A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester

Abstract

The present invention provides a method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester, the method comprising the following steps: reacting a crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester with hydrochloric acid in water to form a hydrochloride, then adding an alkane solvent, adding an alcohol solvent to the aqueous phase, and finally adding an inorganic weak base solution to adjust the pH to ≥7, precipitating a solid, and performing solid-liquid separation to obtain purified 1H-1,2,4-triazole-3-carboxylic acid methyl ester. The method of the present invention can effectively remove impurities in the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester, realize the purification of 1H-1,2,4-triazole-3-carboxylic acid methyl ester, make the purity of the obtained 1H-1,2,4-triazole-3-carboxylic acid methyl ester product ≥98%, and the refining method is simple.

Description

Technical Field

[0001] The present invention relates to the technical field related to drug refining, and more specifically, to a method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester. Background Art

[0002] 1H-1,2,4-triazole-3-carboxylic acid methyl ester, alias: triazole carboxylic acid methyl ester, nucleoside base, its structural formula is shown in Formula I below, it is an important pharmaceutical intermediate, 1,2,4-triazole-3-carboxylic acid methyl ester is an important intermediate of the antiviral drug triazole nucleoside, and its different production processes lead to differences in yield, which directly affects the production of ribavirin;

[0003]

[0004] The finished product obtained by the current process still contains some impurities, the crystal appearance is light yellow, the transparency is poor, and the particle size is uneven. Therefore, the crystal purity has been 90-94%, which affects the application of the product. Summary of the invention

[0005] Based on the problem of low purity of 1H-1,2,4-triazole-3-carboxylic acid methyl ester in the prior art, the present invention provides a method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester, by which the obtained crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester can be effectively refined so that the purity of the obtained 1H-1,2,4-triazole-3-carboxylic acid methyl ester can reach more than 98%.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

[0007] A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0008] The crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester is reacted with hydrochloric acid in water to form a hydrochloride, and then an alkane solvent is added, and an alcohol solvent is added to the aqueous phase, and finally an inorganic weak base solution is added to adjust the pH to ≥7, solids are precipitated, and solid-liquid separation is performed to obtain purified 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

[0009] The above technical solution of the present invention has the following reaction principle:

[0010]

[0011] The crude product of 1H-1,2,4-triazole-3-carboxylic acid methyl ester reacts with hydrochloric acid in water to generate hydrochloride, and the generated hydrochloride is dissolved in water to effectively remove impurities insoluble in water; then, an alkane solvent and methanol are added to remove other solvents, and finally, an inorganic weak base is added to react with the hydrochloride to remove hydrochloric acid, and on the other hand, the pH value is adjusted to make the solution alkaline, which is conducive to the precipitation of 1H-1,2,4-triazole-3-carboxylic acid methyl ester, thereby achieving the purification of 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

[0012] In some embodiments, the alkane solvent is an alkane having 7 to 9 carbon atoms.

[0013] In some embodiments, the alkane solvent is n-heptane.

[0014] In some embodiments, the alcohol solvent is at least one of methanol, ethanol, propanol, and isopropanol.

[0015] In some embodiments, the inorganic weak base is a carbonate and / or bicarbonate of an alkali metal, preferably at least one of a sodium bicarbonate solution, a potassium bicarbonate solution, a sodium carbonate solution, and a potassium carbonate solution.

[0016] In some embodiments, the concentration of the inorganic weak base solution is 5-20%.

[0017] In some embodiments, an inorganic weak base is added to adjust the pH to 7-8.

[0018] In some embodiments, the purity of the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester is 90-94%.

[0019] In some embodiments, the preparation of the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0020] Methanol and thionyl chloride were added to 1H-1,2,4-triazole-3-carboxylic acid, stirred at 40°C for 4 hours, cooled, concentrated, water and defoaming agent were added, and then 5% sodium bicarbonate was added dropwise, the pH was adjusted to 7-8, filtered and washed with water to obtain crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

[0021] In some embodiments, after solid-liquid separation, a washing step is further included, specifically:

[0022] A small amount of methanol is used for washing, and the volume mass ratio of methanol to solid is 1-2 mL:1 g.

[0023] In some embodiments, the refining method comprises the following steps:

[0024] At 10-20° C., the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester is reacted with hydrochloric acid in water to form hydrochloride, and then n-heptane is added, methanol is added to the aqueous phase, and finally an inorganic weak base solution is added to adjust the pH to 7-8, solids are precipitated, and solid-liquid separation is performed to obtain purified 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

[0025] Compared with the prior art, the beneficial effects of this application are as follows:

[0026] The method of the invention comprises the following steps: firstly, 1H-1,2,4-triazole-3-carboxylic acid methyl ester is made into salt, then an alkane solvent and an alcohol solvent are used to remove impurities, and finally, an inorganic weak base reaction is performed and the pH value of the solution is adjusted to precipitate the target product. The impurities in the 1H-1,2,4-triazole-3-carboxylic acid methyl ester can be effectively removed, so that the purity of the obtained 1H-1,2,4-triazole-3-carboxylic acid methyl ester is greater than or equal to 98%, and the yield is high. In addition, the refining method and conditions are simple and the operation is convenient. DETAILED DESCRIPTION

[0027] Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar modifications without violating the connotation of the present invention, so the present invention is not limited to the specific implementation disclosed below.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0029] The crude 1,2,4-triazole-3-carboxylic acid methyl ester used in the following examples and comparative examples is prepared as follows: methanol and thionyl chloride are added to 1H-1,2,4-triazole-3-carboxylic acid, stirred at 40°C for 4 hours, cooled to room temperature, concentrated, water and GP type defoamer are added, and then 5% sodium bicarbonate is added dropwise to adjust the pH to 8, and the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester is filtered and washed with water to obtain the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

[0030] Example 1

[0031] A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0032] Add 40 g of crude 1,2,4-triazole-3-carboxylic acid methyl ester with a purity of about 91% to the reaction bottle, add 100 mL of water, control the temperature at 20°C, add 10% hydrochloric acid dropwise to react until the reaction solution is clear, and then wash twice with n-heptane, 10 mL each time. After washing, add 30 mL of methanol to the aqueous phase, stir evenly, control the temperature at 20°C, adjust the pH to 7 with 5% sodium bicarbonate solution, filter, wash the filter cake with a small amount of methanol (20 mL), and dry the filter cake to obtain 34.6 g of 1,2,4-triazole-3-carboxylic acid methyl ester with a yield of 86.5% and a purity of 98.4%.

[0033] Example 2

[0034] A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0035] Add 50 g of crude 1,2,4-triazole-3-carboxylic acid methyl ester with a purity of about 91% to the reaction bottle, add 150 mL of water, control the temperature at 15 ° C, add 10% hydrochloric acid dropwise to react until the reaction solution is dissolved, and then wash twice with n-heptane, 15 mL each time. After washing, add 40 mL of methanol to the aqueous phase, stir evenly, control the temperature at 10 ° C, adjust the pH to 8 with 5% sodium bicarbonate solution, filter, wash the filter cake with a small amount of methanol (25 mL), and dry the filter cake to obtain 43.7 g of 1,2,4-triazole-3-carboxylic acid methyl ester with a yield of 87.4% and a purity of 98.2%.

[0036] Example 3

[0037] A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0038] Add 50 g of crude 1,2,4-triazole-3-carboxylic acid methyl ester with a purity of about 94% to the reaction bottle, add 150 mL of water, control the temperature at 20 ° C, add 10% hydrochloric acid dropwise to react until the reaction solution is dissolved, and then wash twice with n-heptane, 15 mL each time. After washing, add 40 mL of methanol to the aqueous phase, stir evenly, control the temperature at 10 ° C, adjust the pH to 7-8 with 5% sodium bicarbonate solution, filter, wash the filter cake with a small amount of methanol (10 mL), and bake the filter cake to obtain 45.7 g of 1,2,4-triazole-3-carboxylic acid methyl ester with a yield of 91.4% and a purity of 98.8%.

[0039] Comparative Example 1

[0040] A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps:

[0041] Add 40 g of crude 1,2,4-triazole-3-carboxylic acid methyl ester with a purity of about 91% to the reaction bottle, add 100 mL of water, control the temperature at 20°C, add 10% hydrochloric acid dropwise to react until the reaction solution is clear, then add 30 mL of methanol, stir evenly, control the temperature at 20°C, adjust the pH to 7 with 5% sodium bicarbonate solution, filter, wash the filter cake with a small amount of methanol (20 mL), and dry the filter cake to obtain 32.1 g of 1,2,4-triazole-3-carboxylic acid methyl ester with a yield of 80.3% and a purity of 96.3%.

[0042] Comparative Example 2

[0043] Add 40 g of crude 1,2,4-triazole-3-carboxylic acid methyl ester with a purity of about 91% to the reaction bottle, add 100 mL of water, control the temperature at 20°C, add 10% hydrochloric acid dropwise to react until the reaction solution is clear, then add 30 mL of methanol, stir evenly, control the temperature at 20°C, adjust the pH to 7 with 5% sodium bicarbonate solution, filter, wash the filter cake with a small amount of methanol (20 mL), and dry the filter cake to obtain 31.2 g of 1,2,4-triazole-3-carboxylic acid methyl ester with a yield of 78.0% and a purity of 96.1%.

[0044] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0045] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester, characterized in that: The following steps are involved: The crude product of 1H-1,2,4-triazole-3-carboxylic acid methyl ester is reacted with hydrochloric acid in water to form hydrochloride, and then an alkane solvent is added, and an alcohol solvent is added to the aqueous phase, and finally an inorganic weak base solution is added to adjust the pH to 7-8, solid is precipitated, and solid-liquid separation is performed to obtain purified 1H-1,2,4-triazole-3-carboxylic acid methyl ester; The alkane solvent is an alkane having 7 to 9 carbon atoms; The alcohol solvent is at least one of methanol, ethanol, propanol and isopropanol; The inorganic weak base is a carbonate and / or bicarbonate of an alkali metal; The concentration of the hydrochloric acid is 5 to 20%; The preparation of the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester comprises the following steps: Methanol and thionyl chloride were added to 1H-1,2,4-triazole-3-carboxylic acid, stirred at 40°C for 4 hours, cooled, concentrated, water and defoaming agent were added, and then 5% sodium bicarbonate was added dropwise to adjust the pH to 7-8, filtered and washed with water to obtain crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester.

2. The method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester according to claim 1, characterized in that: The alkane solvent is n-heptane.

3. The method for refining 1H-1,2,4-triazole-3-carboxylic acid methyl ester according to any one of claims 1 to 2, characterized in that: The purity of the crude 1H-1,2,4-triazole-3-carboxylic acid methyl ester is 90-94%.

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