Synthesis process of favipiravir and intermediate thereof

A synthesis process and favipiravir technology are applied in the synthesis of favipiravir intermediate 6-fluoro-3-benzyloxy-2-pyrazinecarboxamide and the field of favipiravir synthesis, which can solve the problem of high cost , unfavorable to large-scale production and other problems, to achieve the effects of low cost, short reaction time and mild reaction conditions

Active Publication Date: 2020-06-30
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, there are various deficiencies in the existing synthesis techniques

Method used

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  • Synthesis process of favipiravir and intermediate thereof
  • Synthesis process of favipiravir and intermediate thereof
  • Synthesis process of favipiravir and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of compound III

[0045]

[0046] materials molecular weight Feeding amount molar weight Proportion 2-aminomalonamide 117 100g 0.85mol 1 40% glyoxal in water 58.01 149.4g 1.03mol 1.2 20% NaOH 40 220ml 1.11mol 1.3 6mol / l hydrochloric acid ethanol 1mol / L NaOH

[0047] In the reaction flask, add 220ml of 20% sodium hydroxide aqueous solution, cool to -10°C, and then add 100g of 2-aminomalonic acid diamide to suspend it in the solution. Then, 149.4 g of 40% glyoxal aqueous solution was added dropwise, and the addition was completed in about 40 minutes. After the addition was complete, the reaction mixture was stirred at -5°C for 1 hour, warmed to 22°C, and stirred for an additional 3 hours.

[0048] After the reaction was completed, it was cooled to below 5° C., and the reaction compound was adjusted to pH 12 by adding 1 mol / l sodium hydroxide and mad...

Embodiment 2

[0049] Embodiment 2: the preparation of compound IV

[0050]

[0051]

[0052]

[0053] In the reaction flask, add 100 g of compound III and 1 L of acetonitrile, and stir. Then add 199g of potassium carbonate, 25.8g of tetrabutylammonium iodide, and 135g of benzyl bromide in sequence, raise the temperature to 55-60°C, and react for 12-14h. The raw materials basically react completely.

[0054] After the reaction, add 1 L of water to the system, extract 1 L x 2 times with ethyl acetate, combine the organic phases, wash once with 1 L of water, and add anhydrous sodium sulfate to dry. Filtration, precipitation under reduced pressure to obtain oily substance IV: 153.3g, yield 93.1%

Embodiment 3

[0055]Embodiment 3: the preparation of compound V (Corning microchannel reactor, its module and structural diagram are as figure 1 shown)

[0056]

[0057] materials molecular weight Feeding amount molar weight Proportion Compound IV 229.09 10g 0.044mol 1 formic acid 90g Fluorine gas 40 2.1g 0.052mol 1.2 Nitrogen 28 18.9g

[0058] Refer to as figure 2 As shown in the flowchart, follow the steps below:

[0059] Compound IV was dissolved in formic acid solution, prepared to 10wt%, cooled to 5-10°C, and kept warm. The number is solution A, the system is about 100ml.

[0060] It is prepared into 10wt% sodium hydroxide solution, and placed at the outlet of the microchannel reactor to stir.

[0061] Lower the temperature of the microchannel reactor to 5-8°C in advance, and use the feed pump to simultaneously inject solution A (10wt%, 10g / min) and fluorine gas (10vol% of nitrogen, 2.1g / min) into the silicon carb...

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Abstract

The invention relates to the technical field of medicine synthesis, and in particular, relates to a synthesis process of favipiravir and an intermediate thereof. The synthesis method of favipiravir comprises the following steps: 1) 2-aminopropanediamide and glyoxal serve as raw materials, and generating a compound III through a cyclization reaction; 2) performing benzyl protection on the compoundIII under the catalysis of potassium carbonate to generate a compound IV; 3) performing fluorine substitution on the compound IV under the action of fluorine gas, a solvent and a catalyst to generatea compound V; and 4) performing debenzylation protection on the compound V to generate favipiravir. Compared with other synthetic routes of favipiravir, the synthetic route provided by the invention has the advantages that the whole process route is shortened by virtue of high-selectivity fluorination reaction, the production cost is greatly reduced, and the synthesis process is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, specifically a method for synthesizing favipiravir intermediate 6-fluoro-3-benzyloxy-2-pyrazinecarboxamide and a process for synthesizing favipiravir through the method. Background technique [0002] Favipiravir (T-705; Favipiravir), whose chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a broad-spectrum antiviral drug of RNA polymerase (RdRp) inhibitors. It itself has no antiviral activity, and can be rapidly converted into the form of favipiravir nucleoside triphosphate through metabolism in the body, and competitively inhibits RNA polymerase dependent on viral RNA by simulating guanosine triphosphate (GTP), inhibiting viral genome replication and Transcription to play an antiviral effect, the form of favipiravir nucleoside triphosphate can also penetrate into the viral gene, and play an antiviral effect by inducing fatal mutations. [0003] Recently, the State Food and Dru...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24Y02P20/55
Inventor 陈本顺江涛尹斌何伟
Owner JIANGSU ALPHA PHARM CO LTD
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