Method for synthesizing phosphino pyridone by taking pyridine as raw material

Abstract

The invention discloses a method for synthesizing phosphino pyridone by using pyridine as a raw material, which is characterized by comprising the following two steps: S1, activating pyridine by using halogenated hydrocarbon as an activating reagent to obtain activated pyridine; an 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, enabling the activated pyridine to react with an organic phosphine reagent in an alkaline environment to obtain phosphino 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. The molar ratio of the activated pyridine to the organic phosphine reagent is 1: (2-3). According to the method, the adopted raw material pyridine is low in price and easy to obtain, the reaction yield is relatively good, the atom economy is relatively good, and the method is applicable to mono-substitution or multi-substitution of common alkyl, halogen, alkoxy, aryl, ester groups and the like.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing phosphinopyridone by taking pyridine as a raw material. Background Art

[0002] 4-Diarylphosphinoylpyridin-2-one is an important organic compound, and its molecular structure is that pyridin-2-one is connected to diarylphosphine oxide at the 4th position. Currently, there is only one scheme for the synthesis of 4-diarylphosphinoylpyridin-2-one in the prior art. This scheme uses quaternary ammonium salt of pyridine as raw material, uses 1,4-diazabicyclo[2.2.2]octane (DABCO) to create an alkaline environment, uses graphene oxide as a catalyst, and reacts with diphenylphosphine oxide under blue light conditions. The specific scheme is:

[0003]

[0004] The disadvantages of this synthesis method are that the reaction requires the catalysis of graphene oxide, which is expensive; the reaction needs to be carried out under blue light conditions, which has high requirements for equipment and is not conducive to large-scale synthesis; secondly, the yield of phosphinoquinolinone obtained by the reaction is high, while the yield of phosphinopyridone is low (43% to 55%). Therefore, a simple, economical and efficient method for synthesizing phosphinopyridone is urgently needed. Summary of the invention

[0005] In view of the technical problem that there is currently a lack of a method for synthesizing phosphinopyridone with readily available raw materials, economical and efficient, the present invention provides a method for synthesizing phosphinopyridone using pyridine as a raw material.

[0006] The method for synthesizing phosphinopyridone using pyridine as a raw material provided by the present invention comprises the following two steps:

[0007] S1. Using halogenated alkane as an activation reagent 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°C, and the reaction time is 12 to 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 a phosphinopyridone; the reaction process is carried out in a mixed solvent of methanol and acetonitrile, the reaction temperature is 60-85° C., and the reaction time is 8 to 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 hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 The number is 1 to 2, R 1 The binding site is at least one of the remaining five unbound sites on the benzene ring; X is selected from any element of O and S; R 2 Any one selected from C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aryloyl.

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

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

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

[0015] The molecular structure of the phosphinopyridone synthesized by the above method is shown in any one of the following four structural formulas:

[0016]

[0017] In the formula, R 1 Any one selected from hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 The number is 1 to 2, R 1 The binding site is at least one of the remaining five unbound sites on the benzene ring; X is selected from any element of O and S; R 2 Any one selected from C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aryloyl.

[0018] Compared with the prior art, the present invention is beneficial in that:

[0019] (1) The method of the present invention first activates pyridine with an activation reagent, and then reacts the activated pyridine with an organic phosphine reagent in an alkaline environment to obtain a phosphinopyridone. The raw material substrate used is pyridine, which is cheap and easy to obtain, and the modification technology for pyridine is mature, simple to operate, rich in functional groups, good reaction yield, good atom economy, good tolerance to functional groups, and is applicable to common alkyl, halogen, alkoxy, aryl, ester groups, etc., either monosubstituted or polysubstituted. And the product is a rich variety of phosphinopyridones.

[0020] (2) The product range and types obtained by the method of the present invention are richer, and the P(V) structure of the product can be reduced to P(III) by a reducing agent, providing a variety of new organic phosphine ligands.

[0021] (3) The method of the present invention has broad prospects. For drug molecules, drug molecule fragments or precursors containing pyridine fragments with ortho- or meta-substituents, the method can be used to modify and modify the pyridine structure fragments to construct products with special drug effects. Through further modification, complex compound molecules and drug molecules with greater application potential can be obtained.

[0022] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0026] Figure 4 4-diphenylphosphinoyl-1-methyl-6-o-methylphenylpyridin-2-one 2-b of Example 2 1 H NMR spectrum;

[0027] Figure 5 4-diphenylphosphinoyl-1-methyl-6-o-methylphenylpyridin-2-one 2-b of Example 2 13 C NMR spectrum;

[0028] Figure 6 4-diphenylphosphinoyl-1-methyl-6-o-methylphenylpyridin-2-one 2-b of Example 2 31 P NMR spectrum;

[0029] Figure 7 4-diphenylphosphinoyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c of Example 3 1 H NMR spectrum;

[0030] Figure 8 4-diphenylphosphinoyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c of Example 3 13 C NMR spectrum;

[0031] Fig. 9 4-diphenylphosphinoyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c of Example 3 31 P NMR spectrum. DETAILED DESCRIPTION

[0032] The preferred embodiments of the present invention are described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0033] Example 1

[0034] A method for synthesizing phosphinopyridone using pyridine as a raw material comprises the following two steps:

[0035] Step 1: In the air, add a magnet, 2-phenylpyridine (20mmol, 2.8mL), iodomethane (40mmol, 2.5mL) to the reaction tube, and then add 2mL acetonitrile, and react at 80℃ for 16h. Transfer the reaction solution to a 100mL conical flask, add a small amount of dichloromethane to dissolve, and then evaporate the solvent under reduced pressure. Place the spin-dried conical flask at the muzzle of a heating gun to heat, add acetonitrile dropwise, and shake the conical flask continuously. When all the solids are dissolved, stop adding acetonitrile, remove the heating device, and let it stand to cool. When the liquid drops to room temperature, add a few drops of ethyl acetate, and a large amount of crystals will precipitate. Continue to stand at room temperature for 4h. Then transfer the crystals precipitated in the conical flask to a sand core funnel padded with filter paper, filter, and wash with a small amount of ethyl acetate. After washing, the sand core funnel was sealed with filter paper, placed in a vacuum drying oven, and dried at 45° C. for 24 h to obtain light yellow N-methyl-2-phenylpyridinium quaternary ammonium salt la.

[0036] Step 2: In air, add a magnetic particle, N-methyl-2-phenylpyridine quaternary ammonium salt 1-a (0.1mmol, 29.7mg), diphenylphosphine (0.2mmol, 40.4mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3mmol, 51μL), acetonitrile (0.5mL), and methanol (0.5mL) to a 25mL reaction tube, plug with a rubber stopper, and react at 80°C for 8 hours; after the reaction, cool the reaction system to room temperature, and evaporate the solvent under reduced pressure; use ethyl acetate as the mobile phase, and use fast silica gel column chromatography to purify to obtain 4-diphenylphosphine-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] The characterization spectrum of 4-diphenylphosphinoyl-1-methyl-6-phenylpyridin-2-one 2-a is shown in Figure 1-3 .

[0040] Figure 1 for 1 H NMR spectrum, 1 H NMR (400MHz, CDCl3) δ7.75–7.65(m,4H),7.61–7.36(m,9H),7.35–7.25(m,2H),6.60(dd,J=14.9,1.7Hz,1H),6.51(dd,J=9.4,1.7Hz,1H),3.38(s,3H).

[0041] Figure 2 for 13 C NMR spectrum, 13 C NMR (101MHz, CDCl3) δ151.03 (d, J = 12.9Hz), 144.78 (d, J = 92.6Hz), 134.69, 132.60 (d, J = 2.8Hz), 131.99 (d, J = 10 .1Hz), 130.78, 129.72, 128.89, 128.79 (d, J = 4.8Hz), 128.40, 123.48 (d, J = 9.1Hz), 107.70 (d, J = 9.0Hz), 34.78.

[0042] Figure 3 for 31 P NMR spectrum, 31 P NMR (162 MHz, CDCl3) δ 27.80.

[0043] Figure 1-3 The characterization results proved that the target compound 4-diphenylphosphinoyl-1-methyl-6-phenylpyridin-2-one was successfully synthesized.

[0044] Example 2

[0045] A method for synthesizing phosphinopyridone using pyridine as a raw material comprises the following two steps:

[0046] Step 1: In air, add a magnet, 2-(2-methylphenyl)pyridine (20mmol, 3.38g), iodomethane (40mmol, 2.5mL) to the reaction tube, and then add 2mL acetonitrile, and react at 80℃ for 16h. Transfer the reaction solution to a 100mL conical flask, add a small amount of dichloromethane to dissolve, and then evaporate the solvent under reduced pressure. Place the spin-dried conical flask at the muzzle of a heating gun to heat, add acetonitrile dropwise, and shake the conical flask continuously. When all the solids are dissolved, stop adding acetonitrile, remove the heating device, and let it stand to cool. When the liquid drops to room temperature, add a few drops of ethyl acetate, and a large amount of crystals will precipitate. Continue to stand at room temperature for 4h. Then transfer the crystals precipitated in the conical flask to a sand core funnel padded with filter paper, filter, and wash with a small amount of ethyl acetate. After washing, the sand core funnel was sealed with filter paper, placed in a vacuum drying oven, and dried at 45° C. for 24 h to obtain white N-methyl-2-(2-methylphenyl)pyridinium quaternary ammonium salt 1-b.

[0047] Step 2: In air, a 25 mL reaction tube was added with a magnetic particle, N-methyl-2-(2-methylphenyl)pyridinium quaternary ammonium salt 1-b (0.1 mmol, 29.7 mg), diphenylphosphine (0.2 mmol, 40.4 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mmol, 51 μL), acetonitrile (0.5 mL), and methanol (0.5 mL), and a rubber stopper was plugged, and the reaction was carried out at 80° C. for 8 hours. After the reaction, the reaction system was cooled to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was used as the mobile phase, and 4-diphenylphosphine-1-methyl-6-o-methylphenylpyridin-2-one 2-b was obtained by rapid silica gel column chromatography as a yellow oily liquid with a yield of 54%.

[0048] The chemical reaction formula of step 2 is as follows:

[0049]

[0050] The characterization spectrum of 4-diphenylphosphinoyl-1-methyl-6-o-methylphenylpyridin-2-one 2-b is shown in Figure 4-6 .

[0051] Figure 4 for 1 H NMR spectrum: 1H NMR (600MHz, CDCl3) δ7.72(dddd,J=12.3,8.3,3.0,1.3Hz,4H),7.59(tdd,J=7.3,3.5,1.5Hz,2H),7.51(ddt,J=11.0,7.4,3.4Hz,4H),7.36(td,J=7 .6,1.4Hz,1H),7.30–7.23(m,3H),7.15(dd,J=7.6,1.4Hz,1H),6.66(dd,J =14.9, 1.7Hz, 1H), 6.46 (dd, J = 9.3, 1.7Hz, 1H), 3.26 (s, 3H), 2.13 (s, 3H).

[0052] Figure 5 for 13 C NMR spectrum: 13 C NMR (151MHz, CDCl3) δ162.30(d,J=16.6Hz),150.40(d,J=12.8Hz),144.89(d,J=92.8Hz),135.87,134.33,132.59,132.02(d,J=4.5Hz),131.95(d,J =4.5Hz),130.62,130.52,129.98(d,J=19.6Hz),129.85,128.86,128.78, 128.59, 126.35, 123.53 (d, J = 9.0Hz), 107.28 (d, J = 9.1Hz), 33.44, 19.38.

[0053] Figure 6 for 31 P NMR spectrum: 31 P NMR (162 MHz, CDCl3) δ 27.69.

[0054] Figure 4-6 The characterization results proved that the target compound 4-diphenylphosphinoyl-1-methyl-6-o-methylphenylpyridin-2-one was successfully synthesized.

[0055] Example 3

[0056] A method for synthesizing phosphinopyridone using pyridine as a raw material comprises the following two steps:

[0057] Step 1: In air, add a magnet, 2-(pentyl-3-yl)pyridine (20mmol, 2.98g), iodomethane (40mmol, 2.5mL) to the reaction tube, and then add 2mL acetonitrile, and react at 80℃ for 16h. Transfer the reaction solution to a 100mL conical flask, add a small amount of dichloromethane to dissolve, and then evaporate the solvent under reduced pressure. Place the spin-dried conical flask at the muzzle of a heating gun to heat, add acetonitrile dropwise, and shake the conical flask continuously. When all the solids are dissolved, stop adding acetonitrile, remove the heating device, and let it stand to cool. When the liquid drops to room temperature, add a few drops of ethyl acetate, and a large amount of crystals will precipitate. Continue to stand at room temperature for 4h. Then transfer the crystals precipitated in the conical flask to a sand core funnel padded with filter paper, filter, and wash with a small amount of ethyl acetate. After washing, the sand core funnel was sealed with filter paper, placed in a vacuum drying oven, and dried at 45° C. for 24 h to obtain light yellow N-methyl-2-(pentan-3-yl)pyridinium quaternary ammonium salt 1-c;

[0058] Step 2: In air, add a magnetic particle, N-methyl-2-(pentan-3-yl)pyridinium quaternary ammonium salt 1-c (0.1mmol, 29.1mg), diphenylphosphine (0.2mmol, 40.4mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3mmol, 51μL), acetonitrile (0.5mL), and methanol (0.5mL) to a 25mL reaction tube, plug with a rubber stopper, and react at 80°C for 8 hours; after the reaction, cool the reaction system to room temperature, and evaporate the solvent under reduced pressure; use ethyl acetate as the mobile phase, and use fast silica gel column chromatography to purify to obtain 4-diphenylphosphine-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c; it is a yellow oily liquid with a yield of 35%.

[0059] The chemical reaction formula of step 2 is as follows:

[0060]

[0061] The characterization spectrum of 4-diphenylphosphinoyl-1-methyl-6-(pentan-3-yl)pyridin-2-one 2-c is shown in Figure 4-6 .

[0062] Figure 7 for 1 H NMR spectrum: 1H 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] Fig. 9 for 31 P NMR spectrum: 31 P NMR (162 MHz, CDCl3) δ 28.75.

[0065] Figure 7-9 The characterization results proved that the target compound 4-diphenylphosphinoyl-1-methyl-6-(pentan-3-yl)pyridin-2-one was successfully synthesized.

[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 evaporated under reduced pressure. The yield was trace according to thin layer chromatography analysis.

[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 evaporated under reduced pressure. The yield was trace according to thin layer chromatography analysis.

[0070] Comparative Example 3

[0071] Based on Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene was replaced with an equimolar amount of cesium carbonate. After the reaction was completed, the reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. Analysis by thin layer chromatography showed that the yield was trace.

[0072] Comparative Example 4

[0073] Based on Example 1, in step 2, 1,8-diazabicyclo[5.4.0]undec-7-ene was replaced with an equimolar amount of potassium tert-butoxide. After the reaction was completed, the reaction system was cooled to room temperature and the solvent was evaporated under reduced pressure. The yield was trace according to thin layer chromatography analysis.

[0074] Comparative Examples 1-4 respectively used other types of bases to form an alkaline environment, and the results showed that the yields of the final products of the four comparative examples were all trace amounts. This shows that in the preparation method of the present invention, only by using 1,8-diazabicyclo[5.4.0]undec-7-ene as a base to form an alkaline environment can the activated pyridine react with the organic phosphine reagent in step 2 to obtain a high yield of phosphinopyridone.

[0075] The above description is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any technician familiar with the profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing phosphinopyridone using pyridine as a raw material, characterized in that: It includes the following two steps: S1, using halogenated alkane as an activation reagent to activate pyridine to obtain activated pyridine; S2. Add the activated pyridine and the organic phosphine reagent to a mixed solvent of methanol and acetonitrile, and add 1,8-diazabicyclo[5.4.0]undec-7-ene to form an alkaline environment, and react at a temperature of 60-85° C. for 8-16 hours to obtain a phosphinopyridone oxide.

2. The method for synthesizing phosphinopyridone using pyridine as a raw material according to claim 1, characterized in that: The pyridine is selected from any one of the following four molecular structural formulas: In the formula, R 1 Any one selected from hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 The number is 1 to 2, R 1 The binding site is at least one of the remaining five unbound sites on the benzene ring; X is selected from any element of O and S; R 2 Any one selected from C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aryloyl.

3. The method for synthesizing phosphinopyridone using pyridine as a raw material according to claim 2, characterized in that: The halogenated alkane is methyl iodide.

4. The method for synthesizing phosphinopyridone using pyridine as a raw material according to claim 2, characterized in that: In step S1, 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°C, and the reaction time is 12 to 24 hours.

5. The method for synthesizing phosphinopyridone using pyridine as a raw material according to claim 4, characterized in that: In step S2, the molar ratio of activated pyridine to the organic phosphine reagent is 1:2-3.

6. A phosphinopyridone, characterized in that The compound is prepared by the synthesis method according to any one of claims 1 to 5.

7. The phosphinopyridone according to claim 6, characterized in that The molecular structure is shown in any of the following four structural formulas: In the formula, R 1 Any one selected from hydrogen, C1-C12 alkyl, aryl, halogen, alkoxy, nitro, cyano, R 1 The number is 1 to 2, R 1 The binding site is at least one of the remaining five unbound sites on the benzene ring; X is selected from any element of O and S; R 2 Any one selected from C1-C5 alkyl, functionalized alkyl, aryl, heteroaryl, aryloyl.

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