CN112592310B - 2-hydroxypyridine compound and synthetic method thereof - Google Patents
2-hydroxypyridine compound and synthetic method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a 2-hydroxypyridine compound, a synthesis method and application thereof. Taking enaminone as a starting material and a tempo salt as an oxidant, and heating the mixtureOxidation reaction and coupling cyclization reaction to produce 2-hydroxypyridine compound. The reaction functional group has strong compatibility, the yield is as high as 80%, and the product has functional group diversity. Can be used as an organic synthesis precursor, and 2-position hydroxyl and 6-position hydrogen atoms in the structure can be further functionalized to obtain a drug molecular skeleton or a compound with potential biological activity, and the like.
Description
Technical Field
The invention relates to chemical medicine, in particular to an unsaturated nitrogen heterocyclic compound 2-hydroxypyridine compound and a synthetic method thereof.
Background
Pyridine is an important skeleton structure of a plurality of natural products and is also an important compound in pharmaceutical research. Pyridine, as a structural unit, is one of the basic biochemical principles, is susceptible to nucleophilic substitution due to its structural specificity, and has a certain basicity due to its nitrogen atom-containing nature, and can interact with many biomolecules through hydrogen bonds. These properties make it important in synthetic drugs and chemical agents, and have the effects of anti-hypertension, anti-thrombosis, anti-inflammation, anti-tuberculosis, anti-convulsion, anti-HIV, analgesia, antibacterial, and insecticidal (Eur. J. Pharmacol.2002441, 203; Eur. J. Med. chem.2014, 73, 97; bioorg. Med. chem.2001, 9, 1993), and the currently marketed pyridine drugs include nifedipine, nimodipine, nitrendipine, etc. (Angew. chem. int. Ed. Engl.1981, 20, 762), loratadine, a respiratory stimulant, Nicorm, flonicamid, cyantranilide, germicide, fluopyramide, clopyralid, metosulam, etc. (as follows).
The current synthesis methods are as follows: (1) condensation reaction of aldehyde, beta-keto ester and ammonia (Hantzsch dihydropyridine synthesis); (2) condensation reaction of aldehyde with ammonia (chihibabin pyridine synthesis reaction); (3) condensation of cyanoacetate, 1, 3-dione and ammonia (Guareschi-Thorpe condensation); (4) the cycloaddition reaction (Hetero-Diels-Alder reaction) of an azadiene and a dienophile has not been reported, but the synthesis of polysubstituted pyridines using enaminone as the starting material.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a 2-hydroxypyridine compound.
The invention also aims to provide a synthetic method of the 2-hydroxypyridine compound.
The technical scheme is as follows: the invention provides a 2-hydroxypyridine compound 1, which has the following molecular structural formula:
R1selected from the following groups: alkyl, aryl or substituted aryl;
R2selected from the following groups: alkyl, aryl, benzyl, or substituted benzyl.
The synthetic route of the 2-hydroxypyridine derivative is shown as the following reaction formula,
taking enaminone 2 as a starting material and Tempo salt 3 as an oxidant, and carrying out oxidation reaction and coupling cyclization reaction under a heating condition to generate a 2-hydroxypyridine compound 1;
the molecular structural formula of the enaminone 2 is as follows:
R1selected from the following groups: alkyl, aryl or substituted aryl; r2Is alkyl, aryl, benzyl, or substituted benzyl;
the synthetic route is as follows:
refluxing 3- (N, N-dimethyl) -2-methyl-1-phenylprop-2-en-1-one A and amine B in an ethanol solvent to generate enaminone 2 (reaction formula 1);
the molecular structural formula of the Tempo salt 3 is as follows:
r is selected from the following groups: hydrogen, methoxy, amide, hydroxy, ester groups; x is tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate, perchlorate and hexafluoroantimonate;
the synthetic route is as follows:
tempo C and acid D are added dropwise with sodium hypochlorite in ether solvent under stirring at low temperature to form Tempo salt 3 (reaction formula 2).
Further, the molar ratio of enaminone 2 to Tempo salt 3 is 1: 0.5 to 1: 5, preferably 1: 1.
Further, the reaction solvent is one or a mixed solvent of two of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), 1, 2-Dichloroethane (DCE), 1, 4-dioxane, acetonitrile or toluene.
Further, the reaction atmosphere is air, nitrogen or argon; the reaction time is 0.1-48h (preferably 0.2 h); the reaction temperature is 10-120 deg.C (preferably 60 deg.C).
Has the advantages that:
1. the synthon enaminone 2 has structural diversity and good functional group tolerance, can be used for synthesizing 2-hydroxypyridine derivatives 1 with different types and structures, and therefore has wide applicability.
2. The synthon 2 and the oxidant 3 are easy to prepare, the preparation raw materials are cheap and easy to obtain, the cost is low, and the industrial production is easy to realize.
3. The synthesis reaction of the 2-hydroxypyridine derivative 1 only needs to use the Tempo salt 3 as an oxidant, and has the advantages of low price, easy synthesis and environmental friendliness.
4. The 2-hydroxyl and 4, 6-hydrogen atoms in the skeleton of the 2-hydroxypyridine derivative 1 are further functionalized to obtain bioactive preparation and chemical product structure intermediate.
5. The application of the derivative in preparing a drug molecular skeleton or a compound with potential biological activity.
In conclusion, the invention utilizes the structural diversity and multiple reaction centers of the enaminone 2 to efficiently synthesize the 2-hydroxypyridine derivatives 1 with different types and structures. The method has the advantages of cheap and easily-obtained raw materials, simple and convenient operation, simple and mild synthesis reaction conditions, strong functional group compatibility, 50-80% yield and diversity of functional groups in products. The 2-hydroxypyridine skeleton synthesized by the method can be used as an organic synthesis precursor, and the 2-hydroxyl and 6-hydrogen atoms in the structure can be further functionalized to obtain a drug molecular skeleton or a compound with potential biological activity and the like.
Detailed Description
3- (N, N-dimethyl) -2-methyl-1-phenylprop-2-en-1-one A and amine B are refluxed in an ethanol solvent to generate enaminone 2 (reaction formula 1).
The specific process is as follows: dissolving 3- (N, N-dimethyl) -2-methyl-1-phenylpropan-2-en-1-one A (10.0mmol) and organic amine B (20.0mmol) in 30mL ethanol, and stirring in an oil bath at 80 ℃ for reaction for 6 h. After cooling to room temperature, the volatile components were removed under reduced pressure and then separated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v 10: 1) to give the desired product 2. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Tempo C and acid D are added dropwise with sodium hypochlorite in ether solvent under stirring at low temperature to form Tempo salt 3 (reaction formula 2).
The specific process is as follows: tempo C (10.0mmol) and p-acid D (12.0mmol) were dissolved in 20mL of diethyl ether, and sodium hypochlorite (5.0mmol) was added dropwise to the ice bath for reaction for 1 h. The reaction mixture was returned to room temperature, filtered, washed with diethyl ether (10mL), saturated sodium bicarbonate (5mL), and water (5mL), and dried to obtain the desired product 3.
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
3- (benzylamino) -1- (4-chlorophenyl) -2-methylpropan-2-en-1-one 2a (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 6mL of DCM was added, stirring was performed at 40 ℃ for 2 minutes in an oil bath, and Tempo salt 3a (0.6mmol) was added and reacted for 1 h. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1) to obtain the desired product 1a- α (75mg, yield 58%), 1a- β (23mg, yield 17%), dr: 77: 23 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
3- (benzylamino) -1- (4-tolyl) -2-methylpropan-2-en-1-one 2b (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 2mL of toluene was added, stirring was performed at 60 ℃ for 2 minutes in an oil bath, and the Tempo salt 3b (0.7mmol) was added and reacted for 0.2 h. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as an eluent) to obtain the desired product 1b- α (73mg, yield 55%), 1b- β (25mg, yield 20%), dr: 74: 26 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 3
3- (benzylamino) -1- (4-methoxyphenyl) -2-methylpropan-2-en-1-one-1-phenyl-3-benzylamino-2-propene 2c (0.6mmol) is weighed in a 25mL Schlenk reaction flask, DMSO 2mL is added, the mixture is stirred for 2 minutes in an oil bath at 80 ℃, Tempo salt 3c (0.6mmol) is added, after the reaction is finished for 0.5h, the mixture is cooled to room temperature, dichloromethane and water are extracted, an organic phase is collected, dried by anhydrous sodium sulfate, filtered, and the volatile components are removed under reduced pressure, then silica gel column chromatography is carried out to separate (eluent is petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 10: 1) to obtain a colorless oily target product 1c (112mg, yield 80%, dr: 95: 5). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 4
3- ((4-methoxybenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2d (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 3mL of DMF was added, stirring was carried out in an oil bath at 80 ℃ for 2 minutes, and Tempo salt 3a (0.6mmol) was added and reacted for 0.2 h. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as the eluent) to give the objective product 1d (101mg, yield 72%, dr: 85: 15) as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 5
3- ((3-methoxybenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2e (0.6mmol) was sequentially weighed into a 25mL Schlenk reaction flask, 2mL of toluene was added, stirring was performed at 120 ℃ for 2 minutes in an oil bath, and Tempo salt 3d (0.8mmol) was added and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as an eluent) to obtain the desired product 1 e-. alpha. (86mg, yield 62%), 1 e-. beta. (24mg, yield 17%), dr: 78: 22 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 6
3- ((2-methoxybenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2f (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 2mL of 1, 4-dioxane was added, stirring was carried out in an oil bath at 80 ℃ for 2 minutes, and Tempo salt 3e (0.6mmol) was added and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as the eluent) to give the objective product 1f (104mg, yield 74%, dr: 86: 14) as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 7
2g (0.6mmol) of 3- ((4-chlorobenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one was weighed into a 25mL Schlenk reaction flask, 2mL of acetonitrile was added, stirring was performed at 80 ℃ for 2 minutes in an oil bath, and Tempo salt 3a (0.6mmol) was added and reacted for 0.2 h. After completion of the reaction, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as the eluent) to give 1g (104mg, yield 73%, dr: 75: 25) of the objective product as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 8
3- ((3-chlorobenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2h (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 2mL of acetonitrile was added, stirring was carried out at 80 ℃ for 2 minutes in an oil bath, and Tempo salt 3a (0.6mmol) was added and reacted for 6 h. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1) to obtain the desired product 1 h-. alpha. (93mg, yield 66%), 1 h-. beta. (12mg, yield 8%), dr: 89: 11 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 9
3- ((2-chlorobenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2i (0.6mmol) was weighed into a 25mL Schlenk reaction flask, 4mL of DCM was added, stirring was carried out in an oil bath at 40 ℃ for 2 minutes, and Tempo salt 3a (0.5mmol) was added and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as an eluent) to obtain the desired product 1i- α (86mg, yield 61%), 1i- β (22mg, yield 15%), dr: 80: 20 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 10
3- ((4-Fluorobenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2i (0.6mmol) was sequentially weighed into a 25mL Schlenk reaction flask, 2mL of acetonitrile was added, stirring was performed at 80 ℃ for 2 minutes in an oil bath, and Tempo salt 3a (0.6mmol) was added and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as an eluent) to give the desired product 1j- α (78mg, yield 55%), 1j- β (24mg, yield 17%), dr: 76: 24 as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 11
3- ((4-bromobenzyl) amino) -2-methyl-1- (p-tolyl) prop-2-en-1-one 2k (0.6mmol) was sequentially weighed into a 25mL Schlenk reaction flask, 5mL of acetonitrile was added, stirring was carried out at 80 ℃ for 2 minutes in an oil bath, and Tempo salt 3a (0.8mmol) was added and reacted for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (the eluent was petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1) to obtain the objective product 1k (96mg, yield 62%, dr: 90: 10) as a brown oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 12
3- (thiophene-2-methylamino) -1- (4-methoxyphenyl) -2-methylpropan-2-en-1-one 2l (0.6mmol) is weighed in turn into a 25mL Schlenk reaction flask, 6mL of acetonitrile is added, stirring is carried out for 2 minutes in an oil bath at 80 ℃, Tempo salt 3a (0.6mmol) is added, and reaction is carried out for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 10: 1 as the eluent) to give the objective product 11(126mg, yield 87%, dr: 93: 7) as a brown oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Typical compound characterization data
1-benzyl-2-hydroxy-3-methyl-3, 5-bis ((4-chlorophenyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1a) as a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.73(d，J＝8.5Hz，2H)，7.40-7.31(m，9H)，7.24(d，J＝7.7Hz，2H)，7.05(s，1H)，4.87(s，1H)，4.58(d，J＝14.6Hz，1H)，4.34(d，J＝14.4Hz，1H)，4.00(s，1H)，3.09(d，J＝16.2Hz，1H)，2.75(d，J＝16.3Hz，1H)，1.13(s，3H).13C{1H}NMR(100MHz，CDCl3) δ 206.29, 192.93, 149.19, 138.73, 138.55, 136.19, 136.08, 135.32, 129.93, 129.88, 129.13, 128.85, 128.55, 128.52, 128.42, 107.43, 82.40, 57.60, 49.52, 25.65, 20.05. minor isomers:1H NMR(400MHz，CDCl3)δ7.55(d，J＝8.1Hz，2H)，7.37-7.31(m，5H)，7.26-7.17(m，4H)，7.13(d，J＝8.0Hz，2H)，6.87(s，1H)，5.26(s，1H)，4.44(d，J＝11.1Hz，1H)，4.35(d，J＝10.6Hz，1H)，3.31(d，J＝14.9Hz，1H)，2.51(d，J＝15.6Hz，1H)，1.50(s，3H).13C{1H}NMR(100MHz，CDCl3)δ204.08，191.14，149.18，137.62，137.38，135.45，135.31，129.09，128.56，128.50，128.09，127.88，127.72，107.11，81.90，57.61，50.18)，25.38，21.02.C27H24Cl2NO3HRMS theoretical value of ([ M + H ]]+): 480.1133, respectively; measurement value: 480.1124.
1-benzyl-2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1b) as a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.76(d，J＝8.1Hz，2H)，7.43-7.30(m，5H)，7.28-7.14(m，7H)，4.87(s，1H)，4.61(d，J＝14.7Hz，1H)，4.32(d，J＝14.5Hz，1H)，4.11(s，1H)，3.22(d，J＝16.3Hz，1H)，2.79(d，J＝16.3Hz，1H)，2.39(s，6H)，1.17(s，3H).13C{1H}NMR(100MHz，CDCl3) δ 206.90, 193.98, 148.83, 142.75, 139.86, 137.20, 136.15, 133.87, 128.80, 128.62, 128.48, 128.41, 128.29, 128.13, 127.94, 107.32, 82.07, 57.10, 49.09, 25.58, 21.30, 21.16, 19.78. minor isomer:1H NMR(400MHz，CDCl3)δ7.51(d，J＝7.9Hz，2H)，7.28-7.26(m，3H)，7.16-7.06(m，6H)，7.01(d，J＝7.8Hz，2H)，6.87(s，1H)，5.19(s，1H)，4.37(d，J＝14.0Hz，1H)，4.23(d，J＝14.4Hz，1H)，3.34(d，J＝16.2Hz，1H)，2.53(d，J＝16.3Hz，1H)，2.30(s，3H)，2.30(s，3H)，1.48(s，3H)13C{1H}NMR(100MHz，CDCl3)δ205.85，193.12，149.51，142.02，139.97，137.16，136.42，135.03，128.93，128.87，128.76，128.70，128.55，128.45，128.09，127.84，127.76，82.62，57.85(s)，50.56，26.17，21.54，21.43.C29H30NO3HRMS theoretical value of ([ M + H ]]+): 440.2226, respectively; measurement value: 440.2220.
1-benzyl-2-hydroxy-3-methyl-3, 5-bis ((4-methoxyphenyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1c) as a colorless oily liquid.1H NMR(400MHz，CDCl3)δ8.01(d，J＝8.5Hz，2H)，7.54(d，J＝8.2Hz，2H)，7.43-7.31(m，5H)，7.19(s，1H)，6.96(d，J＝8.6Hz，2H)，6.92(d，J＝8.4Hz，2H)，4.90(s，1H)，4.66(d，J＝13.8Hz，1H)，4.40(d，J＝13.5Hz，1H)，3.91(s，3H)，3.89(s，3H)，3.34(d，J＝16.1Hz，1H)，2.83(d，J＝16.2Hz，1H)，1.24(s，3H)，1.22(s，1H).13C{1H}NMR(100MHz，CDCl3)δ204.31，192.41，162.03，160.13，147.64，135.44，131.74，130.54，129.40，127.89，127.68，127.49，127.19，112.63，112.27，106.46，81.52，56.48，54.57，54.43，48.19，25.25，18.99.C29H30NO5HRMS theoretical value of ([ M + H ]]+): 472.2124, respectively; measurement value: 472.2128.
1- (4-methoxybenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1d), a colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.77(d，J＝8.2Hz，2H)，7.39(d，J＝7.9Hz，2H)，7.23-7.16(m，6H)，7.12(s，1H)，6.88(d，J＝8.5Hz，2H)，4.82(s，1H)，4.54(d，J＝14.5Hz，1H)，4.27(d，J＝14.5Hz，1H)，3.89(s，1H)，3.81(s，3H)，3.22(d，J＝16.2Hz，1H)，2.75(d，J＝16.3Hz，1H)，2.39(s，6H)，1.15(s，3H).13C{1H}NMR(100MHz，CDCl3)δ207.26，194.13，159.47，148.92，143.11，140.01，137.49，133.95，129.74，129.04，128.79，128.61，128.50，128.21，114.19，107.32，82.05，56.84，55.27，49.27，25.86，21.52，21.37，19.90.C30H32NO4HRMS theoretical value of ([ M + H ]]+): 470.2331, respectively; measurement value: 470.2335.
1- (3-methoxybenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1e), a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.76(d，J＝8.2Hz，2H)，7.40(d，J＝7.9Hz，2H)，7.27(t，J＝7.8Hz，1H)，7.24-7.12(m，6H)，6.91-6.75(m，4H)，4.89(s，1H)，4.58(d，J＝14.8Hz，1H)，4.30(d，J＝14.8Hz，1H)，4.23(s，1H)，3.79(s，3H)，3.20(d，J＝16.3Hz，1H)，2.80(d，J＝16.3Hz，1H)，2.39(s，6H)，1.20(s，3H).13C{1H}NMR(100MHz，CDCl3) δ 207.18, 194.32, 160.00, 149.17, 142.99, 140.17, 138.04, 137.50, 134.27, 129.99, 129.09, 128.73, 128.71, 128.60, 120.59, 114.04, 113.50, 107.68, 82.44, 57.25(s), 55.27, 49.40, 25.83, 21.58, 21.45, 20.17. minor isomer:1H NMR(400MHz，CDCl3)δ7.57(d，J＝8.1Hz，2H)，7.25(t，J＝7.8Hz，1H)，7.15(d，J＝8.1Hz，4H)，7.07(d，J＝7.9Hz，2H)，6.93(s，1H)，6.86-6.79(m，3H)，5.17(s，1H)，4.40(d，J＝14.6Hz，1H)，4.31(d，J＝14.6Hz，1H)，3.80(s，3H)，3.32(d，J＝16.6Hz，1H)，2.97(s，1H)，2.54(d，J＝16.8Hz，1H)，2.34(s，6H)，1.52(s，3H).13C{1H}NMR(100MHz，CDCl3)δ205.78，193.06，160.05，149.04，142.16，139.98，138.15，137.21，134.82，130.03，128.94，128.54，128.41，127.81，126.81，120.65，113.99，113.72，107.97，82.68，57.97，55.29，50.25，26.20，21.51，21.38，21.20.C30H32NO4HRMS theoretical value of ([ M + H ]]+): 470.2331, respectively; measurement value: 470.2328.
1- (2-methoxybenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1f), a colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.72(d，J＝8.1Hz，2H)，7.39(d，J＝7.9Hz，2H)，7.30(t，J＝7.8Hz，1H)，7.23-7.15(m，6H)，6.93(d，J＝7.4Hz，1H)，6.86(d，J＝8.2Hz，1H)，4.93(s，1H)，4.50(d，J＝14.3Hz，1H)，4.36(d，J＝14.3Hz，1H)，4.00(s，1H)，3.73(s，3H)，3.14(d，J＝16.2Hz，1H)，2.71(d，J＝16.2Hz，1H)，2.39(s，3H)，2.37(s，3H)，1.00(s，3H).13C{1H}NMR(100MHz，CDCl3)δ207.18，194.16，157.70，149.89，142.76，139.71，137.85，134.35，130.76，129.86，128.97，128.63，128.52，128.44，124.57，120.63，110.63，106.54，82.26，55.16，53.28，49.06，25.42，21.51，21.41，19.43.C30H32NO4HRMS theoretical value of ([ M + H ]]+): 470.2331, respectively; measurement value: 470.2325.
1- (4-chlorobenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1g), a colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.70(d，J＝8.1Hz，2H)，7.34(d，J＝7.9Hz，2H)，7.28(d，J＝8.2Hz，2H)，7.20-7.12(m，6H)，7.05(s，1H)，4.82(s，1H)，4.55(d，J＝14.8Hz，1H)，4.54(s，1H)，4.25(d，J＝14.9Hz，1H)，3.14(d，J＝16.3Hz，1H)，2.77(d，J＝16.4Hz，1H)，2.37(s，3H)，2.35(s，3H)，1.15(s，3H)13C{1H}NMR(100MHz，CDCl3)δ207.06，194.44，149.01，142.95，140.33，137.37，135.06，134.37，134.08，129.86，129.12，129.07，128.75，128.66，128.61，107.94，82.45，56.51，49.39，25.85，21.61，21.48，20.25.C29H29ClNO3HRMS theoretical value of ([ M + H ]]+): 474.1836, respectively; measurement value: 474.1830.
1- (3-chlorobenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1h), a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.87(d，J＝8.0Hz，2H)，7.49(d，J＝7.8Hz，2H)，7.42-7.36(m，3H)，7.34-7.24(m，5H)，7.19(s，1H)，4.96(s，1H)，4.68(d，J＝14.4Hz，1H)，4.39(d，J＝14.0Hz，1H)，3.33(s，1H)，2.91(d，J＝16.3Hz，1H)，2.50(s，6H)，1.32(s，3H).13C{1H}NMR(100MHz，CDCl3) δ 206.66, 193.86, 148.35, 142.62, 139.84, 138.18, 136.85, 134.28133.64, 129.74, 128.64, 128.26, 128.10, 128.03, 127.89, 126.04, 107.62, 99.49, 82.14, 56.19, 48.97, 25.47, 21.12, 20.98, 19.73. minor isomers:1H NMR(400MHz，CDCl3)δ7.54(d，J＝8.1Hz，2H)，7.24(d，J＝8.1Hz，2H)，7.15-7.08(m，6H)，7.05(d，J＝7.9Hz，2H)，6.82(s，1H)，5.14(s，1H)，4.40(d，J＝14.6Hz，1H)，4.25(d，J＝14.5Hz，1H)，3.72(s，1H)，3.31(d，J＝16.5Hz，1H)，2.51(d，J＝16.4Hz，1H)，2.34(s，6H)，1.50(s，3H).13C{1H}NMR(100MHz，CDCl3)δ148.92，142.25，140.12，136.99，134.73，134.63，133.92，129.98，128.90，128.87，128.51，128.38，127.81，108.27，82.35，56.80，50.45，37.23，26.15，21.48，21.35.C29H29ClNO3HRMS theoretical value of ([ M + H ]]+): 474.1836, respectively; measurement value: 474.1840.
1- (2-chlorobenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1i), a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.85(d，J＝7.9Hz，2H)，7.53-7.43(m，4H)，7.42-7.33(m，3H)，7.33-7.24(m，5H)，4.93(s，1H)，4.80(d，J＝14.7Hz，1H)，4.49(d，J＝14.6Hz，1H)，4.18(s，1H)，3.28(d，J＝16.2Hz，1H)，2.86(d，J＝16.3Hz，1H)，2.48(s，6H)，1.23(s，3H).13C{1H}NMR(100MHz，CDCl3)δ207.07，194.41，149.48，143.09，140.10，137.43，134.37，133.98，133.74，131.29，130.14，129.77，129.06，128.80，128.61，128.56，127.14，107.51，81.91 55.04，49.38，25.73，21.54，21.42，19.73.minorisomer：1H NMR(400MHz，CDCl3)δ7.58(d，J＝7.9Hz，2H)，7.39(d，J＝8.1Hz，1H)，7.36-7.27(m，3H)，7.23(d，J＝7.8Hz，2H)，7.15(d，J＝7.8Hz，2H)，7.12(d，J＝7.7Hz，2H)，7.02(s，1H)，5.23(s，1H)，4.56(d，J＝13.2Hz，1H)，4.44(d，J＝11.8Hz，1H)，3.39(d，J＝15.6Hz，1H)，2.54(d，J＝16.0Hz，1H)，2.37(s，3H)，2.35(s，3H)，1.54(s，3H).13C{1H}NMR(100MHz，CDCl3)δ204.97，192.81，149.19，141.69，139.67，136.73，134.33，133.96，133.47，130.90，129.64，129.27，128.49，128.14，128.11，127.38，126.84，107.55，81.53，55.24，50.00，25.64，21.13，21.02.C29H29ClNO3HRMS theoretical value of ([ M + H ]]+): 474.1836, respectively; measurement value: 474.1841.
1- (4-fluorobenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1j),a colorless oily liquid. Major isomers:1H NMR(400MHz，CDCl3)δ7.84(d，J＝7.9Hz，2H)，7.48(d，J＝7.7Hz，2H)，7.37-7.25(m，6H)，7.20(s，1H)，7.13(t，J＝8.1Hz，2H)，4.96(s，1H)，4.68(d，J＝13.9Hz，1H)，4.41(s，1H)，4.38(d，J＝13.5Hz，1H)，3.29(d，J＝16.2Hz，1H)，2.89(d，J＝16.3Hz，1H)，2.49(s，3H)，2.48(s，3H)，1.27(s，3H).13C{1H}NMR(100MHz，CDCl3) δ 206.48, 193.69, 163.18(s), 161.95(d, J ═ 246.8Hz), 160.72, 148.28, 142.39, 139.62, 136.80, 133.62, 131.67(d, J ═ 3.0Hz), 129.65(d, J ═ 8.2Hz), 128.49, 128.09, 127.97, 115.21(d, J ═ 21.5Hz), 107.19, 81.70, 55.98, 48.77, 25.27, 20.9820.85, 19.53. minor isomers:1H NMR(400MHz，CDCl3)δ7.53(d，J＝7.9Hz，2H)，7.13(m，6H)，7.05(d，J＝7.8Hz，2H)，6.96(t，J＝8.2Hz，2H)，6.85(s，1H)，5.17(s，1H)，4.40(d，J＝13.9Hz，1H)，4.24(d，J＝13.9Hz，1H)，3.33(d，J＝16.2Hz，1H)，2.51(d，J＝16.8Hz，1H)，2.33(s，6H)，1.50(s，3H).13C{1H}NMR(100MHz，CDCl3)δ205.13，192.98，162.27(d，J＝246.5Hz)，148.96，141.94，139.88，136.83，134.55，131.76(d，J＝3.1Hz)，130.25(d，J＝8.3Hz)，128.69，128.29，128.19，127.57，115.40(d，J＝21.5Hz)，107.93，82.08，56.59，50.33，25.91，21.30，21.25，21.15.C29H29FNO3HRMS theoretical value of ([ M + H ]]+): 458.2131, respectively; measurement value: 458.2123.
1- (4-bromobenzyl) -2-hydroxy-3-methyl-3, 5-bis ((4-tolyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1k), brown oily liquid.1H NMR(400MHz，CDCl3)δ7.79(d，J＝8.1Hz，2H)，7.49(d，J＝8.1Hz，2H)，7.37(d，J＝7.9Hz，2H)，7.23(d，J＝8.0Hz，2H)，7.17(t，J＝8.2Hz，4H)，7.07(s，1H)，4.79(s，1H)，4.57(d，J＝14.8Hz，1H)，4.28(d，J＝14.7Hz，1H)，3.95(s，1H)，3.24(d，J＝16.3Hz，1H)，2.78(d，J＝16.3Hz，1H)，2.40(s，3H)，2.40(s，3H)，1.21(s，3H).13C{1H}NMR(100MHz，CDCl3)δ207.14，194.04，148.59，137.20，135.33，133.68，131.90，129.99，129.01，128.74，128.56，128.38，122.10，107.83，82.44，56.47，49.28，25.91，21.46，21.31，19.95.C29H29BrNO3HRMS theoretical value of ([ M + H ]]+): 518.1331, respectively; measurement value: 518.1339.
1- (thiophene-2-methylamino) -2-hydroxy-3-methyl-3, 5-bis ((4-methoxyphenyl) methanone) -2, 4, 4, 6-tetrahydropyridine derivative (1l), brown oily liquid.1H NMR(400MHz，CDCl3)δ8.02(d，J＝8.2Hz，2H)，7.57(d，J＝8.0Hz，2H)，7.35(d，J＝4.3Hz，1H)，7.18(s，1H)，7.08-7.02(m，2H)，6.97(t，J＝7.2Hz，4H)，5.04(s，1H)，4.90(d，J＝8.1Hz，1H)，4.53(d，J＝11.2Hz，1H)，3.93(s，3H)，3.92(s，3H)，3.32(d，J＝16.0Hz，1H)，2.85(d，J＝16.1Hz，1H)，1.29(s，3H).13C{1H}NMR(100MHz，CDCl3)δ203.78，192.09，161.57，159.78，146.42，137.93，131.19，130.07，129.04，127.31，126.07，125.69，124.94，112.21，111.88，106.53，80.87，54.18，54.04，50.53，47.82，24.84，18.62.C27H28NO5HRMS theoretical value of S ([ M + H)]+): 478.1688, respectively; measurement value: 478.1678.
Claims (4)
1. a synthetic method of 2-hydroxypyridine compound 1 is characterized by comprising the following steps:
the synthetic route is shown in the following reaction formula,
taking enaminone 2 as a starting material and Tempo salt 3 as an oxidant, and carrying out oxidation reaction and coupling cyclization reaction under a heating condition to generate a 2-hydroxypyridine compound 1;
the molecular structural formula of the enaminone 2 is as follows:
R1is selected from phenyl; r2Is benzyl, or substituted benzyl;
the synthetic route is as follows:
refluxing A and amine B in an ethanol solvent to generate enaminone 2;
the molecular structural formula of the Tempo salt 3 is as follows:
r is selected from: hydrogen; x is tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate, perchlorate and hexafluoroantimonate;
the synthetic route is as follows:
and adding Tempo C and acid D into an ether solvent, and dropwise adding sodium hypochlorite while stirring at low temperature to generate Tempo salt 3.
2. The method for synthesizing 2-hydroxypyridine compound 1 according to claim 1, wherein: the molar ratio of the enaminone 2 to the Tempo salt 3 is 1: 0.5-1: 5.
3. The method for synthesizing 2-hydroxypyridine compound 1 according to claim 1, wherein: the reaction solvent of the enaminone 2 and the Tempo salt 3 is one or a mixed solvent of two of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile or toluene.
4. The method for synthesizing 2-hydroxypyridine compound 1 according to claim 1, wherein: the reaction atmosphere of the enaminone 2 and the Tempo salt 3 is air, nitrogen or argon; the reaction time is 0.1-48 hours; the reaction temperature is 40-120 ℃.
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