A method for preparing pyridinium chloride 3-carboxylate choline ester

Abstract

The invention discloses a one-pot method for preparing pyridine chloride 3-carboxylic acid choline ester shown in formula I. In the method, 3-pyridine carboxylic acid chloride and trimethylamine are directly reacted in 2-chloroethanol, the operation is convenient, the yield and purity are high, and the method is very suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing 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 pyridinium chloride 3-carboxylate choline ester compound and a preparation method thereof as shown in the following formula I:

[0004]

[0005] The compound has the effect of vasodilation. In addition, Chinese patent CN107540605A discloses that the pyridinium chloride 3-carboxylate choline ester compound has the effects of preventing hair loss and promoting hair regeneration.

[0006] CN107540605A discloses a method for preparing a chlorinated pyridine 3-carboxylic acid choline ester compound, firstly reacting 3-pyridine carboxylic acid chloride with 2-chloroethanol to obtain 2-chloroethyl nicotinate, then reacting the obtained product with NaI to obtain 2-iodoethyl nicotinate, then reacting with trimethylamine to obtain N,N,N-trimethyl-2-(nicotinoyloxy)ethylammonium iodide, and finally reacting with AgCl to obtain the final product chlorinated pyridine 3-carboxylic acid choline ester. This method has many reaction steps, is very complicated to operate, is time-consuming, has high production costs, and is very unsuitable for industrial production.

[0007] CN108329220A discloses another method for preparing a chlorinated pyridine 3-carboxylic acid choline ester compound, firstly reacting pyridine-3-carboxylic acid with a chlorination reagent, concentrating the reaction solution after the reaction is completed, then adding 2-chloroethanol to react, then concentrating again, dissolving the concentrate with water, then extracting multiple times with dichloromethane, concentrating the organic phase to dryness, 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 post-processing of this method is still relatively cumbersome, the yield is low, and it is not suitable for industrial production.

[0008] Therefore, there is still a need to develop a preparation method of pyridinium chloride 3-carboxylate choline ester which is simpler to operate, has lower cost and is more suitable for industrial production, so as to solve the technical problems existing in the prior art. Summary of the invention

[0009] In view of the technical problems existing in the prior art, the inventors have made intensive studies and surprisingly found that if 2-chloroethanol, the raw material required for synthesizing the chlorinated pyridine 3-carboxylic acid choline ester compound shown in I, is used as the reaction solvent, the chlorinated pyridine 3-carboxylic acid choline ester compound can be synthesized by a one-pot method. Compared with the prior art, the operation is simpler, and the time cost and material cost are also significantly reduced, which is very suitable for industrial production, thereby completing the present invention.

[0010] Therefore, the present invention provides a one-pot method for preparing the pyridinium chloride 3-carboxylate choline ester compound shown in formula I,

[0011]

[0012] The method comprises: reacting 3-pyridinecarbonyl chloride with trimethylamine in 2-chloroethanol.

[0013] In the reaction, 2-chloroethanol is used as both the reaction material and the reaction solvent of the reaction. No intermediate product needs to be separated during the reaction, that is, the target product of formula I can be obtained by a "one-pot method".

[0014] In a preferred technical solution, the reaction is carried out in the presence of an alkaline catalyst. The alkaline catalyst is preferably a strong alkaline substance, such as sodium hydroxide, potassium hydroxide, etc. The alkaline catalyst can promote the progress of the reaction, thereby shortening the reaction time.

[0015] In a preferred technical solution, the reaction is carried out at a temperature of 40-60°C, preferably 50-55°C.

[0016] In a preferred technical solution, the reaction time is controlled at 4-8 hours, preferably 5-6 hours.

[0017] In a preferred technical solution, the molar ratio of 3-pyridinecarbonyl chloride to trimethylamine added in the reaction is 1:1-3, preferably 1:2-2.5.

[0018] In a preferred technical solution, after the reaction is completed, the obtained reaction solution is cooled to 20-30° C. and filtered to obtain a solid precipitate of pyridinium chloride 3-carboxylic acid choline ester represented by formula I.

[0019] The 3-pyridinecarbonyl chloride used in the present invention can be prepared by a method known in the art, for example, referring to CN108329220A, 3-pyridinecarbonic acid is reacted with a chlorinating agent, and the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride.

[0020] Technical effects of the present invention:

[0021] The present invention innovatively uses 2-chloroethanol for two purposes, that is, on the one hand, it is used as a reaction material to participate in the reaction, and on the other hand, it is used as a reaction solvent, unexpectedly realizing the "one-pot method" to prepare the pyridinium chloride 3-carboxylate choline ester shown in formula I, and no separation and purification operation of the intermediate is required during the reaction process, thereby improving the product yield and ensuring the purity of the product. DETAILED DESCRIPTION

[0022] The present invention is described in detail below by way of examples. It should be noted that the following examples are used to illustrate the present invention rather than to limit the present invention.

[0023] Example 1

[0024] In a 250 mL reaction bottle, add 60 ml of 2-chloroethanol, then add 5 mmol of 3-pyridinecarbonyl chloride and 5 ml of 2M trimethylamine THF solution, stir evenly, and heat the resulting mixture to 40 ° C for 8 hours. After the reaction is completed, the reaction solution is cooled to 30 ° C, filtered, and the filter cake is dried to constant weight to obtain 1.13 g of pyridinium chloride 3-carboxylic acid choline ester (yield is about 92%, HPLC purity is 98.5%).

[0025] Example 2

[0026] In a 250 mL reaction bottle, add 60 ml of 2-chloroethanol, then add a small amount of NaOH aqueous solution, then add 5 mmol of 3-pyridinecarbonyl chloride and 7.5 ml of 2M trimethylamine THF solution, stir evenly, and heat the resulting mixture to 50 ° C for 5 hours. After the reaction is completed, the reaction solution is cooled to 20 ° C, filtered, and the resulting filter cake is dried to constant weight to obtain 1.17 g of pyridinium chloride 3-carboxylic acid choline ester (yield is about 96%, HPLC purity is 98.4%).

[0027] Example 3

[0028] In a 250 mL reaction bottle, add 60 ml of 2-chloroethanol, then add 5 mmol of 3-pyridinecarbonyl chloride and 2.5 ml of 2M trimethylamine THF solution, stir evenly, and heat the resulting mixture to 60 ° C for 6 hours. After the reaction is completed, the reaction solution is cooled to 25 ° C, filtered, and the resulting filter cake is dried to constant weight to obtain 1.1 g of pyridinium chloride 3-carboxylic acid choline ester (yield is about 90%, HPLC purity is 98.0%).

[0029] Example 4

[0030] In a 250 mL reaction bottle, add 60 ml of 2-chloroethanol, then add a small amount of KOH aqueous solution, then add 5 mmol of 3-pyridinecarbonyl chloride and 2.5 ml of 2M trimethylamine THF solution, stir evenly, and heat the resulting mixture to 55 ° C for 4 hours. After the reaction is completed, the reaction solution is cooled to 20 ° C, filtered, and the resulting filter cake is dried to constant weight to obtain 1.15 g of pyridinium chloride 3-carboxylic acid choline ester (yield is about 94%, HPLC purity is 97.7%).

[0031] Comparative Example

[0032] (Refer to the method of Example 3 of Chinese Patent CN108329220 A for preparing pyridinium chloride 3-carboxylate choline ester)

[0033] In a 250mL reaction bottle, add 40ml of anhydrous pyridine, then add 80mmol of 3-pyridinecarbonyl chloride and 30ml of 2-chloroethanol, stir and react at 40℃ for 10 hours, add 20ml of water to dissolve, extract with 120ml of dichloromethane four times (40ml, 30ml, 30ml, 20ml), combine the dichloromethane layers and evaporate to dryness. Add 40ml of THF to dissolve the residue, add 20ml of 2M trimethylamine THF solution, stir at 35℃, precipitate a white solid, filter, and dry the resulting filter cake to constant weight to obtain 14.5g of pyridinium chloride 3-carboxylic acid choline ester (yield is about 74%, HPLC purity is 98%).

Claims

1. A one-pot method for preparing pyridinium chloride 3-carboxylate choline ester shown in formula I, It is characterized in that The method comprises: 3-pyridinecarbonyl chloride is reacted with trimethylamine in 2-chloroethanol. Wherein, the reaction is carried out in the presence of an alkaline catalyst, and the alkaline catalyst is selected from sodium hydroxide or potassium hydroxide. The reaction temperature of the reaction is 40-60°C. The molar ratio of the 3-pyridinecarbonyl chloride to trimethylamine is 1:1-3.

2. The method according to claim 1, It is characterized in that The reaction temperature of the reaction is 50-55°C.

3. The method according to claim 1 or 2, It is characterized in that The molar ratio of the 3-pyridinecarbonyl chloride to trimethylamine is 1:2-2.

5.

4. The method according to claim 1 or 2, It is characterized in that The 3-pyridinecarbonyl chloride is prepared by the following method: 3-pyridinecarboxylic acid is reacted with a chlorinating agent.

5. The method according to claim 4, It is characterized in that The chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride.

6. The method according to claim 1 or 2, It is characterized in that The method further comprises: after the reaction is completed, cooling the obtained reaction solution to 20-30° C., and filtering to obtain a solid precipitate of pyridinium chloride 3-carboxylic acid choline ester represented by formula I.

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