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Fapiravir and preparation method of intermediate thereof

A technology of favipiravir and intermediates, which is applied in the field of preparation of favipiravir and its intermediates, can solve the problems of redness, swelling and itching at contact parts, increase the separation and purification process, and have potential safety hazards, and achieve low raw material prices , high reaction efficiency, high yield and product purity

Active Publication Date: 2020-11-24
长沙创新药物工业技术研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction route step bromide 6 needs to be chlorinated first and then fluorinated, which increases the reaction steps and the separation and purification process of the chlorinated 7, and the chlorinated 7 is 3,6-dichloropyrazine-2-formonitrile to the human body It is very easy to produce allergies, causing redness, swelling and itching at the contact site
In addition, the diazotization reaction is a type of reaction with a high risk of fire and explosion, and there are potential safety hazards.

Method used

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  • Fapiravir and preparation method of intermediate thereof
  • Fapiravir and preparation method of intermediate thereof

Examples

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Embodiment 1

[0048] The preparation of embodiment 1 compound II

[0049] Into a 5L three-necked reaction flask, add 800g of 20% NaOH solution at 25°C, add 4.2g (0.1mol) of LiCl, add 1171.1g (10mol) of compound I aminomalonamide, stir evenly and start to add 40% glyoxal dropwise The solution was 1741.2g (12mol), and the dropwise addition was completed after 30 minutes. After the dropwise addition, the reaction was continued at 25°C for 3h. After the reaction was completed, it was filtered, and the filter cake was washed with 600mlx2 of 80% acetonitrile solution, and then dried in an oven at 80°C to obtain 1420.9g of yellow solid compound II (8.82mol), with a yield of 88.2%.

Embodiment 2

[0050] The preparation of embodiment 2 compound II

[0051] Into a 5L three-necked reaction flask, add 800g of 20% NaOH solution at 20°C, add 4.2g (0.1mol) of LiCl, add 1171.1g (10mol) of compound I aminomalonamide, stir well and start to add 40% glyoxal dropwise The solution was 1741.2g (15mol), and the dropwise addition was completed after 30 minutes. After the dropwise addition was completed, the reaction was continued at 20°C for 3h. After the reaction was completed, it was filtered, and the filter cake was washed with 600mlx2 of 80% acetonitrile solution, and then dried in an oven at 80°C to obtain 1438.6g of yellow solid compound II (8.93mol), with a yield of 89.3%.

Embodiment 3

[0052] The preparation of embodiment 3 compound II

[0053] Into a 5L three-necked reaction flask, add 800g of 20% NaOH solution at 40°C, add 4.2g (0.1mol) of LiCl, add 1171.1g (10mol) of compound I aminomalonamide, and start to add 40% glyoxal dropwise after stirring evenly The solution was 1741.2g (11mol), and the dropwise addition was completed after 30min, and the reaction was continued at 40°C for 3h after the dropwise addition. After the reaction was completed, it was filtered, and the filter cake was washed with 600mlx2 of 80% acetonitrile solution, and then dried in an oven at 80°C to obtain 1401.5g of yellow solid Compound II (8.7mol), with a yield of 87%.

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Abstract

The invention relates to a fapiravir and a preparation method of an intermediate thereof, and belongs to the field of pharmaceutical chemicals. The invention provides a preparation method of a fapiravir intermediate 3-hydroxy sodium pyrazine-2-formamide, wherein the fapiravir intermediate 3-hydroxy sodium pyrazine-2-formamide is prepared by reacting aminopropanedioide with lithium chloride in thepresence of a NaOH solution and glyoxal. The invention also provides a preparation method of 6-bromo-3-hydroxy pyrazine-2-formamide, wherein the 6-bromo-3-hydroxy pyrazine-2-formamide is prepared froman acetonitrile solution of 3-hydroxy sodium pyrazine-2-formamide and an acetonitrile solution of liquid bromine in a microchannel reactor. The invention also provides a preparation method of 3, 6-difluoropyrazine-2-formamide, wherein the 3, 6-difluoropyrazine-2-formamide is prepared by reacting 6-bromo-3-hydroxy pyrazine-2-formamide with potassium bifluoride in the presence of PEG-400 and DMF. Finally, the invention also provides a total synthesis method for preparing fapiravir from the intermediate. The reactions avoid the use of highly dangerous diazotization reactions, and the methods have the advantages of high safety, low raw material price, short steps, low cost and simple post-treatment, and are suitable for industrial enlarged production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and more specifically relates to a preparation method of Favipiravir and its intermediate. Background technique [0002] Favipiravir (favipiravir), the chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide, and the molecular formula is: C 5 h 4 N 3 o 2 F, molecular weight: 157.1, its structure is as follows: [0003] [0004] Favipiravir (favipiravir), as a new type of broad-spectrum anti-RNA virus drug, was approved for marketing in Japan in March 2014, and is used for the antiviral treatment of influenza A and influenza B. Studies have shown that in addition to influenza virus, the drug also exhibits good antiviral activity against a variety of RNA viruses, such as Ebola virus, arenavirus, bunya virus, rabies virus, etc. The latest research shows that Favipiravir has a certain inhibitory effect on the new coronavirus. [0005] The synthetic technique of favipiravir in ...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24Y02P20/55
Inventor 陈毅征陈仔玲彭南敏唐铠雄余健彭媛媛
Owner 长沙创新药物工业技术研究院有限公司
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