Preparation Method of Levocarnitine Intermediate

Abstract

The present invention discloses a preparation method of a levocarnitine intermediate. It uses S-epichlorohydrin as the starting material, first undergoes an amination reaction with trimethylamine hydrochloride to obtain L-3-chloro-2-hydroxypropyltrimethylammonium chloride, and then undergoes a cyanation reaction with sodium cyanide to obtain the levocarnitine intermediate L-3-cyano-2-hydroxypropyltrimethylammonium chloride; after the amination reaction is completed, a complexing agent is used to treat the reaction system, and the complexing agent is preferably phytic acid; after the cyanation reaction is completed, an adsorbent is used to treat the reaction system; the adsorbent is preferably activated carbon. The method of the present invention can significantly improve the color of the L-quaternary ammonium salt solution by adding a complexing agent for treatment after the amination reaction, and further can significantly improve the color of the L-nitrile compound and reduce its impurity content; the method of the present invention can further improve the color of the L-nitrile compound and further reduce the impurity content of the L-nitrile compound by adding an adsorbent for treatment after the cyanation reaction.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a method for preparing a levocarnitine intermediate. Background Art

[0002] Levocarnitine is an essential natural substance in mammalian energy metabolism, and its main function is to promote lipid metabolism. It can not only bring long-chain fatty acids into the mitochondrial matrix and promote their oxidative decomposition to provide energy for cells, but also export short-chain acyl groups generated in mitochondria. The supplementation of this product can relieve the fat metabolism disorders and dysfunction of tissues such as skeletal muscle and myocardium caused by its deficiency in the body.

[0003] Currently, the most common production method of levocarnitine is to use S-epichlorohydrin as the starting material, first carry out an amination reaction with trimethylamine hydrochloride to obtain L-3-chloro-2-hydroxypropyltrimethylammonium chloride [hereinafter referred to as L-quaternary ammonium salt], then carry out a cyanation reaction with sodium cyanide to obtain L-3-cyano-2-hydroxypropyltrimethylammonium chloride [hereinafter referred to as L-nitrile compound], and finally obtain levocarnitine through hydrolysis, desalting and purification.

[0004] The main problems existing in this method are as follows: the color of the L-quaternary ammonium salt solution obtained by the amination reaction is dark brown, and then the color of the L-nitrile compound obtained by the cyanation reaction is yellowish-brown or yellowish-brown, and the impurity content is significantly higher, which directly affects the quality of the final levocarnitine product. Summary of the Invention

[0005] The purpose of the present invention is to solve the above problems and provide a method for preparing a levocarnitine intermediate that can significantly improve the color of the L-nitrile compound and reduce its impurity content.

[0006] The technical solution for achieving the purpose of the present invention is: a method for preparing a levocarnitine intermediate, which uses S-epichlorohydrin as the starting material, first carries out an amination reaction with trimethylamine hydrochloride to obtain L-3-chloro-2-hydroxypropyltrimethylammonium chloride [hereinafter referred to as L-quaternary ammonium salt], and then carries out a cyanation reaction with sodium cyanide to obtain the levocarnitine intermediate L-3-cyano-2-hydroxypropyltrimethylammonium chloride [hereinafter referred to as L-nitrile compound].

[0007] Among them, both the amination reaction and the cyanation reaction are conventional methods in the prior art.

[0008] The most crucial technical means adopted by the present invention to solve the above technical problems is: after the amination reaction is completed, a complexing agent is used to treat the reaction system.

[0009] The complexing agent is selected from one or more (including two) of phytic acid, disodium edetate, calcium disodium edetate, and sodium gluconate.

[0010] To obtain better treatment effects, the complexing agent is preferably phytic acid.

[0011] The dosage of the complexing agent is 0.1% - 3.0% of the weight of the reaction system to be treated, preferably 0.5% - 2.0%, and more preferably 1.0%.

[0012] Another technical means adopted by the present invention to solve the above technical problems is: after the cyanidation reaction is completed, an adsorbent is used to treat the reaction system.

[0013] The adsorbent is selected from one or more (including two) of activated carbon, diatomaceous earth, activated alumina, and porous silica gel.

[0014] To obtain better treatment effects, the adsorbent is preferably activated carbon.

[0015] The dosage of the adsorbent is 0.1% - 5.0% of the weight of the reaction system to be treated, preferably 1.0% - 3.0%, and more preferably 2.0%.

[0016] The positive effects of the present invention are: (1) The method of the present invention adding a complexing agent for treatment after the amination reaction can significantly improve the color of the L-quaternary ammonium salt solution, and further can significantly improve the color of the L-nitrile compound and reduce its impurity content. (2) The method of the present invention adding an adsorbent for treatment after the cyanidation reaction can further improve the color of the L-nitrile compound and further reduce the impurity content of the L-nitrile compound. Specific embodiments

[0017] (Example 1)

[0018] The preparation method of the levocarnitine intermediate in this example is as follows:

[0019] ① Add 400 g of an aqueous solution of trimethylamine hydrochloride with a concentration of 51 wt% (2.13 mol) and 11.8 g of an aqueous solution of trimethylamine with a concentration of 25 wt% (0.05 mol) to the reaction device, cool down to 5 - 10 °C, and dropwise add 130 g of S-epichlorohydrin (1.40 mol). After dropping, keep the temperature at 5 - 10 °C for heat preservation reaction for 2 h, and then raise the temperature to 3D °C for heat preservation reaction for 4 h.

[0020] After the reaction is completed, add 1% of phytic acid based on the weight of the reaction system, keep the temperature at 30 °C for heat preservation reaction for 0.5 h, and filter to obtain a transparent yellow-brown L-quaternary ammonium salt solution.

[0021] ② Heat the L-quaternary ammonium salt solution obtained in step ① to 40 - 45 °C, and dropwise add 250 g of an aqueous solution of sodium cyanide with a concentration of 30 wt% (1.53 mol). After dropping, keep the temperature at 40 - 45 °C for heat preservation reaction for 4 h.

[0022] After the reaction was completed, the pH was first adjusted to 5-6 with hydrochloric acid, followed by vacuum distillation and filtration to remove salts. Then, 2% by weight of 737 type medicinal activated carbon was added to the filtrate, and the mixture was kept at 60 °C for 0.5 h for decolorization. After filtration to remove carbon, the filtrate was concentrated and crystallized to obtain 188 g of the left carnitine intermediate L-cyanide in off-white color, with a yield of 75%. The total impurity content was detected to be 2.0%.

[0023] (Examples 2 to 4)

[0024] The preparation methods of each example were basically the same as that of Example 1, except for the addition amount of phytic acid, as shown in Table 1 specifically.

[0025] Table 1

[0026] Example 1 Example 2 Example 3 Example 4 Phytic acid addition amount 1% 0.1% 0.5% 3% Color of L-quaternary ammonium salt solution Showing transparent yellowish brown Showing transparent dark brown Showing transparent yellowish brown Showing transparent yellowish brown Total impurity content of L-nitrile 2.0% 3.4% 2.7% 1.8% Color and luster of L-nitrile Off-white Light yellow Pale yellow Off-white

[0027] (Examples 5 to 7)

[0028] The preparation methods of each example were basically the same as that of Example 1, except for the addition amount of activated carbon, as shown in Table 2 specifically.

[0029] Table 2

[0030] Example 1 Example 5 Example 6 Example 7 Activated carbon addition amount 2% 0.1% 1% 5% Total impurity content of L-nitrile 2.0% 2.6% 2.2% 1.9% Color and luster of L-nitrile Off-white Pale yellow Off-white Off-white

[0031] (Examples 8 to 10)

[0032] The preparation methods of each example were basically the same as that of Example 1, except for the type of complexing agent, as shown in Table 3 specifically.

[0033] Table 3

[0034] Example 1 Example 8 Example 9 Example 10 Complexing agent type Phytic acid Disodium edetate Calcium disodium edetate Sodium gluconate Color of L-quaternary ammonium salt solution Showing transparent yellowish brown Showing transparent dark brown Showing transparent dark brown Showing dark brown Total impurity content of L-nitrile 2.0% 3.7% 3.8% 4.4% Color and luster of L-nitrile Off-white Light yellow Light yellow Yellowish brown

[0035] (Examples 11 to 13)

[0036] The preparation methods of each example were basically the same as that of Example 1, except for the type of adsorbent, as shown in Table 4 specifically.

[0037] Table 4

[0038] Example 1 Example 11 Example 12 Example 13 Adsorbent type Activated carbon Diatomite Activated alumina Porous silica gel Total impurity content of L-nitrile 2.0% 2.7% 3.5% 3.6% Color and luster of L-nitrile Off-white Pale yellow Light yellow Light yellow

[0039] (Comparative Examples 1 to 6)

[0040] The preparation methods of each comparative example were basically the same as that of Example 1, with the differences shown in Table 5.

[0041] Table 5

[0042] Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Post-treatment of amination 1% phytic acid / / / 2% activated carbon 2% activated carbon 2% activated carbon Color of L-quaternary ammonium salt solution Showing transparent yellowish brown Showing dark brown Showing dark brown Showing dark brown Showing dark brown Showing dark brown Showing dark brown Post-treatment of cyanidation 2% activated carbon / 2% activated carbon 1% phytic acid / 2% activated carbon 1% phytic acid Total impurity content of L-nitrile 2.0% 5.8% 5.0% 5.6% 5.7% 5.1% 5.5% Color and luster of L-nitrile Off-white Tan Khaki Tan Tan Khaki Tan

Claims

1. A preparation method of a levocarnitine intermediate, which uses S-epichlorohydrin as the starting material, first undergoes an amination reaction with trimethylamine hydrochloride to obtain L-3-chloro-2-hydroxypropyltrimethylammonium chloride, and then undergoes a cyanation reaction with sodium cyanide to obtain the levocarnitine intermediate L-3-cyano-2-hydroxypropyltrimethylammonium chloride, characterized in that: After the amination reaction is completed, a complexing agent is used to treat the reaction system; the complexing agent is phytic acid; the dosage of the complexing agent is 0.1% - 3.0% of the weight of the reaction system to be treated; After the cyanation reaction is completed, an adsorbent is used to treat the reaction system; the adsorbent is activated carbon; the dosage of the adsorbent is 0.1% - 5.0% of the weight of the reaction system to be treated.

2. The preparation method of the L-carnitine intermediate according to claim 1, characterized in that: The dosage of the complexing agent is 0.5% - 2.0% of the weight of the reaction system to be treated.

3. The preparation method of the left carnitine intermediate according to claim 1, characterized in that: The dosage of the adsorbent is 1.0% - 3.0% of the weight of the reaction system to be treated.