Preparation method of 2-acylquinoline compound

Abstract

The invention discloses a preparation method of a 2-acylquinoline compound, which is characterized in that an alkenyl isonitrile compound and an acyl oxime compound are used as reaction raw materials, a series of 2-acylquinoline compounds are prepared at a good yield under a photocatalytic reaction condition, the method has wide reaction substrate universality, and the method is suitable for industrial production. The invention provides a general synthesis approach of the 2-acylquinoline compound.

Description

Technical Field

[0001] The present application belongs to the technical field of organic / pharmaceutical intermediate synthesis, and specifically relates to a method for preparing 2-acylquinoline compounds. Background Art

[0002] Quinoline compounds are a class of widely distributed important heterocyclic compounds, which are various natural products and alkaloids and important skeletons. They have anti-malarial, bactericidal and anti-inflammatory effects and can be used in the synthesis of HIV reverse transcriptase inhibitors (Journal of Medicinal Chemistry, 1972, Vol. 15, No. 5, pp. 490-493; Bioorg. Med. Chem. Lett., 10 (2000), 277-279). In addition, prior art such as WO2017037616A discloses a series of 2-acylquinoline compounds as synthetic intermediates for the preparation of drug compounds for diseases and symptoms associated with calcium-sensitive receptor (CaSR) modulators.

[0003] Due to the wide application of 2-acylquinoline compounds, the prior art discloses many methods for synthesizing 2-acylquinoline compounds (see Chin. J. Org. Chem. 2020, 40, 1337-1344; CN108484498A; Org. Lett., 2019, 21, 6285-6288; Chemistry Select 2022, 7, e202104416 (1 of 7); CN114249689A; Green Chem., 2020, 22, 3506-3511; WO2017037616A; Science of Synthesis (2009), 48, 97-147; Org. Lett., 2022, 24, 1146−1151; Eur.J.Org.Chem.2020,5551–5556; Tetrahedron Letters.,60,(2019),1043–1048; SyntheticCommunications (2017), 47(21), 1940-1954; J.Org.Chem. 2021,86,8381−8388; Org.Lett.,2019,21,4812-4815; ChemistrySelect 2016, 1,6823–6829; Org.Lett.,2014,16,4582−4585, etc.). In the present invention, a new synthetic route for preparing 2-acylquinoline compounds is disclosed. Using alkenyl isonitrile compounds and acyl oxime compounds as reaction raw materials, a series of 2-acylquinoline compounds are prepared with good yield under photocatalytic reaction conditions. The method has wide universality of reaction substrates and provides a general synthetic route for 2-acylquinoline compounds. Summary of the invention

[0004] The purpose of the present invention is to enrich the synthetic routes for preparing 2-acylquinoline compounds in the prior art, and to provide a novel method for preparing 2-acylquinoline compounds. The method uses alkenyl isonitrile compounds and acyl oxime compounds as reaction raw materials, and under photocatalytic reaction conditions, a series of 2-acylquinoline compounds are prepared with good yields. The method has wide reaction substrate universality, and provides a general synthetic route for 2-acylquinoline compounds.

[0005] A method for preparing a 2-acylquinoline compound provided by the present invention comprises the following steps: Add the alkenyl isonitrile compound shown in Formula 1, the acyl oxime compound shown in Formula 2, the catalyst Ir(ppy)3 and the organic solvent into the reactor, replace the atmosphere in the reactor with an inert atmosphere, heat and stir the reaction under light conditions, and obtain the 2-acylquinoline compound shown in Formula 3 after post-treatment. The reaction formula is as follows:

[0006] In the above reaction formula, R is selected from substituted or unsubstituted phenyl and acetyl; wherein the substituent in the substituted or unsubstituted is selected from electron-withdrawing groups such as halogen, NO2, CN, CF3, acetyl, and methanesulfonyl; R1 is selected from C 1-20 Alkyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R2, R3 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy.

[0007] Preferably, R is selected from substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from CF3; R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from fluorine, chlorine, bromine, methyl, methoxy; R2, R3 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, methoxy, trifluoromethyl.

[0008] Further preferably, R1 is selected from 4-trifluoromethylphenyl; R1 is selected from methyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from fluorine, chlorine, bromine, methyl, methoxy; R2, R3 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, methoxy, trifluoromethyl.

[0009] According to the aforementioned preparation method of the present invention, the feeding molar ratio of the alkenyl isonitrile compound shown in Formula 1, the acyl oxime compound shown in Formula 2, and the catalyst Ir(ppy)3 is 1:1~3:0.005~0.05; preferably, the feeding molar ratio of the alkenyl isonitrile compound shown in Formula 1, the acyl oxime compound shown in Formula 2, and the catalyst Ir(ppy)3 is 1:1.5:0.01.

[0010] According to the aforementioned preparation method of the present invention, the organic solvent is selected from acetonitrile or 1,2-dichloroethane, preferably 1,2-dichloroethane. The amount ratio of the alkenyl isonitrile compound shown in Formula 1 to the organic solvent DCE is 0.005-0.5 mmol / mL, preferably 0.1 mmol / mL.

[0011] According to the aforementioned preparation method of the present invention, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.

[0012] According to the aforementioned preparation method of the present invention, the lighting condition is provided by a 1-15W blue light LED lamp, preferably a 3-7W blue light LED lamp, and more preferably a 5W blue light LED lamp.

[0013] According to the aforementioned preparation method of the present invention, the reaction temperature of the heating and stirring reaction is 50-150°C, and the reaction time is 4-48 hours; preferably, the reaction temperature is 80-120°C, and the reaction time is 12-24 hours; more preferably, the reaction temperature is 100°C.

[0014] According to the aforementioned preparation method of the present invention, the post-treatment operation is as follows: after the reaction is complete, a saturated sodium bicarbonate solution is added, extracted with ethyl acetate, the organic layer is separated, water is removed with anhydrous sodium sulfate, and the target product is purified by silica gel column chromatography after reduced pressure rotary evaporation.

[0015] Compared with the prior art, the present invention has the following advantages: (1) The present invention reports for the first time a synthetic route for preparing 2-acylquinoline compounds using alkenyl isonitrile compounds and acyl oxime compounds as reaction raw materials, providing a completely new process.

[0016] (2) The present invention is carried out under light conditions to prepare a series of 2-acylquinoline compounds with good yields, has a wide range of reaction substrates, and provides a general synthetic route for 2-acylquinoline compounds. DETAILED DESCRIPTION

[0017] The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the reagents and raw materials used are purchased from conventional commercial channels without further purification, or are synthesized according to preparation methods known in the art.

[0018] Example 1-19 Reaction Condition Optimization Test Using the alkenyl isonitrile compounds of formula 1a and the acyl oxime compounds of formula 2a as template substrates, the effects of various synthesis process conditions including photocatalyst type, light source, reaction temperature, reaction time, solvent, auxiliary agent and other factors on the yield of the target product 3aa were discussed. The reaction formula and results are as follows:

[0019] Example Response variables Isolation yield% 1 none 81 2 <![CDATA[Ru(bpy)3Cl2 replaces Ir(ppy)3]]> 25 3 <![CDATA[Eosin Y replaces Ir(ppy)3]]> 11 4 <![CDATA[Eosin Y disodium replaces Ir(ppy)3]]> 0 5 Reaction 12h 82 6 Reaction 6h 69 7 120℃, reaction time 12h 63 8 80℃, reaction time 12h 68 9 3W blue LED, reaction time 12h 49 10 7W blue LED, reaction time 12h 77 11 DMSO replaced acetonitrile and reacted for 12 h 23 12 DCE replaces acetonitrile and reacts for 12h 83 13 DMF replaces acetonitrile and reacts for 12h 0 14 Toluene replaces acetonitrile and reacts for 12 hours 0 15 Acetone replaced acetonitrile and reacted for 12h 0 16 1,4-dioxane replaces acetonitrile and reacts for 12 hours 0 17 BuOAc replaced acetonitrile and reacted for 12 h 10 18 THF replaces acetonitrile and reacts for 12h 21 19 Add 2 equivalents of sodium carbonate and react for 12 hours 15 The reaction operation of Example 1 is as follows: In a 25mL Schlenk sealed tube reactor, add the alkenyl isonitrile compound (0.2mmol) of formula 1a and the acyl oxime compound (0.3mmol, 1.5equiv) of formula 2a, Ir(ppy)3 (1mol%) and acetonitrile (2mL), then replace the atmosphere in the reactor with argon three times, place the reactor under 5W blue light LED lamp, stir and react at 100℃ for 24 hours, add saturated sodium bicarbonate solution, extract with 50mL ethyl acetate three times, combine the organic phases and dry with anhydrous sodium sulfate, remove the organic solvent by vacuum rotary evaporation, and separate by silica gel column chromatography to obtain the 2-acetyl-4-phenylquinoline compound shown in formula 3a, with a yield of 81%. White solid, mp: 112.3 - 113.9℃(uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.28 -8.25 (m, 1H), 8.08 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.6 Hz,1H), 7.61 - 7.48 (m, 6H), 2.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ:200.8,152.6, 149.3, 147.8, 137.7, 130.9, 129.7, 129.5, 128.6, 128.5, 128.5, 128.0,125.8, 118.1, 25.6.

[0020] It can be seen from Examples 1-19 that the optimal reaction conditions for the synthesis process of the present invention are the reaction conditions of Example 12: photocatalyst Ir(ppy)3, temperature 100°C, time 12 hours, light source 5W blue LED lamp irradiation, solvent DCE (0.1mmol / mL), and feed molar ratio 1:1.5.

[0021] Substrate extension assay When the optimal reaction conditions were obtained, the universality of the synthesis process was further investigated, that is, reaction raw materials with different substituents were selected to prepare a series of 2-acylquinoline compounds under the same operating conditions as Example 12. The results are as follows:

[0022] Target product 3ab: , yield 53.6 mg, yield 78 %; white solid; mp: 144.3 - 144.6 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 – 8.23 ​​(m,3H), 8.06 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.81 – 7.79 (m, 1H), 7.61 – 7.56(m, 1H), 7.55 – 7.48 (m, 7H); 13 C NMR (100 MHz, CDCl3) δ: 192.4, 153.7, 149.7,147.2, 139.5, 137.5, 134.4, 132.9, 130.8, 129.9, 129.5, 128.7, 128.6, 128.5,128.4, 127.4, 125.8, 120.8.

[0023] Target product 3ac ; Yield 47.2 mg, yield 72 %; yellow solid; mp:151.3 - 152.0 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.38 – 8.27 (m,2H), 8.25 (d, J = 1.2 Hz, 1H), 8.06 – 8.01(m, 2H), 7.82 – 7.78 (m, 1H), 7.64- 7.57 (m, 1H), 7.56 - 7.52 (m, 5H), 7.22 - 7.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 192.1, 167.1, 164.5, 153.9, 149.7, 147.2, 137.5, 134.3, 134.2, 132.4(d, J = 3.0 Hz, 1C), 130.8, 129.9, 129.5, 128.6(d, J = 12.4 Hz, 1C),128.5, 127.4, 125.8, 120.9, 115.4; 19 F NMR (376 MHz, CDCl3) δ: 105.0 (s, 1F).

[0024] Target product 3ad ; Yield 55.1 mg, yield 85 %; white solid; mp:138.3 - 138.6 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 – 8.25 (m,1H), 8.17 (d, J = 8.0 Hz, 2H), 8.00 (t, J = 7.6 Hz, 2H), 7.78 (t, J = 4.0 Hz,1H), 7.60 – 7.52 (m, 6H), 7.32 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13 C NMR (100MHz, CDCl3) δ: 193.5, 154.5, 149.5, 147.2, 144.0, 137.6, 133.5, 131.5, 130.8,129.8, 129.5, 128.9, 128.6, 128.2, 127.3, 125.7, 120.9, 21.7.

[0025] Target product 3ae ; Yield: 41.9 mg, yield 80 %; white solid; mp:132.4 - 133.7 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.26 - 8.24 (m,1H), 8.07 (s, 1H), 7.98 - 7.96 (m, 1H), 7.80 - 7.76 (m, 1H), 7.61 - 7.56 (m,1H), 7.54 - 7.49 (m, 5H), 3.49 - 3.43 (m, 2H), 1.31 - 1.27 (m, 3H); 13 C NMR(100 MHz, CDCl3) δ: 203.2, 152.5, 149.3, 147.7, 137.7, 130.8, 129.7, 129.5,128.6, 128.5, 128.4, 128.0, 125.8, 118.3, 30.9, 8.1.

[0026] Target product 3af ; Yield: 45.2 mg, yield 82 %; white solid; mp:137.6 - 137.8 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.36 - 8.33 (m,1H), 8.16 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.70 - 7.67(m, 1H), 7.66 - 7.33 (m, 5H), 3.40 (d, J = 7.6 Hz, 2H), 1.93 - 1.84 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 199.9, 151.7, 148.4,146.8, 136.7, 130.0, 128.8, 128.6, 127.6, 127.6, 127.5, 127.0, 124.8, 117.2, 42.9, 18.0, 14.4.

[0027] Target product 3ag ; Yield: 43.5 mg, yield 75 %; white solid; mp:144.4 - 145.8 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.27 - 8.25 (m,1H), 8.07 (s, 1H), 7.98 - 7.96 (m, 1H), 7.80 - 7.76 (m, 1H), 7.61 - 7.57 (m,1H), 7.54 - 7.49 (m, 5H), 3.47 - 3.41 (m, 2H), 1.83 - 1.76 (m, 2H), 1.53 -1.46 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 202.9,152.6, 149.3, 147.7, 137.7, 130.9, 129.6, 129.5, 128.6, 128.5, 128.4, 128.0,125.8, 118.3, 37.1, 29.6, 26.4, 25.5, 14.3.

[0028] Target product 3ah ; Yield: 46.8 mg, yield 77 %; white solid; mp: 149.1 - 150.3 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 - 8.25 (m,1H), 8.07 (s, 1H), 7.98 - 7.96 (m, 1H), 7.80 - 7.76 (m, 1H), 7.61 - 7.57 (m,1H), 7.54 - 7.49 (m, 5H), 3.47 - 3.41 (m, 2H), 1.83 - 1.76 (m, 2H), 1.53 -1.46 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 202.9,152.6, 149.3, 147.7, 137.7, 130.9, 129.6, 129.5, 128.6, 128.5, 128.4, 128.0,125.8, 118.3, 37.1, 29.6, 26.4, 25.5, 14.3.

[0029] Target product 3ai ; Yield: 43.1 mg, yield 78 %; white solid; mp:130.2 - 131.3 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 8.8Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.61 - 7.56 (m, 1H), 7.53 - 7.49 (m, 4H), 2.61 - 2.54(m, 1H), 1.75 (d, J = 4.8 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ: 193.9, 154.2,149.6, 147.3, 137.6, 136.1, 131.4, 130.9, 129.8, 128.6, 128.4, 127.4, 125.8,120.9, 37.5, 26.7.

[0030] Target product 3aj ; Yield: 57.1 mg, yield 84 %; white solid; mp: 151.3 - 152.8 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.28 - 8.26 (m,1H), 8.04 - 8.00 (m, 4H), 7.81 - 7.76 (m, 1H), 7.63 - 7.51 (m, 6H), 7.49 -7.38 (m, 2H), 2.44 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 194.2, 154.4, 149.5,147.2, 137.9, 137.6, 136.0, 133.9, 131.6, 130.8, 129.8, 129.5, 128.8, 128.6,128.3, 127.9, 127.3, 125.7, 120.9, 21.4. Target product 3aj; yield: 57.1 mg, yield 84 %; white solid; mp: 151.3 - 152.8 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.28- 8.26 (m, 1H), 8.04 – 8.00 (m, 4H), 7.81 – 7.76 (m, 1H), 7.63 – 7.51 (m,6H), 7.49 – 7.38 (m, 2H), 2.44 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 194.2,154.4, 149.5, 147.2, 137.9, 137.6, 136.0, 133.9, 131.6, 130.8, 129.8, 129.5,128.8, 128.6, 128.3, 127.9, 127.3, 125.7, 120.9, 21.4.

[0031] Target product 3ak ; Yield: 51.8 mg, yield 80 %; white solid; mp:136.5 - 137.9 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.28 - 8.26 (m,1H), 8.04 - 8.00 (m, 4H), 7.81 - 7.77 (m, 1H), 7.63 - 7.51 (m, 6H), 7.46 -7.39 (m, 2H), 2.45 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 194.3, 154.4, 149.5,147.3, 137.9, 137.6, 136.0, 133.9, 131.6, 130.9, 129.8, 129.5, 128.8, 128.6,128.3, 128.1, 127.3, 125.7, 120.9, 21.4.

[0032] Target product 3al ; Yield: 49.2 mg, yield 81 %; white solid; mp:148.6 - 149.3 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.28 - 8.25 (m,1H), 8.07 (s, 1H), 7.99 - 7.96 (m, 1H), 7.81 - 7.76 (m, 1H), 7.61 - 7.57 (m,1H), 7.55 - 7.50 (m, 5H), 3.44 - 3.39 (m, 1H), 3.27 - 3.21 (m, 1H)3.44 - 3.39(m, 1H), 1.59 (s, 2H), 1.54 - 1.45 (m, 1H), 1.39 - 1.30 (m, 1H), 1.02 - 0.95(m, 6H); 13 C NMR (100 MHz, CDCl3) δ: 202.8, 152.8, 149.3, 147.7, 137.7, 130.9,129.6, 129.5, 128.6, 128.5, 128.4, 127.9, 125.8, 118.3, 44.1, 31.3, 29.8,19.6, 11.5.

[0033] Target product 3am ; Yield: 54.3 mg, yield 70 %; white solid; mp: 138.7 - 139.9 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.26 - 8.23 ​​(m,1H), 8.20 - 8.17 (m, 2H), 8.07 (s, 1H), 8.03 - 8.00 (m, 1H), 7.82 - 7.78 (m,1H), 7.69 - 7.60 (m, 3H), 7.57 - 7.51 (m, 5H); 13 C NMR (100 MHz, CDCl3) δ:192.6, 153.6, 149.8, 147.2, 137.5, 134.9, 133.0, 129.5, 128.7, 128.6, 128.5,128.3, 127.5, 125.8, 120.8.

[0034] Target product 3an ; Yield: 51.6 mg, yield 85 %; yellow solid; mp: 134.3 - 135.8 o C (uncorrected).1 H NMR (400 MHz, CDCl3) δ: 8.19 (d, J =8.8 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.89 - 7.86 (m, 1H),7.55 - 7.50 (m, 5H), 2.89 (s, 3H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ:200.9, 171.4, 152.2, 151.7, 149.0, 146.4, 137.9, 130.4, 129.5, 128.7, 128.5,120.7, 118.2, 35.3, 31.0, 25.5.

[0035] Target product 3ao ; Yield: 46.9 mg, yield 81%; yellow solid; mp: 131.1 - 132.7 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.20 - 8.18 (m,1H), 8.04 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.71 - 7.68 (m, 1H), 7.54 - 7.48(m, 5H), 2.88 (s, 3H), 2.04 (s, 2H), 1.28 (d, J = 6.8 Hz, 6H); 13 C NMR (100MHz, CDCl3) δ: 200.8, 171.1, 152.1, 149.5, 148.7, 146.7, 137.9, 130.8, 129.5,129.3, 128.5, 128.4, 122.0, 118.2, 34.5, 25.5, 23.7.

[0036] Target product 3ap ; Yield: 44.1 mg, yield 80 %; yellow solid; mp:124.3 - 125.8 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 8.4Hz, 1H), 8.04 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.54 –7.50 (m, 5H), 2.89 (s, 3H), 2.82 - 2.76 (m, 2H), 1.28 (t, J = 3.2 Hz, 3H); 13 CNMR (100 MHz, CDCl3) δ: 200.8, 152.0, 148.6, 146.6, 145.1, 137.9, 130.9,130.8, 129.5, 128.5, 128.4, 128.0, 123.3, 118.2, 29.2, 25.5, 15.4.

[0037] Target product 3aq ; Yield: 45.1 mg, yield 80 %; white solid; mp:145.1 - 146.4 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.19 (t, J = 8.8Hz, 1H), 8.08 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.57 -7.52 (m, 3H), 7.50 - 7.47 (m, 2H), 2.88 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ:200.3, 152.7, 148.6, 146.1, 137.0, 134.7, 132.4, 130.8, 129.4, 128.8, 128.8,128.7, 124.6, 118.9, 25.5.

[0038] Target product 3ar ; Yield: 52.8 mg, yield 81 %; white solid; mp:146.3 - 147.1 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.14 - 8.08 (m,3H), 7.87 - 7.84 (m, 1H), 7.58 - 7.48 (m, 5H), 2.88 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.4, 152.8, 148.6, 146.4, 146.4, 137.0, 133.4, 132.5, 129.4, 129.1, 128.9, 128.8, 128.0, 123.1, 118.9, 25.5.

[0039] Target product 3as ; Yield: 44.4 mg, yield 80 %; white solid; mp:151.3 - 152.4 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 - 8.25 (m,1H), 8.06 - 8.01 (m, 2H), 7.80 - 7.76 (m, 1H), 7.62 - 7.58 (m, 1H), 7.48 -7.46 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 2.90 (s, 3H); 13 C NMR(100 MHz, CDCl3) δ: 200.9, 159.9, 152.7, 149.1, 147.9, 130.9, 130.8, 130.0,129.6, 128.4, 128.2, 125.8, 118.0, 114.1, 55.4, 25.6.

[0040] Target product 3at ; Yield: 41.4 mg, yield 78 %; yellow solid; mp:122.3 - 123.4 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.29 - 8.25 (m,1H), 8.10 (s, 1H), 7.62 - 7.56 (m, 2H), 7.55 - 7.48 (m, 5H), 2.88 (s, 3H); 13CNMR (100 MHz, CDCl3) δ: 200.9, 161.0, 145.2, 137.5, 133.9, 133.8, 129.6,129.1 (d, J = 3.2 Hz, 1C), 124.2, 120.6, 120.3, 119.0, 109.8, 109.5, 25.8; 19 FNMR (376 MHz, CDCl3) δ: 109.1 (s, 1F).

[0041] Target product 3au ; Yield: 42.2 mg, yield 76 %; white solid; mp:148.6 - 149.2 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 7.86 (d, J = 8.4Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.52 - 7.48 (m, 5H), 7.32 (d, J = 8.4 Hz,2H), 4.02 (s, 3H), 2.89 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.8, 176.3,160.8, 153.0, 149.9, 149.7, 149.2, 145.7, 141.1, 137.8, 137.7, 133.5, 123.2,118.8, 29.6, 20.1.

[0042] Target product 3av ; Yield: 35.6 mg, yield 68 %; white solid; mp:131.1 - 132.4 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.81- 7.79 (m, 1H), 7.67 - 7.62 (m, 1H), 7.54 - 7.52 (m, 1H), 7.51 - 7.47 (m,5H), 2.92 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 201.1, 151.2,149.5, 146.7, 138.9, 138.1, 129.8, 129.5, 129.4, 128.5, 128.4, 128.3, 123.7,117.7, 25.4, 18.2.

[0043] Target product 3aw ; Yield: 42.4 mg, yield 81 %; white solid; mp:133.1 - 134.2 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.54 - 7.44 (m, 7H), 2.92 (d,J = 1.6 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ: 201.1, 149.5, 146.7, 138.9,138.1, 129.8, 129.7, 129.5, 128.5, 128.4, 128.3, 128.1, 123.7, 117.7, 25.4,18.2.

[0044] Target product 3ax ; Yield: 46.8 mg, yield 83 %; white solid; mp:144.2 - 144.9 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.29 - 8.26 (m,1H), 8.05 (s, 1H), 7.93 - 7.90 (m, 1H), 7.82 - 7.78 (m, 1H), 7.64 - 7.59 (m,1H), 7.53 - 7.50 (m, 2H), 7.47 - 7.44 (m, 2H), 2.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.6, 152.6, 148.0, 147.8, 136.1, 134.8, 131.0, 130.8, 129.9, 128.8, 127.7, 125.4, 118.0, 25.5.

[0045] Target product 3ay ; Yield: 37.7 mg, yield 72 %; yellow solid; mp:137.5 - 138.1 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 8.0Hz, 1H), 8.01 (s, 1H), 7.79 - 7.75 (m, 1H), 7.57 - 7.52 (m, 2H), 7.41 - 7.29(m, 3H), 7.20 (d, J = 7.2 Hz, 1H), 2.91 (s, 3H), 2.01 (s, 3H); 13 C NMR (100MHz, CDCl3) δ: 200.8, 152.7, 149.4, 147.4, 137.1, 135.9, 130.8, 130.1, 129.8,129.5, 128.6, 128.5, 128.4, 125.9, 125.8, 118.3, 25.6, 19.9.

[0046] Target product 3az ; Yield: 39.1 mg, yield 71 %; yellow solid; mp:151.3 - 152.0 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.86 (s, 1H), 7.42 - 7.41 (m, 3H), 7.31 - 7.27 (m, 2H), 7.21 (s, 1H), 2.86 (s,3H), 2.52 (s, 3H), 1.99 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.8, 151.3,149.5, 149.2, 142.1, 139.4, 135.2, 134.1, 128.6, 128.5, 127.8, 127.7, 125.6,119.5, 25.4, 24.2, 21.2.

[0047] Target product 3aaa ; Yield: 50.2 mg, yield 77 %; white solid; mp:139.1 - 139.6 oC (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 (d, J = 8.4Hz, 1H), 8.03 (s, 1H), 7.92 - 7.90 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.56 -7.40 (m, 5H), 2.88 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.1, 151.8, 150.2,139.8, 135.7, 131.4, 129.8, 129.4, 128.8, 128.7, 128.1, 127.7, 121.6, 119.2,25.5.

[0048] Target product 3aab ; Yield: 40.8 mg, yield 78 %; yellow solid; mp:129.3 - 130.8 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.27 - 8.25 (m,1H), 8.07 (s, 1H), 8.01 - 7.98 (m, 1H), 7.80 - 7.76 (m, 1H), 7.62 - 7.57 (m,1H), 7.43 - 7.40 (m, 1H), 7.33 - 7.30 (m, 3H), 2.90 (s, 3H), 2.45 (s, 3H); 13 CNMR (100 MHz, CDCl3) δ: 200.8, 152.6, 149.5, 147.8, 138.3, 137.6, 130.8,130.2, 129.7, 129.3, 128.4, 128.0, 126.6, 125.9, 118.0, 25.5, 21.4.

[0049] Target product 3aac ; Yield: 38.9 mg, yield 70 %; white solid; mp:155.8 - 156.4 o C (uncorrected). 1H NMR (400 MHz, CDCl3) δ: 8.27 - 8.25 (m,1H), 8.08 (s, 1H), 8.01 - 7.99 (m, 1H), 7.81 - 7.77 (m, 1H), 7.62 - 7.58 (m,1H), 7.46 - 7.42 (m, 1H), 7.10 - 7.08 (m, 1H), 7.06 - 7.03 (m, 2H), 3.87 (s,3H), 2.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.8, 159.6, 152.6, 149.2,147.8, 139.0, 130.9, 129.7, 129.6, 128.5, 128.0, 125.8, 121.9, 118.0, 115.0,114.1, 55.3, 25.6.

[0050] Target product 3aad ; Yield: 42.0 mg, yield 79 %; yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.28 - 8.26 (m, 1H), 8.05 (s, 1H), 7.94 - 7.92 (m, 1H), 7.82 - 7.78 (m, 1H), 7.63 - 7.59 (m, 1H), 7.52 - 7.48 (m, 2H), 7.26 - 7.21(m, 2H), 2.90 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.7, 164.2, 161.7, 152.6,148.2, 147.8, 133.6 (d, J = 3.4 Hz, 1C), 131.2 (d, J = 8.2 Hz, 1C), 131.0,129.8, 128.7, 125.5, 118.1, 115.7 (d, J = 21.5 Hz, 1C), 25.5; 19 F NMR (376MHz, CDCl3) δ: 112.9 (s, 1F).

[0051] Target product 3aae ; Yield: 41.3 mg, yield 79 %; white solid; mp:147.2 - 148.6 oC (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 8.4Hz, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 7.63 - 7.60 (m, 1H), 7.55 - 7.49 (m,5H), 2.88 (s, 3H), 2.50 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 200.8, 152.0,148.5, 146.3, 138.9, 137.9, 132.0, 130.6, 129.5, 128.5, 128.4, 128.0, 124.5,118.3, 25.5, 22.0.

[0052] Target product 3aaf ; Yield: 44.4 mg, yield 80 %; white solid; mp:153.0 - 154.3 o C (uncorrected). 1 H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.81- 7.79 (m, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.54 - 7.46 (m, 7H), 2.51 (s, 3H), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ: 201.1, 151.2, 149.5, 146.7, 138.9,138.1, 129.8, 129.5, 128.5, 128.4, 128.3, 128.1, 123.7, 117.7, 25.4, 18.2.

[0053] The above-described embodiments are only preferred embodiments of the present invention, and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the claims of the present invention.

Claims

1. A method for preparing a 2-acylquinoline compound, characterized in that: The steps include: Add the alkenyl isonitrile compound shown in Formula 1, the acyl oxime compound shown in Formula 2, the catalyst Ir(ppy)3 and the organic solvent into the reactor, replace the atmosphere in the reactor with an inert atmosphere, heat and stir the reaction under light conditions, and obtain the 2-acylquinoline compound shown in Formula 3 after post-treatment. The reaction formula is as follows:

2. In the above reaction formula, R is selected from substituted or unsubstituted phenyl and acetyl; wherein the substituent in the substituted or unsubstituted is selected from electron-withdrawing groups such as halogen, NO2, CN, CF3, acetyl, and methanesulfonyl; R1 is selected from C 1-20 Alkyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R2, R3 are independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy; in, The organic solvent is selected from acetonitrile or 1,2-dichloroethane.

3. The preparation method according to claim 1, characterized in that: R is selected from substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from CF3; R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from fluorine, chlorine, bromine, methyl, methoxy; R2, R3 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, methoxy, trifluoromethyl.

4. The preparation method according to claim 1, characterized in that: R1 is selected from 4-trifluoromethylphenyl; R1 is selected from methyl, substituted or unsubstituted phenyl; wherein the substituent in the substituted or unsubstituted is selected from fluorine, chlorine, bromine, methyl, methoxy; R2, R3 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, methoxy, trifluoromethyl.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The feeding molar ratio of the alkenyl isonitrile compound shown in formula 1, the acyl oxime compound shown in formula 2, and the catalyst Ir(ppy)3 is 1:1~3:0.005~0.

05.

6. The preparation method according to claim 4, characterized in that: The molar ratio of the alkenyl isonitrile compound shown in Formula 1, the acyl oxime compound shown in Formula 2, and the catalyst Ir(ppy)3 is 1:1.5:0.

01.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The organic solvent is selected from 1,2-dichloroethane.

8. The preparation method according to any one of claims 1 to 3, characterized in that: The lighting condition is provided by a 1-15W blue light LED lamp.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the heating and stirring reaction is 80-120° C., and the reaction time is 12-24 hours.

10. The preparation method according to any one of claims 1 to 3, characterized in that: The inert atmosphere is a nitrogen atmosphere or an argon atmosphere.

11. The preparation method according to any one of claims 1 to 3, characterized in that: The post-treatment operation is as follows: after the reaction is complete, a saturated sodium bicarbonate solution is added, extracted with ethyl acetate, the organic layer is separated, water is removed with anhydrous sodium sulfate, and the target product is purified by reduced pressure rotary evaporation and silica gel column chromatography.

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