Preparation method of key intermediate of baloxavir marboxil

An intermediate and key technology, which is applied in the field of preparation of key intermediates of baloxavir, can solve problems such as low yield and long reaction time, and achieve the effects of convenient use, environmental protection, and shortened reaction time

Active Publication Date: 2021-10-26
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to provide a kind of preparation method of the baloxavir key intermediate shown in formula 4, to solve existing in the method for synthesizing the baloxavir key intermediate shown in formula 4 in the prior art Technical problems of long reaction time and low yield

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  • Preparation method of key intermediate of baloxavir marboxil
  • Preparation method of key intermediate of baloxavir marboxil
  • Preparation method of key intermediate of baloxavir marboxil

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preparation example Construction

[0037] The preparation method of the key intermediate of baloxavir provided by the invention comprises:

[0038]

[0039] S1. Add compound 1 with the structure of formula 1 and compound 2 with the structure of formula 2 into the microwave reactor, under the action of sulfonic acid resin type solid acid catalyst and condensation agent, generate intermediate with the structure of formula 3 in the first solvent Body 3;

[0040] S2. Add intermediate 3 and lithium chloride to the microwave reactor to generate the key intermediate of baloxavir with the structure of formula 4 in the second solvent.

[0041] Wherein, the mass ratio of the sulfonic acid resin type solid acid catalyst to the compound 1 is 3-10:100. For example, it can be 3:100, 5:100, 7:100, 10:100, etc.

[0042] The condensation agent is 1-propyl phosphoric anhydride.

[0043] The molar ratio of condensing agent to compound 1 is 1.5-2.5:1. For example, it can be 1.5:1, 1.8:1, 2:1, 2.4:1, 2.5:1, etc.

[0044] Th...

Embodiment 1

[0055] A preparation method of the key intermediate of baloxavir having the structure shown in formula 4, comprising:

[0056]

[0057] Compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and solid acid catalyst HND-580 (0.132g) were added to a 100mL microwave reactor, and 12mL of 50wt% 1-propylphosphoric anhydride was added (12mL solution contains 20.18mmol of 1-propyl phosphoric anhydride); put the reaction kettle into a microwave reactor (XH-800SP Nanocube multifunctional microwave hydrothermal parallel synthesizer), and set the reaction temperature to 150°C , the maximum power is 300w, the heating time is 50min, and the reaction time is 30min. After setting, click the start button and start stirring; after the reaction is over, pour the reaction solution into ice water, filter and recover the catalyst; the filtrate is extracted with dichloromethane, The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated ...

Embodiment 2

[0078] A preparation method of the key intermediate of baloxavir having the structure shown in formula 4, comprising:

[0079] Compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and solid acid catalyst HND-586 (0.132g) were added to a 100mL microwave reactor, and 12mL of 50wt% 1-propylphosphoric anhydride was added the ethyl acetate solution; put the reaction kettle into the microwave reactor (XH-800SP Nanocube multifunctional microwave hydrothermal parallel synthesizer), set the reaction temperature to 150°C, the maximum power to 300w, the heating time to 50min, and the reaction time After the setting is completed, click the start button and start stirring; after the reaction is completed, pour the reaction solution into ice water, filter and recover the catalyst; Wash with sodium chloride solution and dry over anhydrous sodium sulfate to obtain a yellow oily compound, which is the crude product of compound 3; add the crude product of compound 3 to a 100mL microwave react...

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Abstract

The invention relates to the technical field of synthesis of medical intermediates, and provides a preparation method of a key intermediate of baloxavir marboxil. The preparation method comprises the following steps: adding a substance as shown in a formula 1 in the specification and a substance as shown in a formula 2 in the specification into a microwave reactor, generating a substance as shown in a formula 3 in the specification in a first solvent under the action of a sulfonic acid resin type solid acid catalyst and a condensing agent, adding the substance as shown in the formula 3 and lithium chloride into the microwave reactor, and generating the key intermediate of baloxavir marboxil in a second solvent. According to the preparation method of the key intermediate of the baloxavir marboxil, a microwave technology is adopted, a reaction is carried out under a microwave condition, and the sulfonic acid resin type solid acid catalyst is adopted to replace traditional catalysts such as methanesulfonic acid and p-toluenesulfonic acid, so reaction time is greatly shortened, production efficiency is improved, and product yield is obviously improved.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, and more specifically, relates to a preparation method of a key intermediate of baloxavir. Background technique [0002] Influenza (influenza), referred to as influenza, is an acute respiratory infectious disease caused by influenza virus. It has high morbidity and mortality worldwide. disease first. Human influenza viruses can be divided into three types according to the antigenicity of their nucleoproteins: influenza A virus, influenza B virus, and influenza C virus. At present, the main measures to deal with influenza virus infection are vaccination and drug treatment. However, the vaccine not only has certain limitations in the scope of use, but also has low prevention and control efficiency, and conventional seasonal influenza vaccines cannot effectively prevent and control continuously mutating influenza viruses. Therefore, it is very important to develo...

Claims

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Application Information

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IPC IPC(8): C07D498/14
CPCC07D498/14
Inventor 徐志斌孟子晖吕晓芳王佳如王宜运
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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