Preparation method of isavuconazole hydrolysis impurity

Abstract

The invention discloses a preparation method of an isavuconazole hydrolysis impurity, and belongs to the technical field of chemical synthesis. Comprising the following steps: (1) reacting isavuconazole serving as a raw material with an alkaline reagent in a mixed solution of a first solvent and water; (2) removing the first solvent; (3) carrying out reverse extraction by using a second solvent, and concentrating a water phase; (4) dissolving salt from the water phase by using an acidic reagent, and filtering the solid; and (5) pulping the solid with a mixed solution of a third solvent and n-hexane to obtain hydrolyzed impurities. The synthesis route is simple and easy to operate; raw materials are easy to obtain, reaction conditions are mild, implementation is easy, synthesis difficulty is low, and cost is low; the reaction conversion rate is high, decarboxylation side reactions are few, and the target product yield and purity are high.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing isavuconazole hydrolysis impurities. Background Art

[0002] Isavuconazole is an important intermediate of isavuconazonium sulfate. If the isavuconazole hydrolysis impurities that may be produced during the drug preparation process exceed the standard, it may cause side effects, threaten the patient's life and affect the safety of medication.

[0003] The impurity of isavuconazole hydrolysis is 4-(2-((2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzoic acid. The structure of the impurity is as follows:

[0004] There is no report on the research of the above-mentioned isavuconazole hydrolysis impurities in the prior art. Therefore, how to obtain the above-mentioned impurities simply, with high yield and high purity is worthy of further study. Summary of the invention

[0005] In view of the above shortcomings, the present invention provides a method for preparing isavuconazole hydrolysis impurities. The synthesis route of the present invention is relatively simple and easy to operate; the raw materials are readily available, the reaction conditions are mild and easy to implement, the synthesis difficulty is small, and the cost is low; the reaction conversion rate is high, the decarboxylation side reaction is small, and the yield and purity of the target product are high.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows: A method for preparing an isavuconazole hydrolyzed impurity, wherein the hydrolyzed impurity is 4-(2-((2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazole-4-yl)benzoic acid, comprising the following steps: (1) using isavuconazole as a raw material and reacting it with an alkaline reagent in a mixed solution of a first solvent and water; (2) removing the first solvent; (3) stripping with a second solvent to concentrate the aqueous phase; (4) Use an acidic reagent to desalt the aqueous phase and filter out the solids; (5) The solid is slurried with a mixed solution of a third solvent and n-hexane to obtain hydrolyzed impurities.

[0007] In step (1), the alkaline reagent is solid sodium hydroxide, sodium tert-butoxide or / and potassium hydroxide; the molar ratio of isavuconazole to the alkaline reagent is 1:4-7.

[0008] In step (1), the first solvent is ethanol and / or methanol, and the mass volume ratio of isavuconazole to the first solvent and water is 1:5-10:15 (g / ml / ml).

[0009] The reaction conditions in step (1) are heating to reflux and reacting until isavuconazole is completely hydrolyzed, and the reaction time is about 5-10 hours.

[0010] The method for removing the first solvent in step (2) is rotary evaporation, and the water bath temperature is set to 30-40°C.

[0011] In step (3), the second solvent is ethyl acetate, dichloromethane or / and chloroform, and the mass volume ratio of isavuconazole to the second solvent is 1:3-5 (g / ml).

[0012] In step (4), the acidic reagent is hydrochloric acid, sulfuric acid and / or phosphoric acid, and the acidic reagent is used to adjust the pH to 2-3.

[0013] In step (5), the third solvent is ethyl acetate, dichloromethane or / and chloroform, and the mass volume ratio of isavuconazole to the third solvent and n-hexane is 1:1-3:8 (g / ml / ml).

[0014] The specific steps of the pulping treatment in step (5) are: (1) adding the third solvent and n-hexane to the pulping bottle containing the filtered solid, stirring at room temperature until full crystallization, about 1.5 hours; (2) filtering, rinsing the filter cake with n-hexane, and drying the filter cake under reduced pressure at 45° C. for 12 hours.

[0015] Due to the adoption of the above invention, the present invention has the following technical advances compared with the prior art: The invention prepares isavuconazole hydrolysis impurities, and the synthesis route is relatively simple and easy to operate; the raw materials are readily available, the reaction conditions are mild, easy to implement, the synthesis difficulty is small, and the cost is low; the reaction conversion rate is high, the decarboxylation side reaction is small, and the target product yield and purity are high. The efficient preparation of the invention is conducive to the qualitative and quantitative study of impurities of isavuconazole sulfate, and has important value for the quality research of raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

[0017] Figure 1 It is the liquid chromatogram and peak table of the sample in Example 1.

[0018] Figure 2It is the structural formula of the isavuconazole hydrolysis impurity 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzoic acid. DETAILED DESCRIPTION

[0019] The following is a description of the preferred embodiments of the present invention. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention. Example 1

[0020] Add 30g of isavuconazole, 11g of sodium hydroxide, 180ml of ethanol and 450g of water to a dry three-necked flask under magnetic stirring, heat to reflux, react for 5h, use 40℃ rotary evaporation to remove ethanol, then back-extract the aqueous phase twice with 90ml of ethyl acetate, concentrate the aqueous phase at 30℃ for 15min, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid, and a white solid precipitates. Continue stirring for 2h, filter, and slurry the filter cake with 30ml of ethyl acetate and 240ml of n-hexane, filter, and dry the filter cake at 45℃ under reduced pressure for 12h to obtain 25.8g of white solid, yield: 82.4%, HPLC: 99.10%. Example 2

[0021] In a dry three-necked flask, 30 g of isavuconazole, 36.2 g of sodium tert-butoxide, 240 ml of methanol and 450 g of water were added under magnetic stirring, the temperature was raised to reflux, and the reaction was carried out for 8 h. The methanol was removed by rotary evaporation at 40 ° C., and then the aqueous phase was stripped twice with 120 ml of dichloromethane. The aqueous phase was concentrated at 30 ° C for 15 min, and the pH of the aqueous phase was adjusted to 2.5 with concentrated sulfuric acid. A white solid precipitated, and stirring was continued for 2 h. The filter cake was slurried with 90 ml of dichloromethane and 240 ml of n-hexane, filtered, and the filter cake was dried under reduced pressure at 45 ° C for 12 h to obtain 20.3 g of a white solid, with a yield of 64.8%, and HPLC: 98.05%. Example 3

[0022] Add 30g of isavuconazole, 26.9g of potassium hydroxide, 300ml of methanol and 450g of water to a dry three-necked flask, raise the temperature to reflux under magnetic stirring, react for 10h, use 40℃ rotary evaporation to remove methanol, then back-extract the aqueous phase twice with 150ml of chloroform, concentrate the aqueous phase at 30℃ for 15min, adjust the pH of the aqueous phase to 3 with concentrated phosphoric acid, and a white solid precipitates. Continue stirring for 2h, filter, and slurry the filter cake with 90ml of chloroform and 240ml of n-hexane, filter, and dry the filter cake at 45℃ under reduced pressure for 12h to obtain 21.6g of white solid, yield: 69%, HPLC: 98.52%.

[0023] Comparative Example 1 (the amount of alkaline reagent used is different from that of the present invention, and other conditions are the same as those of Example 1) Add 30g of isavuconazole, 5.5g of sodium hydroxide, 180ml of ethanol, and 450g of water to a dry three-necked flask, raise the temperature to reflux under magnetic stirring, react for 5h, use 40℃ rotary evaporation to remove ethanol, then back-extract the aqueous phase twice with 90ml of ethyl acetate, concentrate the aqueous phase at 30℃ for 15min, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid, and a white solid precipitates. Continue stirring for 2h, filter, and slurry the filter cake with 30ml of ethyl acetate and 240ml of n-hexane, filter, and dry the filter cake at 45℃ under reduced pressure for 12h to obtain 20.0g of white solid, yield: 64%, HPLC: 84.73%.

[0024] Comparative Example 2 (the first solvent type is different from the present invention, and other conditions are the same as Example 1) Add 30g of isavuconazole, 11g of sodium hydroxide, 180ml of acetonitrile and 450g of water to a dry three-necked flask, raise the temperature to reflux under magnetic stirring, react for 5h, use 40℃ rotary evaporation to remove acetonitrile, then back-extract the aqueous phase twice with 90ml of ethyl acetate, concentrate the aqueous phase at 30℃ for 15min, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid, and a white solid precipitates. Continue stirring for 2h, filter, and slurry the filter cake with 30ml of ethyl acetate and 240ml of n-hexane, filter, and dry the filter cake at 45℃ under reduced pressure for 12h to obtain 18.8g of white solid, yield: 60%, HPLC: 78.25%.

[0025] Comparative Example 3 (no stripping, other conditions are the same as in Example 1) Add 30g of isavuconazole, 11g of sodium hydroxide, 180ml of ethanol and 450g of water to a dry three-necked flask, raise the temperature to reflux under magnetic stirring, react for 5h, use 40℃ rotary evaporation to remove ethanol, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid, and a white solid precipitates. Continue stirring for 2h, filter, and slurry the filter cake with 30ml of ethyl acetate and 240ml of n-hexane, filter, and dry the filter cake at 45℃ under reduced pressure for 12h to obtain 26.0g of a white solid, with a yield of 73.8%, and HPLC: 89.38%.

[0026] Comparative Example 4 (no pulping, other conditions are the same as in Example 1) Add 30g of isavuconazole, 11g of sodium hydroxide, 180ml of ethanol and 450g of water to a dry three-necked flask, raise the temperature to reflux under magnetic stirring, react for 5h, use 40℃ rotary evaporation to remove ethanol, then back-extract the aqueous phase twice with 90ml of ethyl acetate, concentrate the aqueous phase at 30℃ for 15min, adjust the pH of the aqueous phase to 2 with concentrated hydrochloric acid, and a white solid precipitates. Continue stirring for 2h, filter, and dry the filter cake under reduced pressure at 45℃ for 12h to obtain 26.6g of white solid, yield: 85%, HPLC: 97.38%.

[0027] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing isavuconazole hydrolyzed impurities, characterized in that: The following steps are involved: (1) using isavuconazole as a raw material and reacting it with an alkaline reagent in a mixed solution of a first solvent and water; (2) removing the first solvent; (3) stripping with a second solvent to concentrate the aqueous phase; (4) Use an acidic reagent to desalt the aqueous phase and filter out the solids; (5) The solid is slurried with a mixed solution of a third solvent and n-hexane to obtain hydrolyzed impurities.

2. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: In step (1), the alkaline reagent is sodium hydroxide, sodium tert-butoxide or / and potassium hydroxide; the molar ratio of isavuconazole to the alkaline reagent is 1:4-7.

3. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: In step (1), the first solvent is ethanol and / or methanol, and the mass volume ratio of isavuconazole to the first solvent and water is 1:5-10:15 (g / ml / ml).

4. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: The reaction conditions in step (1) are heating to reflux and reacting until isavuconazole is completely hydrolyzed.

5. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: The method for removing the first solvent in step (2) is rotary evaporation, and the temperature of the water bath is set to 30-40°C.

6. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: In step (3), the second solvent is ethyl acetate, dichloromethane or / and chloroform, and the mass volume ratio of isavuconazole to the second solvent is 1:3-5 (g / ml).

7. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: In step (4), the acidic reagent is hydrochloric acid, sulfuric acid and / or phosphoric acid, and the acidic reagent is used to adjust the pH to 2-3.

8. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: In step (5), the third solvent is ethyl acetate, dichloromethane or / and chloroform, and the mass volume ratio of isavuconazole to the third solvent and n-hexane is 1:1-3:8 (g / ml / ml).

9. The method for preparing isavuconazole hydrolyzed impurities according to claim 1, characterized in that: The specific steps of the pulping treatment in step (5) are: (1) adding the third solvent and n-hexane to the pulping bottle containing the filtered solid, stirring at room temperature until full crystallization occurs; (2) filtering, rinsing the filter cake with n-hexane, and drying the filter cake under reduced pressure at 45° C. for 12 h.

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