Preparation method of baloxavir marboxil intermediate

A technology for intermediates and solvents, applied in the field of preparation of baloxavir intermediates, can solve problems such as long routes, unsuitable for commercial production of fragments, etc., and achieve the effects of reducing side reactions, reducing harm, and improving reaction yields

Inactive Publication Date: 2019-01-04
NANJING POLYTECHNIC INSITUTE
View PDF7 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above route is tedious and uses foul-smelling and highly toxic thiophenol in the second step. This route is obviously not suitable for commercial production of Fragment A

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of baloxavir marboxil intermediate
  • Preparation method of baloxavir marboxil intermediate
  • Preparation method of baloxavir marboxil intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In a 3L three-necked round-bottomed flask, add 2-bromomethyl-3,4-difluorophenylacetonitrile (100.00g, 430.99mmol), acetone (800ml), stir and clarify, then add sodium thiophenate (113.92 g, 861.98mmol) in water (900ml), triethylamine (91.58g, 905.08mmol). The system was mixed and stirred at room temperature for 5 hours, acetone was distilled off under reduced pressure, extracted with dichloromethane (1L×2), the dichloromethane phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a residue 110.00g, yield 97.7%, was directly put into the next reaction without purification.

[0024] In a 5L three-necked flask, add 3,4-difluoro-2-[(phenylthio)methyl]phenylacetonitrile (100.00g, 382.72mmol) produced by the previous step reaction, and phosphorus pentoxide (271.62g, 1.91mol), xylene (2.5L), diatomaceous earth (270.00g), the system was stirred and refluxed for 5 hours, cooled to r...

Embodiment 2

[0029] In a 3L three-neck round bottom flask, add 2-bromomethyl-3,4-difluorophenylacetonitrile (120.00g, 517.20mmol), ethanol (900ml), stir and clarify, then add sodium thiophenate (132.56 g, 1.003mol) in water (900ml), triethylamine (103.57g, 1.024mol). The system was mixed and stirred at room temperature for 5 hours, and the ethanol was distilled off under reduced pressure, then extracted with dichloromethane (1L×2), the dichloromethane phases were combined, washed with water, washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a residue 124.3g, yield 96.9%, was directly put into the next reaction without purification.

[0030] In a 250ml three-necked flask, add 3,4-difluoro-2-[(phenylthio)methyl]phenylacetonitrile (3.00g, 11.47mmol), phosphorus pentoxide (8.12g), xylene (80ml) , diatomaceous earth (8.00g), the system was stirred and refluxed for 4 hours, cooled to room temperature, filtered, washed with water (30ml) of th...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a preparation method of a baloxavir marboxil intermediate. The preparation method is characterized by comprising the following steps: (1) substituting 2-bromomethyl-3,4-difluorophenylacetonitrile through sodium thiophenolate in a solvent A to obtain 3,4-difluoro-2-[(thiophenyl) methyl] benzyl cyanide; (2) reacting the 3,4-difluoro-2-[(thiophenyl) methyl] benzyl cyanide obtained in the step (1) with a cyclizing agent in a solvent B, and carrying out cyclization to obtain 7,8-difluoro dibenzo [b,e] thia heptacyclic-11(6H)-ketone; and (3) reducing the 7,8-difluoro dibenzo[b,e] thia heptacyclic-11(6H)-ketone obtained in the step (2) to obtain 7,8-difluoro dibenzo [b,e] thia heptacyclic-11(6H)-alcohol. The reaction steps in the preparation method are reduced to a six-step reaction from a five-step reaction in the prior art, so that the generation of a side reaction is reduced, and the reaction efficiency is improved. The sodium thiophenolate is used for replacing thiophenol with foul smell and high toxicity, and harm to experimenters during the production is reduced.

Description

technical field [0001] The invention relates to the field of pharmaceutical production, in particular to a preparation method of a baloxavir intermediate. Background technique [0002] Baloxavir (Baloxavir marboxil, S-033188, RG-6152, Zofluza, Xofluza ® , baloxavir) is a novel cap-dependent endonuclease inhibitor that has been developed for the treatment of influenza A or B. Unlike neuraminidase inhibitors, which inhibit virus release from infected host cells, baloxavir blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. On February 23, 2018, baloxavir was approved in Japan for the treatment of influenza A or B virus infection in pediatric and adult patients. Phase III treatment for influenza A or B virus infection is underway in the United States, the European Union, and other countries. In Japan, baloxavir is also in preclinical studies for influenza A virus subtype H5N1. [0003] At present, there are not many reports on the synthesis...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D337/12
CPCC07D337/12
Inventor 宋俊松何学军冷柏榕吴睿张祥赵明发
Owner NANJING POLYTECHNIC INSITUTE
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap