CN116003317A - Purification method of pyridine chloride 3-choline formate - Google Patents
Purification method of pyridine chloride 3-choline formate Download PDFInfo
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- CN116003317A CN116003317A CN202310136743.0A CN202310136743A CN116003317A CN 116003317 A CN116003317 A CN 116003317A CN 202310136743 A CN202310136743 A CN 202310136743A CN 116003317 A CN116003317 A CN 116003317A
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- pyridine
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- choline
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Abstract
The invention provides a purification method of pyridine 3-formate choline ester chloride shown in a formula I, which is simple to operate, high in product yield and purity, and is very suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a purification method of pyridine 3-formate choline.
Background
Choline is an important component of biological membranes and is also a precursor of acetylcholine in cholinergic neurons. Choline functions are numerous, including promoting brain development, improving memory, promoting fat metabolism and in vivo transmethylation, lowering serum cholesterol, etc.
Based on the choline structure, a series of choline ester derivatives have been developed by humans. U.S. patent No. 3337569a discloses a chlorinated pyridine 3-carboxylic acid choline ester compound having vasodilating effect as shown in the following formula I and a preparation method thereof,
the patent discloses that after the reaction is finished, the compound of the formula I is recrystallized twice in a mixed solvent of ethanol and diethyl ether, on one hand, the purification method uses a mixed organic solvent of ethanol and diethyl ether, which easily leads to the fact that the organic residual solution of a final product does not reach the standard, and on the other hand, the purification method adopts twice recrystallization, but the purification effect is poor, the purity of the product is only about 98%, and the single impurity content is more than 0.5%, so that the medicinal requirement cannot be met.
In addition, chinese patent CN108329220a discloses another method for preparing a pyridine 3-formate compound, firstly reacting pyridine-3-carboxylic acid with a chloro reagent, concentrating the reaction solution after the reaction is finished, then adding 2-chloroethanol for reaction, then concentrating, dissolving the concentrate with water, extracting with dichloromethane for multiple times, concentrating the organic phase to dryness, dissolving with THF, and then reacting with a THF solution of trimethylamine to obtain the final product pyridine 3-formate chloride. The purity of the product prepared by the method disclosed by the patent is not ideal, only about 96 percent, and the medicinal requirement cannot be met.
Therefore, there is still a need to develop a purification method of pyridine 3-formate choline compounds to meet the pharmaceutical demands thereof.
Disclosure of Invention
Aiming at the technical problems that the purity of the pyridine chloride 3-choline formate compound shown in the formula I prepared by the prior art is low and the pharmaceutical requirement can not be met,
the invention provides a method for purifying a pyridine 3-formate choline compound, which is simple and convenient to operate, can ensure high purity and high yield of products, and is very suitable for industrial production.
The invention is realized by the following technical scheme:
the invention provides a method for purifying a pyridine 3-formate choline compound shown in the following formula I,
the method comprises the following steps:
(1) Dissolving the pyridine 3-carboxylic acid choline ester shown in the formula I in water,
(2) Controlling the pH value of the solution to 5-7,
(3) Cooling the temperature of the solution obtained in step (2) to form a solid precipitate of the pyridine 3-carboxylate chloride of formula I,
(4) Filtering and drying the solid precipitate obtained in step (3).
In a preferred embodiment, the temperature of the water in step (1) is controlled between 30 and 60 ℃.
In a more preferred embodiment, the temperature of the water in step (1) is controlled between 50 and 60 ℃.
The inventor has found through research and comparison that the pyridine 3-formate of the formula I is dissolved in water with the temperature of 50-60 ℃, and compared with the water with the temperature of below 50 ℃, the purity of the product can be improved while the yield of the product is ensured.
In a preferred embodiment, the pH of the solution in step (2) is controlled to be between 5.5 and 6.0. An acid such as hydrochloric acid, sulfuric acid, acetic acid, etc. may be added to the solution obtained in step (1) to adjust the pH of the solution, preferably hydrochloric acid.
In a preferred embodiment, the solution obtained in step (2) is cooled to a temperature of 0-10 ℃, preferably 0-5 ℃, so as to form a solid precipitate of choline 3-carboxylate of pyridine chloride of formula I.
Finally, the solid precipitate obtained in step (3) is filtered and dried.
Repeating the steps (1) - (4) one to two times if necessary to achieve the pharmaceutical purity.
Description of the embodiments
The present invention will be described in detail by the following examples, which are given to illustrate the present invention, but not to limit the present invention.
Crude pyridine 3-formate used in examples 1-6 below was prepared according to CN108329220a, example 3, with an HPLC purity of 96.0%.
Example 1
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 30 ℃. The pH of the solution was adjusted to 5.0 with hydrochloric acid, then the resulting solution was cooled to 5 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. Filtration and drying of the filter cake to constant weight gave 0.9g of purified pyridine 3-carboxylate with an HPLC purity of 99.3%.
Example 2
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 50 ℃. The pH of the solution was adjusted to 5.0 with hydrochloric acid, then the resulting solution was cooled to 5 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. Filtration and drying of the filter cake to constant weight gave 0.94g of purified pyridine 3-carboxylate with an HPLC purity of 99.8%.
Example 3
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 30 ℃. The pH of the solution was adjusted to 7.0 with hydrochloric acid, then the resulting solution was cooled to 0 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. Filtration and drying of the filter cake to constant weight gave 0.91g of purified pyridine 3-carboxylate with an HPLC purity of 99.4%.
Example 4
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 60 ℃. The pH of the solution was adjusted to 7.0 with hydrochloric acid, then the resulting solution was cooled to 0 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. Filtration and drying of the filter cake to constant weight gave 0.93g of purified pyridine 3-carboxylate with an HPLC purity of 99.7%.
Example 5
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 40 ℃. The pH of the solution was adjusted to 6.0 with hydrochloric acid, then the resulting solution was cooled to 5 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. Filtration and drying of the filter cake to constant weight gave 0.91g of purified pyridine 3-carboxylate with an HPLC purity of 99.4%.
Example 6
1g of crude pyridine 3-carboxylate is added to 100mL of water and the solution is stirred at 30 ℃. The pH of the solution was adjusted to 5.0 with hydrochloric acid, then the resulting solution was cooled to 5 ℃, and then the solution was allowed to stand sufficiently to precipitate a solid precipitate of pyridine 3-carboxylate. The filter cake was filtered and dissolved again in water at 30 c, the pH of the solution was adjusted to 5.0 with hydrochloric acid, the resulting solution was then cooled to 5 c, and the solution was then allowed to stand sufficiently to precipitate a solid precipitate of choline 3-carboxylate of pyridine chloride. Filtration and drying of the filter cake to constant weight gave 0.85g of purified pyridine 3-carboxylate with an HPLC purity of 99.9%.
Claims (6)
1. A method for purifying choline pyridine 3-formate chloride shown in the following formula I,
(1) Dissolving the pyridine 3-carboxylic acid choline ester shown in the formula I in water,
(2) Controlling the pH value of the solution to 5-7,
(3) Cooling the solution obtained in the step (2) to 0-10 ℃ to form a solid precipitate of the pyridine 3-carboxylic acid choline ester chloride shown in the formula I,
(4) Filtering and drying the solid precipitate obtained in the step (3),
(5) Repeating steps (1) - (4) one to two times if necessary.
2. The method according to claim 1, wherein the temperature of the water in step (1) is controlled between 30 and 60 ℃.
3. The method according to claim 1 or 2, wherein the temperature of the water in step (1) is controlled between 50 and 60 ℃.
4. A method according to claims 1-3, characterized in that in step (2) the pH of the solution is controlled between 5.5 and 6.0.
5. The method according to claims 1-4, wherein the temperature is cooled to 0-10 ℃ in step (3).
6. The method according to claims 1-5, wherein the temperature is cooled to 0-5 ℃ in step (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310136743.0A CN116003317A (en) | 2023-02-20 | 2023-02-20 | Purification method of pyridine chloride 3-choline formate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310136743.0A CN116003317A (en) | 2023-02-20 | 2023-02-20 | Purification method of pyridine chloride 3-choline formate |
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| Publication Number | Publication Date |
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| CN116003317A true CN116003317A (en) | 2023-04-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202310136743.0A Pending CN116003317A (en) | 2023-02-20 | 2023-02-20 | Purification method of pyridine chloride 3-choline formate |
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| CN (1) | CN116003317A (en) |
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- 2023-02-20 CN CN202310136743.0A patent/CN116003317A/en active Pending
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