Preparation method of heterocyclic compound containing phosphorus and nitrogen

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a preparation method of a phosphorus-containing nitrogen heterocyclic ring compound. According to the invention, the diphenyl phosphorus oxide and the vinyl-substituted nitrogen heterocyclic ring compound are used as reaction substrates, and a series of phosphorus-containing nitrogen heterocyclic ring compounds are generated through a one-step reaction. The synthesis of the phosphorus-containing nitrogen heterocyclic compound can be realized through a one-step addition reaction, the reaction steps are simple, the operation is convenient, the synthesis efficiency is remarkably improved, and the method is suitable for synthesis of various vinyl-substituted nitrogen heterocyclic compounds, has a wide substrate application range, and is suitable for industrial production. The method is beneficial to promotion of further application and development of the phosphorus-containing nitrogen heterocyclic ring compounds in various fields, provides an efficient and universal way for synthesis of the compounds, also conforms to the pursuit of green chemistry and sustainable development in nowadays society, and is extremely high in popularization value.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing phosphorus-nitrogen-containing heterocyclic compounds. Background Art

[0002] In the field of organic chemistry, phosphorus-nitrogen heterocycles are a class of extremely valuable organophosphorus compounds. The unique phosphorus-nitrogen heterocyclic structure in their structure gives these compounds many excellent properties, which also makes them widely used in many fields. In the field of synthetic chemistry, phosphorus-nitrogen heterocyclic compounds are often used as key synthetic intermediates and can participate in the construction process of various complex organic molecules, providing organic synthetic chemists with a rich variety of synthetic strategies and route options. In the field of agrochemicals, some phosphorus-nitrogen heterocyclic compounds show good biological activity and can be used to develop new pesticides, which helps to improve the yield and quality of crops and ensure the stable development of agricultural production. In the field of medicinal chemistry, this type of compound plays an even more important role. Some drug molecules containing phosphorus-nitrogen heterocyclic structures have been developed and applied in clinical treatment, making contributions to human health, as shown in the following formula.

[0003]

[0004] McCracken and coworkers performed the synthesis of bis(1-aziridinyl)phosphocarbamates. In vivo studies showed that the synthesized drugs were more toxic to cancer cells and that they did not invade other tissues. Chernov's research showed high activity of phosphazines against transplanted cancers such as bis(aziridin-1-yl)(pyrimidin-2-ylmethyl)phosphine oxide in studies in mice, rats, and rabbits. In 1968, Noell et al. synthesized bis(2-methylaziridin-1-yl)(pyrimidin-2-ylmethyl)phosphine oxide, which showed good activity against leukemia, being more active and less toxic than several clinical drugs.

[0005] At present, in addition to the classic Michaelis-Arbuzov reaction, there are also methods for obtaining phosphorus-nitrogen heterocyclic compounds, such as using a series of halides, sulfonates, boric acid, esters, etc., using secondary phosphorus as raw materials, using metal salts such as palladium, silver, nickel, copper, etc. as catalysts, reacting in the presence of a base or ligand, or cross-coupling with a large amount of base and oxidant. However, these reactions generally have some defects. On the one hand, a large amount of toxic waste will inevitably be produced during the reaction process. The treatment of these toxic wastes not only increases the production cost, but also causes serious pollution to the environment; on the other hand, these reactions are often accompanied by low atomic economy, and the atoms in the reactants cannot be fully converted into target products, resulting in a waste of resources. In addition, the use of a large amount of bases and oxidants will also bring a series of environmental problems, such as increased difficulty in wastewater treatment. In recent reports, boron trifluoride ether was used as a catalyst and toluene as a solvent to synthesize compounds. Although the reaction has become more efficient and simple, the catalysts and solvents used are more harmful to the body, and long-term contact has the risk of carcinogenesis. Therefore, it is particularly important and urgent to develop greener, more economical, mild and friendly methods for preparing phosphorus-nitrogen heterocyclic compounds. Summary of the invention

[0006] In view of the problems that the methods for preparing phosphorus-nitrogen heterocyclic compounds in the prior art generate toxic pollutants and have low atom economic efficiency, the present invention provides a method for preparing phosphorus-nitrogen heterocyclic compounds.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] In one aspect, the present invention provides a method for preparing a phosphorus-nitrogen heterocyclic compound, comprising the following steps:

[0009] Under an inert atmosphere, a diphenylphosphine oxide compound represented by formula (II) and a vinyl-substituted nitrogen-containing heterocyclic compound represented by formula (III) are subjected to an addition reaction in an organic solvent to obtain a phosphorus-nitrogen-containing heterocyclic compound represented by formula (I);

[0010]

[0011] Among them, R 1 , R 2 R is independently selected from phenyl, substituted phenyl, C1-C5 alkyl, C2-C5 alkenyl, biphenyl or C5-C6 cycloalkyl; 3 Selected from nitrogen-containing heterocycles.

[0012] The specific synthetic route is as follows:

[0013]

[0014] The synthesis of phosphorus-containing nitrogen heterocyclic compounds by a one-step method using diphenylphosphine oxide and vinyl-substituted nitrogen heterocyclic compounds as raw materials has not been reported. Using diphenylphosphine oxide and vinyl-substituted nitrogen heterocyclic compounds as reaction substrates, a series of phosphorus-containing nitrogen heterocyclic compounds were generated by a one-step reaction, achieving structural diversification of the target compounds, which is of great value for expanding the application of phosphorus-containing nitrogen heterocyclic compounds in the fields of medicine and industrial production.

[0015] It should be noted that the inert atmosphere is provided by conventional inert gases in the art, such as nitrogen, argon, etc.

[0016] Furthermore, R 3 Selected from Among them, R 4 Selected from H, C 1 -C 5 Alkyl, C 1 -C 5 Alkoxy or halogen.

[0017] Furthermore, the substituted phenyl group is selected from tolyl, methoxyphenyl or halogenated phenyl.

[0018] Furthermore, the halogen is F, Cl or Br.

[0019] Furthermore, the organic solvent is one or more of toluene, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane or hexafluoroisopropanol.

[0020] Preferably, the organic solvent is hexafluoroisopropanol.

[0021] Carrying out the reaction under specific organic solvent conditions can promote the full reaction of the diphenylphosphine oxide compound and the vinyl-substituted nitrogen heterocyclic compound, and greatly improve the yield while ensuring the purity of the target product.

[0022] Furthermore, the molar ratio of the diphenylphosphine oxide compound to the vinyl-substituted nitrogen heterocyclic compound is (1-2):1.

[0023] Preferably, the molar ratio of the diphenylphosphine oxide compound to the vinyl-substituted nitrogen heterocyclic compound is 1.3:1.

[0024] The preferred ratio of the reactants can ensure that the reaction proceeds in the forward direction and the yield of the target product is increased under the condition of using a smaller amount.

[0025] Furthermore, the molar volume ratio of the diphenylphosphine oxide compound to the organic solvent is 1 mmol: (1-3) mL.

[0026] Preferably, the molar volume ratio of the diphenylphosphine oxide to the organic solvent is 1 mmol:1.5 mL.

[0027] Furthermore, the temperature of the addition reaction is 80°C to 120°C.

[0028] The preferred reaction temperature can reduce the occurrence of side reactions while ensuring the yield, thereby improving the yield and purity of the target product.

[0029] It should be noted that, during the addition reaction, thin layer chromatography was used to monitor the reaction progress and determine the reaction completion time.

[0030] Furthermore, the preparation method of the above phosphorus-nitrogen heterocyclic compound further comprises a refining step:

[0031] Ethyl acetate was added to the reaction solution for extraction, and a saturated sodium chloride solution was added to the obtained organic phase for washing, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain a phosphorus-nitrogen heterocyclic compound represented by formula (I).

[0032] Specifically, the eluent for column chromatography separation and purification is a mixed solution of dichloromethane and methanol in a volume ratio of (30-100):1.

[0033] The present invention can realize the synthesis of phosphorus-nitrogen heterocyclic compounds through a one-step addition reaction, the reaction steps are simple, no catalyst is required, and the solvent is green and pollution-free. The operation is convenient, the synthesis efficiency is significantly improved, and the method is applicable to the synthesis of various nitrogen-containing heterocyclic compounds, and has a wide range of substrate applications. It not only helps to promote the further application and development of phosphorus-nitrogen heterocyclic compounds in various fields, but also provides an efficient and universal way for the synthesis of such compounds, and also meets the pursuit of green chemistry and sustainable development in today's society, and has a very high promotion value. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0035] In order to better illustrate the present invention, further examples are given below.

[0036] Example 1

[0037] Preparation of diphenyl (2- (pyridinyl 4-yl) ethyl) phosphine oxide:

[0038] Diphenylphosphine (1.3 mmol) and tetravinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol (HFIP), and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was used for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 30:1) to obtain 125 mg of product with a purity of 94% and a yield of 85%. The reaction equation is as follows:

[0039]

[0040] 1 H NMR (500 MHz, CDCl 3 ): δ8.41(s,2H),7.75–7.64(m,4H),7.47(td,J=7.4,1.6Hz,2H),7.41(td,J=7 .5, 2.8Hz, 4H), 7.02 (d, J = 5.5Hz, 2H), 2.120–2.82 (m, 2H), 2.54–2.47 (m, 2H).

[0041] 13 C NMR (126MHz,,CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.00,26.97.

[0042] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0043] Example 2

[0044] Phenyl (2-(pyridinyl-4-yl)ethyl))-o-methyl)phosphorus oxide:

[0045] Phenyl (o-tolyl) phosphine oxide (1.3 mmol) and 4-vinyl pyridine (1 mmol) were added to a thick-walled pressure bottle containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL). Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 140 mg of product with a purity of 95% and a yield of 92%. The reaction equation is:

[0046]

[0047] 1 H NMR (500 MHz, CDCl 3 ): δ8.49(s,2H),7.74–7.63(m,3H),7.56–7.42(m,4H),7.32(td,J=6.3,5.2,2.4Hz,1H),7.2 5(dd,J=7.8,4.1Hz,1H),7.15(d,J=5.0Hz,2H),3.12–2.54(m,4H),2.40(s,3H),2.05(s,2H).

[0048] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.00,26.97.23.21.

[0049] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0050] Example 3

[0051] Preparation of (4-fluorophenyl)(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0052] (4-Fluorophenyl)(phenyl)phosphine oxide (1.3 mmol) and 4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 142 mg of product with a purity of 98% and a yield of 91.5%. The reaction equation is:

[0053]

[0054] 1 H NMR (500 MHz, CDCl 3 ): δ8.58–8.40(m,2H),7.77(dtdd,J=11.8,8.6,4.3,1.9Hz,4H),7.61–7.47(m ,3H),7.26–7.11(m,4H),3.00–2.120(m,2H),2.66–2.54(m,2H),2.07(s,2H).

[0055] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.03,24.57.

[0056] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0057] Example 4

[0058] [1,1'-Biphenyl]-4-yl(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0059] [1,1'-Biphenyl]-4-yl(phenyl)phosphine oxide (1.3 mmol) and 4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh) with a volume ratio of 50:1 dichloromethane / methanol as eluent to obtain 170 mg of the product with a purity of 96% and a yield of 93%. The reaction equation is:

[0060]

[0061] 1 H NMR (500 MHz, CDCl 3 ): δ8.58–8.35(m,2H),7.120–7.76(m,4H),7.70(dd,J=8.2,2.7Hz,2H),7.6 1–7.36(m,8H),7.13(d,J=5.0Hz,2H),3.02–2.92(m,2H),2.67–2.56(m,2H).

[0062] 13 C NMR (126 MHz, CDCl 3 ): δ173.87,150.53,150.42,149.40,144.96,144.94,139.70,132.17,132.15,131.35,131.27,130.94,130.82,130.74, 130.14,129.00,128.95,128.88,128.86,128.78,128.27,127.56,127.47,127.24,123.69,30.84,30.28,27.03,27.00.

[0063] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0064] Example 5

[0065] Benzyl(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0066] Benzyl (phenyl) phosphine oxide (1.3 mmol) and 4-vinyl pyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh) with a volume ratio of 50:1 (dichloromethane / methanol) as the eluent to obtain 140 mg of the product with a purity of 95% and a yield of 92%. The reaction equation is:

[0067]

[0068] 1 H NMR (500 MHz, CDCl 3 ): δ8.44(d,J=5.0Hz,2H),7.74–7.40(m,5H),7.34–6.93(m,8H),3.50–3.27(m,2H),2.8 8(tdd,J=13.3,8.4,4.9Hz,1H),2.66(tdd,J=13.3,7.9,5.1Hz,1H),2.35–2.09(m,2H).

[0069] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.00,26.97.

[0070] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0071] Example 6

[0072] Preparation of Allyl(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0073] Allyl (phenyl) phosphorus oxide (1.3 mmol) and 4-vinyl pyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 118 mg of product with a purity of 93% and a yield of 91%. The reaction equation is:

[0074]

[0075] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,5H),7.59–7.46(m,2H),7.09(s,2H),4.77(d ,H),4.32(s,2H),3.66–2.98(s,2H),3.00–2.88(m,2H),2.64–2.52(m,2H).

[0076] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,131.98,130.79,130.72,128.87,123.53,30.120,30.34,27.40,28.93.

[0077] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0078] Example 7

[0079] Preparation of (4-methoxyphenyl)(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0080] (4-Methoxyphenyl)(phenyl)phosphine oxide (1.3 mmol) and 4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 149 mg of product with a purity of 95% and a yield of 92.5%. The reaction equation is:

[0081]

[0082] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),4.12–3.76(s,3H),3.00–2.88(m,2H),2.64–2.52(m,2H).

[0083] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,26.97,21.33.

[0084] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0085] Example 8

[0086] Preparation of ethyl(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0087] Ethyl (phenyl) phosphorus oxide (1.3 mmol) and 4-vinyl pyridine (1 mmol) were added to a thick-walled pressure bottle containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 115 mg of product with a purity of 97% and a yield of 93%. The reaction equation is:

[0088]

[0089] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),4.19–3.86(s,3H)2.64–2.52(m,2H).

[0090] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,21.53.

[0091] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0092] Example 9

[0093] Preparation of cyclohexyl(phenyl)(2-(pyridin-4-yl)ethyl)phosphine oxide:

[0094] Cyclohexyl (phenyl) phosphine oxide (1.3 mmol) and 4-vinyl pyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 136 mg of product with a purity of 95% and a yield of 91%. The reaction equation is:

[0095]

[0096] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.88(m,2H),1.94–1.52(m,4H),1.38–1,59(s,7H).

[0097] 13 C NMR (126 MHz, CDCl 3 ): δ153.09,149.69,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,113.53,30.120,30.34,27.70,29.96.

[0098] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0099] Example 10

[0100] Preparation of dibenzyl (2-(pyridin-4-yl) ethyl) phosphine oxide:

[0101] Dibenzylphosphorus oxide (1.3 mmol) and 4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 145 mg of product with a purity of 94% and a yield of 91%. The reaction equation is:

[0102]

[0103] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.91(m,4H),2.64–2.52(m,4H).

[0104] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130 .72,128.87,128.78,123.53,42,77,42,45,30.120,30.34,26.88,26.67.

[0105] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0106] Embodiment 11

[0107] Preparation of (2-(2-methylpyridin-4-yl)ethyl)diphenylphosphine oxide:

[0108] Diphenylphosphine (1.3 mmol) and 2-methyl-4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by column chromatography on a silica gel column (200-300 mesh) with a volume ratio of 50:1 dichloromethane / methanol as eluent to obtain 130 mg of the product with a purity of 98% and a yield of 96%. The reaction equation is:

[0109]

[0110] 1 H NMR (500 MHz, CDCl 3): δ8.52(s,1H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.88(m,2H),2.64–2.52(m,2H),1.67–1.58(s,3H).

[0111] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.00,26.97,21.33.

[0112] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0113] Example 12

[0114] Preparation of (2-bromopyridin-4-yl)ethyl)diphenylphosphine oxide:

[0115] Diphenylphosphine (1.3 mmol) and 2-bromo-4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol in a volume ratio of 50:1) to obtain 100 mg of the product with a purity of 95% and a yield of 95.2%. The reaction equation is:

[0116]

[0117] 1 H NMR (500 MHz, CDCl 3 ): δ8.58(s,1H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.88(m,2H),2.64–2.52(m,2H).

[0118] 13 C NMR (126 MHz, CDCl3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.09,23.37.

[0119] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0120] Example 13

[0121] Preparation of (3-chloropyridin-4-yl)ethyl)diphenylphosphine oxide:

[0122] Diphenylphosphine (1.3 mmol) and 1 mmol of 3-chloro-4-vinylpyridine were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 115 mg of product with a purity of 96% and a yield of 95%. The reaction equation is:

[0123]

[0124] 1 H NMR (500 MHz, CDCl 3 ): δ8.43(s,2H),7.84–7.73(m,3H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.88(m,2H),2.64–2.52(m,2H).

[0125] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.40,26.67.

[0126] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0127] Embodiment 14

[0128] Preparation of (2-methoxypyridin-4-yl)ethyl)diphenylphosphine oxide:

[0129] Diphenylphosphine (1.3 mmol) and 2-methoxy-4-vinylpyridine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90°C and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was quenched with water (15 mL), and ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing, and anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 108.8 mg of the product, with a purity of 95% and a yield of 88%. The reaction equation is:

[0130]

[0131] 1 H NMR (500 MHz, CDCl 3 ): δ8.48(s,2H),7.84–7.73(m,4H),7.59–7.46(m,6H),7.09(s,2H),3.00–2.88(m,2H),2.64–2.52(m,2H),1.68–1,43(s,3H).

[0132] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,123.53,30.120,30.34,27.10,26.69,21.88.

[0133] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0134] Embodiment 15

[0135] Preparation of diphenyl (2- (pyridine-2-) ethyl) phosphine oxide:

[0136] Diphenylphosphine oxide (1.3 mmol) and 2-vinylpyridine (1 mmol) were added to a thick-walled pressure-resistant flask containing 2 mL of hexafluoroisopropanol. The air in the flask was replaced with argon, and the reaction mixture was stirred at 90 °C. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, it was quenched with water (15 mL). Ethyl acetate (3 × 20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 was dried, filtered, and the obtained filtrate was concentrated. It was separated by silica gel column (200 - 300 mesh), and the eluent was dichloromethane / methanol with a volume ratio of 50:1) chromatography to obtain 140.2 mg of the product with a purity of 95% and a yield of 96%. The reaction equation is:

[0137]

[0138] 1 H NMR (500 MHz, CDCl 3 ):δ 8.38 (d, J = 27.9 Hz, 2H), 7.74–7.62 (m, 2H), 7.52–7.29 (m, 7H), 7.25–7.01 (m, 8H), 4.81 (t, J = 7.8 Hz, 1H), 3.88 (t, J = 7.6 Hz, 1H).

[0139] 13 C NMR (126 MHz, CDCl 3 ):δ 150.09, 149.87, 149.84, 132.76, 132.04, 131.02, 131.98, 130.79, 130.72, 128.87, 128.78, 123.53, 30.120, 30.34, 27.03, 26.89.

[0140] Using other reaction conditions and reaction solvents defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0141] Example 16

[0142] Preparation of diphenyl(2-(pyrazin-2-ylethyl)ethyl)phosphine oxide:

[0143] Diphenylphosphine (1.3 mmol) and 2-vinylpyrazine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 140.7 mg of product with a purity of 97% and a yield of 96%. The reaction equation is:

[0144]

[0145] 1 H NMR (500 MHz, CDCl 3 ): δ8.58(s,3H),7.84–7.73(m,4H),7.59–7.46(m,6H),3.08–2.98(m,2H),2.64–2.57(m,2H).

[0146] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,128.87,128.78,30.120,30.34,27.00,26.97.

[0147] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0148] Embodiment 17

[0149] Preparation of (Benzo[d]oxazol-2-yl)ethyl)diphenylphosphine oxide:

[0150] Diphenylphosphine (1.3 mmol) and 2-vinylpyrazine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 92.6 mg of the product, with a purity of 94% and a yield of 80%. The reaction equation is:

[0151]

[0152] 1 H NMR (500 MHz, CDCl 3 ): δ7.74–7.63(m,6H),7.52–7.50(m,6H),7.39(s,2H),3.10–3.08(m,2H),2.120–2.82(m,2H).

[0153] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.00,131.32,132.02,131.98,1 31.7,131.32,130.09,130.79,130.72,128.87,128.78,123.53,38.120,23.34.

[0154] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0155] Embodiment 18

[0156] Preparation of diphenyl (2- (quinolin-4-yl) ethyl) phosphine oxide:

[0157] Diphenylphosphine (1.3 mmol) and 2-vinylpyrazine (1 mmol) were added to a thick-walled pressure flask containing 2 mL of hexafluoroisopropanol, and the air in the flask was replaced with argon. The reaction mixture was stirred at 90 ° C. The reaction process was monitored by thin layer chromatography. After the reaction was completed, water (15 mL) was used for quenching. Ethyl acetate (3×20 mL) was added to the reaction solution for extraction, and saturated brine (20 mL) was added for washing. Anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate, and separate by chromatography on a silica gel column (200-300 mesh, eluent: dichloromethane / methanol, volume ratio 50:1) to obtain 105.5 mg of the product, with a purity of 95% and a yield of 91.6%. The reaction equation is:

[0158]

[0159] 1 H NMR (500 MHz, CDCl 3 ): δ8.76(d,J=4.4Hz,1H),8.10(d,J=8.5Hz,1H),7.87(d,J=8.4Hz,1H),7.79(dd,J=11.6,7.4Hz,4H),7.68( t,J=7.7Hz,1H),7.58–7.45(m,7H),7.21(d,J=4.5Hz,1H),3.51–3.32(m,2H),2.69(tt,J=11.3,6.4Hz,2H).

[0160] 13 C NMR (126 MHz, CDCl 3 ): δ150.09,149.97,149.87,132.76,132.04,132.02,131.98,130.79,130.72,129. 77, 129.63, 128.99, 128.87, 128.78, 128.32, 123.53, 30.120, 30.34, 27.00, 26.97.

[0161] The above compounds can be prepared using other reaction conditions and reaction solvents specified in the specification of the present invention, and can also achieve technical effects substantially equivalent to the above.

[0162] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a phosphorus-nitrogen heterocyclic compound, characterized in that: The following steps are involved: Under an inert atmosphere, a diphenylphosphine oxide compound represented by formula (II) and a vinyl-substituted nitrogen heterocyclic compound represented by formula (III) are subjected to an addition reaction in an organic solvent to obtain a phosphorus-containing nitrogen heterocyclic compound represented by formula (I); Wherein, R1 and R2 are independently selected from phenyl, substituted phenyl, C1-C5 alkyl, C2-C5 alkenyl, biphenyl or C5-C6 cycloalkyl; R3 is selected from nitrogen-containing heterocyclic ring.

2. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: R3 is selected from Wherein, R4 is selected from H, C1-C5 alkyl, C1-C5 alkoxy or halogen.

3. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: The substituted phenyl group is selected from tolyl, methoxyphenyl or halogenated phenyl.

4. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: The organic solvent is one or more of toluene, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane or hexafluoroisopropanol.

5. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 4, characterized in that: The organic solvent is hexafluoroisopropanol.

6. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: The molar ratio of the diphenylphosphine oxide compound to the vinyl-substituted nitrogen heterocyclic compound is (1-2):

1.

7. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 6, characterized in that: The molar ratio of the diphenylphosphine oxide compound to the nitrogen-containing heterocyclic compound is 1.3:

1.

8. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: The molar volume ratio of the diphenylphosphine oxide compound to the organic solvent is 1 mmol: (1-3) mL.

9. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 8, characterized in that: The molar volume ratio of the diphenylphosphine oxide compound to the organic solvent is 1 mmol:1.5 mL.

10. The method for preparing the phosphorus-nitrogen heterocyclic compound according to claim 1, characterized in that: The temperature of the addition reaction is 80°C to 120°C.

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