Alpha, alpha-fluorine chlorine fragrant methyl phosphonate and method for preparing the same

A technology of fluorochloroarylmethylphosphonate and diethyl benzylphosphonate is applied in the field of organic compounds, and can solve the problems of unreported preparation methods, and achieve the effects of high yield and good application prospects

Inactive Publication Date: 2009-07-29
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, α, α-fluorochloroarylmethyl phosphonate and its preparation method have not been reported at home and abroad

Method used

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  • Alpha, alpha-fluorine chlorine fragrant methyl phosphonate and method for preparing the same
  • Alpha, alpha-fluorine chlorine fragrant methyl phosphonate and method for preparing the same
  • Alpha, alpha-fluorine chlorine fragrant methyl phosphonate and method for preparing the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, α, the preparation of α-fluorochlorobenzyl phosphonic acid diethyl ester

[0038] a, the preparation of diethyl α-hydroxybenzylphosphonate

[0039] Weigh 2.50g (23.56mmol, 1.0eq.) of benzaldehyde, add 10mL of dichloromethane to dissolve, and prepare the benzaldehyde solution, and set aside; weigh 2.40g (35.34mmol, 1.5eq.) of sodium ethoxide, add dichloromethane 10mL was dissolved, and then 2.44mL (18.85mmol, 0.8eq.) of diethyl phosphinate was added at -35°C under the protection of argon. After stirring for 30 minutes, the above-mentioned benzaldehyde solution was added, and the reaction was continued. Monitor the reaction process with thin-layer chromatography (TLC) method, add concentration after 3 hours and be the hydrochloric acid termination reaction of 0.1mol / L, reaction solution is extracted with ethyl acetate, get organic layer, dry with anhydrous magnesium sulfate, suction filtration, filtrate The solvent was recovered by distillation under reduce...

Embodiment 2

[0047] Embodiment 2, α, the preparation of α-fluorochloro-(4-fluoro)benzylphosphonic acid diethyl ester

[0048] a, the preparation of α-hydroxyl-(4-fluoro)benzylphosphonic acid diethyl ester

[0049] Weigh 2.00g (16.12mmol, 1.0eq.) of p-fluorobenzaldehyde, add 5mL of dichloromethane to dissolve, and prepare a p-fluorobenzaldehyde solution, and set aside; weigh 1.86g (27.40mmol, 1.7eq.) of sodium ethoxide, Add 10 mL of dichloromethane to dissolve, then add 2.19 mL of diethyl phosphinate (16.92 mmol, 1.05 eq.) at a temperature of -35 °C under the protection of argon, stir and react for 30 minutes, then add the above-mentioned p-fluorobenzaldehyde solution, continue to stir the reaction, monitor the reaction process with the TLC method, add concentration after 3 hours and be the hydrochloric acid termination reaction of 0.1mol / L, the reaction solution is extracted with ethyl acetate, get the organic layer, dry with anhydrous magnesium sulfate, suction filtration, The filtrate w...

Embodiment 3

[0057] Embodiment 3, α, the preparation of α-fluorochloro-(4-chloro) benzyl phosphonic acid diethyl ester

[0058] The preparation of a, α-hydroxyl-(4-chloro) benzyl phosphonic acid diethyl ester

[0059] Referring to Example 2, using p-chlorobenzaldehyde as a starting material for preparation, the product is identified as α-hydroxyl-(4-chloro)benzylphosphonic acid diethyl ester by NMR:

[0060] 1 H NMR (300MHz, CDCl 3 ): δ=1.22~1.30(m, 6H), 3.96~4.13(m, 4H), 5.00(d, 2 J PH =10.7Hz, 1H), 7.34(d, J=8.3Hz, 2H), 7.43(d, J=8.5Hz, 2H)ppm; 13 CNMR (75MHz, CDCl 3 ): δ=16.3(d, 3 J PC =5.5Hz), 63.0(d, 2 J PC =7.4Hz), 63.4(d, 2 J PC =7.0Hz), 69.9(d, 1 J PC =159.6Hz), 128.3, 128.4, 133.6, 135.5ppm.

[0061] B, the preparation of α-chloro-(4-chloro) benzyl phosphonic acid diethyl ester

[0062] Prepared with reference to Example 2, the product yield is 87%, identified as α-chloro-(4-chloro)benzylphosphonic acid diethyl ester by NMR:

[0063] 1 H NMR (300MHz, CDCl 3 ): δ=...

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Abstract

The invention discloses the alpha, alpha-chloro-fluoro-arylmethylphosphonate shown in general formula (I), the preparation method comprises the following steps: aromatic formaldehyde and phosphinate conduct the Pudovik addition reaction in a solvent and under the condition of base catalysis to generate alpha-hydroxy arylmethylphosphonate; and then the alpha-hydroxy arylmethylphosphonate and triphenylphosphine conduct nucleophilic substitution reaction in a solvent to generate alpha-chloro-arylmethylphosphonate; finally, the alpha-chloro-arylmethylphosphonate and N-fluoro bis benzene sulfonic amide conduct electrophilic substitution reaction in a solvent and under the condition of base catalysis to generate the alpha, alpha-chloro-fluoro-arylmethylphosphonate; the alpha, alpha-chloro-fluoro-arylmethylphosphonate of the invention has the potential PTPs inhibition activity, which can also be used as the synthesis intermediate of alpha-fluorine phosphate.

Description

technical field [0001] The invention relates to an organic compound, in particular to α, α-fluorochloroarylmethyl phosphonate, and also to a preparation method for α, α-fluorochloroarylmethyl phosphonate. Background technique [0002] In recent years, α-fluorophosphonates (including α-fluoro monosubstituted and α,α-difluoro disubstituted) have been used as chelate complexes due to their similar structure and electronic effects to the parent phosphate and a wide range of biological activities. The use of ligands, metabolite probes and enzyme inhibitors has received increasing attention in the fields of organic chemistry, biology and medicine (Frank AW.J Org Chem, 1965, 30, 3663; Fonong T et al.J Anal Chem, 1983 , 55, 1089; Halazy Set al.J Am Chem Soc, 1991, 113, 315; Martin SF et al.J Org Chem, 1994, 59, 4821; Yao ZJ et al.Bioorg Med Chem, 1998, 6, 1799; Liu DG et al. Bioorg Med Chem Lett, 2003, 13, 3005; Wang G et al. J Med Chem, 2004, 47, 6902). [0003] At the same time,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
Inventor 官智吴狄何延红
Owner SOUTHWEST UNIV
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