] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0033] KRED reductase, NAD+, and NADP+ were purchased from Shanghai Yingxin Laboratory Equipment Co., Ltd.

[0034] Example 1:

[0035] A synthesis process of L-carnitine specifically comprises the following steps:

[0036] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then, add 30 g of acetone to the flask and mix well. Use an acid burette to slowly drop hydrochloric acid into the flask while stirring continuously until the pH reaches 4. Close the piston of the acid burette, stop adding hydrochloric acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0037] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 30g of a 30% trimethylamine aqueous solution is added with continuous stirring. Then, 45g of sodium carbonate particles are added and stirred until the particles are completely dissolved. At this time, the temperature is raised to 20°C and the reaction is timed for 8 hours to obtain a mixed solution containing sodium trimethylammonium acetoacetate.

[0038] Potassium phosphate buffer with a molar concentration of 0.1 mol / L and a pH of 6.4 was added to a mixed solution containing sodium trimethylammonium acetoacetate and stirred. Hydrochloric acid was then added to adjust the pH to 6.4. Finally, 0.1% by weight of KRED reductase, 0.002% by weight of NAD+, and 10% by weight of ethanol were added, based on the mass percentage of the mixed solution containing sodium trimethylammonium acetoacetate, and the mixture was stirred for reaction. The mixture was then heated to 25°C and reacted for 18 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cutoff of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.29 g on an electronic balance, with a calculated yield of 89.88% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0039] Example 2:

[0040] A synthesis process of L-carnitine specifically comprises the following steps:

[0041] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then, add 30 g of acetone to the flask and mix well. Use an acid burette to slowly drop hydrochloric acid into the flask while stirring continuously until the pH reaches 4. Close the piston of the acid burette, stop adding hydrochloric acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0042] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 30g of a 30% trimethylamine aqueous solution is added with continuous stirring. Then, 45g of potassium carbonate particles are added and stirred until the particles are completely dissolved. At this time, the temperature is raised to 22°C and the reaction is timed for 8 hours to obtain a mixed solution containing trimethylammonium potassium acetoacetate.

[0043] A 0.1 mol / L potassium phosphate buffer solution with a pH of 6.4 was added to a mixed solution containing trimethylammonium potassium acetoacetate, followed by stirring. Hydrochloric acid was then added to adjust the pH to 6.4. Finally, 0.2% by weight of KRED reductase, 0.004% by weight of NAD+, and 10% by weight of ethanol were added, based on the mass percentage of the mixed solution containing trimethylammonium potassium acetoacetate, and the mixture was stirred for reaction. The mixture was then heated to 25°C and reacted for 20 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cutoff of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.36 g on an electronic balance, with a calculated yield of 90.06% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0044] Example 3:

[0045] A synthesis process of L-carnitine specifically comprises the following steps:

[0046] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then, add 30 g of acetone to the flask and mix well. Use an acid burette to slowly drop sulfuric acid into the flask while stirring continuously until the pH reaches 4.5. Close the piston of the acid burette, stop adding sulfuric acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0047] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 40g of a 30% mass concentration trimethylamine aqueous solution is added and continuously stirred. Then, 30g of sodium hydroxide particles are added and mixed and stirred until the particles are completely dissolved. At this time, the temperature is raised to 22°C and the reaction is timed for 9 hours to obtain a mixed solution containing sodium trimethylammonium acetoacetate.

[0048] Potassium phosphate buffer with a molar concentration of 0.1 mol / L and a pH of 6.6 was added to a mixed solution containing sodium trimethylammonium acetoacetate and stirred. Hydrochloric acid was then added to adjust the pH to 6.6. Finally, 0.3% by mass of KRED reductase, 0.006% by mass of NAD+, and 15% by mass of ethanol were added, based on the mass percentage of the mixed solution containing sodium trimethylammonium acetoacetate, and stirred for reaction. The mixture was then heated to 27°C and reacted for 22 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cutoff of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.49 g on an electronic balance, with a calculated yield of 90.50% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0049] Example 4:

[0050] A synthesis process of L-carnitine specifically comprises the following steps:

[0051] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then, add 60 g of acetone to the flask and mix well. Use an acid burette to slowly drop sulfuric acid into the flask while stirring continuously until the pH reaches 4.5. Close the piston of the acid burette, stop adding sulfuric acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0052] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 50g of a 50% trimethylamine aqueous solution is added with continuous stirring. Then, 30g of sodium hydroxide particles are added and mixed with stirring until the particles are completely dissolved. At this time, the temperature is raised to 24°C and the reaction is timed for 9 hours to obtain a mixed solution containing sodium trimethylammonium acetoacetate.

[0053] Potassium phosphate buffer with a molar concentration of 0.1 mol / L and a pH of 6.6 was added to a mixed solution containing sodium trimethylammonium acetoacetate and stirred. Hydrochloric acid was then added to adjust the pH to 6.6. Finally, 0.4% by weight of KRED reductase, 0.008% by weight of NADP+, and 15% by weight of propanol were added, based on the mass percentage of the mixed solution containing sodium trimethylammonium acetoacetate, and the mixture was stirred for reaction. The mixture was then heated to 27°C and reacted for 24 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cutoff of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.61 g on an electronic balance, with a calculated yield of 90.91% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0054] Example 5:

[0055] A synthesis process of L-carnitine specifically comprises the following steps:

[0056] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then, add 60 g of acetone to the flask and mix well. Use an acid burette to slowly drop phosphoric acid into the flask while stirring continuously until the pH reaches 5. Close the piston of the acid burette, stop adding phosphoric acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0057] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 60g of a 50% trimethylamine aqueous solution is added with continuous stirring, and then 30g of potassium hydroxide particles are added and stirred until the particles are completely dissolved. At this time, the temperature is raised to 24°C and the reaction is timed for 10 hours to obtain a mixed solution containing trimethylammonium potassium acetoacetate.

[0058] A 0.1 mol / L potassium phosphate buffer solution with a pH of 6.8 was added to a mixed solution containing trimethylammonium potassium acetoacetate, followed by stirring. Hydrochloric acid was then added to adjust the pH to 6.8. Finally, 0.5% by weight of KRED reductase, 0.01% by weight of NADP+, and 20% by weight of propanol were added, based on the mass percentage of the mixed solution containing trimethylammonium potassium acetoacetate, and the mixture was stirred for reaction. The mixture was then heated to 30°C and reacted for 26 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cutoff of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.66 g on an electronic balance, with a calculated yield of 91.08% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0059] Example 6:

[0060] A synthesis process of L-carnitine specifically comprises the following steps:

[0061] Weigh 30 g of ethyl 4-chloroacetoacetate and add it to a flask. Then add 60 g of acetone to the flask and mix well. Use an acid burette to slowly drop acetic acid into the flask while stirring continuously until the pH reaches 5. Close the piston of the acid burette, stop adding acetic acid, and connect the flask to a rotary evaporator for vacuum distillation to remove acetone to obtain the remaining mixed solution containing 4-chloroacetoacetic acid.

[0062] The temperature of the mixed solution containing 4-chloroacetoacetic acid is controlled within the range of 4°C to 8°C by circulating cooling water, and then 60g of a 50% trimethylamine aqueous solution is added and stirred continuously. Then, 30g of potassium hydroxide particles are added and stirred until the particles are completely dissolved. At this time, the temperature is raised to 25°C and the reaction is timed for 10 hours to obtain a mixed solution containing trimethylammonium potassium acetoacetate.

[0063] Potassium phosphate buffer with a molar concentration of 0.1 mol / L and a pH of 6.8 was added to a mixed solution containing trimethylammonium potassium acetoacetate, followed by stirring. Hydrochloric acid was then added to adjust the pH to 6.8. Finally, 0.5% by weight of KRED reductase, 0.01% by weight of NADP+, and 20% by weight of propanol were added, based on the mass percentage of the mixed solution containing trimethylammonium potassium acetoacetate, and the mixture was stirred for reaction. The mixture was then heated to 30°C and reacted for 30 hours. After the reaction, the solution was poured into a dialysis bag with a molecular weight cut-off of 100 for purification by dialysis. The solution was then concentrated and dried to obtain L-carnitine, which weighed 26.68 g on an electronic balance, with a calculated yield of 91.15% (based on the theoretical yield of ethyl 4-chloroacetoacetate).

[0064] The embodiments described above provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention, and such changes and modifications fall within the scope of the present invention as claimed.

Claims

1. A synthesis process of L-carnitine, characterized in that: The synthesis process comprises the following steps: After ethyl 4-chloroacetoacetate is dissolved in acetone, an acid reagent is added to adjust the pH to 4-5, and a mixed solution containing 4-chloroacetoacetic acid is obtained by vacuum distillation; The mixed solution containing 4-chloroacetoacetic acid is mixed with a trimethylamine aqueous solution and stirred to form a reaction solution, and the reaction solution is mixed with an alkali reagent to react to obtain a mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate; The mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate is adjusted to pH 6.4-6.8 with potassium phosphate buffer, and then ketoreductase, coenzyme and cosolvent are added for mixed reaction to obtain the L-carnitine; The alkaline reagent includes sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; The mass ratio of ethyl 4-chloroacetoacetate: aqueous trimethylamine solution: alkaline reagent is 1:1-2:1-1.5; The reaction conditions of the mixed reaction of the reaction solution and the alkaline reagent include a reaction temperature of 20°C to 25°C and a reaction time of 8h to 10h; The mass percentage of the mixed solution containing trimethylammonium sodium acetoacetate or trimethylammonium potassium acetoacetate: ketoreductase, coenzyme: cosolvent is 100%: 0.1%~0.5%: 0.002%~0.01%: 10%~20%; The reaction conditions for the mixed reaction of adding ketoreductase, coenzyme and cosolvent include a reaction temperature of 25° C. to 30° C. and a reaction time of 18 h to 30 h.

2. A synthesis process of L-carnitine according to claim 1, characterized in that: The acid reagent includes hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

3. A synthesis process of L-carnitine according to claim 1, characterized in that: The ketoreductase is KRED reductase.

4. A synthesis process of L-carnitine according to claim 1, characterized in that: The coenzyme includes NAD+ or NADP+.

5. A synthesis process of L-carnitine according to claim 1, characterized in that: The co-solvent includes ethanol or propanol.

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