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Method for refining favipiravir and/or derivatives thereof

A refining method, the technology of favipiravir, is applied in the field of drug synthesis, which can solve the problems of substandard color, difficulty in removing solvents, and high cost, and achieve the effects of large decolorization, good purification effect, and easy operation

Pending Publication Date: 2021-08-03
BEIJING SIHUAN PHARMA +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] CN102307865B only discloses the obtained solid product, but does not disclose the color of the obtained solid
CN104496917A discloses that a yellow solid is prepared, which does not meet the quality standards of medicines
CN1418220A discloses a method for purifying and refining the crude product through silica gel column chromatography to obtain a light yellow solid, but this method has defects such as high cost, unsuitability for industrial production, non-powder product properties, and failure to meet drug quality standards
CN106478528A discloses that a light yellow solid is obtained through chromatographic column purification and separation, which has defects such as high cost and unsuitability for industrial production
CN101809003A discloses a method for preparing a light yellow-white solid, which has the following defects: First, the light yellow-white solid is the product of a specific intermediate preparation method of dipropylamine salt of 6-fluoro-3-hydroxyl-2-cyanopyrazine , not a routine purification operation; second, it is difficult to remove organic amines and cause solvent residues, which increases the difficulty of drug quality control; third, the product is not a powder, which does not meet the quality standards of the original drug
CN107226794A and CN106866553A disclose methods for obtaining off-white solids by ethanol recrystallization, but when the crude product is heavy in color, it is difficult to obtain white to light yellow solids by using alcohols including ethanol recrystallization, so there is a problem of limited scope of application
[0006] In summary, there are the following defects in the purification method of favipiravir in the prior art: one is that column chromatography purification is not suitable for industrial production; The use of activated carbon for decolorization in the process is still difficult to meet the drug quality standards; third, even if the product in the laboratory test stage is close to light yellow, the color may not meet the standard in the scale-up production, resulting in unpredictable losses

Method used

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  • Method for refining favipiravir and/or derivatives thereof
  • Method for refining favipiravir and/or derivatives thereof
  • Method for refining favipiravir and/or derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] The refining of embodiment 1 Favipiravir

[0088] Get 5.00g of favipiravir crude product (light brown solid, purity: 99.427%, 15 impurities, impurity A: 0.048%, impurity B: 0.105%) and add in 1L single-necked bottle, add 330ml dichloromethane / ethyl acetate= 5:1 (w / w) mixed solvent was stirred and dissolved, and then 25.00g of 200-300 mesh silica gel was evenly spread in the Buchner funnel, filtered, and rinsed with 40ml of the corresponding mixed solvent, the filtrate was collected, concentrated and evaporated under reduced pressure. Dry, then add 45ml of ethyl acetate, heat and stir until the system reflux, add 0.50g of activated carbon, stir and heat for 1h, heat filter, rinse the filter cake with 5ml of ethyl acetate, cool the filtrate to 0-10°C, keep stirring and crystallize for 2h , the filter cake was rinsed with 5ml pre-cooled ethyl acetate, and the filter cake was vacuum-dried at 60° C., and the vacuum degree was greater than or equal to 0.08 MPa. After drying, ...

Embodiment 2

[0089] The refining of embodiment 2 Favipiravir

[0090] Take 5.00g of favipiravir crude product (light brown solid, purity: 99.427%, 15 impurities, impurity A: 0.048%, impurity B: 0.105%,) into a 1L single-necked bottle, add 600ml of dichloromethane / ethyl acetate =10:1 (w / w) mixed solvent was stirred and dissolved, then evenly spread 25.00g of 200-300 mesh silica gel in the Buchner funnel, filtered, and rinsed with 40ml of the corresponding mixed solvent, collected the filtrate, and concentrated under reduced pressure Evaporate to dryness, then add 45ml of ethyl acetate, heat and stir until the system returns to reflux, add 0.50g of activated carbon, stir and heat for 1h, heat filter, rinse the filter cake with 5ml of ethyl acetate, cool the filtrate to 0-10°C, keep stirring and crystallize 2h, the filter cake was rinsed with 5ml of pre-cooled ethyl acetate, and the filter cake was vacuum-dried at 60°C, with a vacuum degree ≥0.08MPa, and dried to obtain 3.40g of off-white pow...

Embodiment 3

[0091] The refining of embodiment 3 Favipiravir

[0092] Take 5.00g of favipiravir crude product (light brown solid, purity: 99.427%, 15 impurities, impurity A: 0.048%, impurity B: 0.105%,) into a 3L single-necked bottle, add 2800ml of dichloromethane solvent and stir to dissolve, Then spread 25.00g of 200-300 mesh silica gel evenly in the Buchner funnel, filter and rinse with 40ml of the corresponding solvent, collect the filtrate, concentrate under reduced pressure and evaporate to dryness, then add 45ml of ethyl acetate, heat and stir until the system refluxes, Add 0.50g of activated carbon, stir and heat for 1h, heat filter, rinse the filter cake with 5ml of ethyl acetate, cool the filtrate to 0-10°C, keep stirring and crystallize for 2h, rinse the filter cake with 5ml of pre-cooled ethyl acetate, filter The cake was vacuum-dried at 60° C., vacuum degree ≥ 0.08 MPa, and dried to obtain 3.46 g of white powder with a yield of 69.2% and a purity of 99.936% (2 impurities, impu...

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Abstract

The invention relates to a method for refining favipiravir and / or derivatives thereof, which comprises the following steps of dissolving favipiravir and / or derivatives thereof to be refined in an organic solvent A, filtering with silica gel, drying and purifying to obtain the favipiravir. The purification is selected from any one or a combination of recrystallization and pulping. According to the refining method, the problem that favipiravir is difficult to decolor is solved, and the obtained product is a white or off-white powdery product and meets related requirements of drug quality standards. In addition, the method is suitable for purification and decoloration of other products and intermediates, and is high in decoloration degree, good in purification effect, simple and convenient to operate, low in cost and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for refining Favipiravir and / or its derivatives. Background technique [0002] Favipiravir (favipiravir) is an RNA-dependent RNA polymerase (RdRp) inhibitor class of broad-spectrum antiviral drugs, which has important practical significance for humans to deal with possible severe viral infectious diseases and possible bioterrorist attacks . [0003] [0004] Japan has proposed Favipiravir as a white to light yellow powder in its national drug quality standards. However, the preparation of Favipiravir requires multi-step continuous reactions (or enlarged production), and it is easy to obtain solids with heavier colors (such as yellow, gray, brown, black, etc.), which do not meet the requirements of drug quality standards. [0005] CN102307865B only discloses the obtained solid product, but does not disclose the color of the obtained solid. CN104496917A discloses that a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24A61K31/4965A61P31/14A61P31/16A61P31/18
CPCC07D241/24A61P31/14A61P31/16A61K31/4965C07B2200/13Y02A50/30
Inventor 邓声菊曾恩佑李成林李强刘会强徐艳君王田园
Owner BEIJING SIHUAN PHARMA
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