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

Preparation method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

An azabicyclo, dimethyl technology is applied in the field of preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and can solve the flammability and equipment requirements of palladium-carbon catalyst High cost, high cost, easy industrial production, high production safety, mild conditions

Active Publication Date: 2022-02-01
江苏省药物研究所有限公司
View PDF8 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016]1) Expensive, flammable and explosive reducing reagent lithium aluminum tetrahydrogen and highly toxic and flammable borane are commonly used in the synthesis process;
[0017]2) Debenzylation by hydrogenation requires high equipment requirements, and the palladium carbon catalyst is flammable, and there is a great safety risk during use;
[0018]3) Caronic anhydride is used as the starting material, and the cost is relatively high

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 6,6-dimethyl-3-azabicyclo[3.1.0]hexane
  • Preparation method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane
  • Preparation method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] (1) Preparation of Compound V

[0083] Add 20.91g (0.1mol) of permethrin into the reaction bottle, 200ml reaction solvent anhydrous tetrahydrofuran (the volume of anhydrous tetrahydrofuran is about 10 times that of permethrin), stir and dissolve at room temperature, and cool to the inner temperature of 0°C in ice water , Add 4.16 g (0.11 mol) of sodium borohydride. 23.42 g (0.165 mol) of boron trifluoride diethyl ether was added dropwise with stirring while insulated.

[0084] After dripping, keep the reaction at 0°C for 1 hour, raise it to room temperature (25±2°C) and react for 8 hours until the raw materials disappear.

[0085] After the reaction, the reaction product was cooled down, 5ml of methanol was added dropwise, and stirred for 20 minutes. After quenching the excess borane, slowly poured into 50ml of ice water, stirred 150ml of ethyl acetate and extracted three times, combined the organic phase, and 100ml of water in two washed with 50 ml of saturated brine...

Embodiment 2

[0106] (1) Preparation of Compound V

[0107]Add 20.91g (0.1mol) of permethrin into the reaction bottle, 200ml reaction solvent anhydrous tetrahydrofuran (the volume of anhydrous tetrahydrofuran is about 10 times that of permethrin), stir and dissolve at room temperature, and cool to the inner temperature of 0°C in ice water , 5.93 g (0.11 mol) of potassium borohydride was added. Add 22.0 g (0.165 mol) of anhydrous aluminum trichloride in batches with heat preservation and stirring.

[0108] After dripping, keep the reaction at 0°C for 1 hour, raise it to room temperature (25±2°C) and react for 8 hours until the raw materials disappear.

[0109] After the reaction is over, cool the reaction product, add dropwise 5ml of methanol, stir for 20 minutes, after quenching excess borane, slowly pour 50ml of ice water, stir 150ml of ethyl acetate for three extractions, combine the organic phase, and 100ml of water twice Wash with 50 ml of saturated brine, and dry the organic phase ov...

Embodiment 3

[0128] (1) Preparation of Compound V

[0129] Add 20.91g (0.1mol) of permethrin into the reaction flask, 200ml reaction solvent anhydrous 2-methyltetrahydrofuran (the volume of anhydrous tetrahydrofuran is about 10 times that of permethrin), stir and dissolve at room temperature, and cool to At an internal temperature of 0°C, 4.16 g (0.11 mol) of sodium borohydride was added. 23.42 g (0.165 mol) of boron trifluoride diethyl ether was added dropwise with stirring while insulated.

[0130] After dripping, keep the reaction at 0°C for 1 hour, raise it to room temperature (25±2°C) and react for 8 hours until the raw materials disappear.

[0131] After the reaction is over, cool the reaction product, add dropwise 5ml of methanol, stir for 20 minutes, after quenching excess borane, slowly pour 50ml of ice water, stir 150ml of ethyl acetate for three extractions, combine the organic phase, and 100ml of water twice Wash with 50 ml of saturated brine, and dry the organic phase over a...

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

In order to solve the problems of high raw material cost, high safety risk in the reaction process and low product purity of an existing preparation method of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, the invention provides a novel preparation method which comprises the following steps: reacting dichlorochrysanthemic acid serving as a raw material with alkali metal hydroboron and lewis acid in a reaction solvent, and converting the dichlorochrysanthemic acid into a compound as shown in a formula V; performing hydrolysis reaction on the compound in the formula V in a sulfuric acid solution to obtain a compound in a formula IV; carrying out halogenation reaction on the compound as shown in the formula IV and a halogenation reagent in a reaction solvent, and then conducting conversion in ammonia water to form a compound as shown in a formula III; reacting the compound shown in the formula III with alkali metal hydroxide and hypochlorite in water to obtain a compound shown in a formula II; and adding the compound in the formula II into a reaction solvent, and carrying out self-cyclization reaction under the action of organic alkali to obtain a compound in the formula I. The method is mild in condition, high in safety and easy for industrial production; the cost is effectively reduced; and the use of highly toxic, flammable, explosive and expensive reducing reagents, high pressure equipment, and flammable noble metal catalysts is avoided.

Description

technical field [0001] The invention relates to a preparation method of an antiviral drug intermediate and its application in the field of antiviral drug intermediates. Background technique [0002] 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane (Formula I) is an important intermediate in the production of Boceprevir, a hepatitis C protease inhibitor, and PF-07321332, an oral drug for the treatment of COVID-19 currently in the clinical stage. The structural formula is as follows: [0003] [0004] The chemical structural formulas of Boceprevir, a hepatitis C protease inhibitor, and PF-07321332, an oral drug for the treatment of COVID-19, are as follows: [0005] Boceprevir: PF-07321332: [0006] At present, there are various documents reporting the synthesis method of formula I. [0007] WO2008082508 reports a method for synthesizing Formula I. Formula I is prepared by using lithium aluminum tetrahydrogen as a reducing agent, followed by hydrogenation to remove the benzyl...

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 徐军李胜徐斌夏超刘媛严海军陈国广
Owner 江苏省药物研究所有限公司
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