Method for purification of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol

Abstract

The present application provides a purification method of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-methyl)-1,3-dioxolane-4-methanol, which comprises the steps of removing other single impurities and / or removing isomer impurities. The purification method of the present application is simple to operate, low in raw material cost, suitable for industrial mass production, can effectively remove other single impurities and isomer impurities contained in 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-methyl)-1,3-dioxolane-4-methanol at the same time, so that the purity of the finally obtained purified product is higher, and the content of isomer impurities is significantly reduced compared with the prior art.

Description

Invention Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol. Background Technology

[0002] The structural formula of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol is shown in Formula I. It is a key intermediate in the chemical synthesis of compounds such as itraconazole, and its quality has a significant impact on the quality of the final product, itraconazole. However, due to limitations in purification methods, existing 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol generally suffers from high levels of other single impurities (generally around 10%), high levels of isomer impurities (generally around 15%), although the isomer impurity content of the intermediate triazole disclosed in Chinese Invention Patent CN101391994B is lower, it is still as high as around 10%), and low purity. As a result, the prepared final product needs to undergo multiple purification processes to meet the standards of the Chinese Pharmacopoeia.

[0003] Summary of the Invention

[0004] In view of the shortcomings mentioned in the background art above, the object of the present invention is to provide a purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, in order to solve the technical problems of high content of other monoimides, high content of isomer impurities, or both in the prior art of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, and to improve the purity of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, thereby reducing the quality risk of the final product itraconazole obtained from this intermediate.

[0005] To achieve the above objectives, the present invention provides a purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, the purification method comprising the steps of removing other monoimides and / or isomer impurities.

[0006] The structure of the isomer impurity is shown below:

[0007]

[0008] Other single impurities refer to impurities other than the aforementioned isomer impurities.

[0009] Preferably, the step of recrystallizing crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol with a mixed solvent of a first good solvent and a poor solvent is preferred.

[0010] Preferably, in the steps excluding other monohydric steps, the first good solvent is selected from any one of methanol, ethanol, acetone, dichloromethane, and ethyl acetate, and is preferably ethanol or ethyl acetate.

[0011] Preferably, in the step of removing other monopolistic solvents, the undesirable solvent is selected from any one of methyl tert-butyl ether, n-hexane, and n-heptane, and is preferably methyl tert-butyl ether or n-hexane.

[0012] Preferably, in the step of removing other impurities, the volume ratio between the first good solvent and the bad solvent is 1:1 to 10, more preferably 1:3 to 5, and more preferably 1:5.

[0013] Preferably, in the step of removing other single impurities, the crystallization temperature is -10℃ to 30℃, more preferably -10℃ to 5℃.

[0014] Preferably, in the step of removing other monopolistic solvents, when the undesirable solvent is methyl tert-butyl ether, the crystallization temperature is -10°C to -5°C; when the undesirable solvent is n-hexane, the crystallization temperature is 0°C to 5°C.

[0015] The inventors discovered that excessive use of a good solvent can lead to poor product precipitation and significant yield loss, while insufficient use can result in incomplete dissolution of the crude product, weakening its impurity removal ability. Preferably, in the step of removing other single impurities, the volume of the first good solvent is 1 to 5 times the mass of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, more preferably 2 to 3 times, and more preferably 2 times.

[0016] Preferably, the process, excluding other impurities, involves adding a first good solvent and a poor solvent to the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stirring and dissolving at a temperature of 40–70°C, cooling to -10–30°C, preferably -10–5°C, maintaining the temperature for crystallization for 1–3 hours, preferably 2 hours, filtering, and collecting the filter cake.

[0017] Preferably, in the step of removing other impurities, the dissolution temperature is preferably 50-60°C. If the temperature is too low, the crude product cannot be fully dissolved, resulting in a weakened impurity removal ability. If the temperature is too high, it will affect the product quality.

[0018] Preferably, in the step of removing other impurities, the filter cake is rinsed with a poor solvent.

[0019] Preferably, in the step of removing other single impurities, the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol is the purified 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol or the product after removing isomer impurities.

[0020] Preferably, the removal of isomer impurities is a step of recrystallizing crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol using a mixture of a second good solvent and water.

[0021] Preferably, in the step of removing isomer impurities, the second good solvent is selected from any one of methanol, ethanol, acetone, tetrahydrofuran and 1,4-dioxane, preferably methanol or acetone, and more preferably acetone.

[0022] Preferably, in the step of removing isomer impurities, the volume ratio of the second good solvent to water is 1:1 to 8, more preferably 1:5 to 8, and even more preferably 1:5.

[0023] Preferably, in the step of removing isomer impurities, the crystallization temperature is 0–30°C, more preferably 10–15°C.

[0024] Preferably, in the step of removing isomer impurities, the volume of the second good solvent is 1 to 5 times the crude mass of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, more preferably 2 to 3 times, and more preferably 2 times.

[0025] Preferably, the removal of isomer impurities includes adding a second good solvent and 0-40 v / v% water to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stirring and dissolving at 40-70°C, preferably 50-60°C, cooling to 0-30°C, preferably 10-15°C, and maintaining the temperature for crystallization for 1-3 hours, preferably 2 hours, filtering, and collecting the filter cake. During this process, the remaining water is added before cooling after dissolution or before crystallization after cooling.

[0026] Preferably, the removal of isomer impurities includes adding a second good solvent and 0-40 v / v% water (total volume) to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stirring and dissolving at 40-70°C, preferably 50-60°C, cooling to 0-30°C, preferably 10-15°C, maintaining the temperature while adding the remaining water, maintaining the temperature for crystallization for 1-3 hours, preferably 2 hours, filtering, and collecting the filter cake. This technique of adding the remaining water after cooling and before crystallization effectively avoids the agglomeration of precipitated crystals compared to adding the remaining water after dissolution and before cooling.

[0027] Preferably, the removal of isomer impurities involves adding a second good solvent and 10-20 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stirring and dissolving at 40-70°C, preferably 50-60°C, cooling to 0-30°C, preferably 10-15°C, maintaining the temperature while adding the remaining water, maintaining the temperature for crystallization for 1-3 hours, preferably 2 hours, filtering, and collecting the filter cake. This technique, which controls the initial water addition to 10-20 v / v%, can significantly improve the removal efficiency of isomer impurities and further increase the yield.

[0028] Preferably, the removal of isomer impurities includes adding a second good solvent and 10-20 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stirring and dissolving at 40-70°C, preferably 50-60°C, adding the remaining 30-60 v / v% of the total water volume after dissolution, cooling to 0-30°C, preferably 10-15°C, maintaining the temperature while adding the remaining water, maintaining the temperature for crystallization for 1-3 hours, preferably 2 hours, filtering, and collecting the filter cake. This three-stage water addition technique can further improve the removal efficiency and yield of isomer impurities.

[0029] Preferably, the removal of isomer impurities includes adding a second good solvent and 10-20 v / v% of the total water volume of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol to the crude product, stirring and dissolving at 40-70°C, preferably 50-60°C, adding the remaining 30-60 v / v% of the total water volume to crystallize for 0.5-2 hours, preferably 1 hour, cooling to 0-30°C, preferably 10-15°C, maintaining the temperature while adding the remaining water, maintaining the temperature for crystallization for 1-3 hours, preferably 1 hour, filtering, and collecting the filter cake. This technique of adding crystallization before cooling results in better crystal properties, more uniform particle size, and a powdery form in the final product.

[0030] More preferably, in the above-mentioned process of removing isomer impurities, the crystal growth temperature is 50-55°C.

[0031] Preferably, in the step of removing isomer impurities, the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol is the purified 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol or the product after removing other single impurities.

[0032] That is, the purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol provided by the present invention can be to remove other single impurities from the 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol to be purified; or it can be to remove other single impurities from the 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol to be purified. Isomerization can be performed by first removing other single impurities from the purified 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, and then performing isomerization on the product after removing other single impurities; or by first removing isomers from the purified 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, and then performing isomerization on the product after removing isomers.

[0033] The purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol provided by this invention refers to the synthetic product prepared by chemical synthesis using Formula II (cis-bromoester) or its precursor as a raw material. Specifically, in the process of synthesizing 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, when Formula II or its precursor is used as the raw material, regardless of the chemical synthesis route used (such as the chemical synthesis route disclosed in Chinese Patent Document CN101391994B or the Journal of...), The chemical synthesis routes disclosed in Medicinal Chemistry, 1983, Vol. 26, No. 4: 611-613, or the chemical synthesis routes used in the experimental examples of this application, etc., in the prior art, can all be purified using the purification method provided by this invention.

[0034]

[0035] Preferably, in the step of removing isomer impurities, the resulting filter cake is rinsed with water.

[0036] Preferably, the process of removing isomer impurities according to the present invention can be repeated multiple times as needed to obtain 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol with an isomer impurity content that meets the predetermined target.

[0037] Beneficial effects

[0038] Compared with existing technologies, the purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol provided by this invention is simple to operate, uses low-cost raw materials, and is suitable for large-scale industrial production. It can remove other mono- or isomer impurities from 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, and can also effectively remove 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol simultaneously. The presence of other single and isomer impurities in (-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol results in a high purity of the final purified product, and the content of isomer impurities is significantly reduced compared to existing technologies. Using the purification method of this invention, the isomer impurity content can be as low as 1.0%, thereby ensuring that the content of impurity B in the final product itraconazole prepared from the purified intermediate is not higher than 0.5%, which meets the standards of the Chinese Pharmacopoeia. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are explanations of the present invention, and the present invention is not limited to the following embodiments.

[0040] Unless otherwise specified, the crude products in the following examples are all crude products of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanoltriazole prepared according to the synthesis method disclosed in Chinese Invention Patent CN101391994B. The purity of the crude product was 82.13%, the content of isomer impurities was 10.23%, and the content of other single impurities was 7.64%.

[0041] Purification method of the present invention—removal of isomer impurities

[0042] Example I-1

[0043] Take 10g of crude product, add 20ml of acetone, stir and dissolve at 50-60℃, cool to 10-15℃ after dissolution, add 100ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 8.0g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 80%, purity of 90.25%, and isomer impurity content of 2.96%.

[0044] Example I-2

[0045] Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, add 80ml of water after dissolution, cool to 10-15℃, keep warm to allow crystallization for 2 hours, filter and dry to obtain 9.2g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 92%, purity of 92.32%, and isomer impurity content of 0.91%, and the purified product has agglomeration.

[0046] Example I-3

[0047] Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, cool to 10-15℃ after dissolution, add 80ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 9.1g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 91%, purity of 92.34%, and isomer impurity content of 0.90%.

[0048] Example I-4

[0049] Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, add 40ml of water after dissolution, cool to 10-15℃, add 40ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 9.2g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 92%, purity of 92.71%, and isomer impurity content of 0.67%.

[0050] Example I-5

[0051] Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, add 40ml of water after dissolution, maintain at 50-55℃ for crystal growth for 1 hour, cool to 10-15℃, add 40ml of water, keep warm for crystallization for 2 hours, filter and dry to obtain 9.2g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 92%, purity of 92.80%, and isomer impurity content of 0.63%. The purified product has better crystal properties, uniform particle size, and is in powder form.

[0052] Example I-6

[0053] Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, cool to 10-15℃ after dissolution, add 80ml of water, keep warm to allow crystals to precipitate for 2 hours, filter, and collect the filter cake.

[0054] Add 20 ml of acetone and 20 ml of water to the above filter cake, stir and dissolve at 50-60°C. After dissolving, cool to 10-15°C, add 80 ml of water, keep warm to allow crystals to precipitate for 2 hours, filter and dry to obtain 8.7 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 87%, purity of 94.35%, and isomer impurity content of 0.26%.

[0055] Comparative Example I-1

[0056] Take 10g of crude product, add 20ml of acetone, stir and dissolve at 50-60℃, cool to 10-15℃ after dissolution, keep warm to allow crystals to precipitate for 2 hours, filter and dry to obtain 5.6g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 56%, purity of 83.89%, and isomer impurity content of 8.95%.

[0057] Comparative Example I-2

[0058] Take 10g of crude product, add 20ml of acetone and 100ml of water, stir and dissolve at 50-60℃, cool to 10-15℃ after dissolution, keep warm to allow crystals to precipitate for 2 hours, filter and dry to obtain 8.6g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 86%, purity of 85.11%, and isomer impurity content of 8.12%.

[0059] The purification method of the present invention—excluding other single impurities

[0060] Example II-1

[0061] Take 10g of crude product, add 20ml of ethanol and 100ml of methyl tert-butyl ether, heat to 50-60℃ and stir to dissolve. After dissolving, cool to -10--5℃ and crystallize for 2 hours. Filter and dry to obtain 9.1g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 91%, purity of 90.56%, and the content of other single impurities totaling 0.88%.

[0062] Example II-2

[0063] Crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared according to the synthetic method disclosed in the Journal of Medicinal Chemistry, 1983, Vol.26, No.4: 611-613. The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 80.26%, and the total content of other impurities was 10.56%.

[0064] Take 10g of the above crude product, add 20ml of ethyl acetate and 100ml of methyl tert-butyl ether, heat to 50-60℃ and stir to dissolve. After dissolving, cool to -10--5℃ and crystallize for 2 hours. Filter and dry to obtain 8.9g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 89%, purity of 90.39%, and the content of other single impurities totaling 0.86%.

[0065] Example II-3

[0066] Take 10g of crude product, add 20ml of ethanol and 60ml of n-hexane, heat to 50-60℃ and stir to dissolve. After dissolving, cool to 0-5℃ and crystallize for 2 hours. Filter and dry to obtain 9.0g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 90%, purity of 90.58%, and the content of other single impurities totaling 0.89%.

[0067] Example II-4

[0068] Crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared according to the synthetic method disclosed in the Journal of Medicinal Chemistry, 1983, Vol.26, No.4: 611-613. The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 80.26%, and the total content of other impurities was 10.56%.

[0069] Take 10g of the above crude product, add 20ml of ethyl acetate and 60ml of n-hexane, heat to 50-60℃ and stir to dissolve. After dissolving, cool to 0-5℃ and crystallize for 2 hours. Filter and dry to obtain 8.8g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 88%, purity of 90.33%, and total content of other impurities of 0.91%.

[0070] The purification method of the present invention—simultaneously removes isomer impurities and other single impurities.

[0071] Example III-1

[0072] Except for other impurities: Take 10g of crude product, add 20ml of ethanol and 100ml of methyl tert-butyl ether, heat to 50-60℃ and stir to dissolve. After dissolving, cool to -10--5℃ and crystallize for 2 hours. Filter and collect the filter cake.

[0073] Removal of isomer impurities: Add 20 ml of acetone and 20 ml of water to the above filter cake, stir and dissolve at 50-60°C. After dissolution, add 40 ml of water, maintain crystal growth at 50-55°C for 1 hour, cool to 10-15°C, add 40 ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 8.5 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 85%, purity of 99.23%, isomer impurity content of 0.56%, and total content of other single impurities of 0.21%.

[0074] Example III-2

[0075] Crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared according to the synthetic method disclosed in the Journal of Medicinal Chemistry, 1983, Vol.26, No.4: 611-613. The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 80.26%, the isomer impurity content was 9.18%, and the total content of other single impurities was 10.56%.

[0076] Except for other impurities: Take 10g of the above crude product, add 20ml of ethyl acetate and 100ml of methyl tert-butyl ether, heat to 50-60℃ and stir to dissolve. After dissolving, cool to -10--5℃ and crystallize for 2 hours. Filter and collect the filter cake.

[0077] Removal of isomer impurities: Add 20 ml of acetone and 20 ml of water to the above filter cake, stir and dissolve at 50-60°C. After dissolution, add 40 ml of water, maintain crystal growth at 50-55°C for 1 hour, cool to 10-15°C, add 40 ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 8.3 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 83%, purity of 99.15%, isomer impurity content of 0.62%, and total content of other single impurities of 0.23%.

[0078] Example III-3

[0079] Except for other impurities: Take 10g of crude product, add 20ml of ethanol and 60ml of n-hexane, heat to 50-60℃ and stir to dissolve. After dissolving, cool to 0-5℃ and crystallize for 2 hours. Filter and collect the filter cake.

[0080] Removal of isomer impurities: Add 20 ml of acetone and 20 ml of water to the above filter cake, stir and dissolve at 50-60°C. After dissolution, add 40 ml of water, maintain crystal growth at 50-55°C for 1 hour, cool to 10-15°C, add 40 ml of water, keep warm to allow crystallization for 2 hours, filter and dry to obtain 8.5 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 85%, purity of 99.20%, isomer impurity content of 0.55%, and total content of other single impurities of 0.25%.

[0081] Example III-4

[0082] Crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared according to the synthetic method disclosed in the Journal of Medicinal Chemistry, 1983, Vol.26, No.4: 611-613. The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 80.26%, the isomer impurity content was 9.18%, and the total content of other single impurities was 10.56%.

[0083] Except for other impurities: Take 10g of the above crude product, add 20ml of ethyl acetate and 60ml of n-hexane, heat to 50-60℃ and stir to dissolve, after dissolving, cool to 0-5℃ and crystallize for 2 hours, filter and collect the filter cake.

[0084] Removal of isomer impurities: Add 20 ml of acetone and 20 ml of water to the above filter cake, stir and dissolve at 50-60°C. After dissolution, add 40 ml of water, maintain crystal growth at 50-55°C for 1 hour, cool to 10-15°C, add 40 ml of water, keep warm to allow crystals to precipitate for 2 hours, filter and dry to obtain 8.4 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 84%, purity of 99.12%, isomer impurity content of 0.65%, and total content of other single impurities of 0.23%.

[0085] Example III-5

[0086] Remove isomer impurities: Take 10g of crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, add 40ml of water after dissolution, maintain crystal growth at 50-55℃ for 1 hour, cool down to 10-15℃, add 40ml of water, keep warm to precipitate crystals for 2 hours, filter and collect the filter cake.

[0087] Except for other single impurities: 20 ml of ethanol and 100 ml of methyl tert-butyl ether were added to the above filter cake, heated to 50-60℃ and stirred to dissolve. After dissolution, the temperature was lowered to -10 to -5℃, and crystallization was allowed to occur for 2 hours. The product was then filtered and dried to obtain 8.3 g of purified 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 83%, purity of 99.19%, isomer impurity content of 0.54%, and total content of other single impurities of 0.27%.

[0088] Example III-6

[0089] Crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared according to the synthetic method disclosed in the Journal of Medicinal Chemistry, 1983, Vol.26, No.4: 611-613. The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 80.26%, the isomer impurity content was 9.18%, and the total content of other single impurities was 10.56%.

[0090] Remove isomer impurities: Take 10g of the above crude product, add 20ml of acetone and 20ml of water, stir and dissolve at 50-60℃, add 40ml of water after dissolution, maintain crystal growth at 50-55℃ for 1 hour, cool down to 10-15℃, add 40ml of water, keep warm to precipitate crystals for 2 hours, filter and collect the filter cake.

[0091] Except for other single impurities: Add 20 ml of ethyl acetate and 60 ml of n-hexane to the above filter cake, heat to 50-60℃ and stir to dissolve. After dissolving, cool to 0-5℃ and crystallize for 2 hours. Filter and dry to obtain 8.2 g of purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, with a yield of 82%, purity of 99.10%, isomer impurity content of 0.67%, and total content of other single impurities of 0.23%.

[0092] Experiment Example 1: Experiment on the Influence of Different Factors

[0093] Preparation of crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol: Following the synthetic route described below, crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was prepared from cis-bromoester (Formula II). The purity of the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was 77.55%, the isomer impurity content was 14.36%, and the total content of other single impurities was 8.09%.

[0094]

[0095] The crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol was purified using the following method. Specific parameters and results are shown in Tables 1-7.

[0096] (1) Remove other impurities: Add the first good solvent and the poor solvent to the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, stir and dissolve at 40-70°C, cool to -10-30°C after dissolution, keep warm to crystallize for 2 hours, filter, collect the filter cake, and test its purity, isomer impurity content, total content of other impurities and yield;

[0097] (2) Removal of isomer impurities: Add a second good solvent and 0-40 v / v% of the total water volume to the above filter cake, stir and dissolve at 40-70°C, cool to 0-30°C after dissolution, maintain the temperature and add the remaining water, keep warm to crystallize for 2 hours, filter and dry to obtain the purified product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, and test its purity, isomer impurity content, total content of other single impurities and yield.

[0098] 1. The effect of mixed solvents in different systems

[0099] Perform the above step (1) to remove other single impurities according to the parameters in Table 1, and the results are shown in Table 1.

[0100] Table 1 (excluding other single-mixed varieties)

[0101]

[0102]

[0103] Conclusion: Ethanol or ethyl acetate are the best solvents, while methyl tert-butyl ether or n-hexane are the worst solvents.

[0104] The product obtained from serial number 2 in Table 1 after removing other monomers was operated according to the method for removing isomers in step (2) above and the parameters in Table 2. The results are shown in Table 2.

[0105] Table 2 (excluding isomers)

[0106]

[0107] Conclusion: Methanol or acetone are the best second solvents.

[0108] 2. Effect of different solvent ratios

[0109] Table 3 (excluding other single-mixed varieties)

[0110]

[0111]

[0112] Conclusion: The optimal ratio of good solvent to poor solvent is 1:3 to 5.

[0113] The product obtained from serial number 7 in Table 3 after removing other single impurities was operated according to the method of isomer removal recrystallization in step (2) above and the parameters in Table 4. The results are shown in Table 4.

[0114] Table 4 (excluding isomers)

[0115]

[0116] Conclusion: The ratio of the second good solvent to the poor solvent should be selected as 1:1 to 8.

[0117] 3. The effect of different crystallization temperatures

[0118] Table 5 (excluding other single-mixed products)

[0119]

[0120] Conclusion: The suitable crystallization temperature is -10 to 5℃.

[0121] The product obtained from serial number 1 in Table 5 after removing other monomers was operated according to the method for removing isomers in step (2) above and the parameters in Table 6. The results are shown in Table 6.

[0122] Table 6 (excluding isomers)

[0123]

[0124]

[0125] Conclusion: The crystallization temperature should be selected from 0 to 30℃, with 10 to 15℃ being the preferred range.

[0126] 4. The effect of different initial water addition volumes

[0127] The product obtained from serial number 1 in Table 5 after removing other monomers was operated according to the method for removing isomers in step (2) above and the parameters in Table 7. The results are shown in Table 7.

[0128] Table 7 (excluding isomers)

[0129]

[0130] Conclusion: The appropriate initial water volume is 10-20 v / v%.

Claims

1. A purification method for 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, comprising the steps of removing other monoimogens and / or isomer impurities, wherein, The structure of the isomer impurity is shown below: Other single impurities refer to impurities other than the aforementioned isomer impurities; The process, excluding other mono-impurities, involves adding a first good solvent and a poor solvent to the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at a temperature of 50-60°C, cooling it to the crystallization temperature after clearing the solution, and maintaining the temperature for crystallization for 1-3 hours. In the steps excluding other monopolistic processes, the first good solvent is ethanol or ethyl acetate, and the poor solvent is methyl tert-butyl ether or n-hexane; the crystallization temperature is -10℃ to 30℃; the volume ratio between the first good solvent and the poor solvent is 1:1 to 10; the volume of the first good solvent is 1 to 5 times the crude mass of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol; The removal of isomer impurities includes adding a second good solvent and 0-40 v / v% water to the crude product of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at 40-70°C, cooling it to the crystallization temperature after clearing the solution, and maintaining the temperature for crystallization for 1-3 hours. During this period, the remaining water is added before cooling down after clearing the solution or before crystallization after cooling down. In the step of removing isomer impurities, the second good solvent is acetone or methanol; the volume ratio of the second good solvent to water is 1:1 to 8; the crystallization temperature is 0 to 30°C; and the volume of the second good solvent is 1 to 5 times the crude mass of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol.

2. The purification method according to claim 1, characterized in that, In the step of removing other impurities, the volume ratio between the first good solvent and the bad solvent is 1:3~5.

3. The purification method according to claim 1, characterized in that, In the step of removing other single impurities, the crystallization temperature is -10℃ to 5℃.

4. The purification method according to claim 1, characterized in that, In the step of removing other monopolistic substances, when the undesirable solvent is methyl tert-butyl ether, the crystallization temperature is -10℃ to -5℃; when the undesirable solvent is n-hexane, the crystallization temperature is 0℃ to 5℃.

5. The purification method according to claim 1, characterized in that, In the step excluding other monomers, the volume of the first good solvent is 2 to 3 times the crude mass of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol.

6. The purification method according to any one of claims 1 to 5, characterized in that, In the step of removing isomer impurities, the volume ratio of the second good solvent to water is 1:5~8.

7. The purification method according to any one of claims 1 to 5, characterized in that, In the step of removing isomer impurities, the volume of the second good solvent is 2 to 3 times the crude mass of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol.

8. The purification method according to any one of claims 1 to 5, characterized in that, The removal of isomer impurities involves adding a second good solvent and 0-40 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at 40-70°C, cooling it to the crystallization temperature after it has been dissolved, maintaining the temperature while adding the remaining water, and keeping it at this temperature for crystallization for 1-3 hours.

9. The purification method according to any one of claims 1 to 5, characterized in that, The removal of isomer impurities involves adding a second good solvent and 10-20 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at 40-70°C, cooling it to the crystallization temperature after it has been completely dissolved, maintaining the temperature while adding the remaining water, and keeping it at this temperature for crystallization for 1-3 hours.

10. The purification method according to any one of claims 1 to 5, characterized in that, The removal of isomer impurities involves adding a second good solvent and 10-20 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at 40-70°C, adding 30-60 v / v% of the remaining water volume after dissolution, cooling to the crystallization temperature, maintaining the temperature while adding the remaining water, and maintaining the temperature for crystallization for 1-3 hours.

11. The purification method according to any one of claims 1 to 5, characterized in that, The removal of isomer impurities involves adding a second good solvent and 10-20 v / v% of the total water volume to the crude 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolane-4-methanol, dissolving it at 40-70°C, adding 30-60 v / v% of the remaining water after dissolution, crystallizing for 0.5-2 hours, cooling to the crystallization temperature, maintaining the temperature while adding the remaining water, and maintaining the temperature for crystallization for 1-3 hours.

12. The purification method according to claim 11, characterized in that, The crystal growth temperature is 50~55℃.

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