Method for synthesizing alpha-aryl ethyl phosphonate

Abstract

The invention discloses a method for synthesizing alpha-aryl ethyl phosphonate.The method comprises the following steps that alpha-aryl vinyl phosphonate, potassium phosphate and o-nitro-benzenesulfonyl hydrazide are added into a reactor; after vacuumizing is conducted, N2 is introduced to remove oxygen; under the protection of N2, anhydrous acetonitrile is added, and stirring is conducted for 5-10 h at room temperature; after the reaction is finished, water is added into a reaction mixture for dilution, extraction is conducted with ethyl acetate, drying is conducted with sodium sulphate anhydrous, mixed liquor of petroleum ether and ethyl acetate serves as eluent, column chromatography isolation is conducted, distillation is conducted finally, and alpha-aryl ethyl phosphonate is obtained.According to the method for synthesizing alpha-aryl ethyl phosphonate, transition metal does not participate, the substrate universality is good, the compatibility of a functional group is high, the reaction condition is mild, the reaction efficiency is high, and operation is safe, easy and convenient.

Description

technical field

[0001] The invention relates to a method for reducing and synthesizing α-aryl ethyl phosphonate by using o-nitrobenzenesulfonyl hydrazide. Background technique

[0002] α-arylethylphosphonate is an important structural fragment of the antimalarial drug fosminomycin, which is also considered to have similar biological activities to α-arylpropionic acid compounds. Therefore, its synthesis research is of great significance for drug screening and the establishment of drug molecular libraries.

[0003] At present, the synthetic methods of α-aryl ethyl phosphonate reported in the literature include Arbuzov reaction of triethyl phosphite and aryl ethyl bromide, ZnBr 2 Promoted reaction of alcohol with triethyl phosphite, copper-catalyzed coupling reaction of diethyl phosphite and p-toluenesulfonyl hydrazone, etc. However, reduction of the carbon-carbon double bond of alkenyl phosphonate is the most straightforward synthetic method. For example, α-aryl alkenyl pho...

Examples

Embodiment 1

[0020] Add 0.3mmol of diethyl α-(4-chlorophenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium carbonate to a Schlenk reaction tube (10mL), vacuumize and release N 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then, the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(4-chlorophenyl) ethyl acetate is obtained by distillation with a rotary evaporator. Diethyl phosphonate 80.3 mg, yield 97%. T...

Embodiment 2

[0023] Add 0.3mmol of diethyl α-(3-chlorophenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium phosphate into a Schlenk reaction tube (10mL). 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then, the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(3-chlorophenyl) ethyl acetate is obtained by distillation with a rotary evaporator. Diethyl phosphonate 74.5 mg, yield 90%. The analysis data is as...

Embodiment 3

[0026] Add 0.3mmol of diethyl α-(4-methylphenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium phosphate into a Schlenk reaction tube (10mL), vacuumize and release N 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(4-methylphenyl) is obtained by distillation with a rotary evaporator. Diethyl ethylphosphonate 76.0 mg, yield 99%. The analy...

technical field

[0001] The invention relates to a method for reducing and synthesizing α-aryl ethyl phosphonate by using o-nitrobenzenesulfonyl hydrazide. Background technique

[0002] α-arylethylphosphonate is an important structural fragment of the antimalarial drug fosminomycin, which is also considered to have similar biological activities to α-arylpropionic acid compounds. Therefore, its synthesis research is of great significance for drug screening and the establishment of drug molecular libraries.

[0003] At present, the synthetic methods of α-aryl ethyl phosphonate reported in the literature include Arbuzov reaction of triethyl phosphite and aryl ethyl bromide, ZnBr 2 Promoted reaction of alcohol with triethyl phosphite, copper-catalyzed coupling reaction of diethyl phosphite and p-toluenesulfonyl hydrazone, etc. However, reduction of the carbon-carbon double bond of alkenyl phosphonate is the most straightforward synthetic method. For example, α-aryl alkenyl pho...

Examples

Embodiment 1

[0020] Add 0.3mmol of diethyl α-(4-chlorophenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium carbonate to a Schlenk reaction tube (10mL), vacuumize and release N 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then, the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(4-chlorophenyl) ethyl acetate is obtained by distillation with a rotary evaporator. Diethyl phosphonate 80.3 mg, yield 97%. T...

Embodiment 2

[0023] Add 0.3mmol of diethyl α-(3-chlorophenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium phosphate into a Schlenk reaction tube (10mL). 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then, the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(3-chlorophenyl) ethyl acetate is obtained by distillation with a rotary evaporator. Diethyl phosphonate 74.5 mg, yield 90%. The analysis data is as...

Embodiment 3

[0026] Add 0.3mmol of diethyl α-(4-methylphenyl)vinylphosphonate, 0.6mmol of o-nitrobenzenesulfonyl hydrazide, and 0.3mmol of potassium phosphate into a Schlenk reaction tube (10mL), vacuumize and release N 2 Cycle three times. in N 2 Under protection, add 2.0 mL of anhydrous acetonitrile, stir at room temperature for 5 h; after TLC confirms that the reaction is complete, add 5 mL of water to the reaction system, extract 3 times with 30 mL of ethyl acetate (10 mL*3), combine the organic phases, and wash with anhydrous sulfuric acid Sodium drying; then filter to remove sodium sulfate, and distill through a rotary evaporator to obtain an organic primary product. Then the above-mentioned organic primary product is separated by column chromatography with a mixture of petroleum ether and ethyl acetate with a volume ratio of 1:1 as an eluent, and finally α-(4-methylphenyl) is obtained by distillation with a rotary evaporator. Diethyl ethylphosphonate 76.0 mg, yield 99%. The analy...

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