CN110105293B - Synthesis method of C-3-difluoromethyl substituted quinoxalinone derivative - Google Patents
Synthesis method of C-3-difluoromethyl substituted quinoxalinone derivative Download PDFInfo
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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Abstract
The invention discloses a method for synthesizing a C-3-bit difluoromethyl substituted quinoxalinone derivative, which comprises the steps of dissolving the quinoxalinone derivative, a bromodifluoromethyl compound, a photocatalyst, an inorganic base and organic amine in an organic solvent, reacting for 6-36 h at the temperature of 20-60 ℃ under the irradiation of visible light, and after the reaction is finished, carrying out post-treatment on a reaction system to obtain a C-3-bit difluoromethyl substituted quinoxalinone derivative target product. The invention realizes the C-3 difluoromethylation of the quinoxalinone by taking light as reaction energy, ensures that the reaction is safer and more green, has lower cost, expands the application range of substrates of the reaction, and enriches the synthesis method of the C-3 substituted quinoxalinone compound.
Description
Technical Field
The invention relates to a method for synthesizing a C-3 difluoromethyl substituted quinoxalinone derivative.
Background
The quinoxalinone structure is a pharmacophore commonly used in the field of drug design, and researches prove that the derivative containing the parent nucleus of the structure has various pharmacological activities, including tumor resistance, bacteria resistance, blood coagulation resistance and the like. As a potential lead compound, the quinoxalinone structure has wide research prospects in the field of research and development of new drugs. In recent years, partial progress has been made in the synthesis of C-3 substituted quinoxalinone derivatives, mainly comprising: (1) an aromatic ring (K.yin, R.H. Zhang,Org. Lett. 2017,19, 1530; J. W. Yuan, S. N. Liu, L. B. Qu,Adv. Synth. Catal. 2017,3594197); (2) an amino group (Y. Li, M. Gao, L.H. Wang, X.L. Cui,Org. Biomol. Chem. 2016,14,8428; A. Gupta, M. S. Deshmukh, N. Jain,J. Org. Chem.2017,824784); (3) the C-3 position of the quinoxalinone is catalyzed by metallic iron or high-valence iodine to introduce methyl (L, Yang, P, Gao, X, H, Duan, Y, R, Gu, L, N, Guo,Org. Lett.2018,20, 1034; L.P. Wang, Y. C. Zhang, F. F. Li,X. Y. Hao, H. Y. Zhang, J. Q. Zhao,Adv. Synth. Catal.2018,3603969); (4) introduction of benzoyl (X.B. Zeng, C.L. Liu, X. Y) in the C-3 position of quinoxalinone by metallic silver or metal-free catalysis.Wang, J. L. Zhang, X. Y. Wang, Y. F. Hu,Org. Biomol. Chem.2017,15, 8929; J.W. Yuan, J. H. Fu, S. N. Liu, Y. M. Xiao, P. Mao, L. B. Qu,Org. Biomol. Chem.2018,16, 3203). The existing synthetic method focuses on introducing aromatic hydrocarbon, amino, alkyl, benzoyl and the like into the C-3 position of the quinoxalinone, and related reports of introducing fluorine-containing groups are less. Although the introduction of the fluorine-containing group at the C-3 position of quinoxalinone is achieved by oxidative decarboxylation coupling or catalysis by a metal copper complex (g.f. Hong, j.w. Yuan, j.h. Fu, g.y. Pan, z.w. Wang, l.r. Yang, y.m. Xiao, p.mao, x.m. Zhang,Org. Chem. Front.2019,6, 1173; L. P. Wang, H. Y. Liu, F. F. Li, J. Q. Zhao, H. Y.Zhang, Y. C. Zhang,Adv. Synth. Catal.2019,3612354), but the prior method still has the defects of harsh conditions, excessive oxidant participation and the like.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide a simple, high-efficiency, safe and environment-friendly method for synthesizing C-3 difluoromethyl substituted quinoxalinone derivatives.
The method for synthesizing the C-3-difluoromethyl substituted quinoxalinone derivative is characterized in that the quinoxalinone derivative shown in the formula (I), the bromodifluoromethyl compound shown in the formula (II), a photocatalyst, inorganic base and organic amine are dissolved in an organic solvent, the mixture reacts for 6 to 36 hours at the temperature of between 20 and 60 ℃ under the irradiation of visible light, and after the reaction is finished, a reaction system is subjected to post-treatment to obtain a C-3-difluoroalkyl substituted quinoxalinone derivative target product shown in the formula (III);
the reaction equation is as follows:
in the formulae (I) and (III), the substituent R1Monosubstituted or polysubstituted, polysubstituted middle substituent R1Identical or different, substituents R1Is H, methyl, methoxy, nitro, trifluoromethyl, tert-butyl, cyano,Fluorine, chlorine or bromine; substituent R2Is H, methyl, ethyl, n-butyl, benzyl, phenethyl, propenyl, propynyl or acetate substituent, and n is 1 or 2;
in the formulae (II) and (III), the substituent R3Is an ester group or an amide group.
The method for synthesizing the C-3-difluoromethyl substituted quinoxalinone derivative is characterized in that the mass ratio of the quinoxalinone derivative shown in the formula (I) to the bromodifluoromethyl compound shown in the formula (II) is 1: 1-4, and preferably 1: 2-3.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the photocatalyst is Ir (ppy)3(i.e., tris (2-phenylpyridine) iridium), Eosin Y (i.e., Eosin Y), Rose Bengal (i.e., Rose Bengal), preferably Ir (ppy)3(ii) a The amount ratio of the quinoxalinone derivative to the photocatalyst is 1: 0.005-0.02, preferably 1: 0.005-0.01.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the inorganic base is potassium carbonate, sodium carbonate or disodium hydrogen phosphate, and preferably potassium carbonate; the ratio of the amount of the inorganic base to the amount of the quinoxalinone derivative represented by formula (I) is 4 to 1:1, preferably 2 to 1: 1.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the visible light is white light or blue light, preferably blue light.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that an organic solvent is DCM (dichloromethane) or MeCN (acetonitrile), preferably MeCN.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the organic amine isN,NDiisopropylethylamine, triethylamine orN,N-dimethylcyclohexylamine, preferablyN,N-diisopropylethylamine.
The method for synthesizing the C-3-difluoromethyl substituted quinoxalinone derivative is characterized in that the mass ratio of the organic amine to the quinoxalinone derivative shown in the formula (I) is 0.05-2: 1, and preferably 0.1-1: 1.
The synthesis method of the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the post-treatment of a reaction system comprises the following steps: adding water and an organic extracting agent into a reaction system for extraction, separating liquid into an organic layer and a water layer, drying the organic layer by anhydrous sodium sulfate, removing the solvent by decompression concentration, separating the concentrated residue by column chromatography, collecting eluent containing a target product by taking a mixed solvent of petroleum ether and ethyl acetate as an eluent, and evaporating the solvent to obtain the target product of the C-3-bit difluoromethyl substituted quinoxalinone derivative shown in the formula (III).
The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative is characterized in that the organic extracting agent is dichloromethane or ethyl acetate, preferably dichloromethane; in the mixed solvent of the petroleum ether and the ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 10-40: 1.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
1) the invention realizes the C-3 difluoroalkylation of the quinoxalinone by using visible light as reaction energy, so that the reaction is safer and more green, and the cost is lower;
2) the method has the advantages of good reaction selectivity, simple and convenient operation and high product yield;
3) according to the invention, difluoroalkyl ester or difluoroalkylamide group can be introduced into the quinoxalinone C-3, so that difluoroalkylation of the C-3 position of the quinoxalinone under mild conditions is realized, and the synthesis method of the C-3 substituted quinoxalinone compound is enriched.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
1-methylquinoxalinone (0.25 mmol, 40 mg), bromodifluoromethylacetic acid ethyl ester (0.5 mmol, 101 mg), Ir(ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, taking a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 30:1 as an eluent, collecting eluent containing a target compound, evaporating the solvent and drying to obtain 51 mg of white solid 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -ethyl acetate, wherein the yield is 80%, and the chemical structural formula is as follows:
。
characterization data: white solid, melting point: 101.4-102.7 ℃,1H NMR (400 MHz, CDCl3) : 8.04(dd,J= 8.1 Hz,J= 1.2 Hz, 1H), 7.73 (t,J= 8.6 Hz 1H), 7.47 (t,J= 8.2Hz 1H), 7.42 (t,J= 8.5 Hz 1H), 4.44 (q,J= 7.2 Hz, 2H), 3.74 (s, 3H), 1.38(t,J= 7.2 Hz, 3H)，13C NMR (100 MHz, CDCl3) : 162.3 (t,J F-C= 31.3 Hz)152.7, 147.9 (t,J F-C= 24.0 Hz), 134.1, 132.8, 131.7, 131.5, 124.5, 114.0,109.6 (t,J F-C= 251.9 Hz), 63.3, 29.0, 13.9，19F NMR (376 MHz, CDCl3) : -110.6. HRMS: C13H12F2N2NaO3[M + Na]+; calculated: 305.0708, found: 305.0704。
example 2
The inorganic base (potassium carbonate) in the system was replaced with sodium carbonate (0.5 mmol, 52.9 mg), and the other operations were carried out in the same manner as in example 1 to obtain 46 mg of 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetic acid ethyl ester as a white solid in a yield of 65%.
Example 3
Will be provided withN,NThe charge of diisopropylethylamine was changed to 0.05 mmol and the other operations were as in example 1 to give 44 mg of white solid ethyl 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetate in 62% yield.
Example 4
The photocatalyst (Ir (ppy) in the system3) By changing to Rose Bengal (1.25. mu. mol, 1.3 mg), the other operations were performed as in example 1 to give 43 mg of white solid ethyl 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetate in a yield of 70%.
Example 5
The solvent (MeCN) was replaced with DCM (1.0 mL) and the other operations were the same as in example 1 to give 42 mg of white solid ethyl 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetate in a yield of 60%.
Example 6
Organic amine (a)N,NDiisopropylethylamine) to triethylamine (0.5 mmol, 51 mg), and the other operations are as in example 1 to give 41 mg of white solid ethyl 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetate in a yield of 58%.
Example 7
The reaction time was prolonged to 24 h and the other operations were as in example 1 to give 56 mg of white solid ethyl 2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetate in 79% yield.
Example 8
1-Ethylquinoxalinone (0.25 mmol, 44 mg), bromodifluoromethylacetic acid ethyl ester (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction is finished, washing the reaction system with water, extracting with dichloromethane, separating the solution into an organic layer and a water layer, drying the organic layer with anhydrous sodium sulfate, and then distilling and concentrating under reduced pressure to remove the solvent to obtain the compoundA yellow oil. Separating the yellow oily substance by column chromatography, taking a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 30:1 as an eluent, collecting eluent containing a target compound, evaporating the solvent and drying to obtain 57 mg of white solid 2, 2-difluoro-2- (4-ethyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -ethyl acetate, wherein the yield is 77 percent, and the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is between 83.9 and 86.7 ℃,1H NMR (400 MHz, CDCl3) : 8.06(d,J= 7.6 Hz, 1H), 7.73 (t,J= 8.0 Hz, 1H), 7.48-7.43 (m, 2H), 4.44 (q,J= 7.2 Hz, 2H), 4.36 (q,J= 7.2 Hz, 2H), 1.43-1.36 (m, 6H)；13C NMR (100 MHz,CDCl3) : 162.3 (t,J F-C= 20.8 Hz) 152.2, 147.9 (t,J F-C= 16.1 Hz), 133.1,132.6, 132.0, 131.8, 124.2, 113.7, 109.7 (t,J F-C= 167.9 Hz), 63.7, 37.4,13.8, 12.3；19F NMR (376 MHz, CDCl3) : -110.5；HRMS: C14H15F2N2O3[M + H]+; found:297.1052, calculated: 297.1045。
example 9
1-Benzyquinoxalinone (0.25 mmol, 59 mg), bromodifluoromethylacetic acid ethyl ester (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, eluting with a mixture of petroleum ether and ethyl acetate at a volume ratio of 30:1, collecting the eluate containing the target compound, evaporating to remove the solvent, and drying to obtain 79 mg of white solid2, 2-difluoro-2- (4-benzyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) -acetic acid ethyl ester, yield 88%, its chemical structural formula is:
。
characterization data: white solid, melting point: 110.7-112.5 ℃ of water,1H NMR (400 MHz, CDCl3) : 8.05(d,J= 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.44-7.40 (m, 1H), 7.38-7.29 (m, 4H),7.26-7.24 (m, 2H), 5.52 (s, 2H), 4.44 (q,J= 7.2 Hz, 2H), 1.36 (t,J= 7.2Hz, 3H)；13C NMR (100 MHz, CDCl3) : 162.2 (t,J F-C= 31.4 Hz), 152.9, 148.0 (t,J F-C= 24.1 Hz),134.4, 133.4, 132.7, 132.0, 131.6, 129.0, 128.0, 126.9,124.5, 114.7, 109.6 (t,J F-C= 252.0 Hz), 63.3, 45.8, 13.8；19F NMR (376 MHz,CDCl3) : -110.4；HRMS: C19H16F2N2NaO3[M + Na]+; found: 381.1012, calculated:381.1021。
example 10
Methyl 2- (2-oxoquinoxalin-1 (2H) -yl) acetate (0.25 mmol, 55 mg), ethyl bromodifluoromethylacetate (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at a volume ratio of 30:1, collecting eluate containing target compound, evaporating to remove solvent, and drying to obtain 70 mg white solid 2, 2-difluoro-2- (4- (2-methoxy-2-oxyethyl) -3-oxo-3, 4-dihydroquinoxalin-2-yl) -ethyl acetate with yield of 82%,
the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is 108.2 to 109.7 ℃,1H NMR (400 MHz, CDCl3) : 8.06(dd,J= 8.0 Hz,J= 0.8 Hz, 1H), 7.72-7.67 (m, 1H), 7.50-7.46 (m, 1H), 7.18(d,J= 8.4 Hz 1H), 5.06 (s, 2H), 4.42 (q,J= 7.2 Hz, 2H), 3.80 (s, 3H),1.35 (t,J= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) : 166.8, 162.1 (t,J F-C=31.3 Hz), 152.2, 147.7 (t,J F-C= 24.3 Hz), 133.2, 133.0, 131.9, 131.7, 124.8,113.4, 109.6 (t,J F-C= 252.1 Hz), 63.3, 53.0, 43.1, 13.8;19F NMR (376 MHz,CDCl3) : -110.4；HRMS: C15H14F2N2NaO5[M + Na]+; found: 363.0758, calculated:363.0763。
example 11
1- (prop-2-yn-1-yl) quinoxalin-2 (1H) -one (0.25 mmol, 46 mg), bromodifluoromethylacetic acid ethyl ester (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, eluting with mixed solution of petroleum ether and ethyl acetate at a volume ratio of 30:1, collecting eluate containing target compound, evaporating to remove solvent, and drying to obtain 42 mg white solid ethyl 2, 2-difluoro-2- (3-oxo-4- (prop-2-yne-1-yl) -3, 4-dihydroquinoxalin-2-yl) acetate with yield of 55%,
the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is between 103.3 and 105.1 ℃,1H NMR (400 MHz, CDCl3) : 8.06(d,J= 8.0 Hz, 1H), 7.76 (t,J= 8.0 Hz, 1H), 7.58 (t,J= 8.4 Hz, 1H), 7.50(t,J= 7.6 Hz, 1H), 5.07 (d,J= 2.0Hz, 2H), 4.44 (q,J= 7.2 Hz, 2H), 2.34(t,J= 2.0 Hz, 2H), 1.38 (t,J= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) :162.1 (t,J F-C= 20.9 Hz), 151.7, 147.8 (t,J F-C=16.3 Hz), 132.8, 132.6,131.8, 131.7, 124.8, 114.5, 109.6 (t,J F-C= 168.9 Hz), 75.9. 73.9, 63.3,31.4, 13.8;19F NMR (376 MHz, CDCl3) : -110.3; HRMS: C15H11F2N2O3[M-H]-; found:305.0749, calculated: 305.0743。
example 12
6-methoxy-1-methylquinolin-2 (1H) -one (0.25 mmol, 48 mg), ethyl bromodifluoromethylacetate (0.5 mmol, 101 mg), Ir (ppy)3(0.01 mmol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN, Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, collecting eluent containing target compound with mixed solution of petroleum ether and ethyl acetate at volume ratio of 30:1 as eluent, evaporating to remove solvent, drying to obtain 63 mg yellow solid ethyl 2, 2-difluoro-2- (7-methoxy-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetate with yield of 81%,
the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is 100.7-102.2 ℃,1H NMR (400 MHz, CDCl3) : 7.50(s, 1H), 7.37-7.32 (m, 2H), 4.44(q,J= 7.2 Hz, 2H), 3.92 (s, 3H), 3.73 (s.3H), 1.38 (t,J= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) : 162.3 (t,J F-C=20.8 Hz), 156.5, 152.4., 148.2 (t,J F-C=15.5 Hz), 132.5, 128.4, 122.6, 114.9,112.1, 109.6 (t,J F-C= 269.7 Hz), 63.2, 55.9, 29.1, 13.8;19F NMR (376 MHz,CDCl3) : -110.6; HRMS: C14H14F2N2NaO4[M + Na]+; calculated: 335.0814, found:335.0816。
example 13
The 6-nitro-1-methylquinoline-2 (1)H) -ketone (0.25 mmol, 51 mg), bromodifluoromethylacetic acid ethyl ester (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, collecting eluent containing target compound with mixed solution of petroleum ether and ethyl acetate at volume ratio of 30:1 as eluent, evaporating to remove solvent, drying to obtain 26 mg yellow solid ethyl 2, 2-difluoro-2- (4-methyl-7-nitro-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetate with yield of 32%,
the chemical structural formula is as follows:
。
white crystals, melting point: 120.0-120.9 ℃;1H NMR (400 MHz, CDCl3) : 8.92 (d,J=2.4 Hz, 1H), 8.56 (dd,J= 9.2 Hz,J= 2.8 Hz, 1H), 7.55 (d,J= 9.2 Hz, 1H),4.44 (q,J= 7.2 Hz, 2H), 3.80 (s, 3H), 1.39 (t,J= 7.2 Hz, 3H);13C NMR (100MHz, CDCl3) : 161.8 (t,J F-C= 31.0 Hz), 152.2, 150.4 (t,J F-C= 24.7 Hz),143.8, 138.4, 130.7, 127.1, 127.0, 114.9, 109.2 (t,J F-C= 253.6 Hz), 63.6,29.6, 13.8；19F NMR (376 MHz, CDCl3) : -110.8. HRMS: C13H11F2N3NaO5[M + Na]+;found: 350.0566, calculated: 350.0559。
example 14
A mixture of 6-fluoro-1-methylquinolin-2 (1H) -one (0.25 mmol, 45 mg), ethyl bromodifluoromethylacetate (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) and triethylamine (0.025 mmol, 3 mg) were charged into a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as a solvent, and the mixture was stirred under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, taking a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 30:1 as an eluent, collecting eluent containing a target compound, evaporating the solvent and drying to obtain 50 mg of yellow solid ethyl 2, 2-difluoro-2- (7-fluoro-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetate, wherein the yield is 66%, and the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is between 82.7 and 84.5 ℃,1H NMR (400 MHz, CDCl3) : 7.74(dd,J= 8.4 Hz,J= 2.8 Hz, 1H), 7.51-7.46 (m, 1H), 7.39 (dd,J= 9.2 Hz,J= 4.4 Hz, 1H), 4.43 (q,J= 7.2 Hz, 2H), 3.74 (s, 3H), 1.38 (t,J= 7.2 Hz,3H);13C NMR (100 MHz, CDCl3) : 162.1 (t,J F-C= 31.1 Hz), 158.9 (d,J F-C=244.6 Hz), 152.3, 149.3 (t,J F-C=24.1 Hz), 132.1 (d,J F-C= 11.3 Hz), 130.8,120.8 (d,J F-C= 24.1 Hz), 116.7 (d,J F-C= 22.6 Hz), 115.2 (d,J F-C= 8.6 Hz),109.5 (t,J F-C= 252.5 Hz), 63.4, 29.3, 13.9;19F NMR (376 MHz, CDCl3) : -110.8, -117.0； HRMS: C13H11F3N2NaO3[M + Na]+; found: 323.0626, calculated:323.0614。
example 15
A mixture of 7-fluoro-1-methylquinolin-2 (1H) -one (0.25 mmol, 45 mg), ethyl bromodifluoromethylacetate (0.5 mmol, 101 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), sodium carbonate (0.5 mmol, 53 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, taking a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 30:1 as an eluent, collecting eluent containing a target compound, evaporating to remove the solvent and drying to obtain 49 mg of yellow oily liquid ethyl 2, 2-difluoro-2- (6-fluoro-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetate, wherein the yield is 65 percent, and the chemical structural formula is as follows:
。
characterization data: a yellow oily liquid which is a mixture of a yellow oily liquid,1H NMR (400 MHz, CDCl3) : 8.03 (dd,J= 8.8 Hz,J= 6.0 Hz, 1H), 7.18 (td,J= 8.8 Hz,J= 2.8 Hz, 1H), 7.09 (dd,J= 9.2 Hz,J= 2.8 Hz, 1H), 4.43 (q,J= 7.2 Hz, 2H), 3.69 (s, 3H), 1.38 (t,J= 7.2 Hz,3H);13C NMR (100 MHz, CDCl3) : 164.9 (d,J F-C= 253.6 Hz), 162.2 (t,J F-C=31.4 Hz), 152.5, 146.7 (td,J F-C= 24.1,J F-C= 3.7 Hz), 135.8 (d,J F-C= 12.0Hz), 133.7 (d,J F-C= 10.9 Hz), 128.4 (d,J F-C= 2.3 Hz), 112.7 (d,J F-C= 12.6Hz), 109.6 (t,J F-C= 252.2 Hz), 101.0 (d,J F-C= 7.9 Hz), 63.3, 29.2, 13.9;19FNMR (376 MHz, CDCl3) : -102.3, -110.5；HRMS: C13H11F3N2NaO3[M + Na]+; found:323.0622, calculated: 323.0614。
example 16
1,6, 7-trimethylquinolin-2 (1H) -one (0.25 mmol, 47 mg), ethyl bromodifluoromethylacetate (0.5 mmol, 101 mg), Rose Bengal (1.25. mu. mol, 1.3 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, taking a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 30:1 as an eluent, collecting eluent containing a target compound, evaporating the solvent and drying to obtain 62 mg of white solid ethyl 2, 2-difluoro-2- (4, 6, 7-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetate, wherein the yield is 83 percent, and the chemical structural formula is as follows:
。
characterization data: white solid, melting point: the temperature of the mixture is between 119.8 and 121.4 ℃,1H NMR (400 MHz, CDCl3) : 7.76(s, 1H), 7.16 (s, 1H), 4.42 (q,J= 7.2 Hz, 2H), 3.70 (s, 3H), 2.47 (s, 3H),2.38 (s, 3H), 1.37 (t,J= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) : 162.5 (t,J F-C= 31.5 Hz), 152.8, 146.4 (t,J F-C=25.8 Hz), 143.4, 133.7, 132.2, 131.3,130.1, 114.4, 109.8 (t,J F-C= 252.5 Hz), 63.2, 28.9, 20.8, 19.2, 13.9;19F NMR(376 MHz, CDCl3) : -110.3；HRMS: C15H17F2N2O3[M + H]+; found: 311.1191;calculated: 311.1202。
example 17
Will be provided withN-methylquinoxalinone (0.25 mmol, 40 mg), 2-bromo-N，NDiethyl-2, 2-difluoroacetamide (0.5 mmol, 115 mg), Ir (ppy)3(1.25. mu. mol, 0.8 mg), potassium carbonate (0.5 mmol, 69 mg) andN,Ndiisopropylethylamine (0.025 mmol, 3.2 mg) was added to a 10 mL solvent storage bottle, MeCN (1.0 mL) was added as solvent, under N2Under the protection of atmosphere, the reaction is carried out for 12 hours under the irradiation of 3 w of blue light and at the temperature of 25 ℃. After the reaction, the reaction system was washed with water, extracted with dichloromethane, and then separated into an organic layer and an aqueous layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated by distillation under reduced pressure to remove the solvent to give a yellow oily substance. Separating the yellow oily substance by column chromatography, eluting with a mixture of petroleum ether and ethyl acetate at a volume ratio of 30:1, collecting the eluate containing the target compound, evaporating to remove solvent, and drying to obtain 45 mg of white solidN,N-diethyl-2, 2-difluoro-2- (4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl) acetamide in 58% yield having the chemical formula:
。
characterization data: white solid, melting point: the temperature of the mixture is between 102.9 and 104.1 ℃,1H NMR (400 MHz, CDCl3) : 7.99(dd,J= 8.0 Hz,J= 1.2 Hz, 1H), 7.67 (t,J= 8.4 Hz, 1H), 7.43-7.36 (m,2H), 3.72 (s, 3H), 3.66 (q,J= 7.2 Hz, 2H), 3.48 (q,J= 7.2 Hz, 2H), 1.35(t,J= 7.2 Hz, 3H), 1.23 (t,J= 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) :161.6 (t,J F-C= 27.3 Hz), 152.6, 149.6 (t,J F-C=24.0 Hz), 134.2, 132.1,131.4, 131.2, 124.0, 113.8, 113.6 (t,J F-C= 259.3 Hz), 41.8 (t,J F-C= 5.7Hz), 41.7, 28.9, 14.3, 12.2;19F NMR (376 MHz, CDCl3) : -105.0；HRMS:C15H17F2N3NaO2[M + Na]+; found: 332.1186, calculated: 332.1181。
the statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (13)
1. A synthesis method of a C-3-difluoromethyl substituted quinoxalinone derivative is characterized in that the quinoxalinone derivative shown in a formula (I), a bromodifluoromethyl compound shown in a formula (II), a photocatalyst, an inorganic base and organic amine are dissolved in an organic solvent, the mixture reacts for 6 to 36 hours at the temperature of 20 to 60 ℃ under the irradiation of visible light, and after the reaction is finished, a reaction system is subjected to post-treatment to obtain a C-3-difluoromethyl substituted quinoxalinone derivative target product shown in a formula (III);
the reaction equation is as follows:
in the formulae (I) and (III), the substituent R1Monosubstituted or polysubstituted, polysubstituted middle substituent R1Identical or different, substituents R1Is H, methyl, methoxy, nitro, trifluoromethyl, tert-butyl, cyano, fluorine, chlorine or bromine; substituent R2Is H, methyl, ethyl, n-butyl, benzyl, phenethyl, propenyl or propynyl;
in the formulae (II) and (III), the substituent R3Is an ester group or an amide group;
the photocatalyst is Ir (ppy)3Eosin Y, Rose Bengal, quinoxalinone derivatives and photocatalystsThe mass ratio of the chemical agent is 1: 0.005-0.02;
the visible light is white light or blue light;
the organic amine isN,NDiisopropylethylamine, triethylamine orN,N-dimethylcyclohexylamine, wherein the mass ratio of the quinoxalinone derivative represented by formula (I) to the bromodifluoromethyl compound represented by formula (II) is 1: 2-3.
2. The method for synthesizing C-3 difluoromethyl-substituted quinoxalinone derivatives according to claim 1, wherein said photocatalyst is Ir (ppy)3(ii) a The ratio of the amounts of the quinoxalinone derivative and the photocatalyst is 1: 0.005-0.01.
3. The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative according to claim 1, wherein the inorganic base is potassium carbonate, sodium carbonate or disodium hydrogen phosphate; the ratio of the amount of the inorganic base to the amount of the quinoxalinone derivative represented by formula (I) is 4 to 1: 1.
4. The method for synthesizing the C-3 difluoromethyl-substituted quinoxalinone derivative according to claim 1, wherein the visible light is blue light.
5. The method for synthesizing a C-3 difluoromethyl-substituted quinoxalinone derivative according to claim 1, wherein the organic solvent is DCM or MeCN.
6. The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative according to claim 1, wherein the mass ratio of the organic amine to the quinoxalinone derivative represented by formula (I) is 0.05-2: 1.
7. The method for synthesizing C-3 difluoromethyl-substituted quinoxalinone derivatives according to claim 1, characterized in that the post-treatment step of the reaction system is: adding water and an organic extracting agent into a reaction system for extraction, separating liquid into an organic layer and a water layer, drying the organic layer by anhydrous sodium sulfate, removing the solvent by decompression concentration, separating the concentrated residue by column chromatography, collecting eluent containing a target product by taking a mixed solvent of petroleum ether and ethyl acetate as an eluent, and evaporating the solvent to obtain the target product of the C-3-bit difluoromethyl substituted quinoxalinone derivative shown in the formula (III).
8. The method for synthesizing the C-3 difluoromethyl-substituted quinoxalinone derivative according to claim 7, wherein the organic extractant is dichloromethane or ethyl acetate; in the mixed solvent of the petroleum ether and the ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 10-40: 1.
9. The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative according to claim 1, wherein the inorganic base is potassium carbonate; the ratio of the amount of the inorganic base to the amount of the quinoxalinone derivative represented by formula (I) is 2 to 1: 1.
10. The method for synthesizing a C-3 difluoromethyl-substituted quinoxalinone derivative according to claim 1, wherein the organic solvent is MeCN.
11. The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative according to claim 1, wherein the organic amine isN,N-diisopropylethylamine.
12. The method for synthesizing the C-3 difluoromethyl substituted quinoxalinone derivative according to claim 1, wherein the mass ratio of the organic amine to the quinoxalinone derivative represented by formula (I) is 0.1-1: 1.
13. The method for synthesizing the C-3 difluoromethyl-substituted quinoxalinone derivative according to claim 8, wherein the organic extractant is dichloromethane.
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