A method for synthesizing phosphinyl pyridinone from pyridine as raw material

Abstract

The application discloses a method for synthesizing phosphine pyridone from pyridine as raw material, and is characterized by comprising the following two steps: S1, pyridine is activated by using halogenated alkane as an activating agent to obtain activated pyridine; the organic solvent used in the activation process is selected from one of acetone, ethanol, methanol, toluene and acetonitrile, the activation reaction temperature is 40-80 DEG C, and the reaction time is 12-24 hours; S2, the activated pyridine is reacted with an organic phosphine reagent in an alkaline environment to obtain phosphine pyridone; the reaction process is carried out in a mixed solvent of methanol and acetonitrile, the reaction temperature is 60-85 DEG C, and the reaction time is 8-16 hours; and the molar ratio of the activated pyridine to the organic phosphine reagent is 1:2-3. The method has the advantages of cheap and easily available raw material pyridine, good reaction yield and better atomic economy, and is applicable to common alkyl, halogen, alkoxy, aryl, ester group and the like which are mono-substituted or multi-substituted.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing phosphine pyridone by taking pyridine as raw material. BACKGROUND

[0002] 4-diaromatic phosphine oxygen pyridine-2-ketone is an important organic compound, and its molecular structure is that diaromatic phosphine oxide is connected to the 4th position of pyridine-2-ketone. At present, there is only one scheme for synthesizing 4-diaromatic phosphine oxygen pyridine-2-ketone in the prior art. The scheme takes pyridine quaternary ammonium salt as raw material, creates an alkaline environment by using 1,4-diazabicyclo[2.2.2]octane (DABCO), and reacts with diphenyl phosphine oxide under the catalysis of graphene oxide and in the condition of blue light. The specific scheme is as follows:

[0003]

[0004] The synthesis method has the following defects: the reaction needs the catalysis of graphene oxide, and the catalyst is high in cost; the reaction needs to be carried out under the condition of blue light, which is high in requirement for equipment and is not conducive to mass synthesis; in addition, the yield of phosphine quinoline ketone obtained by the reaction is high, while the yield of phosphine pyridone is low (43% to 55%). Therefore, there is an urgent need for a simple, economical and efficient method for synthesizing phosphine pyridone. SUMMARY

[0005] In view of the technical problem that there is no method for synthesizing phosphine pyridone by taking raw material which is easy to obtain and economical and efficient, the present application provides a method for synthesizing phosphine pyridone by taking pyridine as raw material.

[0006] The method for synthesizing phosphine pyridone by taking pyridine as raw material provided by the present application comprises the following two steps:

[0007] S1, halogenated alkane is used as an activating agent to activate pyridine to obtain activated pyridine. The organic solvent used in the activation process is selected from one of acetone, ethanol, methanol, toluene and acetonitrile, the activation reaction temperature is 40-80 DEG C, and the reaction time is 12-24 hours.

[0008] S2, the activated pyridine is reacted with an organic phosphine reagent in an alkaline environment formed by 1,8-diazabicyclo[5.4.0]undec-7-ene to obtain phosphine pyridone; the reaction process is carried out in a mixed solvent of methanol and acetonitrile, the reaction temperature is 60-85 DEG C, and the reaction time is 8-16 hours.

[0009] Preferably, in step S1, the pyridine is selected from any one of the following four molecular structural formulas:

[0010]

[0011] In the formula, R1 any one selected from the group consisting of hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 the number of R 1 is at least one of the remaining 5 unbound sites on the benzene ring; X is any one selected from the group consisting of O, S; R 2 is any one selected from the group consisting of C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aroyl.

[0012] In step S1, the halogenated alkane is preferably methyl iodide.

[0013] Preferably, in step S2, the molar ratio of the activated pyridine to the organic phosphine reagent is 1:2-3. The organic phosphine reagent is preferably diphenyl phosphine oxide.

[0014] Preferably, in step S2, the reaction temperature is 80℃, and the reaction time is 8 hours.

[0015] The phosphine-based pyridone synthesized by the above method has a molecular structure as shown in any one of the following four structural formulas:

[0016]

[0017] In the formula, R 1 any one selected from the group consisting of hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 the number of R 1 is at least one of the remaining 5 unbound sites on the benzene ring; X is any one selected from the group consisting of O, S; R 2 is any one selected from the group consisting of C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aroyl.

[0018] Compared with the prior art, the present application has the following advantages:

[0019] (1) The method of the present application first activates pyridine with an activating agent, and then reacts the activated pyridine with an organic phosphine reagent in an alkaline environment to obtain a phosphine-based pyridone. The raw material substrate used is pyridine, which is inexpensive and easy to obtain. The modification technology for pyridine is mature, the operation is simple, the functional groups are rich, the reaction yield is good, the atomic economy is better, the functional group tolerance is good, and the single substitution or multiple substitution of common alkyl, halogen, alkoxy, aryl, ester group, etc. can be applied. And the product is a kind of phosphine-based pyridone with rich types.

[0020] (2) The method of the present application obtains products with a wider range and more types, and the P(V) structure of the product can be reduced by a reducing agent to P(III), providing a variety of new organic phosphine ligands.

[0021] (3) The method has wide prospect. For a drug molecule, a drug molecule fragment or a precursor containing a pyridine fragment substituted at ortho and meta positions, the pyridine structure fragment can be modified and changed by the method to construct a product containing special drug effect, and through further modification, a complex compound molecule and a drug molecule with greater application potential can be obtained.

[0022] Other advantages, objects, and features of the present application will be understood by those skilled in the art from the following description, and will be appreciated upon reading the specification and claims. The advantages, objects, and features of the present application will become more fully apparent in the following detailed description. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 1 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0024] Figure 2 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 13 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0025] Figure 3 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 31 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0026] Figure 4 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 1 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0027] Figure 5 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 13 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0028] Figure 6 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 31 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0029] Figure 7 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 1 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0030] Figure 8 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1; 13 H NMR spectrum of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a of Example 1;

[0031] Figure 9 For Example 3, 4-diphenylphosphoryl-1-methyl-6-(pent-3-yl)pyridin-2-one 2-c 31 P NMR spectrum. DETAILED DESCRIPTION

[0032] The preferred embodiments of the present application will be described herein below with reference to the accompanying drawings, in which it is understood that the preferred embodiments described herein are merely for the purpose of illustration and explanation of the present application, and are not intended to limit the present application.

[0033] Example 1

[0034] A method for synthesizing phosphine-based pyridinone from pyridine includes the following two steps:

[0035] Step 1: In the air, add a magnetic stirrer, 2-phenylpyridine (20 mmol, 2.8 mL), methyl iodide (40 mmol, 2.5 mL) to a reaction test tube, then add 2 mL of acetonitrile, and react at 80°C for 16 h. Transfer the reaction solution to a 100 mL conical flask, dissolve in a small amount of dichloromethane, and evaporate the solvent under reduced pressure. Place the conical flask after rotary evaporation in the mouth of a heating gun, add acetonitrile dropwise, and continuously shake the conical flask. Stop adding acetonitrile when all the solids are dissolved, remove the heating device, and let it cool. When the liquid cools to room temperature, add a few drops of ethyl acetate, at which time a large amount of crystals will precipitate, and continue to cool at room temperature for 4 h. Then transfer the crystals precipitated in the conical flask to a sand core funnel lined with filter paper, filter, and wash with a small amount of ethyl acetate. After washing, seal the sand core funnel with filter paper, place it in a vacuum drying oven, and dry at 45°C for 24 h. After drying, N-methyl-2-phenylpyridine quaternary ammonium salt l-a is obtained as a light yellow solid.

[0036] Step 2: In the air, add a magnetic stirrer, N-methyl-2-phenylpyridine quaternary ammonium salt l-a (0.1 mmol, 29.7 mg), diphenylphosphoryl (0.2 mmol, 40.4 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mmol, 51 μL), acetonitrile (0.5 mL), methanol (0.5 mL) to a 25 mL reaction test tube, plug with a rubber stopper, and react at 80°C for 8 h; after the reaction is completed, cool the reaction system to room temperature, and evaporate the solvent under reduced pressure; select ethyl acetate as the mobile phase, and purify by flash silica gel column chromatography to obtain 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a. It is a yellow oily liquid with a yield of 92%.

[0037] The chemical reaction formula of Step 2 is as follows:

[0038]

[0039] 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a was successfully synthesized. Figures 1-3 .

[0040] Figure 1 To 1 H NMR spectrum, 1 H NMR (400 MHz, CDCI3) δ 7.75 - 7.65 (m, 4H), 7.61 - 7.36 (m, 9H), 7.35 - 7.25 (m, 2H), 6.60 (dd, J = 14.9, 1.7 Hz, 1H), 6.51 (dd, J = 9.4, 1.7 Hz, 1H), 3.38 (s, 3H).

[0041] Figure 2 To 13 H NMR spectrum, 13 C NMR (101 MHz, CDCI3) δ 151.03 (d, J = 12.9 Hz), 144.78 (d, J = 92.6 Hz), 134.69, 132.60 (d, J = 2.8 Hz), 131.99 (d, J = 10.1 Hz), 130.78, 129.72, 128.89, 128.79 (d, J = 4.8 Hz), 128.40, 123.48 (d, J = 9.1 Hz), 107.70 (d, J = 9.0 Hz), 34.78.

[0042] Figure 3 To 31 H NMR spectrum, 31 P NMR (162 MHz, CDCI3) δ 27.80.

[0043] Figures 1-3 The characterization results of 4-diphenylphosphoryl-1-methyl-6-phenylpyridin-2-one 2-a proved that the target product was successfully synthesized.

[0044] Example 2

[0045] A method for synthesizing phosphine-based pyridinone from pyridine includes the following two steps:

[0046] Step 1: In air, a 25 mL reaction tube was charged with a magnetic stir bar, 2-(2- methylphenyl)pyridine (20 mmol, 3.38 g), iodomethane (40 mmol, 2.5 mL), and 2 mL of acetonitrile. The reaction was stirred at 80 °C for 16 h. The reaction was transferred to a 100 mL conical vial, dissolved in a small amount of dichloromethane, and the solvent was removed under reduced pressure. The conical vial was placed in the mouth of a heating gun and acetonitrile was added dropwise while the conical vial was shaken. The addition of acetonitrile was stopped when all the solid was dissolved, the heating was removed, and the conical vial was allowed to cool. When the liquid was cooled to room temperature, a few drops of ethyl acetate were added and a large amount of crystals precipitated. The conical vial was allowed to cool to room temperature for 4 h. The crystals that precipitated in the conical vial were transferred to a fritted funnel lined with filter paper, suction filtered, and washed with a small amount of ethyl acetate. The fritted funnel was sealed with filter paper and placed in a vacuum oven at 45 °C for 24 h. The white N-methyl-2-(2-methylphenyl)pyridinium salt 1-b was obtained after drying.

[0047] Step 2: In air, a 25 mL reaction tube was charged with a magnetic stir bar, N-methyl-2-(2- methylphenyl)pyridinium salt 1-b (0.1 mmol, 29.7 mg), diphenylphosphine oxide (0.2 mmol, 40.4 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mmol, 51 μL), acetonitrile (0.5 mL), methanol (0.5 mL), and a rubber septum. The reaction was stirred at 80 °C for 8 h. After the reaction was complete, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel using ethyl acetate as the mobile phase to give 4-diphenylphosphinoyl-1-methyl-6-o-tolylpyridin-2-one 2-b as a yellow oil in 54% yield.

[0048] The chemical reaction scheme for Step 2 is as follows:

[0049]

[0050] The characterization spectra of 4-diphenylphosphinoyl-1-methyl-6-o-tolylpyridin-2-one 2-b are shown in Figures 4-6 .

[0051] Figure 4 1 H NMR spectrum: 1 ​H NMR (600 MHz, CDC13) δ 7.72 (dddd, J = 12.3, 8.3, 3.0, 1.3 Hz, 4H), 7.59 (tdd, J = 7.3, 3.5, 1.5 Hz, 2H), 7.51 (ddt, J = 11.0, 7.4, 3.4 Hz, 4H), 7.36 (td, J = 7.6, 1.4 Hz, 1H), 7.30 - 7.23 (m, 3H), 7.15 (dd, J = 7.6, 1.4 Hz, 1H), 6.66 (dd, J = 14.9, 1.7 Hz, 1H), 6.46 (dd, J = 9.3, 1.7 Hz, 1H), 3.26 (s, 3H), 2.13 (s, 3H).

[0052] Figure 5 The characterization results of Table 1 prove that the target compound 4-diphenylphosphoryl-1-methyl-6-p-tolylpyridin-2-one is successfully synthesized. 13 C NMR spectrum: 13 C NMR (151 MHz, CDC13) δ 162.30 (d, J = 16.6 Hz), 150.40 (d, J = 12.8 Hz), 144.89 (d, J = 92.8 Hz), 135.87, 134.33, 132.59, 132.02 (d, J = 4.5 Hz), 131.95 (d, J = 4.5 Hz), 130.62, 130.52, 129.98 (d, J = 19.6 Hz), 129.85, 128.86, 128.78, 128.59, 126.35, 123.53 (d, J = 9.0 Hz), 107.28 (d, J = 9.1 Hz), 33.44, 19.38.

[0053] Figure 6 The characterization results of Table 1 prove that the target compound 4-diphenylphosphoryl-1-methyl-6-p-tolylpyridin-2-one is successfully synthesized. 31 P NMR spectrum: 31 P NMR (162 MHz, CDC13) δ 27.69.

[0054] Figures 4-6 The characterization results of Table 1 prove that the target compound 4-diphenylphosphoryl-1-methyl-6-p-tolylpyridin-2-one is successfully synthesized.

[0055] Example 3

[0056] A method for synthesizing a phosphine-based pyridinone from pyridine, comprising the following two steps:

[0057] Step 1: In air, to a reaction tube was added a magnetic stir bar, 2-(pentan-3-yl)pyridine (20 mmol, 2.98 g), iodomethane (40 mmol, 2.5 mL), and 2 mL of acetonitrile, and the reaction was stirred at 80 °C for 16 h. The reaction was transferred to a 100 mL conical vial, dissolved in a small amount of dichloromethane, and the solvent was removed under reduced pressure. The conical vial was placed in the mouth of a heating gun, acetonitrile was added dropwise, and the conical vial was shaken constantly. When all of the solid was dissolved, the acetonitrile was stopped, the heating was removed, and the conical vial was allowed to cool. When the liquid had cooled to room temperature, a few drops of ethyl acetate were added, and a large amount of crystals precipitated. The conical vial was allowed to sit at room temperature for 4 h. The crystals that precipitated in the conical vial were then transferred to a fritted funnel lined with filter paper, suction filtered, and washed with a small amount of ethyl acetate. After washing, the fritted funnel was capped with filter paper and placed in a vacuum oven at 45 °C for 24 h. The N-methyl-2-(pentan-3-yl)pyridinium salt 1-c was obtained as a light yellow solid after drying.

[0058] Step 2: In air, to a 25 mL reaction tube was added a magnetic stir bar, N-methyl-2-(pentan-3-yl)pyridinium salt 1-c (0.1 mmol, 29.1 mg), diphenylphosphine oxide (0.2 mmol, 40.4 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mmol, 51 μί), acetonitrile (0.5 mL), methanol (0.5 mL), and the reaction was stirred at 80 °C for 8 h. After the reaction was complete, the reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The product was purified by flash chromatography using ethyl acetate as the mobile phase to give 4-diphenylphosphinyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c as a yellow oil in 35% yield.

[0059] The chemical reaction scheme for Step 2 is shown below:

[0060]

[0061] The characterization spectra for 4-diphenylphosphinyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c are shown below. Figures 4-6 .

[0062] Figure 7 1 H NMR Spectrum: 1 ​H NMR (400MHz, CDCl3) δ7.64 (ddt, J=12.2, 6.9, 1.4Hz, 4H), 7.59–7.52 (m, 2H), 7.46 (ddd, J=8.5, 6.8, 3.0Hz, 4H), 6.43 (dd, J= 7.2, 2.1Hz, 1H), 6.40 (dd, J=11.7, 1.9Hz, 1H), 3.59 (s, 3H), 2.73 (t, J=6.9Hz, 1H), 1.72–1.47 (m, 4H), 0.81 (t, J=7.4Hz, 6H).

[0063] Figure 8 for 13 C NMR spectrum: 13 C NMR (101MHz, CDCl3) δ161.73 (d, J = 17.3Hz), 143.19 (d, J = 93.9Hz), 131.50 (d, J = 2.9Hz), 130.93 (d, J =10.1Hz), 129.93, 128.88, 127.72 (d, J = 12.3Hz), 120.57 (d, J = 9.7Hz), 30.17, 28.67, 26.25, 10.56.

[0064] Figure 9 for 31 p NMR spectrum: 31 P NMR (162MHz, CDCl3) δ 28.75.

[0065] Figures 7-9 Characterization results confirmed the successful synthesis of the target compound 4-diphenylphosphoxy-1-methyl-6-(pent-3-yl)pyridin-2-one.

[0066] Comparative Example 1

[0067] Based on Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene was replaced with an equimolar amount of sodium hydroxide. After the reaction was completed, the reaction system was cooled to room temperature and the solvent was removed under reduced pressure. The yield was trace according to the analysis of thin-layer chromatography.

[0068] Comparative Example 2

[0069] Based on Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene was replaced with an equimolar amount of 4-dimethylaminopyridine. After the reaction was completed, the reaction system was cooled to room temperature and the solvent was removed under reduced pressure. The yield was trace according to the analysis by thin-layer chromatography.

[0070] Comparative Example 3

[0071] On the basis of Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene is replaced by an equimolar amount of cesium carbonate, after the reaction is completed, the reaction system is cooled to room temperature, and the solvent is evaporated under reduced pressure; through thin layer chromatography plate analysis, the yield is trace amount.

[0072] Comparative Example 4

[0073] On the basis of Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene is replaced by an equimolar amount of potassium tert-butoxide, after the reaction is completed, the reaction system is cooled to room temperature, and the solvent is evaporated under reduced pressure; through thin layer chromatography plate analysis, the yield is trace amount.

[0074] Comparative Examples 1-4 respectively use other types of bases to form an alkaline environment, and the results show that the yield of the final product of the four comparative examples is trace amount. Thus, it is illustrated that, in the preparation method of the present application, only 1,8-diazabicyclo[5.4.0]undec-7-ene is used as a base to form an alkaline environment, so that the activated pyridine can react with the organic phosphine reagent in step 2 to obtain a high yield of phosphine-based pyridone.

[0075] The above is only a preferred embodiment of the present application, and does not limit the present application in any form. Although the present application has been disclosed as above with a preferred embodiment, it is not intended to limit the present application. Any person skilled in the art can make some changes or modifications to the above disclosed technical content without departing from the scope of the technical solution of the present application, and any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present application are still within the scope of the technical solution of the present application.

Claims

1. A method for synthesizing phosphopyridone from pyridine, characterized in that, It includes the following two steps: S1. Pyridine is activated using a haloalkane as an activating agent to obtain activated pyridine; The pyridine is selected from any one of 2-phenylpyridine, 2-(2-methylphenyl)pyridine, and 2-(pent-3-yl)pyridine. The haloalkane is iodomethane; S2. The activated pyridine and organophosphorus reagent are added to a mixed solvent of methanol and acetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene is added to form an alkaline environment. The reaction is carried out at a temperature of 60-85℃ for 8-16 hours to obtain phosphin-pyridone oxide; the organophosphorus reagent is diphenylphosphine.

2. The method for synthesizing phosphopyridone from pyridine as described in claim 1, characterized in that, In step S1, the organic solvent used in the activation process is selected from acetone, ethanol, methanol, toluene, and acetonitrile. The activation reaction temperature is 40-80℃, and the reaction time is 12-24 hours.

3. The method for synthesizing phosphopyridone from pyridine as described in claim 1, characterized in that, In step S2, the molar ratio of activated pyridine to organophosphorus reagent is 1:2~3.

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