Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

Synthesis method of alpha,alpha-difluoromethylene vinyl phosphonate

A technology of difluoromethylene alkenyl phosphonate and difluoromethylene, which is applied in the field of synthesis of natural phosphate analogs of biologically active substances, and can solve the problem of unfriendly, difluoromethylene alkenyl phosphonic acid There are few literature reports on ester synthesis methods, etc., to achieve the effects of high selectivity, high position, and high yield

Inactive Publication Date: 2016-02-24
NANJING NORMAL UNIVERSITY
View PDF2 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] From 2003 to 2005, Oh's research group reported the organic boronic acid and alkyne catalyzed by zero-valent palladium under acidic conditions. [6-7] and allene [8] The addition reaction of this system can obtain better yield, but needs to add the acetic acid (formula 5) that is unfriendly to the environment
[0016] In 2009, E. Kianmehr reported the addition of phenyl isocyanate to arylboronic acid, the reaction was Pd(OAc) 2 with PPh 3 As a catalyst, the aryl group is added on C=N with higher selectivity [9] , but in moderate yields, accompanied by comparable yields of aryl self-coupling products (Eq. 6)
[0023] In addition, from the investigation of the previous literature, we found that the synthesis method of the difluoromethylene alkenyl phosphonate of the three-substituted E configuration is rarely reported in the literature.

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 method of alpha,alpha-difluoromethylene vinyl phosphonate
  • Synthesis method of alpha,alpha-difluoromethylene vinyl phosphonate
  • Synthesis method of alpha,alpha-difluoromethylene vinyl phosphonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] N 2 Add Pd(OAc) to the reaction tube under protection 2 (2.2mg, 0.01mmol), PPh 3 (5.2mg, 0.02mmol), phenylboronic acid (0.4mmol), α,α-difluoromethylene-β-alkenylphosphonate diethyl ester (45.2mg, 0.2mmol), 2mL 1,4-dioxane The ring was placed in an oil bath at 50 °C and stirred. TLC monitored the disappearance of the raw material α,α-difluoromethylene-β-alienphosphonate diethyl ester, added 10 mL of water to quench the reaction, and extracted with ethyl acetate (5 mL × 3), the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by petroleum ether-ethyl acetate column chromatography to obtain the product.

[0065] The obtained α,α-difluoromethylene alkenyl phosphonate had the following structure, and the yield was 87%.

[0066]

[0067] (E)-diethyl(1,1-difluoro-3-phenylbut-2-en-1-yl)phosphonate

[0068] yellow oily liquid; 1 H-NMR (400MHz, CDCl 3 ): δ7.40-7.30(m, 5H), 5.80(t, J=16.4Hz, 1H), 4.32-4.2...

Embodiment 2

[0071] N 2 Add Pd(OAc) to the reaction tube under protection 2 (2.2mg, 0.01mmol), PPh 3 (5.2mg, 0.02mmol), 2-methylphenylboronic acid (0.4mmol), α,α-difluoromethylene-β-alienphosphonate diethyl ester (45.2mg, 0.2mmol), 2mL1,4 -Dioxane, placed in a 50°C oil bath and stirred, TLC monitored the disappearance of the raw material α,α-difluoromethylene-β-alienphosphonate diethyl ester, added 10 mL of water to quench the reaction, ethyl acetate Extraction (5 mL × 3), the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by petroleum ether-ethyl acetate column chromatography to obtain the product.

[0072] The structure of the obtained α,α-difluoromethylene alkenyl phosphonate was as follows, and the yield was 83%.

[0073]

[0074] (E)-diethyl(1,1-difluoro-3-(o-tolyl)but-2-en-1-yl)phosphonate

[0075] Yellow oily liquid; 1H-NMR (400MHz, CDCl3): δ7.28-7.15(m, 4H), 5.54(t, J=16.4Hz, 1H), 4.43-4.34(m, 4H), 2.38(s,...

Embodiment 3

[0077] N 2 Add Pd(OAc) to the reaction tube under protection 2(2.2mg, 0.01mmol), PPh 3 (5.2mg, 0.02mmol), 3-thiopheneboronic acid (0.4mmol), α,α-difluoromethylene-β-alienphosphonate diethyl ester (45.2mg, 0.2mmol), 2mL 1,4-dioxo The hexacyclic ring was placed in an oil bath at 50°C and stirred. TLC monitored the disappearance of the raw material α,α-difluoromethylene-β-alienphosphonate diethyl ester, added 10 mL of water to quench the reaction, and extracted with ethyl acetate (5 mL). ×3), the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by petroleum ether-ethyl acetate column chromatography to obtain the product.

[0078] The obtained α,α-difluoromethylene alkenyl phosphonate had the following structure, and the yield was 71%.

[0079]

[0080] (E)-diethyl(1,1-difluoro-3-(thiophen-3-yl)but-2-en-1-yl)phosphonate

[0081] yellow oily liquid; 1 H-NMR (400MHz, CDCl 3 ): δ7.36-7.23(m, 3H), 5.93(t, J=1...

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

A synthesis method of alpha,alpha-difluoromethylene vinyl phosphonate having a structure represented by the formula I and having high position and high stereoselectivity is characterized by comprising the steps: with alpha,alpha-difluoromethylene-beta-allene phosphonate as a raw material, adding aryl or aromatic vinyl boric acid RB(OH)2, and under the action of a catalyst palladium acetate Pd(OAc)2 and a phosphine ligand, undergoing an aryl / vinyl hydrogenation reaction, to obtain alpha,alpha-difluoromethylene vinyl phosphonate having the E structure, wherein a substituent R is aromatic vinyl, aryl or heteroaryl. The synthesis method is simple and convenient, mild in conditions, and high in productive rate, the yield of the target fluorine-containing vinyl phosphonate can reach 71%-94%, and the E structure has high selectivity.

Description

technical field [0001] The invention relates to a method for synthesizing natural phosphate analogs of biologically active substances, in particular to a method for synthesizing an α,α-difluoromethylene alkenyl phosphonate. Background technique [0002] Natural phosphates are a very important class of substances in organisms and play a key role in the signal transduction process in organism cells. However, in addition to being used as prodrugs, phosphates are easily hydrolyzed by phosphatases because they enter the body, and the structure of phosphates generally has no practical value in drug design. Therefore, the research on the mimetics of natural phosphates that are not recognized and hydrolyzed by phosphatases has attracted the attention of chemists, pharmacists and biologists. Using bioisosteric principle to convert O in phosphate to CF 2 The α,α-difluoromethylene phosphonates obtained by substitution are a very effective class of natural phosphate mimetics, and many...

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
IPC IPC(8): C07F9/40
Inventor 林云张俊松蔡湘
Owner NANJING NORMAL UNIVERSITY
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
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