Preparation method of a cyclic substituted 2-pyridone compound

Abstract

The present invention discloses a preparation method of a cyclic substituted 2-pyridone compound, and the preparation method includes: in the presence of visible light and an inert atmosphere, contacting a compound represented by formula (I a ') or formula (I b ') with an organic solvent, a catalyst, a reducing agent, and a base to cause a reaction. The preparation method of the present invention can efficiently, economically, and greenly prepare a cyclic substituted 2-pyridone compound, and the raw materials are easily available, the operation is simple, the reaction conditions are mild, the substrate generality is good, the yield is high, and the prepared cyclic substituted 2-pyridone compound can be widely applied in the fields of medicinal chemistry and organic chemistry;

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a cyclic substituted 2-pyridone compound. Background Art

[0002] The cyclic substituted 2-pyridone structural unit widely exists in natural products and drug molecules and has various important biological activities. In addition, it can also be used as an intermediate to construct indolizidine and quinolizidine alkaloids (H. Hu, S. Wang, C. Zhang, L. Wang, L. Ding, J. Zhang, Q. Wu, Bioorg. Med. Chem. Lett., 2010, 20, 7537 - 7539). At present, there are few reports on the synthesis methods of cyclic substituted 2-pyridone compounds. Currently, there are two main known synthesis methods: one is to synthesize 1,6-cyclic substituted 2-pyridone through ligand-controlled nickel / aluminum co-catalyzed intramolecular C6-position regioselective alkylation reaction of olefins (P. A. Dones, N. Cramer, Angew. Chem., Int. Ed. 2015, 54, 633.). The second is to perform an intramolecular 1,6-addition to 2-pyridone under strong base conditions and then oxidize to obtain 1,6-cyclic substituted 2-pyridone compounds (D. Gray, T. Gallagher, Angew. Chem. Int. Ed. 2006, 45, 2419). These strategies have technical problems such as regioselectivity and complex conditions. Summary of the Invention

[0003] In view of the deficiencies of the prior art, the present invention provides a preparation method of a cyclic substituted 2-pyridone structural compound, which uses an easily available N-alkyl substituted 2-pyridone compound as a raw material to construct a cyclic substituted 2-pyridone compound in one step. This method has the advantages of easily available raw materials, simple operation, mild conditions, wide substrate scope, and high yield, providing a simple and efficient synthesis method for the synthesis of cyclic substituted 2-pyridone.

[0004] The present invention provides a preparation method of a cyclic substituted 2-pyridone compound represented by formula (Ⅰ a ) or formula (Ⅰ b ), which includes: in the presence of visible light and an inert atmosphere, contacting the compound represented by formula (Ⅰ a ′) with an organic solvent, a catalyst, a reducing agent, and a base to react to obtain the compound represented by formula (Ⅰ a ); or, in the presence of visible light and an inert atmosphere, contacting the compound represented by formula (Ⅰ b ′) with an organic solvent, a catalyst, a reducing agent, and a base to react to obtain the compound represented by formula (Ⅰ b ), and the reaction formula is as follows:

[0005]

[0006] Wherein, R1 and R2 are the same or different and each independently selected from one of hydrogen, alkyl, aryl, halogen, alkoxy, and ester group; R3 is aryl; X is selected from one of halogen and alkylsulfonyl; n is an integer from 0 to 10.

[0007] According to the specific embodiments of the present invention, R1 is selected from one of hydrogen, C1-C6 alkyl, fused aryl, halogen, C1-C6 alkoxy, and C1-C6 ester group, preferably selected from one of hydrogen, C1-C3 alkyl, fused C6-C20 aryl, halogen, C1-C3 alkoxy, and C1-C3 ester group, more preferably selected from one of hydrogen, methyl, fused phenyl, bromine, iodine, methoxy, and methyl ester group; R2 is selected from one of hydrogen and C1-C6 alkyl, preferably selected from one of hydrogen and C1-C3 alkyl, more preferably selected from one of hydrogen and methyl; R3 is C6-C20 aryl, preferably benzyl; X is selected from one of halogen and C1-C3 alkylsulfonyl, preferably selected from one of bromine, iodine, and methylsulfonyl.

[0008] According to the specific embodiments of the present invention, formula (Ⅰ aThe compound shown in formula (Ⅰ′) is selected from 1-(4-iodobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)pyridin-2(1H)-one, 4-(2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-3-methylpyridin-2(1H)-one, 1-(4-bromobutyl)-3-methylpyridin-2(1H)-one, 4-(3-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-4-methylpyridin-2(1H)-one, 4-(4-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-5-methylpyridin-2(1H)-one, 4-(5-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 4-bromo-1-(4-bromobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)-4-iodopyridin-2(1H)-one, 1-(4-bromobutyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester, 1-(4-bromobutyl)-4-methoxypyridin-2(1H)-one, 5-bromo-1-(4-bromobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester, 5-bromo-1-(4-bromobutyl)-3-methylpyridin-2(1H)-one, 1-(4-bromopentyl)-3-methylpyridin-2(1H)-one, 1-(5-iodopentyl)-3-methylpyridin-2(1H)-one, 2-(4-iodobutyl)isoquinolin-1(2H)-one, 2-(4-iodobutyl)isoquinolin-3(2H)-one.

[0009] According to a specific embodiment of the present invention, the compound shown in formula (Ⅰ b ′) is 1-benzyl-5-(4-bromobutoxy)pyridin-2(1H)-one.

[0010] According to a specific embodiment of the present invention, the molar ratio of the compound shown in formula (Ⅰ a ′) or formula (Ⅰ b ′) to the catalyst is 20:1; the catalyst has the structure shown in formula (Ⅱ):

[0011]

[0012] Among them, R4 is one of phenyl, methyl, and hydrogen; R5 and R6 are the same or different and each independently selected from one of chlorine, bromine, quinoline, DMAP, n-butylamine, oxazine, 4-hydroxypyridine, 3-hydroxypyridine, 4-methylpyridine, 4-methoxypyridine, 4-phenylpyridine, 3,5-dimethylpyridine, ethane, and n-butane; preferably, R5 is selected from one of chlorine, bromine, quinoline, DMAP, n-butylamine, oxazine, 4-hydroxypyridine, 3-hydroxypyridine, 4-methylpyridine, 4-methoxypyridine, 4-phenylpyridine, 3,5-dimethylpyridine; R6 is selected from one of chlorine, bromine, ethane, and n-butane.

[0013] According to a specific embodiment of the present invention, the molar ratio of the compound represented by formula (Ⅰ a ′) or formula (Ⅰ b ′) to the reducing agent is 2:1; the reducing agent is selected from one of borosilicate, lithium aluminum hydride, sodium borohydride, lithium borohydride, potassium borohydride, sodium formate, sodium hydride, sodium cyanoborohydride, and preferably borosilicate.

[0014] According to a specific embodiment of the present invention, the molar ratio of the compound represented by formula (Ⅰ a ′) or formula (Ⅰ b ′) to the base is 1:2; the base is selected from one of Barton base, triethylamine, pyridine, sodium tert-butoxide, potassium tert-butoxide, diisopropylamine, sodium methoxide, sodium ethoxide, sodium amide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium thiosulfate, and preferably Barton base.

[0015] According to a specific embodiment of the present invention, the organic solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, chlorobenzene, trifluorotoluene, toluene, o-xylene, and n-heptane, and preferably chlorobenzene.

[0016] According to a specific embodiment of the present invention, the reaction temperature is 0 to 80 °C, and the heating process can use an oil bath (such as silicone oil, paraffin oil, etc.) or other heating methods, and the reaction time is 0 to 50 h; preferably, the reaction is carried out at room temperature for 20 to 30 h.

[0017] According to a specific embodiment of the present invention, it also includes post-treatment of the reaction product; preferably, the post-treatment includes filtering, concentrating, and column chromatography separation and purification of the reaction product. Specifically, the filtering process can use a sintered glass funnel to filter under reduced pressure. The concentrating process can adopt methods such as atmospheric distillation and vacuum distillation, for example, vacuum concentration with a rotary evaporator.

[0018] The beneficial effects of the present invention are:

[0019] (1) The main raw materials of the method of the present invention are easily available 2-pyridone compounds. Most of the raw materials can be commercial reagents, without special treatment, and are inexpensive. The preparation method is simple and convenient for industrial production;

[0020] (2) The light wavelength used in the method of the present invention is within 400 - 800 nm, which is visible light, saving costs and reducing environmental pollution, in line with the development concept of green chemistry;

[0021] (3) The reaction conditions involved in the method of the present invention have good functional group tolerance and substrate generality, and can be produced on a gram scale;

[0022] (4) The method of the present invention is efficient and diverse, constructing a bicyclic structure in one step reaction, with high yield and extremely high step economy. Detailed implementation mode

[0023] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention. In the following examples, the wavelength in blue light is 470 nanometers.

[0024] Example 1: Preparation of 6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0025]

[0026] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample bottle equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equivalents) were added to the vial. Then 1-(4-iodobutyl)pyridin-2(1H)-one (27.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5W) was stirred at room temperature for 24 hours. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (yellow liquid, 54%).

[0027] Method 2: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-bromobutyl)pyridin-2(1H)-one (22.9 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (yellow liquid, 66%).

[0028] Method 3: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 4-(2-oxopyridin-1(2H)-yl)butyl methanesulfonate (24.5 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (yellow liquid, 62%). 1 HNMR(600MHz,CDCl3,23℃,δ):7.23(dd,J=9.1,6.9Hz,1H),6.43(d,J=9.0Hz,1H),5.99(d,J=6.9Hz,1H),4.00(t,J=6.4Hz,2H),2.77(t,J=6.7Hz,2H),1.94(p,J=6.5Hz,2H),1.79(p,J=6.7Hz,2H). 13 CNMR(100MHz,CDCl3,23℃,δ):163.6,147.7,138.7,116.7,105.1,41.6,28.8,22.2,18.7.

[0029] Example 2: Preparation of 3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0030]

[0031] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-iodobutyl)-3-methylpyridin-2(1H)-one (29.1 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (14.8 mg, 91%).

[0032] Method 2: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-bromobutyl)-3-methylpyridin-2(1H)-one (24.4 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (colorless liquid, 93%).

[0033] Method 3: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 4-(3-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate (25.9 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (colorless liquid, 98%). 1 HNMR(600MHz,CDCl3,23℃,δ):7.11(d,J=7.0Hz,1H),5.91(d,J=6.9Hz,1H),4.02(t,J=6.4Hz,2H),2.74(t,J=6.7Hz,2H),2.13(s,3H),1.94(p,J=6.5Hz,2H),1.78(p,J=6.7Hz,2H). 13CNMR (100 MHz, CDCl3, 23 °C, δ): 163.7, 144.6, 136.2, 125.3, 104.5, 41.7, 28.6, 22.4, 18.8, 17.2.

[0034] Example 3: Preparation of 2-Methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0035]

[0036] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-iodobutyl)-4-methylpyridin-2(1H)-one (29.1 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (colorless liquid, 64%).

[0037] Method 2: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 4-(4-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate (25.9 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (colorless liquid, 82%). 1 HNMR (600 MHz, CDCl3, 23 °C, δ): 6.18 (s, 1H), 5.78 (d, J = 1.9 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 2.05 (s, 3H), 1.86 (p, J = 6.5 Hz, 2H), 1.71 (p, J = 6.7 Hz, 2H). 13 CNMR (100 MHz, CDCl3, 23 °C, δ): 162.6, 149.1, 145.3, 114.4, 106.6, 40.3, 27.7, 21.3, 20.1, 17.8.

[0038] Example 4: Preparation of 1-Methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0039]

[0040] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-iodobutyl)-5-methylpyridin-2(1H)-one (29.1 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (white solid, 60%).

[0041] Method 2: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 4-(5-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate (25.9 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (white solid, 74%). 1 HNMR(600 MHz, CDCl3, 23 °C, δ): 7.08 (d, J = 9.1 Hz, 1H), 6.33 (d, J = 9.1 Hz, 1H), 3.93 (t, J = 6.2 Hz, 2H), 2.63 (t, J = 6.7 Hz, 2H), 1.96 (s, 3H), 1.84 (q, J = 6.5 Hz, 2H), 1.75 (p, J = 6.6 Hz, 2H). 13 CNMR(100 MHz, CDCl3, 23 °C, δ): 162.0, 142.7, 141.0, 114.9, 111.1, 41.8, 25.2, 21.0, 17.9, 15.9.

[0042] Example 5: Preparation of 2-Bromo-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0043]

[0044] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 4-bromo-1-(4-bromobutyl)pyridin-2(1H)-one (30.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (white solid, 76%). 1 HNMR(600MHz,CDCl3,23℃,δ):6.59(d,J=2.1Hz,1H),6.11(dd,J=2.3,1.1Hz,1H),3.86(t,J=6.4Hz,2H),2.69(t,J=6.7Hz,2H),1.90-1.85(m,2H),1.74(p,J=6.7Hz,2H). 13 CNMR(100MHz,CDCl3,23℃,δ):161.3,147.1,134.0,117.8,108.1,40.8,27.6,21.0,17.5.

[0045] Example 6: Preparation of 2-iodo-6,7,8,9-tetrahydro-4H-quinazolin-4-one

[0046]

[0047] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-bromobutyl)-4-iodopyridin-2(1H)-one (35.5 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (colorless liquid, 36%). 1HNMR(600MHz, CDCl3, 23℃, δ): 6.94(s, 1H), 6.36 - 6.35(m, 1H), 3.92(t, J=6.4Hz, 2H), 2.72(t, J=6.7Hz, 2H), 1.94(q, J=6.5Hz, 2H), 1.80(q, J=6.7Hz, 2H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 161.3, 147.1, 134.0, 117.8, 108.1, 40.8, 27.6, 21.0, 17.5.

[0048] Example 7: Preparation of methyl 6 - oxo - 1,3,4,6 - tetrahydro - 2H - quinazine - 8 - carboxylate

[0049]

[0050] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then methyl 1 - (4 - bromobutyl)-2 - oxo - 1,2 - dihydropyridine - 4 - carboxylate (28.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (white solid, 48%). 1 HNMR(600MHz, CDCl3, 23℃, δ): 6.97 - 6.96(m, 1H), 6.43(s, 1H), 3.94(t, J=6.4Hz, 2H), 3.82(s, 3H), 2.76(t, J=6.7Hz, 2H), 1.90(p, J=6.6Hz, 2H), 1.75(p, J=6.7Hz, 2H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 165.6, 163.4, 148.3, 139.4, 118.1, 103.5, 52.7, 42.1, 29.1, 22.1, 18.5.

[0051] Example 8: Preparation of 2 - methoxy - 6,7,8,9 - tetrahydro - 4H - quinazin - 4 - one

[0052]

[0053] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-bromobutyl)-4-methoxypyridin-2(1H)-one (25.9 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (white solid, 83%). 1 1H NMR (600 MHz, CDCl3, 23 °C, δ): 5.84 (d, J = 2.8 Hz, 1H), 5.73 - 5.71 (m, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.74 (s, 3H), 2.71 (t, J = 6.7 Hz, 2H), 1.92 (p, J = 6.6 Hz, 2H), 1.78 (p, J = 6.7 Hz, 2H). 13 13C NMR (100 MHz, CDCl3, 23 °C, δ): 167.4, 165.2, 147.4, 99.0, 94.4, 55.2, 41.2, 28.8, 22.3, 18.8.

[0054] Example 9: Preparation of 1-bromo-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0055]

[0056] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 5-bromo-1-(4-bromobutyl)pyridin-2(1H)-one (30.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (colorless liquid, 59%). 1HNMR(600MHz, CDCl3, 23℃, δ): 7.41 (d, J = 9.2Hz, 1H), 6.36 (d, J = 9.6Hz, 1H), 3.98 (d, J = 6.3Hz, 2H), 2.86 (t, J = 6.7Hz, 2H), 1.92 (q, J = 6.3Hz, 2H), 1.85 (q, J = 6.5Hz, 2H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 145.0, 142.4, 117.7, 99.5, 43.7, 29.7, 22.0, 19.0.

[0057] Example 10: Preparation of Methyl 6 - oxo - 1,3,4,6 - tetrahydro - 2H - quinazine - 9 - carboxylate

[0058]

[0059] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then methyl 1 - (4 - bromobutyl)-6 - oxo - 1,6 - dihydropyridine - 3 - carboxylate (28.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (white solid, 47%). 1 HNMR(600MHz, CDCl3, 23℃, δ): 7.90 (d, J = 9.7Hz, 1H), 6.42 (d, J = 9.6Hz, 1H), 4.06 (t, J = 6.3Hz, 2H), 3.83 (s, 3H), 3.38 (t, J = 6.7Hz, 2H), 1.93 (p, J = 6.5Hz, 2H), 1.82 (p, J = 6.8Hz, 2H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 165.8, 163.0, 155.8, 139.7, 115.4, 107.6, 51.8, 42.5, 26.9, 21.4, 18.2.

[0060] Example 11: Preparation of 1 - Bromo - 3 - methyl - 6,7,8,9 - tetrahydro - 4H - quinazin - 4 - one

[0061]

[0062] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 5-bromo-1-(4-bromobutyl)-3-methylpyridin-2(1H)-one (32.1 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (colorless liquid, 66%). 1 HNMR(600MHz,CDCl3,23℃,δ):7.32(s,1H),3.99(t,J=6.2Hz,2H),2.83(t,J=6.8Hz,2H),2.13(s,3H),1.93-1.89(m,2H),1.82(q,J=6.5Hz,2H). 13 CNMR(100MHz,CDCl3,23℃,δ):162.8,141.7,139.7,126.9,99.0,43.7,29.3,22.1,19.1,16.9.

[0063] Example 12: Preparation of 3,9-dimethyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one

[0064]

[0065] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-(4-bromopentyl)-3-methylpyridin-2(1H)-one (25.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (colorless liquid, 89%). 1HNMR(600MHz, CDCl3, 23℃, δ): 7.17(dd, J=7.1, 1.1Hz, 1H), 6.00(dd, J=7.1, 1.3Hz, 1H), 4.53(dt, J=14.2, 5.3Hz, 1H), 3.64(ddd, J=14.6, 9.4, 5.3Hz, 1H), 2.82(dt, J=9.1, 6.4Hz, 1H), 2.13 - 2.13(m, 3H), 2.02 - 1.90(m, 2H), 1.90 - 1.84(m, 2H), 1.30(d, J=6.8Hz, 3H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 163.5, 149.6, 136.1, 125.2, 102.6, 40.8, 32.0, 27.3, 20.5, 19.6, 17.2.

[0066] Example 13: Preparation of 3 - methyl - 7,8,9,10 - tetrahydropyrido[1,2 - a]azepin - 4(6H) - one

[0067]

[0068] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton base (34.3 mg, 2.0 equiv) were added to the vial. Then 1 - (5 - iodopentyl) - 3 - methylpyridin - 2(1H) - one (30.5 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (yellow liquid, 75%). 1 HNMR(600MHz, CDCl3, 23℃, δ): 7.05(d, J=6.9Hz, 1H), 5.89(d, J=6.9Hz, 1H), 4.42 - 4.34(m, 2H), 2.76 - 2.72(m, 2H), 2.10(s, 3H), 1.77 - 1.73(m, 6H). 13 CNMR(100MHz, CDCl3, 23℃, δ): 163.6, 149.4, 136.3, 126.2, 104.9, 43.7, 34.9, 29.8, 27.9, 27.5, 17.6.

[0069] Example 14: Preparation of 1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one

[0070]

[0071] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 2-(4-iodobutyl)isoquinolin-1(2H)-one (32.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2 * 5 W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly purified by column chromatography to obtain the target product (white solid, 87%). 1 HNMR(600MHz,CDCl3,23℃,δ):8.38(dd,J = 8.0,1.3Hz,1H),7.57(ddd,J = 8.2,7.0,1.4Hz,1H),7.42 - 7.36(m,2H),6.30(s,1H),4.11(t,J = 6.4Hz,2H),2.81(td,J = 6.7,1.3Hz,2H),1.96(p,J = 6.7Hz,2H),1.82(p,J = 6.8Hz,2H). 13 CNMR(100MHz,CDCl3,23℃,δ):162.9,141.0,136.8,132.0,128.0,125.6,125.0,124.4,103.8,41.0,28.9,22.4,19.1.

[0072] Example 15: Preparation of 1,2,3,4-tetrahydro-6H-pyrido[2,1-a]isoquinolin-6-one

[0073]

[0074] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 2-(4-iodobutyl)isoquinolin-3(2H)-one (32.7 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (white solid, 74%). 1 HNMR (600 MHz, CDCl3, 23 °C, δ): 8.79 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.87 - 7.85 (m, 1H), 7.60 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.39 (ddd, J = 8.0, 6.8, 1.0 Hz, 1H), 4.20 - 4.16 (m, 2H), 3.15 - 3.11 (m, 2H), 2.05 - 2.01 (m, 2H), 1.84 (dd, J = 7.8, 3.8 Hz, 2H). 13 CNMR (100 MHz, CDCl3, 23 °C, δ): 161.6, 148.2, 136.7, 129.2, 127.3, 125.5, 123.8, 121.4, 118.1, 30.1, 24.4, 23.4.

[0075] Example 16: Preparation of 7-benzyl-3,4,5,7-tetrahydrooxazolo[3,2-c]pyridin-6(2H)-one

[0076]

[0077] Method 1: Under an argon atmosphere, Co(quinoline)(dmgH)2Cl (3.5 mg, 5 mol%) was added to a 4 mL borosilicate sample vial equipped with a magnetic stir bar. Then chlorobenzene (1.0 mL, c = 0.1 M) and Barton's base (34.3 mg, 2.0 equiv) were added to the vial. Then 1-benzyl-5-(4-bromobutoxy)pyridin-2(1H)-one (33.5 mg, 0.1 mmol) was added to the same vial. The vial was sealed with a septum cap. The reaction mixture irradiated with a blue LED (2*5W) was stirred at room temperature for 24 h. The product was filtered through diatomaceous earth, washed with ethyl acetate, the solvent was removed under reduced pressure, and the crude product was directly separated and purified by column chromatography to obtain the target product (colorless liquid, 69%). 11H NMR (600 MHz, CDCl3, 23 °C, δ): 7.31 (t, J = 7.5 Hz, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 10.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.48 (dd, J = 9.6, 1.5 Hz, 1H), 5.48 - 5.40 (m, 2H), 3.90 (t, J = 5.5 Hz, 2H), 2.82 - 2.79 (m, 2H), 1.85 (q, J = 5.6 Hz, 2H), 1.40 (q, J = 5.6 Hz, 2H). 13 13C NMR (100 MHz, CDCl3, 23 °C, δ): 162.2, 143.2, 142.8, 137.0, 136.7, 128.8, 127.3, 126.3, 117.4, 73.3, 47.5, 31.5, 29.2, 23.1.

[0078] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. Process for preparing a cyclic substituted 2-pyridone compound represented by formula (I a ), characterized in that The preparation method includes: In the presence of a blue LED and an argon atmosphere, a compound represented by formula (I a ′) is contacted with chlorobenzene, Co(quinoline)(dmgH)2Cl, borosilicate, and Barton's base and reacted at room temperature for 20 to 30 h to obtain a compound represented by formula (I a ), and the reaction formula is as follows: Wherein, R1 is selected from one of hydrogen, C1-C6 alkyl, halogen, C1-C6 alkoxy, and C1-C6 ester group; R2 is selected from one of hydrogen and C1-C6 alkyl; X is selected from one of halogen and C1-C3 alkylsulfonyl; n is an integer from 1 to 2.

2. The preparation method according to claim 1, characterized in that, The R1 is selected from one of hydrogen, C1-C3 alkyl, halogen, C1-C3 alkoxy, and C1-C3 ester group; the R2 is selected from one of hydrogen and C1-C3 alkyl.

3. The preparation method according to claim 1, wherein The R1 is selected from one of hydrogen, methyl, bromine, iodine, methoxy, and methyl ester group; the R2 is selected from one of hydrogen and methyl; the X is selected from one of bromine, iodine, and methylsulfonyl.

4. The preparation method according to claim 1, characterized in that, The compound represented by the formula (Ⅰ a ′) is selected from 1-(4-iodobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)pyridin-2(1H)-one, 4-(2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-3-methylpyridin-2(1H)-one, 1-(4-bromobutyl)-3-methylpyridin-2(1H)-one, 4-(3-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-4-methylpyridin-2(1H)-one, 4-(4-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 1-(4-iodobutyl)-5-methylpyridin-2(1H)-one, 4-(5-methyl-2-oxopyridin-1(2H)-yl)butyl methanesulfonate, 4-bromo-1-(4-bromobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)-4-iodopyridin-2(1H)-one, 1-(4-bromobutyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester, 1-(4-bromobutyl)-4-methoxypyridin-2(1H)-one, 5-bromo-1-(4-bromobutyl)pyridin-2(1H)-one, 1-(4-bromobutyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester, 5-bromo-1-(4-bromobutyl)-3-methylpyridin-2(1H)-one, 1-(4-bromopentyl)-3-methylpyridin-2(1H)-one, 1-(5-iodopentyl)-3-methylpyridin-2(1H)-one.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (Ⅰ a ˊ) to the borosilicate is 100:1 - 1:

1.

6. The preparation method according to claim 1, wherein, The molar ratio of the compound shown in formula (Ⅰ a ˊ) to Barton base is 100:1 - 1:

1.

7. The preparation method according to claim 1, characterized in that, It also includes post-treatment of the reaction product.

8. The preparation method according to claim 7, characterized in that, The post-treatment includes filtering, concentrating, and column chromatography separation and purification of the reaction product.

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