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CN110950906A - β -amino phosphoric acid derivative and preparation method thereof - Google Patents

β -amino phosphoric acid derivative and preparation method thereof Download PDF

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CN110950906A
CN110950906A CN201911304386.4A CN201911304386A CN110950906A CN 110950906 A CN110950906 A CN 110950906A CN 201911304386 A CN201911304386 A CN 201911304386A CN 110950906 A CN110950906 A CN 110950906A
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CN110950906B (en
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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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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5333—Arylalkane phosphine oxides or thioxides
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • 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
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • 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
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C07F9/4009—Esters containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • 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
    • C07F9/4056—Esters of arylalkanephosphonic acids
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses an β -amino phosphoric acid derivative and a preparation method thereof, wherein olefin is used as an initiator, raw materials are easy to obtain and wide in variety, products obtained by the method are various in types and wide in application, can be directly used and can be used for synthesizing organic phosphine medicines, and in addition, the method disclosed by the invention is simple in steps, mild in reaction conditions, high in yield of target products, small in pollution, simple in reaction operation and post-treatment process and suitable for industrial production.

Description

β -amino phosphoric acid derivative and preparation method thereof
The invention relates to an β -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 an β -amino phosphoric acid derivative and a preparation method thereof.
Background
The nitrogen-containing organic Phosphorus compound has wide biological activity, has important application in aspects of resisting hypercalcemia, resisting HIV virus, resisting bacteria, serving as an enzyme inhibitor and the like, and the β -phosphoryl oxime free radical compound can also be used for biomolecular markers (Il' yasov A.V. phosphor-binding imino and nitroyl free chemical as stimulating protein labels).Biophysics, 2013, 58(2): 167.）。
D.M. Mizrahi et al discloses a synthesis method of β -amino diphosphate compounds, and tests the inhibitory activity of the compounds on induced hypercalcemia, and the results show that the compounds show good activity and the effect is better than that of clinical anti-osteoporosis drug disodium chlorophosphate, but the reaction steps of the disclosed synthesis route of the compounds are complicated, and a strong corrosive reagent thionyl chloride is needed to be used, in 2003, A. Obojska et al synthesize several β -amino phosphate derivatives, and test the inhibitory activity on streptococci, and the results show that the compounds have good inhibitory activity on Streptomyces violaceorubidus, Saccharopolyspora erythraea and the like, in 2013, Lyzwa reports that nitrogen-containing organophosphorus compounds have the activity of inhibiting HIV protease, serine protease and the like, but the disclosed synthesis method of the compounds has the defects of difficult availability of raw materials, harsh reaction conditions, many reaction steps and the like, so the development of the synthesis method with mild reaction conditions, simple and concise application range, simple and easily-available raw materials is very important.
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, the technical scheme is that the preparation method of the β -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 β -hydroxyiminophosphono derivatives.
The invention also discloses a preparation method of the β -hydroxyiminobis-phosphono derivative, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, reacting at 10-50 ℃ to obtain a β -hydroxyiminophosphonium derivative, and preparing the β -hydroxyiminobis-phosphono derivative by using β -hydroxyiminophosphonium derivative as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide.
The invention also discloses a preparation method of the β -hydroxyiminohydroxyphosphonoyl derivative, which comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, reacting at 10-50 ℃ to obtain a β -hydroxyiminophosphono derivative, preparing a β -hydroxyiminodiphosphonoyl derivative by using β -hydroxyiminophosphono derivative as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide, and preparing a β -hydroxyiminohydroxyphosphonoyl derivative by using β -hydroxyiminodiphosphonoyl derivative as a raw material in the presence of cesium carbonate and phosphite ester.
The invention also discloses a preparation method of the β -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, reacting at 10-50 ℃ to obtain a β -hydroxyl imido phosphono derivative, preparing a β -hydroxyl imido diphosphonic derivative by taking β -hydroxyl imido phosphono derivative as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide, preparing a β -hydroxyl imido phosphono derivative by taking β -hydroxyl imido diphosphonic derivative as a raw material in the presence of cesium carbonate and phosphite ester, and preparing a β -amino hydroxyl phosphono derivative by taking β -hydroxyl imido phosphono derivative as a raw material under the condition of nickel catalysis and alkalinity;
the invention also discloses a preparation method of the β -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, reacting at 10-50 ℃ to obtain a β -hydroxyiminophosphono derivative, preparing a β -hydroxyiminodiphosphonic acid derivative from β -hydroxyiminophosphono derivative serving as a raw material in the presence of phosphite ester, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide, preparing a β -hydroxyiminohydroxyphosphonoyl derivative from β -hydroxyiminodiphosphonic derivative serving as a raw material in the presence of cesium carbonate and phosphite ester, preparing a β -amino hydroxyphosphonoyl derivative from β -hydroxyiminohydroxyphosphonoyl derivative serving as a raw material under nickel catalysis and an alkaline condition, and preparing an β -amino phosphoric acid derivative from β -amino hydroxyphosphonoyl derivative serving as a raw material in the presence of hydrochloric acid.
The invention also discloses a preparation method of the β -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, reacting at 10-50 ℃ to obtain a β -hydroxyiminophosphono derivative, and irradiating with an ultraviolet lamp to react in the presence of 2-methyl-2-nitropropane by using β -hydroxyiminophosphono derivative as a raw material to obtain the β -phosphoryl oxime free radical compound.
In the present invention, the olefin is represented by the following general chemical structure:
Figure 340176DEST_PATH_IMAGE001
、
Figure 991737DEST_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 240316DEST_PATH_IMAGE003
、
Figure 367016DEST_PATH_IMAGE004
、
Figure 650230DEST_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 207113DEST_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 β -hydroxyiminophosphono derivatives are represented by the following general chemical structure formula:
Figure 942988DEST_PATH_IMAGE007
or
Figure 876309DEST_PATH_IMAGE008
。
In the invention, the β -hydroxyiminobis (phosphoryl) derivative is represented by the following chemical structural general formula:
Figure 14029DEST_PATH_IMAGE009
or
Figure 741814DEST_PATH_IMAGE010
In the invention, the β -hydroxyiminohydroxyphosphonoyl derivative is represented by the following general chemical structure formula:
Figure 964985DEST_PATH_IMAGE011
or
Figure 436417DEST_PATH_IMAGE012
In the invention, the β -amino hydroxyl phosphonic acid derivative is shown as the following chemical structural general formula:
Figure 428644DEST_PATH_IMAGE013
or
Figure 592909DEST_PATH_IMAGE014
In the invention, the β -aminophosphonic acid derivative is represented by the following chemical structural general formula:
Figure 303376DEST_PATH_IMAGE015
or
Figure 312921DEST_PATH_IMAGE016
In the invention, the β -phosphoryl oxime free radical compound is shown as the following chemical structural general formula:
Figure 425233DEST_PATH_IMAGE017
or
Figure 494820DEST_PATH_IMAGE018
。
In the technical scheme, 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, β -methylstyrene, 2-naphthylethylene, benzocyclohexene, benzocyclopentene, α -cyclohexenone, 2-vinylpyridine, 4-vinylpyridine, N-vinylbutylphthalimide, N-vinylphthalimide, 4-phenylbutene, ethyl acrylate and ethyl 4-ethoxyformylpent-1-enoate, and the phosphorus reagent is selected from one of dimethyl phosphite, diethyl phosphite, diphenoxyphosphine, 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 692583DEST_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 974660DEST_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 207058DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 447547DEST_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):δ11.47 (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 132606DEST_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 481023DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 567928DEST_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):δ10.85 (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 979318DEST_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 151673DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 41132DEST_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):δ11.37 (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 982543DEST_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 830413DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 224485DEST_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):δ11.38 (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 183214DEST_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 713553DEST_PATH_IMAGE021
TLC tracking reverseShould be completed until complete completion;
Figure 732324DEST_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):δ11.54 (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 613693DEST_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 376112DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 26536DEST_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):δ11.28 (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 950630DEST_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 584874DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 619826DEST_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):δ12.08 (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 655915DEST_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 485331DEST_PATH_IMAGE021
TLC tracing reaction till completionFinishing;
Figure 606870DEST_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):δ11.94 (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 445513DEST_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 70530DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 333496DEST_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):δ11.57 (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 676753DEST_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 319087DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 798610DEST_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):δ11.60 (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 235407DEST_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 65960DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 246406DEST_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):δ11.61 (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= 8.5Hz, 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 846014DEST_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 453713DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 771562DEST_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):δ10.94 (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= 8.0Hz, 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 490119DEST_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 944235DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 988414DEST_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):δ11.09 (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 527980DEST_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 315807DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 624429DEST_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):δ11.38 (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
β -methyl styrene and diphenyl phosphine oxide are used as raw materials, and the reaction steps are as follows:
Figure 839509DEST_PATH_IMAGE020
β -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) are added into a reaction flask to react at 10 ℃;
Figure 600792DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 192310DEST_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):δ11.78 (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 355438DEST_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 750209DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 264367DEST_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):δ11.65 (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 128418DEST_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 411632DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 968515DEST_PATH_IMAGE022
the crude product obtained after the reaction is separated by column chromatography (acetic acid B)Ester petroleum ether = 1:1) to obtain the desired product (yield 77%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ11.18 (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 969969DEST_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 637711DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 775431DEST_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):δ11.75 (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 503216DEST_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), ethanol (2.5 mL) are added into a reaction bottle to react at 50 ℃;
Figure 726387DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 197819DEST_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):δ11.75 (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 190046DEST_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 354311DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 799199DEST_PATH_IMAGE022
separating the crude product obtained after the reaction by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtainTo the desired product (73% yield). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ11.98 (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= 5.8Hz, 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 808743DEST_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 186635DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 990643DEST_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):δ10.81 (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= 14.7Hz, 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 453986DEST_PATH_IMAGE020
adding N-vinyl phthalimide (0.069 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), ethanol (2.5 mL) into a reaction bottle, and reacting at 30 ℃;
Figure 1642DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 234040DEST_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):δ11.98 (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 206019DEST_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 156658DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 508005DEST_PATH_IMAGE022
the crude product obtained after the reaction is finished is subjected to column chromatographySeparation (ethyl acetate: petroleum ether = 1:1) gave the desired product (yield 82%). Analytical data for the product are as follows:1H NMR (400 MHz, CDCl3):δ10.75 (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 594909DEST_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 6299DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 178654DEST_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):δ13.06 (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 68113DEST_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 9524DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 591815DEST_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):δ9.05 (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 251467DEST_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 944616DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 740534DEST_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):δ11.93 (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 759306DEST_PATH_IMAGE024
Acrolein and diisopropyl phosphite ester are used as raw materials, and the reaction steps are as follows:
Figure 640674DEST_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 137514DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 787939DEST_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):δ11.91 (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)。
⑷ Compound A is obtained by adding compound 29 and 2-methyl-2-nitropropane into a quartz glass tube and irradiating with an ultraviolet lamp.
Example twenty-eight: synthesis of 1-hydroxy-2-amino-3-phenylpropyl diphosphate (B1)
Figure 977611DEST_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):δ10.73 (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:1HNMR (400 MHz, CDCl3):δ10.73 (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, 1.0mmol), 30-2 (C: (M:) (M: (M)) were charged into a reaction flask0.210 g, 0.5 mmol) and dimethylsulfoxide (2.0 mL), 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):δ10.73 (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):δ7.64 – 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):δ7.64 – 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 346276DEST_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):δ10.73 (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:1HNMR (400 MHz, CDCl3):δ11.23 (s, 1H), 4.19 – 3.97 (m, 8H), 3.63 (d,J= 23.3Hz, 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, 1.0mmol), 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 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 31-3 (yield)80%). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3):δ10.93 (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):δ4.19 – 3.97 (m, 9H), 3.73 – 3.67 (m, 1H), 3.46 (dd,J= 7.0, 6.8Hz, 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):δ4.16 (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 381228DEST_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):δ10.73 (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):δ3.99 – 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):δ16.90 (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) adding compound C1 (0.169 g, 1 mmol), ammonia water solution (1 mmol) and methanol (0.5 mL) into a reaction flask, stirring at room temperature until the reaction is completed, concentrating, drying, and recrystallizing the crude product with ethanol/water to obtain the final productTarget product C2 (74% yield). Analytical data for the product are as follows:1H NMR (300 MHz, CDCl3):δ8.77 (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):δ10.73 (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 ℃. 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 34-2 (yield 78%). Analytical data for the product are as follows:1HNMR (400 MHz, CDCl3):δ10.73 (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) and triethyl were added to a reaction flaskPhosphite (0.167 g, 1.0mmol), 34-2 (0.235 g, 0.5 mmol) and dimethylsulfoxide (2.0 mL) were stirred under an oxygen atmosphere at room temperature 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):δ10.73 (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):δ7.64 – 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):δ7.64 – 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 620579DEST_PATH_IMAGE032
Heptene and diisopropyl phosphite ester are used as raw materials, and the reaction steps are as follows:
Figure 978224DEST_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 834184DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 407248DEST_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):δ11.91 (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);
⑷ the compound 35-1 and 2-methyl-2-nitropropane were added to a quartz glass tube and then irradiated with an ultraviolet lamp to obtain the 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 32265DEST_PATH_IMAGE020
styrene (0.042 g, 0.4 mmol) was added to the reaction flaskDiisopropyl 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) at room temperature;
Figure 298161DEST_PATH_IMAGE021
TLC tracing the reaction until the reaction is completely finished;
Figure 375838DEST_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):δ11.91 (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)；
⑷ Compound 36-1 and 2-methyl-2-nitropropane were added to a quartz glass tube and then irradiated with an ultraviolet lamp to give Compound 36-2.

Claims (5)

1. An β -amino phosphoric acid derivative preparation method comprises the following steps of dissolving olefin, a phosphorus reagent, tert-butyl nitrite and a silver catalyst in a solvent, reacting at 10-50 ℃ to obtain a β -hydroxyiminophosphono derivative, preparing a β -hydroxyiminophosphono derivative from β -hydroxyiminophosphono derivative in the presence of phosphite, cuprous trifluoromethanesulfonate and di-tert-butyl peroxide, preparing a β -hydroxyiminophosphono derivative from β -hydroxyiminophosphono derivative in the presence of cesium carbonate and phosphite, preparing a β -amino hydroxyphosphonoyl derivative from β -hydroxyiminophosphono derivative in the presence of nickel catalyst and under an alkaline condition, and preparing an β -amino phosphoric acid derivative from β -aminohydroxyphosphonoyl derivative in the presence of hydrochloric acid.
2. The method of claim 1, wherein the olefin is represented by the following general chemical structure:
Figure DEST_PATH_IMAGE001
、
Figure 345108DEST_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 268064DEST_PATH_IMAGE003
、
Figure 515506DEST_PATH_IMAGE004
、
Figure 258334DEST_PATH_IMAGE005
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 46161DEST_PATH_IMAGE006
wherein R is3One selected from alkoxy or aryl;
the chemical formula of the silver catalyst is AgX, wherein X is NO3、CO3One of, OAc;
the solvent is selected from: 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.
4. The application of the silver compound as the catalyst in the preparation of β -amino phosphoric acid derivatives is characterized in that the chemical formula of the silver catalyst is AgX, wherein X is NO3、CO3And OAc, preparing β -amino phosphoric acid derivative with olefin, phosphorus reagent and tert-butyl nitrite as reactants.
5. The application of the derivative as claimed in claim 4, wherein the olefin, the phosphorus reagent, the tert-butyl nitrite and the silver compound are dissolved in a solvent and react at 10-50 ℃ to obtain the β -aminophosphonic acid derivative.
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