Method for preparing baloxavir intermediate and intermediate obtained by method

A technology for intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve the problems of unsuitability for industrial production, irritating odor of thiophenol, high toxicity and the like

Active Publication Date: 2020-12-11
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, thiophenol is used to stimulate stench and is highly toxic, so it is not suitable for industrial production

Method used

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  • Method for preparing baloxavir intermediate and intermediate obtained by method
  • Method for preparing baloxavir intermediate and intermediate obtained by method
  • Method for preparing baloxavir intermediate and intermediate obtained by method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of Compound A-1

[0044]

[0045] Add 3,4-difluorobromobenzene (20g) and tetrahydrofuran (40ml) into the reaction flask, under the protection of nitrogen, control the internal temperature below -50°C, drop lithium diisopropylamide (LDA, 62ml, 2mol / L tetrahydrofuran solution), the dropwise addition is completed, the internal temperature is controlled below -50°C, and the reaction is carried out for 1 hour, then the temperature is controlled below -20°C, and dimethyl sulfate (15.6g) is added dropwise, after the dropwise addition is completed, the temperature is naturally raised and stirred React for 1 to 2 hours. After the reaction was completed by the central control monitoring, post-processing steps such as quenching and extraction were carried out, and most of the solvent was removed by rotary evaporation to obtain the crude product of compound A-1 (containing part of the solvent). The H NMR spectrum of compound A-1 is shown in figure 1 .

[0046] Synt...

Embodiment 2

[0062]

[0063] Under nitrogen protection, the temperature was controlled below -70°C, dry methyl tert-butyl ether and LDA (40mmol) were added to the reaction flask, the temperature was controlled below -60°C, and the raw material (30mmol) of formazan was added dropwise. Base tert-butyl ether solution; keep the temperature at -40°C, add iodomethane (42mmol), the reaction system immediately produces a yellow solid, and the reaction is exothermic violently. After the addition, the temperature of the system was raised to room temperature, and the reaction solution turned yellow with a large amount of solids. The reaction was carried out at room temperature for 3 hours, and the reaction was stopped by monitoring in the central control system. After post-processing, 13.5 g of the crude product of A-1 was obtained.

[0064] Synthesis of Compound A-2

[0065]

[0066] Add compound A-1 (482g) and tetrahydrofuran (250ml) into the reaction flask, protect it with nitrogen, control ...

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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a method for preparing a balosavir intermediate. The method comprises the following steps: (1) methylating 3,4-difluorobromobenzene to obtain a compound A-1; (2) reacting the compound A-1 with a Grignard reagent, then introducing carbon dioxide gas for reaction, and adding acid for acidification to obtain a compound A-2; (3) brominating the compound A-2 to obtain a compound A-3; (4) adding diphenyl disulfide and a reducing agent 1 into THF, dropwise adding methanol, dropwise adding the compound A-3, and reacting to obtain a compound A-4; (5) carrying out ring closing reaction on the compound A-4 in polyphosphoric acid to obtain a compound A-5; and (6) reducing the compound A-5 into alcohol by adopting a reducing agent 2 to obtain a compound A-6. According to the method, highly toxic and foul thiophenol is prevented from being used while expensive reagents are prevented from being used, so that the processcost is reduced. The invention also provides an intermediate compound prepared by the method.

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 and an intermediate compound prepared by the method. 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D337/12C07C63/70
CPCC07C63/70C07D337/12
Inventor 李文森张文琦
Owner HEADING NANJING PHARMTECH CO LTD
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