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A kind of synthetic method of favipiravir

A technology of favipiravir and a synthesis method, which is applied in the field of drug synthesis, can solve the problems of difficult industrialized production requirements, low yield and low efficiency, and achieves the effects of simple operation, high yield and simplified preparation process

Inactive Publication Date: 2020-02-04
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In order to solve the problem of key impurities, the existing technology often adopts chromatographic purification methods. This type of treatment method has a series of defects such as large solvent consumption, low efficiency, and low yield, which is difficult to meet the needs of industrial production; The yield is high, and the synthetic method of target product quality controllability just seems particularly important; The inventor has developed a kind of synthetic method of favipiravir without chromatographic purification, product quality controllable, and high yield through a large amount of research, as follows Shown:

Method used

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  • A kind of synthetic method of favipiravir
  • A kind of synthetic method of favipiravir
  • A kind of synthetic method of favipiravir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] The first step: preparation of 3-amino-2-ester pyrazine (2)

[0139]

[0140] Add methanol (50ml) to compound 1 (5g, leq), add concentrated sulfuric acid (4eq) under an ice-water bath, stir at room temperature, TLC shows that the reaction is complete, concentrate, adjust the pH to 8 with saturated sodium carbonate, filter with suction, and dry at 50°C for 2h. Obtained 2 as a brown solid (4.18 g, 76%).

[0141] The second step: preparation of methyl 3-amino-6-bromopyrazine-2-carboxylate (3)

[0142]

[0143]Add acetonitrile (276ml) to compound 2 (27.6g, leq), stir at room temperature, add NBS (25.1g, 1.01eq) in batches, stir overnight at room temperature, TLC shows that after the reaction is complete (20-30h), add water (300ml), use Na 2 CO 3 The solution was adjusted to pH=7, extracted with ethyl acetate (3×50ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 3...

Embodiment 2

[0163] Compared with Example 1, the difference is only in:

[0164] The fifth step: preparation of 3,6-dichloropyrazine-2-carbonitrile (6)

[0165] Compound 5 (2g, 1eq) was dissolved in chlorobenzene (10ml), POCl was slowly added dropwise 3 (5.6g, 4eq), heated to 70°C to form a homogeneous solution, lowered to room temperature, added DIEA (3.57g, 3eq) dropwise, stirred for 1h at 60°C, 1h at 80°C, and 4h at 100°C. Afterwards, it was poured into ice water (110ml) and stirred vigorously to react for 2h, suction filtered, and 20 times of petroleum ether was used for the filter cake (the weight ratio of the obtained crude product to petroleum ether was 1:10-30) to obtain a brown solid 6 in a yield of 60 %.

[0166] The remaining steps are the same as in Example 1.

Embodiment 3

[0168] Compared with embodiment 1, the difference only lies in:

[0169] The crude product of 3-amino-6-bromopyrazine-2-carboxylic acid methyl ester obtained in the second step was added 30 times of dichloromethane (the weight ratio of the obtained crude product to dichloromethane was 1:25~50) and refluxed for 0.5h Afterwards, suction filtration, the dichloromethane was evaporated from the mother liquor, and then recrystallized with 20 times of methanol (the weight ratio of rotary steamed product and methanol was 1:5-30) to obtain light yellow solid 3 with a yield of 76%.

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Abstract

The invention discloses a method for synthesis of favipiravir. The method comprises an esterification reaction of 3-aminopyrazine-2-carboxylic acid and an alcohol, a bromination reaction, a diazotization reaction, an ammonolysis reaction, a chlorination-dehydration reaction, a one-pot series connection aromatic ring fluorination reaction, a cyan-hydrolysis reaction, an aromatic ring hydroxyl substitution reaction, and purification treatment so that favipiravir is obtained. The method utilizes 3-amino-2-carboxypyrazine as a raw material to synthesize favipiravir through 8-step reactions and has a total yield of 26%. The key intermediates 3 and 6 in the method are purified by recrystallization so that column chromatography separation in the literature is avoided. The final three reactions are finished by a one-pot method so that the operation is simplified. The synthesis method improves a yield, realizes a low cost and green economy and is conducive to industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a new preparation method of Favipiravir. 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, has the following structural formula: [0003] [0004] Favipiravir was researched and developed by Toyama Chemical Co., Ltd., Japan. In 2011, it completed Phase III clinical trials in Japan. It was approved for marketing in 2014. It is mainly used for influenza treatment in clinical practice. It is a wide range of RNA-dependent RNA polymerase inhibitors. Spectrum antiviral drugs. Studies have shown that Favipiravir forms Favipiravir-ribofuranosyl-5-triphosphate (T-705RTP) under the action of intracellular enzymes, which competitively inhibits viral RNA-dependent RNA polymerase, thereby inhibiting the viral genome Replication and t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 刘丰良李翠钦
Owner CENT SOUTH UNIV
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