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Method for preparing baloxavir intermediate

A technology for intermediates and compounds is applied in the field of preparation of baloxavir intermediates of anti-influenza drugs, can solve problems such as being unsuitable for industrial production, serious environmental pollution, environmental pollution, etc., and achieves low cost, high safety factor, and avoidance of Effects of use under high temperature conditions

Active Publication Date: 2021-01-01
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, methanesulfonyl chloride is more serious to environmental pollution
The oxidation step of the fifth step uses a combination of expensive ruthenium catalyst and sodium periodate, and the cost is relatively high
To sum up, the route disclosed in WO2010 / 11816A1 has high cost, serious environmental pollution, and is not suitable for industrial production

Method used

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  • Method for preparing baloxavir intermediate
  • Method for preparing baloxavir intermediate
  • Method for preparing baloxavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0050] Synthesis of compounds of formula II

[0051]

[0052] Acetone (200g), H 2 O (250g) was added to a 10L reaction flask, followed by adding the compound of formula I (50g, 1.0eq), TEMPO (11.0g, 0.2eq), sodium bicarbonate (44g, 1.5eq), KBr (8.2g, 0.2eq ). Slowly cool down to 0°C. Add sodium hypochlorite (520g, 2.0eq) solution dropwise under temperature control at 0-10°C, after the dropwise addition, keep warm at 5-10°C for 30min, monitor by liquid phase HPLC, and the reaction is complete. Keep warm at 5-10°C, add Na 2 SO 3 (8g, 0.2eq) quenched and stirred for 0.5h. Acetone was distilled off under reduced pressure at 40-50°C. The impurities were extracted twice with dichloromethane (200g*2), and the aqueous phase was transferred to a kettle. The kettle was kept warm at 15-20°C, and 12N HCl was added dropwise until pH = 1-2. After beating at 25°C for 10 hours, filtered, the filter cake was rinsed twice with 25°C water, and the crude product was dried at 60°C for 10...

Embodiment 3

[0060] Synthesis of compounds of formula II

[0061]

[0062] Dichloromethane (20g), H 2 O (25g) was added to a 10L reaction flask, followed by adding the compound of formula I (5g, 1.0eq), TEMPO (0.28g, 0.05eq), sodium bicarbonate (4g, 1.5eq), KBr (0.8g, 0.2eq ). Slowly cool down to 0°C. Add sodium hypochlorite (52g, 2.0eq) solution dropwise under temperature control at 0-10°C, after the dropwise addition, keep warm at 5-10°C for 30min, monitor by liquid phase HPLC, and the reaction is complete. Keep warm at 5-10°C, add Na 2 SO 3 (0.8g, 0.2eq) quenched and stirred for 0.5h. Separate the layers and transfer the aqueous phase to a kettle. Keep the kettle warm at 15-20°C, add 12N HCl dropwise until pH = 1-2. After beating at 25°C for 10 hours, filter, rinse the filter cake twice with 25°C water, and dry the crude product at 60°C for 10 hours to obtain compound 4.2 of formula II g, yield 76%

[0063] Synthesis of compounds of formula III

[0064]

[0065] Methanol ...

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Abstract

The invention belongs to the technical field of chemical synthesis and provides a method for preparing a balosavir intermediate. According to the method disclosed by the invention, cheap and easily available 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-ketone (a compound shown as a formula I) is used as a starting material; TEMPO oxidation, benzyl protection and hydrolysis reaction are carried out; so that the intermediate compound---3-benzyloxy-4-oxo-4H-pyran-2-formic acid shown as a formula Baloxavir is prepared. According to the method, highly toxic chemicals such as methylsulfonyl chloride and selenium dioxide are prevented from being used, and reaction reagents are common materials. In each step of the method, the temperature is controlled below 60 DEG C, high-temperature reaction is avoided, and the safety coefficient is high. The method has the advantages of short synthesis route, short reaction steps, simple operation, common and easily purchased reagents and low price, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an anti-influenza drug baloxavir intermediate. Background technique [0002] Baloxavir is a new drug against influenza A and B viruses discovered by Shionogi Co in Japan and jointly developed by it and Roche. Baloxavir, a novel cap-dependent endonuclease inhibitor, was approved by the U.S. Food and Drug Administration (FDA) on October 24, 2018 for the treatment of children 12 years of age and older with influenza symptoms lasting no longer than 48-hour acute uncomplicated influenza patients. It is also one of the few new drugs in the world that can inhibit the proliferation of influenza virus. Because it has no effect on host cells and has few side effects, it is expected to replace oseltamivir and become the ace drug in the field of influenza. The molecular structure of baloxavir is shown below. [0003] [0004] At present, there...

Claims

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Application Information

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IPC IPC(8): C07D309/40
CPCC07D309/40
Inventor 李文森张文琦田雷
Owner HEADING NANJING PHARMTECH CO LTD
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