A preparation method of L-acetylcarnitine hydrochloride

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically discloses a preparation method of acetyl-L-carnitine hydrochloride. The method comprises the following steps: using L-cyanoacetamide as a raw material, adding glacial acetic acid, water, potassium permanganate and sodium nitrite thereto, reacting at 40-50 °C for 1-4 h, then dropping acetyl chloride, heating up to 118-130 °C and reacting for 1-4 h, concentrating under reduced pressure to obtain acetyl-L-carnitine amide chloride; adding absolute ethanol and a certain amount of 36 wt% concentrated hydrochloric acid, reacting at 20-60 °C for 0.5-2.5 h, cooling for crystallization, filtering to obtain an ethanol solution of acetyl-L-carnitine hydrochloride; adding absolute ethanol to make the mass percentage concentration of ethanol in the ethanol solution reach 85%-95%, heating for dissolution, cooling for crystallization, filtering, and drying under vacuum to obtain pure acetyl-L-carnitine hydrochloride. The reaction conditions in the whole process are mild, and no crotonobetaine hydrochloride impurity is generated, greatly reducing the post-treatment steps and significantly increasing the purity of the product.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of acetyl-L-carnitine hydrochloride. Background Art

[0002] Acetyl-L-carnitine hydrochloride is the acetylated product of L-carnitine and is also the most abundant L-carnitine derivative naturally present in organisms. It has a variety of physiological activities, including nutritional effects, neuroprotective effects, analgesic effects on the peripheral nervous system, promoting energy metabolism, transporting long-chain fatty acids to the inner mitochondrial membrane to participate in oxidative phosphorylation and generating ATP for energy supply, regulating antioxidant enzymes under pathological conditions to play an antioxidant role, and its role in the male reproductive system, etc.

[0003] Currently, the method for preparing acetyl-L-carnitine hydrochloride is to add L-carnitine to a mixed solution of acetic acid and acetyl chloride and react at a high temperature to obtain the target product (Helvetica Chimica Acta, 1987, 70: 2085 - 8064). However, this method has some drawbacks: (1) It has a high requirement for the purity of raw materials. The price of L-carnitine is relatively high, resulting in a high cost; (2) Since the reaction temperature is relatively high (above 118 °C), it is easy to generate L-carnitine impurity A (i.e., crotonobetaine hydrochloride) during the reaction process; (3) Carnitine intermediates and related products are all amino acid-like products, and there is a high risk of bacterial contamination during the preparation process. How to solve the above problems, reduce the reaction cost, improve the purity of the product, and improve production efficiency has become a difficult problem in the preparation process of acetyl-L-carnitine hydrochloride. Summary of the Invention

[0004] In order to solve the deficiencies existing in the prior art, the purpose of the present invention is to provide a preparation method of acetyl-L-carnitine hydrochloride.

[0005] In order to achieve the above technical purpose, the present invention adopts the following specific technical solutions:

[0006] A preparation method of acetyl-L-carnitine hydrochloride, comprising the following steps:

[0007] S1. Add glacial acetic acid, water, potassium permanganate, and sodium nitrite to L-cyanocarnitine ((R)-3-cyano-2-hydroxy-N,N,N-trimethyl-1-propanaminium chloride), react at temperature T1 for a period of time, then dropwise add acetyl chloride, and raise the temperature to temperature T2. React at this temperature for a period of time, and concentrate under reduced pressure to obtain acetyl-L-carnitine amide chloride;

[0008] S2. Add absolute ethanol and a certain amount of 36 wt% concentrated hydrochloric acid to the acetyl-L-carnitine amide chloride obtained in step S1, react at temperature T3 for a period of time, cool down to crystallize, filter, and obtain an ethanol solution of acetyl-L-carnitine hydrochloride;

[0009] S3. Add absolute ethanol to the ethanol solution of acetyl-L-carnitine hydrochloride obtained in step S2 to make the mass percentage concentration of ethanol in the ethanol solution reach 85% - 95%, heat up to dissolve, cool down to crystallize, filter, and vacuum dry to obtain pure acetyl-L-carnitine hydrochloride.

[0010] Further, in step S1, the molar ratio of L-cyanoacetamide: potassium permanganate: sodium nitrite: water: acetyl chloride: glacial acetic acid is 1:(0.01 - 0.05):(2.015 - 2.075):(1 - 1.2):(1.2 - 2.5):(5 - 10). Preferably, the molar ratio is 1:(0.02 - 0.04):(2.03 - 2.06):(1 - 1.1):(2.0 - 2.5):(8 - 9).

[0011] Further, in step S1, react at T1 = 40 - 50 °C for 1 - 4 h. Preferably, react at 50 °C for 2 h.

[0012] Further, in step S1, react at T2 = 118 - 130 °C for 1 - 4 h. Preferably, react at 120 °C for 2 h.

[0013] Further, in step S2, the molar ratio of acetyl-L-carnitine amide chloride: HCl in 36 wt% concentrated hydrochloric acid: absolute ethanol is 1:2 - 4:5 - 10. Preferably, the molar ratio is 1:2 - 3:8 - 10.

[0014] Further, in step S2, react at T3 = 20 - 60 °C for 0.5 - 2.5 h. Preferably, react at T3 = 30 - 40 °C for 1 h.

[0015] Further, in step S2, cool down to 0 °C to crystallize.

[0016] Further, in step S3, the mass percentage concentration of ethanol in the ethanol solution is preferably 90%.

[0017] Further, in step S3, after adding an appropriate amount of absolute ethanol, heat up to 80 °C to dissolve, and cool down to 0 °C to crystallize.

[0018] Further, the ethanol liquid containing a small amount of acetyl-L-carnitine hydrochloride obtained by filtration in step S3 can be used as a solvent for recycling.

[0019] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0020] First, the present invention uses L - levocarnitril, an intermediate of L - carnitine, as a raw material, which has a lower cost compared to L - carnitine.

[0021] Second, in the present invention, through the redox reaction between potassium permanganate and sodium nitrite, the in - situ generated catalyst, manganese dioxide, has higher catalytic activity. It catalyzes the reduction of the substrate, L - levocarnitril, to (R)-4 - amino - 2 - hydroxy - N,N,N - trimethyl - 4 - oxobutanamine, and then acetylation is carried out. The reaction conditions throughout the process are milder and do not produce impurity A, crotonobetaine hydrochloride (since the cyano group in L - levocarnitril is hydrolyzed to an amide, and the electron - withdrawing ability of the amide is very weak, and it is difficult to undergo an elimination reaction during acetylation). This greatly reduces the post - treatment steps, and the purity of the product is also greatly increased, with a purity above 97%.

[0022] Third, the present invention catalyzes the acid hydrolysis of acetyl - L - carnitine amide chloride with sodium nitrite, greatly reducing the hydrolysis reaction temperature (usually, the hydrolysis temperature of amides with hydrochloric acid or sulfuric acid is above 100°C), reducing the occurrence of side reactions and lowering energy consumption.

[0023] Fourth, since carnitine series intermediates and products are all amino - acid - like substances, bacterial contamination may occur during the reaction process. However, in the reaction process of the present invention, a certain amount of sodium nitrite exists in the system, which can effectively play an antibacterial and antiseptic role.

[0024] Fifth, by - products generated during the entire reaction process, recycled solvents, etc. can all be recycled, greatly reducing the generation of waste residues and waste liquids, being more environmentally friendly, and also improving the comprehensive utilization efficiency of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a flow chart for preparing acetyl - L - carnitine hydrochloride according to the present invention.

[0026] Figure 2 is the liquid chromatogram of the acetyl - L - carnitine hydrochloride standard.

[0027] Figure 3 is the liquid chromatogram of the acetyl - L - carnitine hydrochloride prepared in Example 1.

[0028] Figure 4 is the liquid chromatogram of the acetyl - L - carnitine hydrochloride prepared in Example 2.

[0029] Figure 5 is the liquid chromatogram of the acetyl - L - carnitine hydrochloride prepared in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0030] To make the purpose and technical solution of the present invention more clear, the technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described 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.

[0031] Example 1

[0032] In 178.5g (1mol) L-carnitrile, 500mL glacial acetic acid (8.75mol), 19.8g water (1.1mol), 6.32g (0.04mol) potassium permanganate and 142.14g sodium nitrite (2.06mol) were added, and the reaction was carried out at 50 ℃ for 2 hours. After the reaction was completed, 150g (2mol) acetyl chloride was added dropwise, and the reaction was heated to 120 ℃ of reflux reaction times for 2 hours to obtain acetyl-L-carnitine amide chloride reaction solution; the reaction solution was concentrated under reduced pressure to near dryness, and acetic acid and acetyl chloride were reclaimed to obtain acetyl-L-carnitine amide chloride; 500mL absolute ethanol (8.59mol) and 170mL of 36wt% concentrated hydrochloric acid (2.04molHCl) were added to the acetyl-L-carnitine amide chloride, and the reaction mixture was reacted for 1 hour at 40 ℃, and the mixture was cooled to 0 ℃ of crystallizations, and filtered to obtain ammonium chloride and sodium nitrite solids and acetyl-L-carnitine hydrochloride ethanolic solution. 1806 mL of anhydrous ethanol was added to the ethanol solution of acetyl-L-carnitine hydrochloride to make the ethanol content in the ethanol solution reach 90% (mass percentage concentration), the temperature was raised to 80° C. for dissolution, the temperature was lowered to 0° C. for crystallization, the solution was filtered, and the solution was vacuum dried to obtain pure acetyl-L-carnitine hydrochloride. The total yield of the product was 95% and the purity was 99%.

[0033] The purity of the samples was determined using the external standard method:

[0034] Liquid phase conditions: Use a Hysililaps-2 liquid phase column (size: 5µm x 250mm x 4.6mm). Mobile phase: A: Add 6.81g of potassium dihydrogen phosphate to 800mL of ultrapure water, adjust the pH to 4.7 with 0.1M sodium hydroxide solution, and then dilute to 1000mL with ultrapure water. B: Chromatographic grade acetonitrile. A :V B =35:65, flow rate: 1 mL / min, column temperature: 30°C.

[0035] The liquid chromatography spectrum of acetyl-L-carnitine hydrochloride standard is shown in Figure 2 , the sample purity is 99.2%.

[0036] The liquid phase spectrum of acetyl-L-carnitine hydrochloride prepared in Example 1 is shown in Figure 3, the peak time of acetyl-L-carnitine hydrochloride was 5.5 min, and the purity of the pure acetyl-L-carnitine hydrochloride obtained in Example 1 was 99.0%.

[0037] Example 2

[0038] To 178.5 g (1 mol) of L-cyanoacetamide, 500 mL of glacial acetic acid (8.75 mol), 21.6 g of water (1.2 mol), 4.74 g (0.03 mol) of potassium permanganate, and 141.1 g of sodium nitrite (2.045 mol) were added. The reaction was carried out at 50 °C for 2 hours. After the reaction was completed, 150 g (2 mol) of acetyl chloride was added dropwise, and the temperature was raised to 120 °C for reflux reaction for 2 hours to obtain a reaction solution of acetyl-L-carnitine amide chloride. The reaction solution was concentrated under reduced pressure until nearly dry to recover acetic acid and acetyl chloride, and acetyl-L-carnitine amide chloride was obtained. To the acetyl-L-carnitine amide chloride, 500 mL of absolute ethanol (8.59 mol) and 170 mL of 36 wt% concentrated hydrochloric acid (2.04 mol HCl) were added, and the reaction was carried out at 40 °C for 1 hour. The temperature was lowered to 0 °C for crystallization, and ammonium chloride solid, sodium nitrite solid, and an ethanol solution of acetyl-L-carnitine hydrochloride were obtained by filtration. 1806 mL of absolute ethanol was added to the ethanol solution of acetyl-L-carnitine hydrochloride to make the ethanol content in the ethanol solution reach 90% (mass percentage concentration). The temperature was raised to 80 °C for dissolution, and then the temperature was lowered to 0 °C for crystallization, followed by filtration and vacuum drying to obtain pure acetyl-L-carnitine hydrochloride. The total yield of the product was 92%, and the purity was 97.7%.

[0039] The external standard method was used to determine the sample purity. The liquid phase conditions were the same as those in Example 1. The liquid phase chromatogram of the acetyl-L-carnitine hydrochloride prepared in Example 2 is shown in Figure 4 .

[0040] Example 3

[0041] 178.5 g (1 mol) of L-carnitronitrile was added with 500 mL of glacial acetic acid (8.75 mol), 19.8 g of water (1.1 mol), 3.16 g (0.02 mol) of potassium permanganate and 140.1 g of sodium nitrite (2.03 mol). The reaction was carried out at 50 °C for 2 hours. After the reaction was completed, 187.5 g (2.5 mol) of acetyl chloride was added dropwise, and the temperature was raised to 120 °C for reflux reaction for 2 hours to obtain a reaction solution of acetyl-L-carnitine amide chloride; the reaction solution was concentrated under reduced pressure to nearly dryness to recover acetic acid and acetyl chloride to obtain acetyl-L-carnitine amide chloride; 600 mL of absolute ethanol (10 mol) and 170 mL of 36 wt% concentrated hydrochloric acid (2.04 mol HCl) were added to the acetyl-L-carnitine amide chloride, and the reaction was carried out at 40 °C for 1 hour. The temperature was lowered to 0 °C for crystallization, and the solid ammonium chloride, solid sodium nitrite and ethanol solution of acetyl-L-carnitine hydrochloride were obtained by filtration. 1347 mL of absolute ethanol was added to the ethanol solution of acetyl-L-carnitine hydrochloride to make the ethanol content in the ethanol solution reach 90% (mass percentage concentration). The temperature was raised to 80 °C for dissolution, and the temperature was lowered to 0 °C for crystallization, filtration, and vacuum drying to obtain pure acetyl-L-carnitine hydrochloride. The total yield of the product was 90%, and the purity was 98.9%.

[0042] The purity of the sample was determined by the external standard method. The liquid phase conditions were the same as those in Example 1. The liquid phase chromatogram of the acetyl-L-carnitine hydrochloride prepared in Example 3 is shown in Figure 5 。

[0043] The above is only the specific implementation manner of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the protection scope of the claims of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several deformations and improvements can be made, and these all belong to the protection scope of the present invention.

Claims

1. A preparation method of acetyl-L-carnitine hydrochloride, characterized in that, It includes the following steps: S1. Add glacial acetic acid, water, potassium permanganate and sodium nitrite to L-carnitril, react at T1 = 40 - 50 °C for 1 - 4 h to obtain (R)-4-amino-2-hydroxy-N,N,N-trimethyl-4-oxobutanamine, then dropwise add acetyl chloride, raise the temperature to T2 = 118 - 130 °C and react for 1 - 4 h, concentrate under reduced pressure to obtain acetyl-L-carnitine amide chloride; S2. Add absolute ethanol and a certain amount of 36 wt% concentrated hydrochloric acid to the acetyl-L-carnitine amide chloride obtained in step S1, react at T3 = 20 - 60 °C for 0.5 - 2.5 h, cool down for crystallization, filter to obtain an ethanol solution of acetyl-L-carnitine hydrochloride; S3. Add absolute ethanol to the ethanol solution of acetyl-L-carnitine hydrochloride obtained in step S2 to make the mass percentage concentration of ethanol in the ethanol solution reach 85% - 95%, heat up to dissolve, cool down for crystallization, filter, and dry under vacuum to obtain pure acetyl-L-carnitine hydrochloride; In step S1, the molar ratio of L-carnitril: potassium permanganate: sodium nitrite: water: acetyl chloride: glacial acetic acid is 1: (0.01 - 0.05): (2.015 - 2.075): (1 - 1.2): (1.2 - 2.5): (5 - 10).

2. The preparation method of acetyl-L-carnitine hydrochloride according to claim 1, wherein In step S2, the molar ratio of acetyl-L-carnitine amide chloride: HCl in 36 wt% concentrated hydrochloric acid: absolute ethanol is 1: 2 - 4: 5 - 10.

3. The preparation method of acetyl-L-carnitine hydrochloride according to claim 1, wherein T2 = 120 °C and / or T3 = 30 - 40 °C.

4. A method for preparing acetyl-L-carnitine hydrochloride according to claim 1, characterized in that, In step S1, the molar ratio of L-carnitril: potassium permanganate: sodium nitrite: water: acetyl chloride: glacial acetic acid is 1: (0.02 - 0.04): (2.03 - 2.06): (1 - 1.1): (2.0 - 2.5): (8 - 9).

5. The preparation method of acetyl-L-carnitine hydrochloride according to claim 1, wherein, In step S2, the molar ratio of acetyl-L-carnitine amide chloride: HCl in 36 wt% concentrated hydrochloric acid: absolute ethanol is 1: 2 - 3: 8 - 10.

6. The preparation method of acetyl-L-carnitine hydrochloride according to claim 1, wherein In step S3, the mass percentage concentration of ethanol in the ethanol solution is 90%.

7. The preparation method of acetyl-L-carnitine hydrochloride according to claim 1, wherein, In step S3, after adding an appropriate amount of absolute ethanol, heat up to 80 °C to dissolve, and cool down to 0 °C for crystallization.

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