Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthesis process of intermediate bicyclic imine of novel coronavirus pneumonia resisting drug Paxlovid

A bicyclic imine and synthesis method technology, applied in the field of intermediates of the drug named Paxlovid, can solve the problems of safety risks, unsuitability for large-scale industrial production, poor yield, etc., and achieve easy availability of raw materials, significant market value and innovation Sexuality and low cost effect

Pending Publication Date: 2022-06-21
LANZHOU UNIVERSITY
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The following routes have been reported in the literature for the synthesis of Paxlovid (CN114057627, CN104163759B, CN101384551B), but due to the need to pass through diazo intermediates, there is a high safety risk
The cyclization reaction of diazo compounds has poor yields and safety risks, and is not suitable for large-scale industrial production

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
  • Synthesis process of intermediate bicyclic imine of novel coronavirus pneumonia resisting drug Paxlovid
  • Synthesis process of intermediate bicyclic imine of novel coronavirus pneumonia resisting drug Paxlovid
  • Synthesis process of intermediate bicyclic imine of novel coronavirus pneumonia resisting drug Paxlovid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In a solution of dichloroacetamide (1.0mol) and isopentenyl chloride (1.1mol) in THF (1L) at a temperature between 0 and 10 degrees, add 1.05 times the molar amount of NaH (60%, dispersed in mineral oil) in batches. ), continue to stir the reaction for 2 hours after the addition, and detect that one of the raw materials disappears, and the saturated aqueous ammonium chloride solution is added dropwise to neutralize the reaction. After extraction with ethyl acetate, the organic phase was concentrated to obtain compound C.

[0024] Dissolve C with THF, add substrate 0.05 mol of cobalt chloride, 0.1 mol of ligand L2 and 1.2 mol of zinc powder, heat to 50-60 degrees and react for 3 hours until the substrate disappears, and then concentrate to dryness to obtain compound D.

[0025] Compound D was dissolved in water and isopropanol, then 2.0 moles of sodium borohydride and 2.0 moles of trimethylchlorosilane were added simultaneously in batches until the reaction was complete,...

Embodiment 2

[0028] In the solution DMF (1L) of dichloroacetamide (1.0mol) and isopentenyl bromide (0.9mol) at room temperature, 1.5mol potassium carbonate was added in batches, and the stirring reaction was continued for 5 hours after the addition. The raw materials disappeared, the solid was removed by filtration, 3 L of ethyl acetate and 2 L of water were added to the mother liquor, stirred, stood, separated, extracted, and the organic phase was concentrated to obtain compound C.

[0029] Dissolve C with dioxane, add substrate 0.05 mol of cobalt bromide, 0.1 mol of zinc bromide, 0.1 mol of ligand L2 and 1.5 mol of zinc powder, heat to 80-90 degrees and react for 2 hours until the substrate disappears, It was then concentrated to dryness to give compound D.

[0030] Compound D was dissolved in THF, and then 1.5 mol of red aluminum solution was added in batches at the same time until the reaction was complete. After quenching with hydrochloric acid, most of the alcohol was evaporated by c...

Embodiment 3

[0033] In the toluene (1 L) solution of dichloroacetamide (1.0 mol) and isopentenyl bromide (0.9 mol) at room temperature, 1.1 mol of potassium tert-butoxide was added in batches, and after the addition, the reaction was continued for 1 hour, and water ( 1L) quenched, stirred, stood, layered, extracted, and the organic phase was concentrated to obtain compound C.

[0034] Dissolve C with methyl tert-butyl ether, add 0.05 mol of nickel chloride, 0.1 mol of ligand L1 and 1.0 mol of zinc powder as the substrate, heat to 40-50 degrees and react for 2 hours until the substrate disappears to obtain compound D. THF solution.

[0035] To the THF solution of the above compound D, 1.2 moles of tetrahydroaluminum lithium were added in batches until the reaction was complete. After quenching with hydrochloric acid, most of the THF was evaporated under reduced pressure, extracted with dichloromethane, and the organic phase was concentrated under normal pressure. The residue was distilled ...

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 relates to a synthesis process of an intermediate bicyclic imine of a novel coronavirus pneumonia resisting drug Paxlovid. The synthesis process comprises the following steps: taking dichloroacetamide and isopentenyl halide as raw materials; the key intermediate 3-aza-6, 6-dimethyl bicyclo '5, 1, 0' hexane of the anti-new crown drug Paxlovid, namely the bicyclo-imine intermediate, is obtained through a coupling reaction under the action of alkali, a zinc carbene cyclization reaction under the catalysis of a cobalt or nickel catalyst and a reaction of reducing amide into imine. A synthesis route is shown in the specification.

Description

technical field [0001] The invention relates to a synthesis process of an organic compound, specifically an intermediate whose drug name is Paxlovid, and the structures of the intermediate and paxlovid are respectively the following formula I and formula II. [0002] Background technique [0003] Paxlovid is a drug developed by Pfizer in the United States for the treatment of novel coronavirus pneumonia and will enter Phase III clinical trials in October 2021. Paxlovid is an oral small molecule anti-COVID-19 drug for the treatment of adult patients with mild to moderate novel coronavirus pneumonia (COVID-19) with high risk factors for progression to severe disease, such as advanced age, chronic kidney disease, diabetes, heart disease Patients with severe high-risk factors such as vascular disease and chronic lung disease. Paxlovid is a compound preparation of 3CL protease inhibitor PF-07321332 and low-dose Ritonavir. Ritonavir helps to slow down the metabolism or decompo...

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): C07D209/52
CPCC07D209/52
Inventor 张虹锐肖明兴薛吉军
Owner LANZHOU UNIVERSITY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com