CN115583970A

CN115583970A - Method for preparing alpha- (hydroxy amino) diaryl phosphine oxide from nitrone

Info

Publication number: CN115583970A
Application number: CN202211267152.9A
Authority: CN
Inventors: 刘春艳; 孟爱国; 赵碰飞; 肖剑; 钟启迪
Original assignee: North China University of Science and Technology
Current assignee: North China University of Science and Technology
Priority date: 2022-10-17
Filing date: 2022-10-17
Publication date: 2023-01-10

Abstract

The invention belongs to the technical field of medicines, and relates to a method for preparing alpha- (hydroxy amino) diaryl phosphine oxide from nitrone. The invention establishes a simple method for synthesizing alpha- (hydroxyl amino) phosphine oxide without catalyst by taking nitrone and diaryl phosphorus oxide as raw materials under mild conditions. The reaction of the invention can be carried out in the absence of solvent or in a low-added solvent, the reaction atom has high economy, can be purified by a simple recrystallization method, shows wide substrate range and good functional group tolerance, and has the characteristics of cheap and easily obtained raw materials, high yield, simple and convenient operation, high safety, no pollution, wide substrate application range and suitability for industrial production. Pharmacological activity experiments show that the compounds have good cancer inhibition activity, no obvious cytotoxicity and potential medicinal value, and are expected to be used for preparing various anti-cancer medicaments.

Description

Method for preparing alpha- (hydroxy amino) diaryl phosphine oxide from nitrone

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a method for preparing alpha- (hydroxy amino) diaryl phosphine oxide from nitrone.

Background

Organophosphorus compounds are of considerable importance as important compounds for organic synthesis in the fields of medicinal chemistry, agricultural industry and the like, for example: pharmaceuticals (antiviral and anticancer agents), agrochemicals (pesticides and herbicides), catalytic ligands and industrial additives (e.g. polymers and flame retardants). The classical synthesis processes of these compounds are affected by the use of stoichiometric additives, the need for protecting groups, and poor functional group tolerance. This prompted studies to add P (O) -H bonds directly to C = N unsaturated bonds, which is likely to have 100% atomic efficiency.

The alpha- (hydroxyl amino) phosphine oxide has not been synthesized in large quantity by people, may have unique biological activity and medicinal value, and can be used as an intermediate for synthesizing alpha-aminophosphine compounds, and the alpha-aminophosphine compounds have antiviral, antibacterial, anticancer and enzyme inhibition activities. Therefore, the organic phosphorus oxide has important application value in the fields of natural product synthesis, chemical industry, medicine and the like as an important organic synthesis intermediate, and researches on developing a green, efficient and economic synthesis method of the organic phosphorus oxide are widely concerned by researchers in related fields.

In the prior art, methods of adding P (O) -H bonds to alkenes or alkynes without adding solvents or catalysts have been developed. The prior art also discloses a catalyst-free, low-solvent process for the hydrophosphonylation of isocyanates and isothiocyanates. However, no method has been studied for adding a P (O) -H bond to an unsaturated C = N double bond of nitrone. Therefore, the development of an economical, environment-friendly and efficient synthetic method is of great significance, and the structural diversity of the organic phosphine compound is increased.

Malignant tumors are serious diseases threatening human health and life, and are one of the main causes of death in china. The search and discovery of new drugs for the treatment and prevention of tumors is also a major issue currently facing. The research on the antitumor activity of the alpha- (hydroxyl amino) phosphine oxide is not reported at present.

Disclosure of Invention

Based on the technical problems, the invention aims to provide a green synthesis method of alpha- (hydroxy amino) diaryl phosphine oxide, so as to prepare a novel organic phosphorus compound, and the method has the characteristics of cheap and easily obtained raw materials, high yield, simple and convenient operation, high safety, no pollution, wide substrate application range and suitability for industrial production.

The compound prepared by the invention shows good results in-vitro antitumor activity tests, and has no obvious cytotoxicity.

According to the method for preparing alpha- (hydroxy amino) diaryl phosphine oxide from nitrone, nitrone shown as a formula (2) and diaryl phosphine oxide shown as a formula (3) are used as raw materials and react under the heating condition to obtain alpha- (hydroxy amino) diaryl phosphine oxide shown as a formula (1),

wherein R is ₁ Is selected from C ₁ -C ₁₀ Alkyl, furyl, thienyl, C ₅ -C ₆ One of an alkylene ring, a phenyl group or an aromatic group,

R ₂ is selected from C ₁ -C ₁₀ Alkyl of (C) ₅ -C ₆ One of an alkylene ring, a substituted or unsubstituted phenyl;

R ₃ 、R ₄ each independently selected from phenyl and aryl.

The term "alkyl" refers to a saturated or unsaturated aliphatic hydrocarbon group, which may be straight or branched and has 1 to 10 atoms in the chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain. "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "lower alkyl" means having 1 to 4 carbon atoms in the chain, which may be straight or branched. The alkyl group may be substituted with one or more "alkyl substituents" which may be the same or different, including, for example, halogen, cycloalkyl, hydroxy, alkoxy, amino, amido, arylamido, carboxy.

A process for preparing alpha- (hydroxyamino) diarylphosphine oxides from nitrones according to an embodiment of the present invention, R ₁ Selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl, halophenyl, alkyl-substituted phenyl, methoxy-substituted phenyl, methylamino-substituted phenyl, acetoxy-substituted phenyl, naphthyl, or biphenyl.

The term "halo" means substituted by an atom of a halogen in the periodic table of elements, and specifically includes fluorine, chlorine, bromine and iodine atoms.

A process for preparing alpha- (hydroxyamino) diarylphosphine oxides from nitrones according to an embodiment of the present invention, R ₂ Selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl, phenyl or benzyl.

Preferably, R ₁ 、R ₂ Each independently selected from C ₅ -C ₆ An alkylene ring.

The method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone according to the embodiment of the present invention is applicable as long as the amount of raw material capable of promoting the above nucleophilic addition reaction is available, and in order to improve the reaction yield and the raw material utilization rate, the ratio of nitrone to diarylphosphine oxide compound is 1:1-2, preferably, the ratio of nitrone to diarylphosphine oxide compound is 1.5.

In the method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone according to the embodiment of the present invention, it is possible to use the solvent capable of promoting the above nucleophilic addition reaction without causing denaturation of the raw material and the product, and the amount of the solvent is effective for the reaction, and the reaction is promoted, and in one embodiment, the nitrone and the diarylphosphine oxide compound are used as the raw material, and water or n-hexane is used as the solvent, preferably, the amount of the water may be 50 to 100 times that of the nitrone, and the amount of the n-hexane may be 50 to 100 times that of the nitrone.

The method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone according to the embodiment of the present invention has a reaction time of 1-3 hours.

According to the method for preparing alpha- (hydroxyl amino) diaryl phosphine oxide from nitrone, the nitrone shown as the formula (2) and the diaryl phosphine oxide compound shown as the formula (3) are used as raw materials and react at the temperature of 60-90 ℃.

According to the method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone of the embodiment of the present invention, alpha- (hydroxyamino) diarylphosphine oxide represented by formula (1) is obtained and then purified, and the purification steps are: removing solvent, and purifying by recrystallization or pulping to obtain pure product.

Preferably, the step of recrystallization is: dissolving the product by using ethyl acetate, separating out the product by using normal hexane, and performing suction filtration to obtain a pure product;

the pulping method comprises the following steps: firstly, adding normal hexane into the product, quickly stirring to dissolve impurities, and carrying out suction filtration to obtain a pure product.

In the preparation method, the recrystallization solvent consists of 1-5 parts by volume of n-hexane and 1 part by volume of ethyl acetate. The normal hexane can be replaced by petroleum ether, the product and other impurities can be effectively separated through recrystallization, and the yield is extremely high.

The invention also provides the application of the alpha- (hydroxyl amino) diaryl phosphine oxide in preparing antitumor drugs. The medicament comprises alpha- (hydroxyamino) diarylphosphine oxide, pharmaceutically acceptable salts of alpha- (hydroxyamino) diarylphosphine oxide.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and is not biologically or otherwise undesirable. In many examples, the compounds of the present invention may form acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids, while pharmaceutically acceptable base addition salts may be prepared from inorganic or organic bases. For example, such salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, methanesulfonic, toluenesulfonic and the like.

Wherein the tumor refers to solid tumor, including breast cancer, prostatic cancer, lung cancer, gastric cancer, liver cancer and the like.

The invention has the beneficial effects that:

the preparation method of alpha- (hydroxyl amino) diaryl phosphine oxide provided by the invention is to mix aromatic or aliphatic nitrone derivative and diaryl phosphorus oxide in a solvent and then carry out nucleophilic addition reaction to realize the synthesis of alpha- (hydroxyl amino) diaryl phosphine oxide.

The preparation method can be carried out under the conditions of air and no solvent, and the reaction condition is mild and easy to control; the obtained raw materials are easy to obtain, and the application range of the substrate is wide; the reaction process can be carried out under the condition of no catalyst; the reaction specificity is strong, the yield can be higher in a shorter time, the post-treatment is simple and convenient, and the method is green and environment-friendly and is suitable for large-scale industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a schematic diagram of the mechanism for preparing alpha- (hydroxyamino) diarylphosphine oxides by the process of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without making any creative effort, shall fall within the protection scope of the present invention.

The reaction formula for preparing alpha- (hydroxy amino) diaryl phosphine oxide of the invention is as follows:

as shown in formula (5):

the reaction mechanism is shown in FIG. 1, initially, the proton on the diaryl phosphine oxide 2 is transferred and combined with the oxyanion on the nitrone 1 to form an intermediate I and a nucleophilic moiety II, wherein N is in the form of cation and P is in the form of anion. And secondly, the P negative ions attack carbon atoms of carbon-nitrogen double bonds in II, so that the whole electrons of the carbon-nitrogen double bonds are transferred to N to generate the required hydrophosphonylation product 3. In addition, under acidic conditions, the diarylphosphine oxide is less likely to undergo proton transfer, and the production of intermediate II is suppressed, thereby suppressing the progress of the reaction. Under alkaline conditions, nitrone 2 is difficult to bind with a proton, inhibiting the formation of intermediate II, so that nitrone exists mainly in the form of 1. Therefore, the central N atom has a small positive charge density, an insufficient electron transfer tendency, and OH ^- Will surround N ⁺ Peripheral, strong solvation, weakening of N ⁺ The electron deficiency property of (3) reduces the attack of P negative ions on carbon-nitrogen double bonds, and inhibits the formation of the product 3. Thus, the reaction of the present invention is a nucleophilic addition reaction mechanism.

Example 1 synthesis of (((hydroxy) benzylamino) (phenyl) methyl) diphenylphosphine oxide compound (compound 1).

Compound 1 has the structural formula:

the first synthesis process comprises: adding N-benzyl-alpha-phenyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 2 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 93%.

The second method comprises the following synthetic processes: adding N-benzyl-alpha-phenyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and water (10 ml) into a round bottom flask with the volume of 25ml in sequence, putting a magnetic stirrer, placing the flask on the magnetic stirrer, stirring every minute at 500 revolutions per minute, reacting at the temperature of 90 ℃ for 4 hours, monitoring the reaction by TLC, extracting the reaction solution with 50ml of multiplied by 3 ethyl acetate for three times when no nitrone compound is left, separating and combining organic layers, drying the organic phase with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent to obtain the initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 93%.

The third synthesis process comprises: adding N-benzyl-alpha-phenyl nitrone (0.001 mol) and phosphorus diphenoxylate (0.002 mol) into a round-bottom flask with the volume of 10ml in sequence, reacting for 2 hours at the temperature of 65 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 94%.

In the actual synthesis process, the synthesis method can be reasonably selected according to the aspects of reaction amount, cost, operation difficulty, whether the reaction is green, reaction yield and the like.

The structure of the compound 1 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.86(t,J＝9.2Hz,2H),7.50(ddt,J＝25.1,19.5,8.5Hz,7H),7.38–6.98(m,11H),6.72(s,1H),4.64(d,J＝7.2Hz,1H),4.10(d,J＝13.1Hz,1H),3.64(d,J＝13.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.59,131.43,131.32,131.23,130.99,130.91,129.10,128.21,128.09,128.04,127.88,127.77,127.16,77.16,76.84,76.53,61.20.

EXAMPLE 2 Synthesis of (((hydroxy) benzylamino) (2-naphthyl) methyl) diphenylphosphine oxide Compound (Compound 2)

Compound 2 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha- (2-naphthyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 4 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain a primary product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 92%.

The structure of the compound 2 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.93–7.85(m,3H),7.80–7.76(m,2H),7.74–7.67(m,2H),7.63(dd,J＝8.5,1.6Hz,1H),7.60–7.54(m,2H),7.52–7.43(m,8H),7.25–7.23(m,2H),7.12(dt,J＝7.3,2.4Hz,3H),4.80(d,J＝7.4Hz,1H),4.09(d,J＝13.2Hz,1H),3.63(d,J＝13.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.92,133.10,132.96,132.70,132.68,131.77,131.75,131.67,131.60,131.58,131.38,131.31,131.27,131.19,130.87,130.76,129.41,129.34,129.12,129.08,128.95,128.75,128.55,128.43,128.36,128.25,128.22,128.10,127.99,127.70,127.66,127.60,127.49,127.46,126.58,126.37,126.08,125.99,77.48,77.16,76.84,61.56,61.45.

example 3 synthesis of (((hydroxy) benzylamino) (cyclohexyl) methyl) diphenylphosphine oxide (compound 3).

Compound 3 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha-cyclohexyl nitrone (0.001 mol), diphenyl oxide phosphorus (0.0015 mol) and water (10 ml) into a round bottom flask with the volume of 25ml in sequence, putting a magnetic stirrer, placing the flask on the magnetic stirrer, stirring every minute at 500 revolutions per minute, reacting at the temperature of 90 ℃ for 3 hours, monitoring the reaction by TLC, extracting the reaction solution with 50ml of multiplied by 3 ethyl acetate for three times when no nitrone compound is left, separating and combining organic layers, drying the organic layer with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent to obtain the initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 95%.

The structure of the compound 3 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.68(tdd,J＝8.4,4.6,1.5Hz,1H),7.62–7.56(m,3H),7.46(td,J＝7.2,1.6Hz,2H),7.41–7.35(m,5H),7.06(dd,J＝5.1,2.1Hz,1H),6.35(d,J＝7.4Hz,1H),4.73(s,2H),2.86(tdt,J＝11.1,7.4,3.7Hz,1H),1.77–1.69(m,2H),1.58–1.53(m,2H),1.27–1.16(m,2H),1.15–1.08(m,1H),1.01(qd,J＝11.7,3.4Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ143.37,137.66,133.26,132.67,132.64,131.97,131.73,131.31,131.21,131.13,131.04,130.96,130.83,130.72,129.10,129.04,128.95,128.92,128.83,128.64,128.57,128.52,128.46,128.43,128.21,127.24,77.48,77.16,76.84,69.38,35.09,28.83,26.76,26.13,25.99,25.28.

EXAMPLE 4 Synthesis of (((hydroxy) benzylamino) (2-furan) methyl) diphenylphosphine oxide Compound (Compound 4)

Compound 4 has the structural formula:

adding N-benzyl-alpha- (2-furan) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, placing the mixture on the magnetic stirrer for 500 revolutions per minute, stirring at the temperature (60 ℃) for 3 hours, monitoring the reaction by TLC, and when no nitrone compound remains, distilling the mixed solution under reduced pressure to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 70). The yield thereof was found to be 91%.

The structure of the compound 4 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.67–7.60(m,2H),7.50–7.30(m,7H),7.27–7.14(m,6H),7.10–7.01(m,2H),6.61(t,J＝2.6Hz,1H),6.25(dd,J＝3.3,1.9Hz,1H),4.73(d,J＝11.1Hz,1H),4.07(d,J＝12.6Hz,1H),3.58(d,J＝12.7Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ144.85,144.80,142.48,142.46,136.15,131.67,131.64,131.63,131.60,131.33,131.24,130.83,130.78,130.69,129.84,129.41,128.27,128.15,128.09,127.97,127.31,113.52,113.48,110.76,77.16,76.84,76.52,61.45.

EXAMPLE 5 Synthesis of (((hydroxy) benzylamino) (4-fluorophenyl) methyl) diphenylphosphine oxide Compound (Compound 5)

Compound 5 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha- (4-fluorophenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 80. The yield thereof was found to be 82%.

The structure of the compound 5 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.86–7.78(m,2H),7.56(td,J＝7.3,1.5Hz,1H),7.52–7.28(m,8H),7.27–7.19(m,5H),7.12–7.05(m,2H),6.93(t,J＝8.6Hz,2H),6.72(s,1H),4.59(d,J＝7.6Hz,1H),4.06(d,J＝13.1Hz,1H),3.58(d,J＝13.1Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.35,133.25,133.18,131.51,131.34,131.29,131.21,130.89,130.80,129.07,128.25,128.13,128.09,128.01,127.89,127.26,114.96,114.75,77.16,76.84,76.52,61.17,61.05.

EXAMPLE 6 Synthesis of (((hydroxy) benzylamino) (4-chlorophenyl) methyl) diphenylphosphine oxide Compound (Compound 6)

Compound 6 has the structural formula:

adding N-benzyl-alpha- (4-chlorphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, placing the mixture on the magnetic stirrer for 500 revolutions per minute, stirring at the temperature (60 ℃) for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 80). The yield thereof was found to be 84%.

The structure of the compound 6 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.87–7.81(m,2H),7.59(td,J＝7.3,1.5Hz,1H),7.53–7.41(m,6H),7.36(td,J＝7.3,1.4Hz,1H),7.30–7.22(m,7H),7.13–7.04(m,2H),6.69(s,1H),4.61(d,J＝7.6Hz,1H),4.08(d,J＝13.1Hz,1H),3.60(d,J＝13.1Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ132.82,132.75,131.58,131.50,131.31,131.22,130.90,130.82,129.10,128.30,128.18,128.14,128.10,127.98,127.34,77.16,76.84,76.53,61.21,61.10.

EXAMPLE 7 Synthesis of (((hydroxy) benzylamino) (4-bromophenyl) methyl) diphenylphosphine oxide Compound (Compound 7)

Compound 7 has the structural formula:

adding N-benzyl-alpha- (4-bromophenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 80. The yield thereof was found to be 84%.

The structure of the compound 7 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.85–7.78(m,2H),7.56(td,J＝7.3,1.5Hz,1H),7.51–7.45(m,2H),7.44–7.31(m,7H),7.27–7.20(m,5H),7.11–7.03(m,2H),6.72(s,1H),4.58(d,J＝7.6Hz,1H),4.05(d,J＝13.1Hz,1H),3.58(d,J＝13.1Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.19,133.11,133.05,131.58,131.48,131.30,131.21,131.03,130.89,130.80,130.06,129.09,128.28,128.16,128.12,128.10,127.98,127.32,122.48,77.16,76.84,76.53,61.21,61.10.

EXAMPLE 8 Synthesis of (((hydroxy) benzylamino) (4- (trifluoromethyl) phenyl) methyl) diphenylphosphine oxide Compound (Compound 8)

Compound 8 has the structural formula:

adding N-benzyl-alpha- (4- (trifluoromethyl) phenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring every minute at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 80. The yield thereof was found to be 85%.

The structure of the compound 8 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.76(ddd,J＝11.4,8.3,1.4Hz,2H),7.50(td,J＝8.0,7.4,1.4Hz,3H),7.41(ddt,J＝6.6,5.2,2.1Hz,4H),7.36–7.28(m,2H),7.24(td,J＝7.4,1.5Hz,1H),7.19–7.10(m,5H),7.01(dd,J＝7.4,2.2Hz,2H),6.71(s,1H),4.58(d,J＝7.3Hz,1H),3.99(d,J＝13.1Hz,1H),3.50(d,J＝13.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.50,135.78,132.72,132.10,132.04,131.96,131.93,131.86,131.83,131.72,131.64,131.56,131.27,131.16,131.08,130.54,130.29,130.22,129.40,128.63,128.51,128.46,128.41,128.30,127.68,125.46,125.00,124.96,124.92,122.75,77.48,77.36,77.16,76.84,69.11,68.23,61.76,61.65.

EXAMPLE 9 Synthesis of (((hydroxy) benzylamino) (3-chlorophenyl) methyl) diphenylphosphine oxide Compound (Compound 9)

Compound 9 has the structural formula:

adding N-benzyl-alpha- (3-chlorphenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: petroleum ether/ethyl acetate, 80. The yield thereof was found to be 84%.

The structure of the compound 9 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.90–7.83(m,2H),7.60(td,J＝7.4,1.7Hz,1H),7.54–7.42(m,6H),7.36(td,J＝7.4,1.6Hz,1H),7.31–7.23(m,6H),7.22–7.13(m,3H),7.12–6.74(m,1H),4.62(d,J＝7.1Hz,1H),4.13(d,J＝13.2Hz,1H),3.64(d,J＝13.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.31,133.62,133.37,132.51,131.49,131.47,131.40,131.37,131.27,131.21,131.18,131.03,130.88,130.80,130.05,129.61,129.55,129.09,129.01,128.23,128.18,128.17,128.11,128.05,127.98,127.86,127.22,77.16,76.84,76.52,61.39,61.28.

EXAMPLE 10 Synthesis of (((hydroxy) benzylamino) (3-fluorophenyl) methyl) diphenylphosphine oxide Compound (Compound 10)

Compound 10 has the structural formula:

adding N-benzyl-alpha- (3-fluorophenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 87%.

The structure of the compound 10 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.90–7.82(m,2H),7.62–7.58(m,1H),7.57–7.43(m,5H),7.36(td,J＝7.3,1.5Hz,1H),7.27(tq,J＝10.8,3.7Hz,8H),7.13(dd,J＝7.2,2.4Hz,2H),7.01–6.94(m,1H),4.63(d,J＝7.4Hz,1H),4.12(d,J＝13.1Hz,1H),3.65(d,J＝13.1Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ136.63,133.93,132.88,132.72,131.88,131.85,131.74,131.72,131.62,131.53,131.38,131.23,131.15,130.89,130.78,130.40,129.56,129.48,129.42,129.09,128.97,128.59,128.47,128.42,128.33,128.22,127.60,118.84,118.77,118.56,115.53,115.31,77.48,77.16,76.84,61.66.

EXAMPLE 11 Synthesis of (((hydroxy) benzylamino) (2-bromophenyl) methyl) diphenylphosphine oxide (Compound 11) Compound 11:

adding N-benzyl-alpha- (2-bromophenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 85%.

The structure of the compound 11 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.33(d,J＝7.9Hz,1H),8.05(ddd,J＝11.3,8.1,1.6Hz,2H),7.66–7.51(m,6H),7.45–7.42(m,1H),7.36–7.31(m,2H),7.26(td,J＝5.1,4.7,2.2Hz,6H),7.11(t,J＝7.7Hz,1H),6.71(s,1H),5.57(d,J＝6.0Hz,1H),3.97–3.87(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.43,133.68,133.64,133.41,132.38,132.30,131.72,131.69,131.53,131.50,131.40,131.38,131.29,131.14,131.05,129.81,129.79,129.02,128.60,128.48,128.05,127.98,127.86,127.50,127.48,127.15,126.25,126.16,77.43,77.11,76.79,62.20,62.08.

EXAMPLE 12 Synthesis of (((hydroxy) benzylamino) (4-nitrophenyl) methyl) diphenylphosphine oxide Compound (Compound 12)

Compound 12 has the structural formula:

adding N-benzyl-alpha- (4-nitrophenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring every minute at 500 revolutions per minute on the magnetic stirrer, reacting for 4 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then purifying the primary product by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 83%.

The structure of the compound 12 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.07(d,J＝8.4Hz,2H),7.87–7.81(m,2H),7.64(d,J＝8.3Hz,2H),7.58(dd,J＝7.5,1.6Hz,1H),7.49(td,J＝7.6,3.1Hz,2H),7.44–7.36(m,3H),7.33(dd,J＝7.5,1.6Hz,1H),7.28–7.22(m,5H),7.12–7.07(m,2H),4.72(d,J＝7.0Hz,1H),4.07(d,J＝13.1Hz,1H),3.59(d,J＝13.1Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ147.60,139.45,136.12,132.52,132.46,131.99,131.97,131.94,131.91,131.50,131.41,131.00,130.92,129.33,128.59,128.47,128.44,128.41,128.32,127.71,122.96,77.40,77.08,76.76,68.82,67.95,61.97,61.86.

EXAMPLE 13 Synthesis of (((hydroxy) benzylamino) (2-chlorophenyl) methyl) diphenylphosphine oxide Compound (Compound 13)

Compound 13 has the structural formula:

adding N-benzyl-alpha- (2-chlorphenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 84%.

The structure of the compound 13 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.27(d,J＝7.8Hz,1H),7.97(ddd,J＝11.3,8.2,1.5Hz,2H),7.59(dd,J＝7.2,1.6Hz,1H),7.57–7.51(m,3H),7.50–7.48(m,1H),7.35–7.30(m,1H),7.29–7.20(m,7H),7.17(dt,J＝8.6,5.1Hz,3H),6.59(s,1H),5.49(d,J＝6.5Hz,1H),3.96–3.76(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.32,133.71,133.68,133.40,132.68,132.40,131.84,131.81,131.65,131.63,131.48,131.39,131.10,131.01,130.89,130.77,130.48,130.38,129.63,129.61,129.38,129.13,129.07,128.96,128.67,128.55,128.14,128.12,128.00,127.28,126.95,126.93,77.48,77.16,76.84,62.28,62.16.

EXAMPLE 14 Synthesis of (((hydroxy) benzylamino) (2,6-dichlorophenyl) methyl) diphenylphosphine oxide Compound (Compound 14)

Compound 14 is of the formula:

adding N-benzyl-alpha- (2,6-dichlorophenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent to obtain an initial product when no nitrone compound is left. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 81%.

The structure of compound 14 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.17–8.07(m,2H),7.72–7.64(m,2H),7.57(dt,J＝6.1,2.6Hz,3H),7.46–7.40(m,2H),7.36–7.22(m,7H),7.13(dd,J＝8.0,1.3Hz,1H),7.03(td,J＝8.0,1.5Hz,1H),6.70(s,1H),6.09(d,J＝4.2Hz,1H),3.92–3.76(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.34,136.82,136.78,136.19,136.12,135.60,134.59,131.51,131.28,131.26,131.14,131.11,130.99,130.97,130.90,130.88,130.14,130.12,129.43,129.40,128.86,128.41,128.30,127.83,127.77,127.30,127.18,126.89,77.16,76.84,76.53,71.22,70.38,62.43,62.32.

EXAMPLE 15 Synthesis of (((hydroxy) benzylamino) (4-methylphenyl) methyl) diphenylphosphine oxide Compound (Compound 15)

Compound 15 has the structural formula:

sequentially adding N-benzyl-alpha- (4-methylphenyl) nitrone (0.001 mol) and phosphorus diphenoxylate (0.002 mol) into a round-bottom flask with the volume of 10ml, enabling the reactants to be in a molten state at the temperature of 65 ℃, reacting for 2 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 91%.

The structure of compound 15 was examined by nmr and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.73(ddd,J＝11.2,8.3,1.4Hz,2H),7.47(td,J＝6.5,5.8,1.5Hz,1H),7.37(dddd,J＝12.6,11.0,7.4,2.3Hz,4H),7.24(ddd,J＝11.9,7.6,1.4Hz,3H),7.17–7.10(m,5H),7.01(dd,J＝7.3,2.3Hz,2H),6.96(d,J＝7.8Hz,2H),6.58(s,1H),4.48(d,J＝7.4Hz,1H),3.97(d,J＝13.2Hz,1H),3.50(d,J＝13.1Hz,1H),2.20(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ138.16,137.00,133.28,131.73,131.67,131.63,131.54,131.50,131.32,131.24,129.41,128.93,128.49,128.37,128.33,128.21,128.10,127.41,77.48,77.16,76.84,61.37,61.26,21.32.

EXAMPLE 16 Synthesis of (((hydroxy) benzylamino) (3-methylphenyl) methyl) diphenylphosphine oxide Compound (Compound 16)

Compound 16 has the structural formula:

the synthesis process comprises the following steps: sequentially adding N-benzyl-alpha- (3-methylphenyl) nitrone (0.001 mol) and phosphorus diphenoxylate (0.002 mol) into a round-bottom flask with the volume of 10ml, enabling the reactants to be in a molten state at the temperature of 65 ℃, reacting for 2 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 90%.

The structure of the compound 16 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.85(ddd,J＝11.2,8.3,1.4Hz,2H),7.78–7.70(m,1H),7.62–7.57(m,1H),7.57–7.53(m,1H),7.53–7.49(m,2H),7.47(d,J＝1.3Hz,1H),7.46–7.42(m,2H),7.36–7.31(m,1H),7.28–7.23(m,6H),7.16–7.14(m,2H),7.07(d,J＝7.6Hz,1H),4.61(d,J＝6.9Hz,1H),4.10(d,J＝13.2Hz,1H),3.65(d,J＝13.2Hz,1H),2.28(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.76,137.01,132.72,132.69,132.41,132.35,132.29,131.69,131.66,131.64,131.55,131.51,131.49,131.36,131.33,131.28,130.89,130.78,129.42,129.36,129.15,129.13,129.09,128.97,128.81,128.75,128.50,128.44,128.38,128.32,128.12,128.03,128.01,127.43,77.48,77.16,76.84,61.55,61.44,21.50.

EXAMPLE 17 Synthesis of (((hydroxy) benzylamino) (3,4-dimethylphenyl) methyl) diphenylphosphine oxide (Compound 17)

Compound 17 has the structural formula:

sequentially adding N-benzyl-alpha- (3,4-dimethylphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent to obtain a primary product when no nitrone compound is left. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 60. The yield thereof was found to be 89%.

The structure of compound 17 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.88–7.82(m,2H),7.75(ddd,J＝13.8,8.1,1.4Hz,1H),7.61–7.58(m,1H),7.58–7.55(m,1H),7.51(dq,J＝6.9,4.0,3.0Hz,4H),7.44(d,J＝6.9Hz,1H),7.38–7.33(m,1H),7.26(dd,J＝5.1,2.0Hz,4H),7.20(d,J＝8.0Hz,1H),7.15–7.13(m,1H),7.04(d,J＝7.7Hz,1H),6.66(s,1H),4.60(d,J＝7.5Hz,1H),4.11(d,J＝13.2Hz,1H),3.64(d,J＝13.2Hz,1H),2.22(d,J＝6.8Hz,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.02,136.71,136.69,136.22,132.85,132.79,132.62,132.59,131.57,131.54,131.51,131.49,131.39,131.36,131.29,131.20,130.79,130.68,129.72,129.67,129.32,129.29,129.23,129.19,129.13,128.99,128.95,128.90,128.87,128.37,128.33,128.25,128.20,128.05,127.94,127.27,126.49,71.00,61.26,61.15,19.77,19.54.

EXAMPLE 18 Synthesis of (((hydroxy) benzylamino) (4-methoxyphenyl) methyl) diphenylphosphine oxide Compound (Compound 18)

Compound 18 has the structural formula:

adding N-benzyl-alpha- (4-methoxyphenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and water (10 ml) into a round bottom flask with the volume of 25ml in sequence, putting a magnetic stirrer, placing the flask on the magnetic stirrer for 500 revolutions per minute, stirring, reacting at the temperature of 90 ℃ for 4 hours, monitoring the reaction by TLC, extracting the reaction solution with 50ml of multiplied by 3 ethyl acetate for three times when no nitrone compound is left, separating and combining organic layers, drying the organic layer with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent to obtain the initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 93%.

The structure of compound 18 was examined by nmr and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.79(ddd,J＝11.2,6.9,1.9Hz,2H),7.53–7.49(m,1H),7.47–7.34(m,6H),7.28(d,J＝1.7Hz,1H),7.24–7.16(m,5H),7.10–7.01(m,2H),6.79–6.50(m,3H),4.53(t,J＝7.5Hz,1H),4.03(dd,J＝13.1,3.9Hz,1H),3.73(d,J＝4.3Hz,3H),3.56(dd,J＝13.1,2.6Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ159.62,137.05,133.11,131.67,131.56,131.31,131.23,129.40,128.51,128.40,128.36,128.27,128.15,127.44,113.63,77.48,77.16,76.84,61.33,61.21,55.29,29.84.

EXAMPLE 19 Synthesis of (((hydroxy) benzylamino) (3-methoxyphenyl) methyl) diphenylphosphine oxide Compound (Compound 19)

Compound 19 is of the formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha- (3-methoxyphenyl) nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and water (10 ml) into a round bottom flask with the volume of 25ml in sequence, putting a magnetic stirrer, placing the flask on the magnetic stirrer for 500 revolutions per minute, stirring, reacting at the temperature of 90 ℃ for 4 hours, monitoring the reaction by TLC, extracting the reaction solution with 50ml of multiplied by 3 ethyl acetate for three times when no nitrone compound is left, separating and combining organic layers, drying the organic layer with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent to obtain the initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 92%.

The structure of compound 19 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.84–7.77(m,2H),7.69(ddd,J＝13.7,8.2,1.4Hz,2H),7.54(dt,J＝3.8,1.7Hz,1H),7.51(dd,J＝4.1,2.2Hz,1H),7.48–7.45(m,3H),7.41(dt,J＝3.7,1.2Hz,1H),7.39(d,J＝1.6Hz,1H),7.31–7.28(m,1H),7.21(dd,J＝5.2,2.1Hz,3H),7.12–7.09(m,2H),7.05–7.00(m,1H),6.98–6.94(m,1H),6.79–6.74(m,1H),4.59(d,J＝6.8Hz,1H),4.07(d,J＝13.2Hz,1H),3.81(s,1H),3.70(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ159.32,132.72,132.69,131.76,131.62,131.53,131.35,131.26,130.89,130.78,129.51,129.38,129.36,129.12,129.09,128.97,128.54,128.42,128.34,128.20,128.09,127.52,121.83,114.60,112.34,55.35.

EXAMPLE 20 Synthesis of (((hydroxy) benzylamino) (2-methoxyphenyl) methyl) diphenylphosphine oxide Compound (Compound 20)

Compound 20 is of the formula:

adding N-benzyl-alpha- (2-methoxyphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring every minute at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 92%.

The structure of the compound 20 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ8.10(d,J＝7.7Hz,1H),7.93–7.86(m,2H),7.57–7.39(m,5H),7.30–7.10(m,9H),6.92(td,J＝7.5,1.1Hz,1H),6.65(dt,J＝8.3,1.1Hz,1H),6.57(s,1H),5.42(d,J＝6.8Hz,1H),3.95(d,J＝13.5Hz,1H),3.69(d,J＝13.4Hz,1H),3.60(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ156.80,156.74,137.20,133.51,132.52,131.62,131.22,131.20,131.17,131.13,130.97,130.94,130.72,130.63,129.12,129.10,128.89,128.12,128.00,127.66,127.45,127.34,126.81,120.36,120.34,120.18,109.37,77.16,76.84,76.52,61.78,61.66,54.78.

EXAMPLE 21 Synthesis of (((hydroxy) benzylamino) (3,5-dimethoxyphenyl) methyl) diphenylphosphine oxide Compound (Compound 21)

Compound 21 is of the formula:

adding N-benzyl-alpha- (3,5-dimethoxyphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature (60 ℃), monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 90%.

The structure of the compound 21 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.86–7.77(m,2H),7.60–7.39(m,7H),7.37–7.31(m,1H),7.23(dt,J＝4.9,2.4Hz,4H),7.13(dd,J＝6.6,2.9Hz,2H),6.63–6.56(m,2H),6.33(d,J＝1.2Hz,1H),4.55(d,J＝6.7Hz,1H),4.09(d,J＝13.2Hz,1H),3.79(s,1H),3.68(s,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ160.36,133.63,133.11,132.68,132.12,131.77,131.74,131.64,131.60,131.55,131.38,131.29,130.89,130.78,130.73,129.47,129.38,129.13,129.09,128.96,128.54,128.42,128.34,128.21,128.09,127.50,109.62,109.56,100.94,77.48,77.16,76.84,55.59,55.47.

EXAMPLE 22 Synthesis of (((hydroxy) benzylamino) (4- (acetoxy) phenyl) methyl) diphenylphosphine oxide Compound (Compound 22)

Compound 22 has the structural formula:

adding N-benzyl-alpha- (4- (acetoxyl) phenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, placing the flask on the magnetic stirrer for 500 revolutions per minute, stirring at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and when no nitrone compound remains, distilling the mixed solution under reduced pressure to remove the solvent to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 84%.

The structure of compound 22 was examined by nmr and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.85–7.78(m,2H),7.73–7.66(m,1H),7.54(dd,J＝7.6,1.6Hz,1H),7.48–7.43(m,4H),7.42–7.35(m,3H),7.30(dd,J＝7.5,1.6Hz,1H),7.24–7.20(m,4H),7.10(dt,J＝7.4,3.5Hz,2H),6.97(d,J＝8.3Hz,2H),4.62(d,J＝7.2Hz,1H),4.07(d,J＝13.2Hz,1H),3.61(d,J＝13.2Hz,1H),2.26(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.11,150.76,136.79,132.71,132.68,132.65,131.78,131.75,131.65,131.62,131.53,131.25,131.16,130.87,130.75,130.03,129.40,129.31,129.10,129.07,128.95,128.53,128.42,128.36,128.30,128.19,127.50,121.74,121.25,77.48,77.16,76.84,21.29.

EXAMPLE 23 Synthesis of (((hydroxy) benzylamino) (4- (dimethylamino) phenyl) methyl) diphenylphosphine oxide Compound (Compound 23)

Compound 23 is of the formula:

adding N-benzyl-alpha- (4- (dimethylamino) phenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring every minute at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and when no nitrone compound remains, distilling the mixed solution under reduced pressure to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 88%.

The structure of the compound 23 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ9.44(s,3H),7.57–7.51(m,5H),7.30(td,J＝7.4,1.4Hz,3H),7.26(s,2H),7.19(dp,J＝7.3,2.9Hz,7H),7.12(d,J＝6.0Hz,5H),3.43(s,2H),1.30–1.22(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ134.00,131.30,131.21,130.26,128.66,128.18,128.11,127.98,77.48,77.16,76.84,42.74.

EXAMPLE 24 Synthesis of (((hydroxy) benzylamino) (4-isopropylphenyl) methyl) diphenylphosphine oxide Compound (Compound 24)

Compound 24 is of the formula:

adding N-benzyl-alpha- (4-isopropylphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 95%.

The structure of the compound 24 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.82(ddd,J＝11.2,8.3,1.4Hz,2H),7.57–7.51(m,1H),7.46(ddd,J＝8.5,6.6,3.1Hz,2H),7.42–7.34(m,4H),7.31–7.26(m,1H),7.24–7.15(m,5H),7.14–7.05(m,4H),6.66(s,1H),4.59(d,J＝7.0Hz,1H),4.08(d,J＝13.1Hz,1H),3.62(d,J＝13.2Hz,1H),2.83(p,J＝6.9Hz,1H),1.22–1.14(m,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ149.00,148.98,137.08,133.33,132.34,131.86,131.65,131.61,131.58,131.56,131.37,131.34,131.32,131.24,130.88,129.38,128.62,128.44,128.33,128.28,128.07,127.96,127.36,126.23,77.48,77.16,76.84,61.47,61.35,33.85,23.99,23.95.

EXAMPLE 25 Synthesis of (((hydroxy) benzylamino) (1,1' -biphenyl) methyl) diphenylphosphine oxide Compound (Compound 25)

Compound 25 structural formula:

adding N-benzyl-alpha- (1,1' -biphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 88%.

The structure of compound 25 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.84(dd,J＝11.2,7.6Hz,2H),7.71(dd,J＝13.8,7.4Hz,2H),7.63(dd,J＝10.7,8.0Hz,2H),7.55(d,J＝7.5Hz,3H),7.51–7.47(m,6H),7.43(d,J＝7.2Hz,4H),7.36–7.33(m,1H),7.29(d,J＝7.4Hz,1H),7.25–7.22(m,3H),7.13(dd,J＝6.8,2.6Hz,2H),5.08(s,1H),4.12(d,J＝13.0Hz,1H),3.67(d,J＝13.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ141.02,140.56,140.25,136.74,132.72,132.70,132.18,132.12,131.79,131.66,131.58,131.34,131.25,130.89,130.78,129.51,129.38,129.24,129.12,129.09,128.99,128.97,128.88,128.56,128.44,128.38,128.27,128.16,127.95,127.55,127.18,127.14,127.11,126.83,77.48,77.16,76.84,71.31,61.60.

example 26 Synthesis of (1- ((hydroxy) benzylamino) propyl) diphenylphosphine oxide (Compound 26).

Compound 26 has the structural formula:

adding N-benzyl-alpha-ethyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 82%.

The structure of the compound 26 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.75(ddd,J＝11.1,8.3,1.5Hz,4H),7.52–7.40(m,7H),7.21(dd,J＝5.0,1.9Hz,3H),7.09–7.03(m,2H),4.25(d,J＝13.2Hz,1H),3.99(d,J＝13.2Hz,1H),3.64(td,J＝7.0,5.2Hz,1H),2.23(ddt,J＝14.9,11.4,7.4Hz,1H),1.76(dddd,J＝19.3,9.6,7.5,5.2Hz,1H),0.92(t,J＝7.5Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.48,133.07,132.70,132.67,132.56,132.11,131.92,131.89,131.72,131.69,131.65,131.39,131.30,131.20,130.85,130.74,129.43,129.29,129.06,129.01,128.93,128.73,128.62,128.51,128.31,127.36,66.02,65.21,61.67,61.57,17.29,17.25,13.92,13.84.

EXAMPLE 27 Synthesis of (1- ((hydroxy) benzylamino) butyl) diphenylphosphine oxide Compound (Compound 27)

Compound 27 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha-propyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, placing a magnetic stirrer, placing the magnetic stirrer on a magnetic stirrer for 500 revolutions per minute, stirring at the temperature (60 ℃) for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 85%.

The structure of compound 27 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.80–7.72(m,4H),7.51–7.47(m,2H),7.44(dt,J＝8.1,3.3Hz,4H),7.38(s,1H),7.20(dd,J＝5.0,2.0Hz,2H),7.05(dd,J＝6.7,2.8Hz,2H),6.40(s,1H),4.24(d,J＝13.2Hz,1H),3.97(d,J＝13.2Hz,1H),3.73(td,J＝7.1,5.1Hz,1H),2.26–2.10(m,1H),1.73–1.60(m,1H),1.51–1.41(m,1H),1.22–1.11(m,1H),0.79(t,J＝7.3Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.46,133.04,132.69,132.66,132.50,132.08,131.93,131.90,131.71,131.68,131.59,131.43,131.34,131.28,131.19,130.85,130.74,129.38,129.28,129.06,129.00,128.98,128.93,128.70,128.61,128.59,128.50,128.29,127.35,77.48,77.16,76.84,64.24,63.43,61.66,61.57,25.91,25.87,22.26,22.18,14.20,14.07.

EXAMPLE 28 Synthesis of (1- ((hydroxy) benzylamino) isobutyl) diphenylphosphine oxide Compound (Compound 28)

Compound 28 is of the formula:

adding N-benzyl-alpha-isopropyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 83%.

The structure of compound 28 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.80(dddd,J＝11.1,8.4,3.1,1.5Hz,4H),7.62–7.34(m,7H),7.19(dd,J＝5.1,2.0Hz,3H),7.04–6.93(m,2H),6.73(s,1H),4.24(d,J＝13.2Hz,1H),4.09(d,J＝13.2Hz,1H),3.63(dd,J＝7.9,4.6Hz,1H),2.45(dpd,J＝11.4,6.9,4.6Hz,1H),1.06(dd,J＝24.9,6.9Hz,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.54,134.71,133.78,132.89,131.70,131.67,131.48,131.45,131.30,131.20,131.05,130.96,130.79,130.67,129.14,129.05,128.99,128.93,128.86,128.62,128.58,128.51,128.46,128.19,127.25,77.38,77.06,76.74,69.12,68.40,62.61,62.54,28.12,28.06,22.23,22.16,21.82,21.78.

example 29 Synthesis of (1- ((hydroxy) benzylamino) pentyl) diphenylphosphine oxide Compound (Compound 29)

Compound 29 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha-butyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 88%.

The structure of compound 29 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.75(tt,J＝8.5,2.2Hz,4H),7.51–7.47(m,2H),7.43(dq,J＝7.7,3.7Hz,4H),7.37(s,1H),7.20(dd,J＝4.9,2.0Hz,3H),7.07–7.04(m,1H),6.46(s,1H),4.24(d,J＝13.1Hz,1H),3.96(d,J＝13.2Hz,1H),3.70(q,J＝6.5Hz,1H),2.20(dtt,J＝16.6,11.4,5.7Hz,1H),1.78–1.61(m,1H),1.43(ddt,J＝13.9,8.7,5.3Hz,1H),1.24–1.05(m,3H),0.75(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.47,132.99,132.66,132.63,132.49,132.03,131.88,131.85,131.66,131.63,131.57,131.41,131.33,131.27,131.18,130.81,130.70,129.35,129.27,129.02,128.96,128.93,128.90,128.65,128.61,128.57,128.54,128.49,128.45,128.25,127.30,77.48,77.16,76.84,64.39,63.58,61.58,61.48,31.20,31.12,27.65,26.55,23.28,23.24,22.70,13.80.

EXAMPLE 30 Synthesis of (1- ((hydroxy) benzylamino) -3-methylbutyl) diphenylphosphine oxide Compound (Compound 30)

Compound 30 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha-isobutyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 93%.

The structure of compound 30 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.82–7.75(m,3H),7.69(ddd,J＝13.7,8.2,1.4Hz,1H),7.57–7.43(m,7H),7.38(s,1H),7.19(dd,J＝5.0,1.9Hz,2H),7.10–7.01(m,2H),4.25(d,J＝13.3Hz,1H),3.99(d,J＝13.3Hz,1H),3.85(td,J＝7.6,4.9Hz,1H),2.13(dddd,J＝14.1,10.8,7.8,5.8Hz,1H),1.65–1.39(m,2H),0.84(d,J＝6.5Hz,3H),0.71(d,J＝6.5Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ137.61,133.14,133.06,132.68,132.65,132.48,132.18,131.94,131.91,131.76,131.74,131.57,131.46,131.38,131.29,130.85,130.74,129.35,129.19,129.05,129.01,128.97,128.92,128.69,128.66,128.58,128.54,128.26,127.30,77.48,77.16,76.84,62.62,61.83,61.61,61.52,32.99,32.95,26.25,26.17,26.07,23.02,22.68,21.93.

EXAMPLE 31 Synthesis of (1- ((hydroxy) benzylamino) phenylpropyl) diphenylphosphine oxide Compound (Compound 31)

Compound 31 has the structural formula:

adding N-benzyl-alpha-phenethyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. Then the primary product is purified by a pulping method (solvent: petroleum ether or normal hexane) to obtain a pure product. The yield thereof was found to be 82%.

The structure of the compound 31 is detected by nuclear magnetic resonance, and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.76–7.64(m,5H),7.55–7.52(m,2H),7.50–7.42(m,4H),7.29(s,1H),7.26–7.19(m,5H),7.07–7.01(m,2H),6.97(d,J＝1.8Hz,1H),6.68–6.36(m,1H),4.27(d,J＝13.1Hz,1H),4.00(d,J＝13.1Hz,1H),3.81–3.72(m,1H),2.85(t,J＝4.2Hz,1H),2.65–2.54(m,2H),2.09–1.96(m,1H). ¹³ C NMR(101MHz,CDCl ₃ )δ132.95,132.70,132.04,131.80,131.42,131.35,131.32,131.26,130.90,130.79,129.44,129.10,129.03,128.97,128.84,128.75,128.72,128.66,128.59,128.42,127.48,126.41,126.19,62.76,61.87,61.78,34.22,34.14,26.09,26.04.

example 32 Synthesis of ((hydroxy (methyl) amino) (phenyl) methyl) diphenylphosphine oxide Compound (Compound 32)

Compound 32 has the structural formula:

the synthesis process comprises the following steps: adding N-methyl-alpha-phenyl nitrone (0.001 mol), phosphorus diphenoxylate (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 3 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 88%.

The structure of compound 32 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.97–7.86(m,2H),7.54–7.41(m,5H),7.31(ddd,J＝8.8,7.0,1.6Hz,3H),7.25–7.05(m,6H),4.61(d,J＝5.3Hz,1H),2.59(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ133.39,132.41,132.12,131.84,131.81,131.68,131.62,131.56,131.53,131.49,131.48,131.26,131.20,130.70,128.63,128.52,128.34,128.33,128.18,128.14,128.02,46.75,46.64.

example 33 Synthesis of ((hydroxy (methyl) amino) (4-methylphenyl) methyl) diphenylphosphine oxide Compound (Compound No. 33)

Compound 33 has the structural formula:

adding N-methyl-alpha- (4-methylphenyl) nitrone (0.001 mol), phosphorus diphenoxy (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring every minute at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature of 60 ℃, monitoring the reaction by TLC, and when no nitrone compound remains, distilling the mixed solution under reduced pressure to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 92%.

The structure of compound 33 was examined by nmr and the results are as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.88(ddd,J＝11.1,8.2,1.5Hz,2H),7.55–7.45(m,5H),7.37–7.32(m,1H),7.25(d,J＝5.7Hz,2H),7.21–7.16(m,2H),6.98(d,J＝7.8Hz,2H),6.76(s,1H),4.53(d,J＝5.9Hz,1H),2.55(s,3H),2.25(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ131.66,131.64,131.57,131.24,128.92,128.65,128.53,128.18,128.07,77.48,77.16,76.84,46.55,46.43,21.29.

EXAMPLE 34 Synthesis of (((hydroxy) benzylamino) (phenyl) methyl) (3,5-xylyl) phosphine oxide (Compound 34)

Compound 34 has the structural formula:

the synthesis process comprises the following steps: adding N-benzyl-alpha-phenyl nitrone (0.001 mol), 3,5-dimethylphenyl oxyphosphorus (0.0015 mol) and N-hexane (5 ml) into a round-bottom flask with the volume of 10ml in sequence, putting a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting for 3 hours at the temperature (60 ℃), monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 75%.

The structure of compound 34 was examined by nmr and the results were as follows:

¹ H NMR(400MHz,CDCl ₃ )δ7.30(dddd,J＝17.2,7.0,3.4,2.0Hz,5H),7.15–7.10(m,6H),7.07–6.98(m,3H),6.86(dd,J＝11.4,1.6Hz,2H),6.78(s,1H),4.41(d,J＝8.0Hz,1H),3.94(d,J＝13.1Hz,1H),3.49(d,J＝13.2Hz,1H),2.24(s,6H),2.01(s,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ138.15,138.03,137.76,137.64,136.95,133.54,133.51,133.27,131.99,131.93,129.45,129.38,129.17,129.12,129.09,128.98,128.89,128.75,128.59,128.35,128.28,128.24,128.03,127.45,77.48,77.16,76.84,21.53,21.24.

example 35 Synthesis of (2-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl) diphenylphosphine oxide (Compound 35)

Compound 35 is of the formula:

the synthesis process comprises the following steps: adding 3,4-dihydroisoquinoline-2-oxide (0.001 mol), phosphorus diphenoxylate (0.0012 mol) and n-hexane (5 ml) into a round bottom flask with the volume of 10ml in sequence, adding a magnetic stirrer, stirring at 500 revolutions per minute on the magnetic stirrer, reacting at the temperature of 60 ℃ for 5 hours, monitoring the reaction by TLC, and distilling the mixed solution under reduced pressure to remove the solvent when no nitrone compound remains to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 85%.

The structure of compound 35 was examined by nmr and the results are as follows:

¹ H NMR(500MHz,CDCl ₃ )δ7.87–7.78(m,4H),7.57–7.45(m,6H),7.24–7.14(m,2H),7.12(dd,J＝4.8,1.2Hz,2H),4.60(p,J＝6.0Hz,1H),4.40(ddd,J＝11.5,6.0,1.0Hz,1H),3.99(d,J＝6.4Hz,1H),2.99(dddd,J＝14.8,8.0,5.7,1.1Hz,1H),2.77(dddd,J＝14.8,7.9,5.7,0.9Hz,1H),2.05(ddt,J＝13.7,7.9,5.7Hz,1H),1.87(ddt,J＝13.6,8.1,5.7Hz,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ134.88,133.46,132.56,131.76,131.30,129.35,128.59,127.21,126.92,126.68,70.81,48.93,28.60,27.28.

example Synthesis of ((2R, 3S, 4R) -2,3-bis (benzyloxy) -4- ((benzyloxy) methyl) -5-hydroxycyclopentyl) diphenyl oxide (Compound 36)

Compound 36 is of the formula:

the synthesis process comprises the following steps: a round bottom flask with the volume of 10ml is sequentially added with (2S, 3S, 4S) -3,4-bis (benzyloxy) -2- ((benzyloxy) methyl) -3,4-dihydro-2H-pyrrole 1-oxide (0.001 mol), diphenoxy phosphorus (0.0012 mol) and n-hexane (5 ml), a magnetic stirrer is placed in the round bottom flask, the round bottom flask is placed on the magnetic stirrer for 500 revolutions per minute, the temperature (60 ℃) is reacted for 5 hours, the reaction is monitored by TLC, when no nitrone compound is left, the mixed solution is decompressed and distilled to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 88%.

The structure of compound 36 was examined by nmr and the results were as follows:

¹ H NMR(500MHz,CDCl ₃ )δ7.87(ddt,J＝13.3,6.8,1.4Hz,4H),7.56–7.48(m,2H),7.46(tdd,J＝8.0,4.0,1.0Hz,4H),7.34(tddd,J＝5.0,3.3,2.3,1.2Hz,4H),7.34–7.24(m,11H),4.73(dd,J＝6.6,5.9Hz,1H),4.62(ddt,J＝12.1,6.0,0.9Hz,2H),4.56–4.49(m,2H),4.49–4.38(m,3H),4.29(dd,J＝5.9,4.2Hz,1H),4.07(dd,J＝11.4,6.6Hz,1H),3.83(dd,J＝10.6,4.6Hz,1H),3.69(dd,J＝10.5,4.7Hz,1H),3.31(q,J＝4.5Hz,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ137.82,137.59,137.42,131.79,130.98,130.72,128.62,128.43,128.41,128.40,128.22,128.13,128.10,128.08,128.07,127.99,127.95,81.64,81.29,73.30,72.87,72.39,67.00,61.80,58.93.

example 37 ((3R, 4S, 5S) -3,4-bis (benzyloxy) -5- ((S) -1,2-bis (benzyloxy) ethyl) -1-hydroxypyrrolidin-2-yl) diphenylphosphine oxide

Compound 37 has the structural formula:

the synthesis process comprises the following steps: a round bottom flask with the volume of 10ml is sequentially added with (2S, 3S, 4S) -3,4-bis (benzyloxy) -2- ((S) -1,2-bis (benzyloxy) ethyl) -3,4-dihydro-2H-pyrrole-1-oxide (0.001 mol), diphenoxy phosphorus (0.0012 mol) and n-hexane (5 ml), a magnetic stirrer is placed in the round bottom flask, the round bottom flask is placed on a magnetic stirrer for 500 revolutions per minute to be stirred, the temperature (60 ℃) is reacted for 8 hours, TLC monitors the reaction, when no nitrone compound remains, the mixed solution is decompressed and distilled to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 82%.

The structure of compound 37 was examined by nmr and the results were as follows:

¹ H NMR(500MHz,CDCl ₃ )δ7.90–7.81(m,4H),7.55–7.48(m,2H),7.46(tdd,J＝7.9,3.9,1.0Hz,4H),7.38–7.24(m,20H),4.93(dd,J＝6.6,5.9Hz,1H),4.77(s,1H),4.72(dt,J＝12.1,1.1Hz,1H),4.62(dt,J＝12.1,1.1Hz,1H),4.58–4.50(m,2H),4.52–4.45(m,2H),4.42(ddt,J＝15.9,12.1,1.0Hz,2H),4.25(t,J＝5.9Hz,1H),4.07(dd,J＝11.5,6.6Hz,1H),3.80–3.70(m,2H),3.56(dd,J＝11.0,5.9Hz,1H),3.23(dd,J＝6.2,5.3Hz,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ137.79,137.76,137.50,137.43,131.74,130.94,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.15,128.14,128.07,128.01,128.00,81.98,80.73,74.53,73.60,72.94,72.50,71.18,70.95,62.88,61.85.

example 38 ((3R, 4S, 5R) -3,4-bis (benzyloxy) -5- ((S) -1,2-bis (benzyloxy) ethyl) -1-hydroxypyrrolidin-2-yl) diphenylphosphine oxide

Compound 38 structural formula is:

the synthesis process comprises the following steps: a round bottom flask with the volume of 10ml is sequentially added with (2R, 3S, 4S) -3,4-bis (benzyloxy) -2- ((S) -1,2-bis (benzyloxy) ethyl) -3,4-dihydro-2H-pyrrole-1-oxide (0.001 mol), diphenoxy phosphorus (0.0012 mol) and n-hexane (5 ml), a magnetic stirrer is placed in the round bottom flask, the round bottom flask is placed on a magnetic stirrer for 500 revolutions per minute to be stirred, the temperature (60 ℃) is reacted for 8 hours, TLC monitors the reaction, when no nitrone compound remains, the mixed solution is decompressed and distilled to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 80%.

The structure of compound 38 was examined by nmr and the results are as follows:

¹ H NMR(500MHz,CDCl ₃ )δ7.89(ddt,J＝13.2,6.8,1.4Hz,4H),7.55–7.48(m,2H),7.46(tdd,J＝7.9,3.9,1.1Hz,4H),7.38–7.24(m,20H),4.98(dd,J＝6.6,5.9Hz,1H),4.62(dt,J＝12.0,1.1Hz,1H),4.58–4.47(m,4H),4.51–4.37(m,3H),4.35(dt,J＝12.1,1.0Hz,1H),4.16(dd,J＝5.8,5.1Hz,1H),4.07(dd,J＝11.6,6.6Hz,1H),3.80–3.69(m,2H),3.49(dd,J＝11.3,5.4Hz,1H),3.27(t,J＝5.2Hz,1H).13C NMR(125MHz,CDCl ₃ )δ137.79,137.76,137.50,137.43,131.74,130.94,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.15,128.14,128.07,128.01,128.00,81.98,80.73,74.53,73.60,72.94,72.50,71.18,70.95,62.88,61.85.

example 38 ((3R, 4S,5S, 6R) -3,4,5-tris (benzyloxy) -6- ((benzyloxy) methyl) -1-hydroxypiperidin-2-yl) diphenylphosphine oxide

Compound 39 has the structural formula:

the synthesis process comprises the following steps: a round bottom flask with the volume of 10ml is sequentially added with (2R, 3S,4S, 5S) -3,4,5-tri (benzyloxy) -2- ((benzyloxy) methyl) -2,3,4,5-tetrahydropyridine-1-oxide (0.001 mol), diphenoxy phosphorus (0.0012 mol) and n-hexane (5 ml), a magnetic stirrer is placed in the round bottom flask, the round bottom flask is placed on the magnetic stirrer for 500 revolutions per minute, the temperature (60 ℃) is reacted for 5 hours, the reaction is monitored by TLC, when no nitrone compound is left, the mixed solution is decompressed and distilled to remove the solvent to obtain an initial product. The crude product was then purified by recrystallization (solvent: n-hexane/ethyl acetate, 80). The yield thereof was found to be 85%.

The structure of compound 39 was examined by nmr and the results are as follows:

¹ H NMR(500MHz,CDCl ₃ ))δ7.86–7.77(m,5H),7.55–7.48(m,2H),7.45(tdd,J＝7.8,3.9,1.0Hz,4H),7.40–7.32(m,6H),7.35–7.24(m,15H),4.80(ddt,J＝11.9,3.5,1.0Hz,2H),4.63(dt,J＝12.1,1.0Hz,2H),4.51(dt,J＝12.1,0.9Hz,1H),4.48–4.36(m,4H),4.04(dd,J＝11.5,6.6Hz,1H),3.99(dd,J＝7.6,5.2Hz,1H),3.86(dd,J＝5.2,3.6Hz,1H),3.80(dd,J＝10.5,6.3Hz,1H),3.74(dd,J＝10.5,6.3Hz,1H),3.16(td,J＝6.3,3.7Hz,1H). ¹³ C NMR(125MHz,CDCl ₃ ))δ138.39,137.73,137.51,137.43,131.74,130.69,130.67,128.63,128.46,128.45,128.43,128.41,128.39,128.27,128.24,128.21,128.18,128.17,128.15,128.07,128.01,128.00,76.61,75.83,75.42,73.24,72.40,71.92,71.80,71.75,64.30,57.25.

example 40

The in vitro anti-tumor activity test of the synthetic compound and the cytotoxicity test on normal cells.

The experimental principle is as follows: the tetrazolium salt (MTT) reduction method was tested in vitro. Camptothecin (Camptothecin) was selected as a positive control.

Cell lines: human lung adenocarcinoma cells (A549), human breast cancer cells (MCF-7), and mouse lung epithelial cells (TC-1).

The experimental method comprises the following steps:

prepared at a concentration of 1X 10 ⁵ mu.g/mL of the cell suspension, adding to a 96-well plate at 100. Mu.L per well, at 37 ℃,5% CO ₂ Incubate in incubator for 24h.

The test substances with different concentrations are added into a 96-well plate of cultured tumor cells and normal cells, and the culture is continued for 24 hours and observed under an inverted microscope.

The culture medium was discarded, and 100. Mu.L of 0.05% MTT application solution was added to each well, followed by culture for 4 hours.

The culture solution was discarded, 100. Mu.L of DMSO was added to each well, formazan crystals were dissolved by shaking for 5min, and the absorbance (OD value) of the cells was measured at 490 nm.

The experimental data processing method comprises the following steps:

the absorbance of the cells in the wells without drug was used as the absorbance (OD value) of the blank control group, and the calculation formula was as follows:

inhibition (%) = (blank OD average value-sample OD average value)/blank OD average value x 100%,

and (3) obtaining a concentration and time-growth inhibition rate curve according to the growth inhibition rate mapping at different time and different dosage, adopting GraphPad Prism 9.0 software to map, and calculating the half inhibition concentration IC50 of the target compound to the two tumor cells by using the software. See table below.

The results in the table show that the compound has a certain inhibiting effect on A549/MCF-7 tumor cells, and has no obvious toxicity on normal cells TC-1, which indicates that the compound has potential medicinal value and is expected to be used for preparing various anti-cancer medicaments.

The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims

1. A method for preparing alpha- (hydroxyl amino) diaryl phosphine oxide by nitrone is characterized in that nitrone shown in formula (2) and diaryl phosphine oxide shown in formula (3) are used as raw materials to react under heating condition to obtain alpha- (hydroxyl amino) diaryl phosphine oxide shown in formula (1),

wherein R is ₁ Is selected from C ₁ -C ₁₀ Alkyl, furyl, thienyl, C ₅ -C ₆ One of alkylene ring, phenyl group or aromatic group,

R ₂ is selected from C ₁ -C ₁₀ Alkyl of (C) ₅ -C ₆ One of an alkylene ring, a substituted or unsubstituted phenyl group;

R ₃ 、R ₄ each independently selected from phenyl and aryl.

2. A process for preparing an α - (hydroxyamino) diarylphosphine oxide from a nitrone according to claim 1, wherein R is ₁ Selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl, halophenyl, alkyl-substituted phenyl, methoxy-substituted phenyl, methylamino-substituted phenyl, acetoxy-substituted phenyl, naphthyl, or biphenyl.

3. A process for preparing an α - (hydroxyamino) diarylphosphine oxide from a nitrone according to claim 1, wherein R is ₂ Selected from ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl, phenyl or benzyl, preferably, R ₁ 、R ₂ Each independently selected from C ₅ -C ₆ An alkylene ring.

4. The method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone according to claim 1, wherein the ratio of nitrone to diarylphosphine oxide is 1:1-2.

5. A method for preparing α - (hydroxyamino) diarylphosphine oxide from nitrone according to claim 1, wherein nitrone, diarylphosphine oxide compound is used as raw material, water or n-hexane is used as solvent, and preferably, the amount of water and n-hexane is 50-100 times of the amount of nitrone.

6. A process for preparing α - (hydroxyamino) diarylphosphine oxide from nitrone according to claim 1, wherein the reaction time is 1-3 hours.

7. The method for preparing alpha- (hydroxyamino) diarylphosphine oxide from nitrone according to claim 1, wherein nitrone represented by formula (2) and diarylphosphine oxide compound represented by formula (3) are used as raw materials, and the reaction is carried out at 60-90 ℃.

8. The method for preparing α - (hydroxyamino) diarylphosphine oxide from nitrone according to claim 1, wherein α - (hydroxyamino) diarylphosphine oxide represented by formula (1) is obtained and then purified by the steps of: removing solvent, and purifying by recrystallization or pulping to obtain pure product.

9. A process for the preparation of α - (hydroxyamino) diarylphosphine oxides from nitrones according to claim 8, wherein the step of recrystallization is: dissolving the product by using ethyl acetate, separating out the product by using normal hexane, and performing suction filtration to obtain a pure product; or

The pulping steps are as follows: firstly, adding normal hexane into the product, quickly stirring to dissolve impurities, and carrying out suction filtration to obtain a pure product.

10. Use of an α - (hydroxyamino) diarylphosphine oxide prepared by the method of claim 1 in the preparation of an anti-tumor medicament.