Refining method of favipiravir

Abstract

The invention provides a refining method of favipiravir. The method specifically comprises the following steps: 6-fluoro-3-hydroxy-2-cyanopyrazine reacts with hydrogen peroxide under an alkaline condition to obtain 6-fluoro-3-hydroxy-2-pyrazinamide; the 6-fluoro-3-hydroxy-2-pyrazinamide is prepared into an organic alkali salt in an anhydrous organic solvent, and then the pH value in water is adjusted to prepare high-purity 6-fluoro-3-hydroxy-2-pyrazinamide; and 6-fluoro-3-hydroxy-2-pyrazinamide and organic alkali are salified in an organic solvent, the salt has excellent crystallinity, high-purity favipiravir can be prepared with high yield through simple operation, the yield can reach 90% or above, and the HPLC purity reaches 99.9% or above.

Description

technical field

[0001] The invention relates to a novel refining method of Favipiravir. Background technique

[0002] Favipiravir (favipiravir, T-705, trade name Avigan, 1), the chemical name is 6-fluoro-3-hydroxy-2-pyrazine carboxamide, is a target RNA-dependent drug developed by Japan Toyama Chemical Pharmaceutical Co., Ltd. A new broad-spectrum antiviral drug based on RNA polymerase (RdRp), which was approved for marketing in Japan in March 2014, for the treatment of new and recurrent influenza. At present, phase III clinical research on anti-influenza A has been completed in the United States. Favipiravir has a good therapeutic effect on patients infected with Ebola virus, and phase II clinical research on anti-Ebola virus is being conducted in the United States. The mechanism of action of favipiravir is mainly that after entering the body, under the action of a series of cellular phosphokinases, it generates the form of its nucleoside analog triphosphate, thereby inter...

Examples

Embodiment 1

[0026] Embodiment 1: Preparation of 6-fluoro-3-hydroxyl-2-cyanopyrazine

[0027] Add 250mL of N,N-dimethylformamide and 52g of potassium fluoride into a 1L reaction flask, add 3,6-dichloro-2-cyanopyrazine (50g) into the reaction kettle, and then raise the temperature to 105- 112°C, heat preservation and stirring for 4-5 hours. After the heat preservation is over, the cold water is cooled to 30-40°C, and then the ice salt is continued to cool down to 0-15°C. Control the temperature at 0-15°C, add 30.3g of glacial acetic acid to the reaction bottle, after the addition is complete, continue to add 52g of triethylamine, and keep stirring at 0-15°C for 1 hour.

[0028] After the heat preservation is over, add 250g of water, stir for 20 minutes, add 85g of liquid caustic soda, adjust the pH to about 9.0, add 250ml of toluene, and extract once. Adjust the pH of the water phase to about 2 with concentrated hydrochloric acid, consume 12g of concentrated hydrochloric acid, add 300ml o...

Embodiment 2

[0030] Add 67.2g30% liquid caustic soda to 350 milliliters of water, then add 35 grams of 6-fluoro-3-hydroxyl-2-cyanopyrazine prepared in Example 1, control the temperature at 10-20°C, add dropwise 30% hydrogen peroxide (85.6 g), reacted for 1 h, and TLC detected that the reaction of the raw materials was complete. Adjust the pH to 2.5-3 with hydrochloric acid, filter, rinse and dry. Dissolve the dried 28g of favipiravir in 400ml of ethyl acetate, raise the temperature to 70°C, add 24.4g of triethylamine dropwise, keep stirring for 1h, cool down to 0-5°C to crystallize for 1h, filter, and dry to obtain 63.5g. The dried Favipiravir (see the Raman spectrum figure 1 ) was dissolved in 150ml of water, adjusted to pH 2.5-3 with hydrochloric acid, filtered, rinsed, and dried to obtain 26.6g, with a molar yield of 95.5% and a purity of 99.9%.

Embodiment 3

[0032] Add 67.2g30% liquid caustic soda to 350 milliliters of water, then add 35 grams of 6-fluoro-3-hydroxyl-2-cyanopyrazine prepared in Example 1, control the temperature at 10-20°C, add dropwise 30% hydrogen peroxide (85.6 g), reacted for 1 h, and TLC detected that the reaction of the raw materials was complete. Adjust the pH to 2.5-3 with hydrochloric acid, filter, rinse and dry. Dissolve the dried 28g of Favipiravir in 400ml of ethyl acetate, raise the temperature to 80°C, add 35.7g of N,N-diisopropylethylamine dropwise, keep stirring for 1h, cool down to 0-5°C to crystallize for 1h, Filter and dry to obtain 68.4g. The dried Favipiravir (see the Raman spectrum figure 1 ) was dissolved in 150ml of water, adjusted to pH 2.5-3 with hydrochloric acid, filtered, rinsed, and dried to obtain 26.9g, with a molar yield of 96.1% and a purity of 99.9%.

technical field

[0001] The invention relates to a novel refining method of Favipiravir. Background technique

[0002] Favipiravir (favipiravir, T-705, trade name Avigan, 1), the chemical name is 6-fluoro-3-hydroxy-2-pyrazine carboxamide, is a target RNA-dependent drug developed by Japan Toyama Chemical Pharmaceutical Co., Ltd. A new broad-spectrum antiviral drug based on RNA polymerase (RdRp), which was approved for marketing in Japan in March 2014, for the treatment of new and recurrent influenza. At present, phase III clinical research on anti-influenza A has been completed in the United States. Favipiravir has a good therapeutic effect on patients infected with Ebola virus, and phase II clinical research on anti-Ebola virus is being conducted in the United States. The mechanism of action of favipiravir is mainly that after entering the body, under the action of a series of cellular phosphokinases, it generates the form of its nucleoside analog triphosphate, thereby inter...

Examples

Embodiment 1

[0026] Embodiment 1: Preparation of 6-fluoro-3-hydroxyl-2-cyanopyrazine

[0027] Add 250mL of N,N-dimethylformamide and 52g of potassium fluoride into a 1L reaction flask, add 3,6-dichloro-2-cyanopyrazine (50g) into the reaction kettle, and then raise the temperature to 105- 112°C, heat preservation and stirring for 4-5 hours. After the heat preservation is over, the cold water is cooled to 30-40°C, and then the ice salt is continued to cool down to 0-15°C. Control the temperature at 0-15°C, add 30.3g of glacial acetic acid to the reaction bottle, after the addition is complete, continue to add 52g of triethylamine, and keep stirring at 0-15°C for 1 hour.

[0028] After the heat preservation is over, add 250g of water, stir for 20 minutes, add 85g of liquid caustic soda, adjust the pH to about 9.0, add 250ml of toluene, and extract once. Adjust the pH of the water phase to about 2 with concentrated hydrochloric acid, consume 12g of concentrated hydrochloric acid, add 300ml o...

Embodiment 2

[0030] Add 67.2g30% liquid caustic soda to 350 milliliters of water, then add 35 grams of 6-fluoro-3-hydroxyl-2-cyanopyrazine prepared in Example 1, control the temperature at 10-20°C, add dropwise 30% hydrogen peroxide (85.6 g), reacted for 1 h, and TLC detected that the reaction of the raw materials was complete. Adjust the pH to 2.5-3 with hydrochloric acid, filter, rinse and dry. Dissolve the dried 28g of favipiravir in 400ml of ethyl acetate, raise the temperature to 70°C, add 24.4g of triethylamine dropwise, keep stirring for 1h, cool down to 0-5°C to crystallize for 1h, filter, and dry to obtain 63.5g. The dried Favipiravir (see the Raman spectrum figure 1 ) was dissolved in 150ml of water, adjusted to pH 2.5-3 with hydrochloric acid, filtered, rinsed, and dried to obtain 26.6g, with a molar yield of 95.5% and a purity of 99.9%.

Embodiment 3

[0032] Add 67.2g30% liquid caustic soda to 350 milliliters of water, then add 35 grams of 6-fluoro-3-hydroxyl-2-cyanopyrazine prepared in Example 1, control the temperature at 10-20°C, add dropwise 30% hydrogen peroxide (85.6 g), reacted for 1 h, and TLC detected that the reaction of the raw materials was complete. Adjust the pH to 2.5-3 with hydrochloric acid, filter, rinse and dry. Dissolve the dried 28g of Favipiravir in 400ml of ethyl acetate, raise the temperature to 80°C, add 35.7g of N,N-diisopropylethylamine dropwise, keep stirring for 1h, cool down to 0-5°C to crystallize for 1h, Filter and dry to obtain 68.4g. The dried Favipiravir (see the Raman spectrum figure 1 ) was dissolved in 150ml of water, adjusted to pH 2.5-3 with hydrochloric acid, filtered, rinsed, and dried to obtain 26.9g, with a molar yield of 96.1% and a purity of 99.9%.

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