CN110964059B - Beta-amino hydroxyl phosphonic derivative and preparation method thereof - Google Patents

Beta-amino hydroxyl phosphonic derivative and preparation method thereof Download PDF

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CN110964059B
CN110964059B CN201911304391.5A CN201911304391A CN110964059B CN 110964059 B CN110964059 B CN 110964059B CN 201911304391 A CN201911304391 A CN 201911304391A CN 110964059 B CN110964059 B CN 110964059B
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邹建平
应志耀
张沛之
陶泽坤
李建安
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Chinasun Specialty Products Co ltd
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
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    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
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    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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    • C07F9/40—Esters thereof
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Abstract

The invention discloses a beta-amino hydroxyl phosphonic derivative and a preparation method thereof. The invention uses olefin as the starting material, the raw materials are easy to obtain, and the variety is wide; the product obtained by the method has various types and wide application, can be directly used, and can also be used for synthesizing organic phosphine medicines; in addition, the method disclosed by the invention has the advantages of simple steps, mild reaction conditions, high yield of target products, small pollution, simple reaction operation and post-treatment process, and suitability for industrial production.

Description

Beta-amino hydroxyl phosphonic derivative and preparation method thereof
The invention relates to a beta-hydroxyiminophosphono derivative and a preparation method thereof, and relates to a divisional application with the application number of 2017108074967 and the application date of 2017, 9 and 8, and a part of a preparation method of another product.
Technical Field
The invention belongs to the technical field of preparation of organic compounds, and particularly relates to a beta-amino hydroxyl phosphonic derivative and a preparation method thereof.
Background
The nitrogen-containing organophosphorus compound has wide biological activity and important application in aspects of resisting hypercalcemia, resisting HIV virus, resisting bacteria, serving as an enzyme inhibitor and the like; in addition, β -phosphoryloxime free radical compounds can also be used as biomolecular markers (Il' yasov A.V. Phosphorus-containing imino and nitroyl free radials as conditioning spin labels).Biophysics, 2013, 58(2): 167.）。
D.M. Mizrahi et al disclose a synthetic method of beta-amino diphosphonic acid compounds, and test the inhibitory activity of the compounds on induced hypercalcemia, the results show that the compounds show good activity, and the effect is superior to that of the clinical anti-osteoporosis drug disodium chlorophosphate; however, the reaction steps of the disclosed synthetic routes of the compounds are complicated, and a strong corrosive reagent thionyl chloride is required to be used. In 2003, A, Obojska et al synthesize several beta-aminophosphonic acid derivatives and test the inhibitory activity on streptococci, and the results show that the compounds have better inhibitory activity on Streptomyces lavendulae, saccharopolyspora erythraea and the like, and in 2013, Lyzwa reports that nitrogen-containing organophosphorus compounds have the activity of inhibiting HIV protease, serine protease and the like; however, the disclosed compound synthesis method has the defects of difficult raw material availability, severe reaction conditions, more reaction steps and the like. Therefore, it is very important to develop a synthesis method with mild reaction conditions, wide application range, simple reaction steps and simple and easily-obtained raw materials.
Disclosure of Invention
The invention aims to provide a preparation methodβThe method for preparing the (E) -hydroxyiminophosphono derivatives and the related derivative products has the advantages of simple raw material source, mild reaction conditions, simple post-treatment, high yield and the like.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a preparation method of beta-hydroxyiminophosphono derivatives comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyiminophosphono derivatives.
The invention also discloses a preparation method of the beta-hydroxyiminophosphoroamidate derivatives, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyiminophosphoroamidate derivatives; the beta-hydroxyiminophosphono derivatives are prepared by taking the beta-hydroxyiminophosphono derivatives as raw materials in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide.
The invention also discloses a preparation method of the beta-hydroxyiminophosphono derivatives, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyiminophosphono derivatives; preparing a beta-hydroxyiminophosphoroamidite derivative serving as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide to obtain the beta-hydroxyiminophosphoroamidite derivative; the beta-hydroxyiminophosphorohydroxyl phosphono derivative is prepared by taking the beta-hydroxyiminophosphorohydroxyl derivative as a raw material in the presence of cesium carbonate and phosphite ester.
The invention also discloses a preparation method of the beta-amino hydroxyl phosphono derivative, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyl imido phosphono derivative; preparing a beta-hydroxyiminophosphoroamidite derivative serving as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide to obtain the beta-hydroxyiminophosphoroamidite derivative; preparing a beta-hydroxyiminohydroxyphosphonoyl derivative by taking a beta-hydroxyiminodiphosphonoyl derivative as a raw material in the presence of cesium carbonate and phosphite ester; preparing a beta-amino hydroxyl phosphonic derivative by taking a beta-hydroxyl imino hydroxyl phosphonic derivative as a raw material under nickel catalysis and alkaline conditions;
the invention also discloses a preparation method of the beta-amino phosphoric acid derivative, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyimino phosphono derivative; preparing a beta-hydroxyiminophosphoroamidite derivative serving as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide to obtain the beta-hydroxyiminophosphoroamidite derivative; preparing a beta-hydroxyiminohydroxyphosphonoyl derivative by taking a beta-hydroxyiminodiphosphonoyl derivative as a raw material in the presence of cesium carbonate and phosphite ester; preparing a beta-amino hydroxyl phosphonic derivative by taking a beta-hydroxyl imino hydroxyl phosphonic derivative as a raw material under nickel catalysis and alkaline conditions; beta-aminophosphonic acid derivatives are taken as raw materials to prepare the beta-aminophosphonic acid derivatives in the presence of hydrochloric acid.
The invention also discloses a preparation method of the beta-phosphoryl oxime free radical compound, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyimino phosphono derivatives; beta-hydroxyiminophosphono derivatives are used as raw materials, and are irradiated by an ultraviolet lamp to react in the presence of 2-methyl-2-nitropropane, so that a beta-phosphoryloxime free radical compound is obtained.
In the present invention, the olefin is represented by the following general chemical structure:
Figure 64816DEST_PATH_IMAGE001
、
Figure 716377DEST_PATH_IMAGE002
wherein R is selected from one of alkyl, N-alkyl phthalimide group, aryl alkyl, ethyl acetate group and ethoxy formyl group; x is selected from one of alkyl, aryl and hydrogen; ar is represented by the following chemical structural general formula:
Figure 27273DEST_PATH_IMAGE003
、
Figure 219219DEST_PATH_IMAGE004
、
Figure 564750DEST_PATH_IMAGE005
wherein R is1One selected from alkyl, alkoxy, aryl, halogen, nitro, cyano and ester group; y is selected from O, S, N; r2Is selected from one of alkyl, alkoxy and halogen.
In the present invention, the phosphorus reagent is represented by the following general structural formula:
Figure 121633DEST_PATH_IMAGE006
wherein R is3One selected from alkoxy or aryl.
In the invention, the chemical formula of the silver catalyst is AgX, wherein X is NO3、CO3And OAc.
In the present invention, the solvent is selected from: methanol, ethanol, acetonitrile, acetone, water or N, N-dimethylformyl.
In the invention, the beta-hydroxyiminophosphono derivatives are shown as the following chemical structural general formula:
Figure 185404DEST_PATH_IMAGE007
or
Figure 915463DEST_PATH_IMAGE008
。
In the invention, the beta-hydroxyiminodiphosphonic acid derivative is shown as the following chemical structural general formula:
Figure 318762DEST_PATH_IMAGE009
or
Figure 843285DEST_PATH_IMAGE010
In the invention, the beta-hydroxyiminohydroxyphosphonoyl derivatives are shown as the following chemical structural general formula:
Figure 394352DEST_PATH_IMAGE011
or
Figure 662522DEST_PATH_IMAGE012
In the invention, the beta-amino hydroxyl phosphonic acid derivative is shown as the following chemical structural general formula:
Figure 920328DEST_PATH_IMAGE013
or
Figure 146910DEST_PATH_IMAGE014
In the invention, the beta-aminophosphonic acid derivative is shown as the following chemical structural general formula:
Figure 922624DEST_PATH_IMAGE015
or
Figure 932168DEST_PATH_IMAGE016
In the invention, the beta-phosphoryl oxime free radical compound is shown as the following chemical structural general formula:
Figure 106797DEST_PATH_IMAGE017
or
Figure 238701DEST_PATH_IMAGE018
。
In the above technical solution, the olefin is selected from: one of styrene, 2-methylstyrene, 4-methylstyrene, 2-methoxystyrene, 3-methoxystyrene, 4-nitrostyrene, 4-cyanostyrene, 4-fluorostyrene, 4-bromostyrene, 4-chlorostyrene, 3-chlorostyrene, 2, 6-dichlorostyrene, beta-methylstyrene, 2-naphthylethylene, benzocyclobutene, alpha-cyclohexenone, 2-vinylpyridine, 4-vinylpyridine, N-alkenylbutylphthalimide, N-vinylphthalimide, 4-phenylbutene, ethyl acrylate, and ethyl 4-ethoxyformylpent-1-enoate; the phosphorus reagent is selected from: one of dimethyl phosphite, diethyl phosphite, diphenyl phosphine oxide, bis (4-methoxyphenyl) phosphine oxide and bis (4-cyanophenyl) phosphine oxide.
In the above technical scheme, the reaction is followed by Thin Layer Chromatography (TLC) until complete completion.
In the technical scheme, the mol ratio of the olefin, the phosphorus reagent, the tert-butyl nitrite and the silver catalyst is 1: 1-3: 0.1-0.3.
In the technical scheme, after the reaction is finished, the product is subjected to column chromatography separation and purification treatment.
The reaction process of the above technical scheme can be expressed as follows:
Figure 498782DEST_PATH_IMAGE019
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention uses olefin as the starting material, and has the advantages of easily obtained raw materials, low toxicity, low cost and various types.
2. The invention has wide application range, is not only suitable for aryl olefin, but also suitable for common alkyl olefin.
3. The tert-butyl nitrite used in the invention is easy to obtain and low in cost.
4. The method disclosed by the invention has the advantages of mild reaction conditions, short reaction time, high yield of target products, simple reaction operation and post-treatment process, and suitability for industrial production.
Detailed Description
The invention is further described below with reference to the following examples:
the first embodiment is as follows: synthesis of 2-phenyl-2-hydroxyiminoethyl diphenylphosphine
Styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 108754DEST_PATH_IMAGE020
styrene (0.042 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), methanol (2.5 mL) are added into a reaction bottle for reaction at 10 ℃;
Figure 137890DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 440696DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 80%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.47 (s, 1H), 7.80 – 7.73 (m, 4H), 7.65 – 7.55 (m, 2H), 7.57 – 7.51 (m, 2H), 7.50 –7.45(m, 4H), 7.32 – 7.25 (m, 3H), 4.11 (d, J = 15.4 Hz, 2H)。
example two: synthesis of 2- (2-methylphenyl) -2-hydroxyiminoethyldiphenylphosphine
2-methyl styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 922493DEST_PATH_IMAGE020
2-methylstyrene (0.047 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver nitrate (0.14g, 0.08 mmol), ethanol (2.5 mL) are added into a reaction bottle to react at room temperature;
Figure 539419DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 219799DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 75%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 7.80 – 7.71 (m, 4H), 7.53 – 7.37 (m, 6H), 7.12 – 6.97 (m, 4H), 3.78 (d, J = 11.0 Hz, 2H), 2.07 (s, 3H)。
example three: synthesis of 2- (4-methylphenyl) -2-hydroxyiminoethyldiphenylphosphine
4-methyl styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 896768DEST_PATH_IMAGE020
4-methylstyrene (0.047 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.21g, 0.12 mmol), acetonitrile (2.5 mL) are added into a reaction flask to react at 30 ℃;
Figure 131440DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 83215DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.37 (s, 1H), 7.81 – 7.72 (m, 4H), 7.55 – 7.47 (m, 8H), 7.08 (d, J = 7.5 Hz, 2H), 4.08 (d, J = 15.4 Hz, 2H), 2.28 (s, 3H)。
example four: synthesis of 2- (2-methoxyphenyl) -2-hydroxyiminoethyl diphenylphosphine
2-methoxy styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 86944DEST_PATH_IMAGE020
2-methoxystyrene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver carbonate (0.01g, 0.04 mmol), acetone (2.5 mL) are added into a reaction bottle to react at 40 ℃;
Figure 934814DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 391203DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 72%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.38 (s, 1H), 7.75 – 7.59 (m, 4H), 7.54-7.49 (m, 2H), 7.41-7.50(m, 4H), 7.29 – 7.14 (m, 1H), 6.97-6.91 (m, 1H), 6.86 – 6.71 (m, 2H), 4.13 (d, J = 14.9 Hz, 2H), 3.67 (s, 3H)。
example five: synthesis of 2- (3-methoxyphenyl) -2-hydroxyiminoethyl diphenylphosphine
3-methoxy styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 412249DEST_PATH_IMAGE020
3-methoxystyrene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver carbonate (0.02g, 0.08 mmol), water (2.5 mL) are added into a reaction bottle to react at 50 ℃;
Figure 4904DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 23676DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.54 (s, 1H), 7.85 – 7.74 (m, 4H), 7.65 – 7.41 (m, 6H), 7.30 – 7.12 (m, 3H), 6.90 (d, J = 7.4 Hz, 1H), 4.13 (d, J = 15.4 Hz, 2H), 3.72 (s, 3H)。
example six: synthesis of 2- (4-methoxyphenyl) -2-hydroxyiminoethyl diphenylphosphine
4-methoxy styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 964431DEST_PATH_IMAGE020
4-methoxystyrene (0.054 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver carbonate (0.01g, 0.04 mmol), N, N-dimethylformamide (2.5 mL) are added into a reaction flask, and the reaction is carried out at 50 ℃;
Figure 789168DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 705171DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 83%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.28 (s, 1H), 7.77 (s, 4H), 7.52 (d, J = 31.1 Hz, 8H), 6.83 (d, J = 5.3 Hz, 2H), 4.07 (d, J= 14.6 Hz, 2H), 3.75 (s, 3H)。
example seven: synthesis of 2- (4-nitrophenyl) -2-hydroxyiminoethyl diphenylphosphine
4-nitrostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 426002DEST_PATH_IMAGE020
4-Nitrostyrene (0.060 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver acetate (0.007g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction flask and reacted at room temperature;
Figure 122563DEST_PATH_IMAGE021
TLC follow-up reactionUntil the completion;
Figure 219832DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 87%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 12.08 (s, 1H), 8.13 (d, J = 7.5 Hz, 2H), 7.92 (d, J = 7.5 Hz, 2H), 7.79 (d, J = 8.6 Hz, 4H), 7.55 – 7.42 (m, 6H), 4.25 (d, J = 14.8 Hz, 2H)。
example eight: synthesis of 2- (4-cyanophenyl) -2-hydroxyiminoethyldiphenylphosphine
4-cyanostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 255921DEST_PATH_IMAGE020
4-cyanostyrene (0.052 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver acetate (0.014g, 0.08 mmol), N, N-dimethylformamide (2.5 mL) were charged into a reaction flask and reacted at 50 ℃;
Figure 147654DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 331510DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 88%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.94 (s, 1H), 7.86-7.77 (m, 8H), 7.64 – 7.54 (m, 2H), 7.53-7.50 (m, J = 3.5 Hz, 4H), 4.21 (d, J = 15.2 Hz, 2H)。
example nine: synthesis of 2- (4-fluorophenyl) -2-hydroxyiminoethyl diphenylphosphine
4-fluorostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 232470DEST_PATH_IMAGE020
4-fluorostyrene (0.049 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver acetate (0.007g, 0.04 mmol), N, N-dimethylformamide (2.5 mL) are added into a reaction flask to react at 50 ℃;
Figure 857487DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 451279DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.57 (s, 1H), 7.84-7.78 (m, 4H), 7.73-7.68( m, 2H), 7.58-7.54 (m, 2H), 7.51 (d, J = 5.4 Hz, 4H), 4.17 (d, J = 15.3 Hz, 2H)。
example ten: synthesis of 2- (4-bromophenyl) -2-hydroxyiminoethyl diphenylphosphine
4-bromostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 591273DEST_PATH_IMAGE020
4-bromostyrene (0.073 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 499187DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 41026DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 79%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.60 (s, 1H), 7.79-7.72( m, 4H), 7.59-7.52 (m, 4H), 7.51-7.45 (m, 6H), 4.12 (d, J = 15.3 Hz, 2H)。
example eleven: synthesis of 2- (4-chlorphenyl) -2-hydroxyiminoethyl diphenoxy phosphate
4-chlorostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 805720DEST_PATH_IMAGE020
4-chlorostyrene (0.055 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction flask and reacted at 50 ℃;
Figure 636273DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 879035DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.61 (s, 1H), 7.79-7.73(m, 4H), 7.64 (d, J = 8.5 Hz, 2H), 7.58 – 7.42 (m, 6H), 7.34 (d, J = 8.5 Hz, 2H), 4.12 (d, J = 15.3 Hz, 2H)。
example twelve: synthesis of 2- (3-chlorphenyl) -2-hydroxyiminoethyl diphenoxy phosphate
3-chlorostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 540961DEST_PATH_IMAGE020
3-chlorostyrene (0.055 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver nitrate (0.14g, 0.08 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction flask and reacted at 40 ℃;
Figure 210976DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 528825DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.94 (s, 1H), 7.83–7.77 (m, 4H), 7.48–7.35 (m 8H), 7.18 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 4.01 (d, J = 15.1 Hz, 2H)。
example thirteen: synthesis of 2- (2-chlorphenyl) -2-hydroxyiminoethyl diphenoxy phosphate
2-chlorostyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 309700DEST_PATH_IMAGE020
2-chlorostyrene (0.055 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction flask and reacted at 30 ℃;
Figure 94640DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 935557DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 70%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.09 (s, 1H), 7.82 (s, 4H), 7.50 (d, J = 14.9 Hz, 6H), 7.36 (d, J = 6.8 Hz, 1H), 7.28–7.20 (m, 3H), 3.82 (d, J = 10.3 Hz, 2H)。
example fourteen: synthesis of 2- (2, 6-dichlorophenyl) -2-hydroxyiminoethyl diphenylphosphine
The method takes 2, 6-dichlorostyrene and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
Figure 740702DEST_PATH_IMAGE020
2, 6-dichlorostyrene (0.069 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction flask and reacted at room temperature;
Figure 590847DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 961785DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 71%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.38 (s, 1H), 7.92 – 7.77 (m, 4H), 7.59 – 7.46 (m, 6H), 7.45 – 7.39 (m, 2H), 7.38–7.32(m, 1H), 3.79 (d, J = 13.3 Hz, 2H)。
example fifteen: synthesis of 1-methyl-2-phenyl-2-hydroxyiminoethyl diphenylphosphine
Beta-methylstyrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 176866DEST_PATH_IMAGE020
adding beta-methylstyrene (0.047 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver nitrate (0.14g, 0.08 mmol), water (1 mL) and ethanol (1.5 mL) into a reaction flask, and reacting at 10 ℃;
Figure 465DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 654301DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 74%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.78 (s, 1H), 8.08 – 7.94 (m, 2H), 7.91 (d, J = 3.9 Hz, 2H), 7.83 – 7.73 (m, 2H), 7.65 (s, 3H), 7.53 – 7.45 (m, 1H), 7.44–7.36 (m, 5H), 5.07 – 4.94 (m, 1H), 1.24 (dd, J= 15.5, 7.1 Hz, 3H)。
example sixteen: synthesis of 2- (2-naphthyl) -2-hydroxyiminoethyl diphenylphosphine
2-vinyl naphthalene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 879746DEST_PATH_IMAGE020
2-vinyl naphthalene (0.062 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (2.5 mL) are added into a reaction bottle and reacted at 10 ℃;
Figure 265728DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 107782DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 80%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.65 (s, 1H), 8.07 (d, J = 20.6 Hz, 1H), 7.92 – 7.73 (m, 8H), 7.62 – 7.41 (m, 8H), 4.28 (d, J = 15.2 Hz, 2H)。
example seventeen: synthesis of 2-diphenylphosphoryl benzocyclohex-1-one oxime
1, 2-dihydronaphthalene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 34149DEST_PATH_IMAGE020
1, 2-dihydronaphthalene (0.052 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) are added into a reaction bottle and reacted at room temperature;
Figure 317363DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 936563DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 77%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.18 (s, 1H), 8.07 – 7.90 (m, 2H), 7.72 – 7.66 (m, 3H), 7.64 – 7.56 (m, 3H), 7.47 – 7.44 (m, 1H), 7.39 – 7.34 (m, 2H), 7.26 – 7.22 (m, 1H), 7.16 – 7.10 (m, 2H), 4.84 – 4.75 (m, 1H), 3.54 – 3.35 (m, 2H), 2.65 – 2.55 (m, 1H), 2.33 – 2.04 (m, 1H)。
example eighteen: synthesis of 2- (2-furyl) -2-hydroxyiminoethyl diphenylphosphine
2-vinyl furan and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 334DEST_PATH_IMAGE020
2-vinyl furan (0.038 g, 0.4 mmol), phosphorus diphenoxylate (0.162 g, 0.8 mmol), tert-butyl nitrite (0.082 g, 0.8 mmol), silver nitrate (0.14g, 0.08 mmol), water (2.5 mL) are added into a reaction bottle for reaction at 50 ℃;
Figure 730393DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 868113DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 77%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.75 (s, 1H), 7.78 – 7.72 (m, 4H), 7.53 – 7.47 (m, 7H), 6.36-6.30 (m, 1H), 6.13-6.09 (m, 1H), 4.30 (d, J = 7.8 Hz, 2H)。
example nineteenth: synthesis of 2- (2-pyridyl) -2-hydroxyiminoethyldiphenylphosphine
2-vinylpyridine and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 923794DEST_PATH_IMAGE020
2-vinylpyridine (0.042 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol) were added to the reaction flask) Ethanol (2.5 mL), 50 ℃;
Figure 209282DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 680714DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 75%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.75 (s, 1H), 8.39 (s, 1H), 7.53 (t, J = 93.9 Hz, 13H), 4.30 (d, J = 7.8 Hz, 2H)。
example twenty: synthesis of 2- (4-pyridyl) -2-hydroxyiminoethyldiphenylphosphine
4-vinylpyridine and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 735258DEST_PATH_IMAGE020
4-vinylpyridine (0.042 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 696261DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 212255DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 73%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.98 (s, 1H), 8.51 (d, J = 4.5 Hz, 2H), 7.84–7.77 (m, 4H), 7.63–7.56 (m, 4H), 7.52 (t, J = 5.8 Hz, 4H), 4.18 (d, J = 15.2 Hz, 2H)。
example twenty one: synthesis of N- (4-diphenylphosphoryl-3-hydroxyiminobutyl) phthalimide
N-alkene butyl phthalimide and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 549695DEST_PATH_IMAGE020
adding N-alkene butyl phthalimide (0.080 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.07g, 0.04 mmol), ethanol (2.5 mL) into a reaction bottle, and reacting at 40 ℃;
Figure 724324DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 590649DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 70%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.81 (s, 1H), 7.87–7.77 (m, 8H), 7.60–7.48 (m, 6H), 3.80 (t, J = 6.5 Hz, 2H), 3.71 (d, J = 14.7 Hz, 2H), 2.62 (d, J = 5.3 Hz, 2H)。
example twenty two: synthesis of N- (2-diphenyl phosphoryl-1-hydroxyimino ethyl) phthalimide
The method takes N-vinyl phthalimide and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
Figure 53992DEST_PATH_IMAGE020
n-vinyl phthalimide (0.069 g, 0.4 mmol) and phosphorus diphenoxylate (0.08 mmol) were added to the reaction flask1g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), ethanol (2.5 mL), at 30 ℃;
Figure 663965DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 958680DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 71%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.98 (s, 1H), 11.72 (s, 0.7H), 7.86 (d, J = 17.7 Hz, 7H), 7.81 – 7.67 (m, 7H), 7.52 – 7.38 (m, 10H), 4.04 (d, J = 14.1 Hz, 2H), 3.88 (d, J = 13.0 Hz, 1.4H)。
example twenty three: synthesis of 4-phenyl-2-hydroxyiminobutyldiphenylphosphine
Taking alkene butyl benzene and diphenyl phosphine oxide as raw materials, and the reaction steps are as follows:
Figure 995906DEST_PATH_IMAGE020
charging alkene butylbenzene (0.053 g, 0.4 mmol), phosphorus diphenoxylate (0.243 g, 1.2 mmol), tert-butyl nitrite (0.123 g, 1.2 mmol), silver nitrate (0.07g, 0.04 mmol), ethanol (2.5 mL) into a reaction flask, and reacting at room temperature;
Figure 743282DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 156946DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 82%). Analytical data of the productThe following were used:1H NMR (400 MHz, CDCl3): δ 10.75 (s, 0.3H), 10.73 (s, 1H), 7.92 – 7.74 (m, 5H), 7.64 – 7.42 (m, 8H), 7.33 – 7.19 (m, 2.5H), 7.18–7.09 (m, 4H), 3.72 (d, J = 15.0 Hz, 0.6H), 3.46 (d, J = 13.7 Hz, 2H), 2.83 – 2.68 (m, 2.6H), 2.59–2.54 (m, 2.6H)。
example twenty-four: synthesis of 3-diphenyl phosphoryl-2-hydroxyimino ethyl propionate
The method takes ethyl acrylate and diphenyl phosphine oxide as raw materials, and comprises the following reaction steps:
Figure 243850DEST_PATH_IMAGE020
adding ethyl acrylate (0.040 g, 0.4 mmol), phosphorus diphenoxylate (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) into a reaction bottle, and reacting at room temperature;
Figure 717557DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 686650DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 81%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 13.06 (s, 1H), 7.87–7.82 (m, 4H), 7.57 – 7.47 (m, 2H), 7.47 – 7.35 (m, 4H), 4.06 (q, J = 7.1 Hz, 2H), 3.93 (d, J = 14.9 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H)。
example twenty-five: synthesis of 2- (3-diphenylphosphoryl-2-hydroxyiminopropyl) diethyl malonate
Taking 2-allyl diethyl malonate and diphenyl phosphine oxide as raw materials, and the reaction steps are as follows:
Figure 904005DEST_PATH_IMAGE020
diethyl 2-allylmalonate (0.080 g, 0.4 mmol), diphenylphosphine (0.081 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 907733DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 490024DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 76%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 7.96 – 7.74 (m, 4H), 7.57 – 7.36 (m, 6H), 4.17 – 3.98 (m, 4H), 3.77 (t, J = 7.5 Hz, 1H), 3.61 (d, J = 14.9 Hz, 2H), 2.92 (dd, J = 7.5, 2.0 Hz, 2H), 1.16 (t, J = 7.1 Hz, 6H)。
example twenty-six: synthesis of 2- (2-pyridyl) -2-hydroxyiminoethyl diethyl phosphite
2-vinylpyridine and diethyl phosphite are used as raw materials, and the reaction steps are as follows:
Figure 211992DEST_PATH_IMAGE020
2-vinylpyridine (0.042 g, 0.4 mmol), diethyl phosphite (0.055 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), acetone (2.5 mL) were added to the reaction flask and reacted at room temperature;
Figure 967459DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 28956DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective product (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.93 (s, 1H), 8.62 (t, J = 6.8 Hz, 1H), 7.86 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 4.4 Hz, 1H), 3.99 – 3.92 (m, 4H), 3.66 (d, J = 23.3 Hz, 2H), 1.13 (t, J = 7.0 Hz, 6H)。
example twenty-seven: synthesis of 3-phosphoric acid diisopropyl propionaldehyde-2-ketoxime free radical (A)
Figure 110044DEST_PATH_IMAGE024
Acrolein and diisopropyl phosphite ester are used as raw materials, and the reaction steps are as follows:
Figure 56659DEST_PATH_IMAGE020
acrolein (0.022 g, 0.4 mmol), diisopropyl phosphite (0.066 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 553499DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 266241DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 29 (yield 73%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.91 (s, 1H), 8.92 (s, 1H), 3.99 – 3.92 (m, 2H), 3.66 (d, J = 19.3 Hz, 2H), 1.33 (d, J = 7.0 Hz, 12H)。
compound 29 and 2-methyl-2-nitropropane were added to a quartz glass tube, and then irradiated with an ultraviolet lamp to obtain compound a.
Example twenty-eight: synthesis of 1-hydroxy-2-amino-3-phenylpropyl diphosphate (B1)
Figure 518230DEST_PATH_IMAGE026
Allyl benzene and diethyl phosphite ester are used as raw materials, and the reaction steps are as follows:
(1) allyl benzene (0.053 g, 0.4 mmol), diethyl phosphite (0.055 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 30-1 (yield 71%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 3.99 – 3.92 (m, 4H), 3.63 (d, J = 23.3 Hz, 2H), 3.46 (s, 2H), 1.13 (t, J = 7.0 Hz, 6H)；
(4) 30-1 (0.285 g, 1 mmol), triethyl phosphite (0.498 g, 7 mmol), cuprous trifluoromethanesulfonate (0.021 g, 0.1 mmol), di-tert-butyl peroxide (1.022 g, 7 mmol) and N, N-dimethylformamide (5 mL) were charged into a reaction flask and reacted at 80 ℃ until completion. 20 mL of water was added, extracted with ethyl acetate, dried, concentrated, and the crude product was isolated by column chromatography (ethyl acetate: petroleum ether = 1:1) to give the objective compound 30-2 (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 3.99 – 3.87 (m, 9H), 3.46 (s, 2H), 1.13 – 1.07 (m, 12H)；
(5) cesium carbonate (0.033 g, 0.1 mmol), triethyl phosphite (0.167 g, 1.0 mmol), 30-2 (0.210 g, 0.5 mmol) and dimethyl sulfoxide (2.0 mL) were charged into a reaction flask, and the reaction was stirred at room temperature under an oxygen atmosphere for 24 hours. After completion of the reaction, 20 mL of saturated brine was added to the reaction system, and the mixture was extracted with ethyl acetate (3X 5 mL) and dried over anhydrous Na2SO4Drying, distilling, concentrating, and separating the crude product by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 30-3 (yield 80%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 4.16 (s, 1H), 3.99 – 3.87 (m, 8H), 3.46 (s, 2H), 1.13 – 1.07 (m, 12H)；
(6) adding 2 mL of methanol solution of nickel (0.058 g, 0.1 mmol) and compound 30-3 (0.437 g, 1 mmol) into a reaction flask, dropwise adding sodium hydroxide solution (2 mL, 5.0M) and sodium borohydride (0.12 g, 3 mmol) methanol solution (2 mL) into the solution at room temperature, reacting for 3 hours at room temperature after dropwise adding, filtering, neutralizing the solution with concentrated hydrochloric acid until the pH is approximately equal to 9, extracting with ethyl acetate (3X 5 mL), and adding anhydrous Na2SO4Drying, distillation, concentration, and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 30-4 (80% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 7.64 – 7.42 (m, 5H), 4.16 (s, 1H), 3.99 – 3.87 (m, 8H), 3.46 (s, 2H), 1.61 (s, 2H), 1.13 – 1.07 (m, 12H)；
(7) 30-4 (0.423 g, 1 mmol) and concentrated hydrochloric acid (20 mL) were added to a reaction flask, and after heating and refluxing to completion of the reaction, 50 mL of water was added, extracted with dichloromethane, concentrated, dried, and the crude product was recrystallized from ethanol/water to give the desired product B1 (84% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 7.64 – 7.42 (m, 5H), 4.81 (s, 4H), 4.16 (s, 1H), 3.46 (s, 2H), 1.61 (s, 2H)。
example twenty-nine: synthesis of 1-hydroxy-2-amino-4-methylpentyl diphosphate (B2)
Figure 152474DEST_PATH_IMAGE028
4-methylpentene and diethyl phosphite ester are used as raw materials, and the reaction steps are as follows:
(1) 4-methylpentene (0.034 g, 0.4 mmol), diethyl phosphite (0.055 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 31-1 (yield 72%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 4.19 – 4.02 (m, 4H), 3.63 (d, J = 23.3 Hz, 2H), 3.46 (d, J = 7.0 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.13 (t, J = 7.0 Hz, 6H), 0.94 (d, J = 6.8 Hz, 6H)；
(4) 31-1 (0.251 g, 1 mmol), triethyl phosphite (0.498 g, 7 mmol), cuprous trifluoromethanesulfonate (0.021 g, 0.1 mmol), di-t-butyl peroxide (1.022 g, 7 mmol) and N, N-dimethylformamide (5 mL) were charged into a reaction flask and reacted at 80 ℃ until completion. 20 mL of water was added, extracted with ethyl acetate, dried, concentrated, and the crude product was isolated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the objective compound 31-2 (yield 80%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.23 (s, 1H), 4.19 – 3.97 (m, 8H), 3.63 (d, J= 23.3 Hz, 1H), 3.46 (d, J = 7.0 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.17 – 1.03 (m, 12H), 0.94 (d, J = 6.8 Hz, 6H)；
(5) cesium carbonate (0.033 g, 0.1 mmol), triethyl phosphite (0.167 g, 1.0 mmol), 31-2 (0.194 g, 0.5 mmol) and dimethyl sulfoxide (2.0 mL) were charged into a reaction flask, and the reaction was stirred at room temperature under an oxygen atmosphere for 24 hours. After the reaction, 20 mL of saturated food was added to the systemBrine, ethyl acetate extraction (3X 5 mL), anhydrous Na2SO4Drying, distillation, concentration and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 31-3 (80% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 10.93 (s, 1H), 4.19 – 3.97 (m, 9H), 3.46 (d, J = 7.0 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.17 – 1.03 (m, 12H), 0.94 (d, J = 6.8 Hz, 6H)；
(6) adding 2 mL of methanol solution of nickel (0.058 g, 0.1 mmol) and a compound 31-3 (0.403 g, 1 mmol) into a reaction flask, dropwise adding sodium hydroxide solution (2 mL, 5.0M) and sodium borohydride (0.12 g, 3 mmol) methanol solution (2 mL) into the solution at room temperature, reacting for 3 hours at room temperature after dropwise adding for 2 hours, filtering, neutralizing the solution with concentrated hydrochloric acid until the pH is approximately equal to 9, extracting with ethyl acetate (3X 5 mL), and adding anhydrous Na2SO4Drying, distillation, concentration and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 31-4 (yield 70%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 4.19 – 3.97 (m, 9H), 3.73 – 3.67 (m, 1H), 3.46 (dd, J = 7.0, 6.8 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.61 (s, 2H), 1.17 – 1.03 (m, 12H), 0.94 (d, J= 6.8 Hz, 6H)；
(7) 31-4 (0.389 g, 1 mmol) and concentrated hydrochloric acid (20 mL) were added to a reaction flask, and after heating and refluxing to completion, 50 mL of water was added, extraction was performed with dichloromethane, concentration, drying, and the crude product was recrystallized from ethanol/water to give the desired product B2 (74% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 4.16 (s, 1H), 3.73 – 3.67 (m, 1H), 3.46 (dd, J = 7.0, 6.8 Hz, 2H), 1.79 – 1.70 (m, 1H), 1.61 (s, 2H), 0.94 (d, J = 6.8 Hz, 6H)。
example thirty: synthesis of 2-amino-3-phosphopropionic acid (C1) and 2-amino-3-phosphopropionamide (C2)
Figure 249743DEST_PATH_IMAGE030
Taking ethyl acrylate and diethyl phosphite ester as raw materials, and the reaction steps are as follows:
(1) a reaction flask was charged with ethyl acrylate (0.040 g, 0.4 mmol), diethyl phosphite (0.055 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) and reacted at room temperature;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 32-1 (yield 71%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 3.99 – 3.87 (m, 6H), 3.63 (d, J = 23.3 Hz, 2H), 1.16 – 1.03 (m, 9H)；
(4) adding 2 mL of methanol solution added with nickel (0.058 g, 0.1 mmol) and compound 32-1 (0.267 g, 1 mmol) into a reaction flask, dropwise adding sodium hydroxide solution (2 mL, 5.0M) and sodium borohydride (0.12 g, 3 mmol) methanol solution (2 mL) into the solution at room temperature, reacting for 3 hours at room temperature, filtering, neutralizing the solution with concentrated hydrochloric acid until the pH is approximately equal to 9, extracting with ethyl acetate (3X 5 mL), and adding anhydrous Na2SO4Drying, distillation, concentration and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 32-2 (80% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 3.99 – 3.87 (m, 7H), 3.63 (dd, J = 23.3, 7.0 Hz, 2H), 1.61 (s, 2H), 1.16 – 1.03 (m, 9H)；
(5) 32-2 (0.253 g, 1 mmol) and concentrated hydrochloric acid (20 mL) were added to a reaction flask, and after heating and refluxing to completion, 50 mL of water was added, extracted with dichloromethane, concentrated, dried, and the crude product was recrystallized from ethanol/water to give the desired product C1 (84% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 16.90 (s, 1H), 8.76 (s, 2H), 4.80 (s, 2H), 3.63 (dd, J = 23.3, 6.8 Hz, 2H), 3.46-3.39 (m, 1H)；
(6) compound C1 (0.169 g, 1 mmol), aqueous ammonia (1 mmol) and methanol (0.5 mL) were added to a reaction flask, stirred at room temperature until the reaction was complete, concentrated, dried and the crude product recrystallized from ethanol/water to give the desired product C2 (74% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 8.77 (s, 2H), 7.23 (s, 2H), 4.80 (s, 2H), 3.63 (dd, J = 23.3, 6.8 Hz, 2H), 3.46-3.39 (m, 1H)。
example thirty one: synthesis of 1-hydroxy-2-amino-2-phenylethyldiphosphonic acid (34-5)
Figure DEST_PATH_IMAGE031
Styrene and diethyl phosphite ester are used as raw materials, and the reaction steps are as follows:
(1) styrene (0.042 g, 0.4 mmol), diethyl phosphite (0.055 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
(2) TLC tracing the reaction until the reaction is completely finished;
(3) the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 34-1 (yield 78%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 3.99 – 3.92 (m, 4H), 3.63 (d, J = 23.3 Hz, 2H), 1.13 (t, J = 7.0 Hz, 6H)；
(4) a reaction flask was charged with 34-1 (0.271 g, 1 mmol), triethyl phosphite (0.498 g, 7 mmol), cuprous trifluoromethanesulfonate (0.021 g, 0.1 mmol), di-t-butyl peroxide (1.022 g, 7 mmol) and N, N-dimethylformamide (5 mL), and the reaction was completed at 80 ℃. Adding 20 mL of water, extracting with ethyl acetate, drying, concentrating, and separating the crude product by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the target compound34-2 (78% yield). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 3.99 – 3.87 (m, 9H), 1.13 – 1.07 (m, 12H)；
(5) cesium carbonate (0.033 g, 0.1 mmol), triethyl phosphite (0.167 g, 1.0 mmol), 34-2 (0.235 g, 0.5 mmol) and dimethyl sulfoxide (2.0 mL) were charged into a reaction flask, and the reaction was stirred at room temperature under an oxygen atmosphere for 24 hours. After completion of the reaction, 20 mL of saturated brine was added to the reaction system, and the mixture was extracted with ethyl acetate (5 mL. times.3) and anhydrous Na2SO4Drying, distillation, concentration and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 34-3 (80% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 10.73 (s, 1H), 7.64 – 7.42 (m, 5H), 4.16 (s, 1H), 3.99 – 3.87 (m, 8H), 1.13 – 1.07 (m, 12H)；
(6) adding 2 mL of methanol solution of nickel (0.058 g, 0.1 mmol) and compound 34-3 (0.423 g, 1 mmol) into a reaction flask, dropwise adding sodium hydroxide solution (2 mL, 5.0M) and sodium borohydride (0.12 g, 3 mmol) methanol solution (2 mL) into the solution at room temperature, reacting for 3 hours at room temperature after dropwise adding, filtering, neutralizing the solution with concentrated hydrochloric acid until the pH is approximately equal to 9, extracting with ethyl acetate (3X 5 mL), and adding anhydrous Na2SO4Drying, distillation, concentration and column chromatography of the crude product (ethyl acetate: petroleum ether = 1:1) gave compound 34-4 (80% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 7.64 – 7.42 (m, 5H), 4.16 (s, 1H), 3.99 – 3.87 (m, 8H), 1.61 (s, 2H), 1.13 – 1.07 (m, 12H)；
(7) 34-4 (0.423 g, 1 mmol) and concentrated hydrochloric acid (20 mL) are added into a reaction flask, and after the reaction is completed by heating and refluxing, 50 mL of water is added, and the mixture is extracted with dichloromethane, concentrated, dried, and the crude product is recrystallized with ethanol/water to obtain the target product 34-5 (yield 84%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3): δ 7.64 – 7.42 (m, 5H), 4.81 (s, 4H), 4.16 (s, 1H), 1.61 (s, 2H)。
example thirty-two: synthesis of 1-phosphodiisopropoxypeptyl-2-ketoxime free radical (35-2)
Figure 816991DEST_PATH_IMAGE032
Heptene and diisopropyl phosphite ester are used as raw materials, and the reaction steps are as follows:
Figure 974302DEST_PATH_IMAGE020
heptene (0.039 g, 0.4 mmol), diisopropyl phosphite (0.066 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 158159DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 793540DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 35-1 (yield 79%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.91 (s, 1H), 3.99 – 3.92 (m, 2H), 3.66 (d, J = 19.3 Hz, 2H), 3.08 (t, J = 4.7 Hz, 2H), 1.41 – 1.20 (m, 18H), 0.85 (t, J = 6.9 Hz, 3H);
compound 35-1 and 2-methyl-2-nitropropane were added to a quartz glass tube, and then irradiated with an ultraviolet lamp to obtain compound 35-2.
Example thirty-six: synthesis of 1-diisoproply-propylphenyl ethyl ketoxime phosphate free radical (36-2)
Styrene is used as a raw material, and the styrene is used as a raw material,
Figure DEST_PATH_IMAGE033
styrene and diisopropyl phosphite ester are used as raw materials, and the reaction steps are as follows:
Figure 480873DEST_PATH_IMAGE020
styrene (0.042 g, 0.4 mmol), diisopropyl phosphite (0.066 g, 0.4 mmol), tert-butyl nitrite (0.041 g, 0.4 mmol), silver nitrate (0.07g, 0.04 mmol), water (1 mL) and ethanol (1.5 mL) were added to a reaction flask and reacted at room temperature;
Figure 809086DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 152343DEST_PATH_IMAGE022
the crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound 36-1 (yield 75%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3): δ 11.91 (s, 1H), 7.61 – 7.41. (m, 5H), 3.99 – 3.92 (m, 2H), 3.66 (d, J = 19.3 Hz, 2H), 1.33 (d, J = 7.0 Hz, 12H)；
compound 36-1 and 2-methyl-2-nitropropane were added to a quartz glass tube, and then irradiated with an ultraviolet lamp to obtain compound 36-2.

Claims (3)

1. A preparation method of beta-amino hydroxyl phosphono derivatives comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, and reacting at 10-50 ℃ to obtain the beta-hydroxyl imido phosphono derivatives; preparing a beta-hydroxyiminophosphoroamidite derivative serving as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide to obtain the beta-hydroxyiminophosphoroamidite derivative; preparing a beta-hydroxyiminohydroxyphosphonoyl derivative by taking a beta-hydroxyiminodiphosphonoyl derivative as a raw material in the presence of cesium carbonate and phosphite ester; preparing a beta-amino hydroxyl phosphonic derivative by taking a beta-hydroxyl imino hydroxyl phosphonic derivative as a raw material under nickel catalysis and alkaline conditions;
the beta-hydroxyiminophosphono derivative is shown as the following chemical structural general formula:
Figure 521363DEST_PATH_IMAGE001
or
Figure 62066DEST_PATH_IMAGE002
The beta-hydroxyiminodiphosphonic acid derivative is shown as the following chemical structural general formula:
Figure DEST_PATH_IMAGE003
or
Figure 236695DEST_PATH_IMAGE004
The beta-hydroxyiminohydroxyphosphonoyl derivative is shown as the following chemical structural general formula:
Figure DEST_PATH_IMAGE005
or
Figure 368600DEST_PATH_IMAGE006
The beta-amino hydroxyl phosphonic derivative is shown as the following chemical structural general formula:
Figure DEST_PATH_IMAGE007
or
Figure 894259DEST_PATH_IMAGE008
The olefin is represented by the following chemical structural general formula:
Figure DEST_PATH_IMAGE009
、
Figure 504232DEST_PATH_IMAGE010
wherein R is selected from one of alkyl, N-alkyl phthalimide group, aryl alkyl, ethyl acetate group and ethoxy formyl group; x is selected from one of alkyl, aryl and hydrogen; ar is represented by the following chemical structural general formula:
Figure DEST_PATH_IMAGE011
、
Figure 798947DEST_PATH_IMAGE012
、
Figure DEST_PATH_IMAGE013
wherein R is1One selected from alkyl, alkoxy, aryl, halogen, nitro, cyano and ester group; y is selected from O, S, N; r2One selected from alkyl, alkoxy and halogen;
the phosphorus reagent is represented by the following structural general formula:
Figure 101752DEST_PATH_IMAGE014
wherein R is3One selected from alkoxy or aryl;
the silver catalyst is one of silver nitrate, silver carbonate and silver acetate.
2. The method according to claim 1, wherein the solvent is selected from the group consisting of: methanol, ethanol, acetonitrile, acetone, water or N, N-dimethylformyl.
3. The method according to claim 1, wherein the molar ratio of the olefin, the phosphorus reagent, the tert-butyl nitrite and the silver catalyst is 1: 1-3: 0.1-0.3.
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