A method for purifying pyridinium chloride 3-carboxylate choline ester

Abstract

The invention provides a method for purifying pyridinium chloride 3-formate choline ester shown in formula I. The method of the invention is simple to operate, has high product yield and high purity, and is very suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a method for purifying pyridinium chloride 3-carboxylate choline ester. Background Art

[0002] Choline is an important component of biological membranes and a precursor of acetylcholine in cholinergic neurons. Choline has many functions, including promoting brain development, improving memory, promoting fat metabolism and transmethylation metabolism in the body, and lowering serum cholesterol.

[0003] Based on the structure of choline, humans have developed a series of choline ester derivatives. U.S. Patent No. 3,337,569A discloses a choline ester compound having the effect of vasodilation and a preparation method thereof as shown in the following formula I:

[0004]

[0005] The patent discloses that after the reaction is completed, the compound of formula I is recrystallized twice in a mixed solvent of ethanol-ether. On the one hand, the purification method uses a mixed organic solvent of ethanol-ether, which easily leads to substandard organic residual solvent in the final product. On the other hand, although the purification method uses two recrystallizations, the purification effect is not good, the product purity is only about 98%, and the single impurity content is greater than 0.5%, which cannot meet the pharmaceutical requirements.

[0006] In addition, Chinese patent CN108329220A discloses another method for preparing chlorinated pyridine 3-carboxylic acid choline ester compounds, first reacting pyridine-3-carboxylic acid with a chlorination reagent, concentrating the reaction solution after the reaction, then adding 2-chloroethanol to react, and then concentrating again, dissolving the concentrate with water, and then extracting it several times with dichloromethane, concentrating the organic phase to dryness and then dissolving it with THF, and then reacting with a THF solution of trimethylamine to obtain the final product chlorinated pyridine 3-carboxylic acid choline ester. The purity of the product prepared according to the method disclosed in the patent is not ideal, only about 96%, and cannot meet the requirements for medicinal use.

[0007] Therefore, a purification method for pyridinium chloride 3-carboxylate choline ester compound still needs to be developed to meet its pharmaceutical needs. Summary of the invention

[0008] Aiming at the technical problem that the pyridinium chloride 3-carboxylate choline ester compound shown in the following formula I prepared by the prior art has low purity and cannot meet the pharmaceutical needs,

[0009]

[0010] The invention provides a method for purifying a pyridinium chloride 3-carboxylate choline ester compound. The method is simple to operate, can ensure high purity and high yield of the product, and is very suitable for industrial production.

[0011] The present invention is achieved through the following technical solutions:

[0012] The present invention provides a method for purifying a pyridinium chloride 3-carboxylate choline ester compound as shown in the following formula I:

[0013]

[0014] The method comprises the following steps:

[0015] (1) dissolving the pyridinium chloride 3-carboxylate choline ester represented by formula I in water,

[0016] (2) Control the pH value of the solution to 5-7,

[0017] (3) cooling the solution obtained in step (2) to form a solid precipitate of pyridinium chloride 3-carboxylate choline ester represented by formula I,

[0018] (4) Filter and dry the solid precipitate obtained in step (3).

[0019] In a preferred technical solution, the temperature of water in step (1) is controlled at 30-60°C.

[0020] In a more preferred technical solution, the temperature of water in step (1) is controlled at 50-60°C.

[0021] The inventors have found through research and comparison that dissolving the pyridinium chloride 3-carboxylate choline ester shown in Formula I in water at a temperature of 50-60°C can improve the purity of the product while ensuring the product yield, compared with dissolving it in water at a temperature below 50°C.

[0022] In a preferred technical solution, the pH value of the solution is controlled at 5.5-6.0 in step (2). Acid, such as hydrochloric acid, sulfuric acid, acetic acid, etc., can be added to the solution obtained in step (1) to adjust the pH value of the solution, preferably hydrochloric acid.

[0023] In a preferred technical solution, the temperature of the solution obtained in step (2) is cooled to 0-10°C, preferably 0-5°C, so as to form a solid precipitate of pyridinium chloride 3-carboxylate choline ester represented by formula I.

[0024] Finally, the solid precipitate obtained in step (3) is filtered and dried.

[0025] If necessary, repeat steps (1)-(4) one or two times to ensure that the product purity meets pharmaceutical requirements. Implementation

[0026] The present invention is described in detail below by examples. It must be pointed out that the following examples are used to illustrate the present invention rather than to limit the present invention.

[0027] The crude product of pyridinium chloride 3-carboxylate cholinester used in the following Examples 1-6 was prepared according to Example 3 of CN108329220A, and its HPLC purity was 96.0%. Example 1

[0028] 1 g of crude pyridinium 3-carboxylate choline chloride was added to 100 mL of water and stirred at 30°C to dissolve. The pH of the solution was adjusted to 5.0 with hydrochloric acid, and then the resulting solution was cooled to 5°C, and then the solution was allowed to stand to precipitate a solid precipitate of pyridinium 3-carboxylate choline chloride. The filter cake was filtered and dried to constant weight to obtain 0.9 g of refined pyridinium 3-carboxylate choline chloride, with an HPLC purity of 99.3%. Example 2

[0029] 1 g of crude pyridinium 3-carboxylate choline chloride was added to 100 mL of water and stirred at 50°C to dissolve. The pH of the solution was adjusted to 5.0 with hydrochloric acid, and then the resulting solution was cooled to 5°C, and then the solution was allowed to stand to precipitate a solid precipitate of pyridinium 3-carboxylate choline chloride. The filter cake was filtered and dried to constant weight to obtain 0.94 g of refined pyridinium 3-carboxylate choline chloride, with an HPLC purity of 99.8%. Example 3

[0030] 1 g of crude pyridinium 3-carboxylate choline chloride was added to 100 mL of water and stirred at 30°C to dissolve. The pH of the solution was adjusted to 7.0 with hydrochloric acid, and then the resulting solution was cooled to 0°C, and then the solution was allowed to stand to precipitate a solid precipitate of pyridinium 3-carboxylate choline chloride. The filter cake was filtered and dried to constant weight to obtain 0.91 g of refined pyridinium 3-carboxylate choline chloride, with an HPLC purity of 99.4%. Example 4

[0031] 1 g of crude pyridinium 3-carboxylate choline chloride was added to 100 mL of water and stirred at 60°C to dissolve. The pH of the solution was adjusted to 7.0 with hydrochloric acid, and then the resulting solution was cooled to 0°C, and then the solution was allowed to stand to precipitate a solid precipitate of pyridinium 3-carboxylate choline chloride. The filter cake was filtered and dried to constant weight to obtain 0.93 g of refined pyridinium 3-carboxylate choline chloride, with an HPLC purity of 99.7%. Example 5

[0032] 1 g of crude pyridinium 3-carboxylate choline chloride was added to 100 mL of water and stirred at 40°C to dissolve. The pH of the solution was adjusted to 6.0 with hydrochloric acid, and then the resulting solution was cooled to 5°C, and then the solution was allowed to stand to precipitate a solid precipitate of pyridinium 3-carboxylate choline chloride. The filter cake was filtered and dried to constant weight to obtain 0.91 g of refined pyridinium 3-carboxylate choline chloride, with an HPLC purity of 99.4%. Example 6

[0033] Add 1g of crude pyridinium 3-carboxylate choline chloride to 100mL of water and stir to dissolve at 30°C. Adjust the pH of the solution to 5.0 with hydrochloric acid, then cool the resulting solution to 5°C, and then let the solution stand to precipitate solid precipitates of pyridinium 3-carboxylate choline chloride. Filter and dissolve the filter cake in 30°C water again, adjust the pH of the solution to 5.0 with hydrochloric acid, then cool the resulting solution to 5°C, and then let the solution stand to precipitate solid precipitates of pyridinium 3-carboxylate choline chloride. Filter and dry the filter cake to constant weight to obtain 0.85g of refined pyridinium 3-carboxylate choline chloride with an HPLC purity of 99.9%.

Claims

1. A method for purifying pyridinium chloride 3-carboxylate choline ester as shown in the following formula I, It is characterized in that The method comprises the following steps: (1) dissolving pyridinium chloride 3-carboxylate choline ester represented by formula (I) in water, (2) Control the pH value of the solution to 5-7, (3) cooling the solution obtained in step (2) to a temperature of 0-10° C., thereby forming a solid precipitate of pyridinium chloride 3-carboxylate choline ester represented by formula I, (4) filtering and drying the solid precipitate obtained in step (3), (5) If necessary, repeat steps (1)-(4) one or two more times.

2. The method according to claim 1, characterized in that In step (1), the temperature of water is controlled at 30-60°C.

3. The method according to claim 1 or 2, characterized in that: In step (1), the temperature of water is controlled at 50-60°C.

4. The method according to claim 1 or 2, characterized in that: In step (2), the pH value of the solution is controlled at 5.5-6.

0.

5. The method according to claim 1 or 2, characterized in that: In step (3), the temperature is cooled to 0-10°C.

6. The method according to claim 5, characterized in that In step (3), the temperature is cooled to 0-5°C.

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