Synthesis method of pyrrolo [1, 2-a] quinoxaline-4 (5H)-ketone compound

Abstract

The invention relates to a synthesis method of a pyrrolo [1, 2-a] quinoxaline-4 (5H)-ketone compound, which comprises the following steps: under the irradiation of visible light, utilizing a visible light catalyst, a hydrogen transfer (HAT) catalyst and an acidic additive, and through hydrogen atom transfer of an N = Csp2-H bond of quinoxalinone (a), initiating nucleophilic imine free radical to carry out a reaction on electron-deficient alpha-cyano-alpha, beta-diamino-alpha, beta-diamino-alpha-diamino-alpha-diamino-alpha-diamino-alpha-diamino-alpha-diamino-alpha-diamino-alpha-diamino The pyrrolo [1, 2-a] quinoxaline-4 (5H)-ketone compound is prepared by carrying out addition and cyclization on the pyrrolo [1, 2-a] quinoxaline-4 (5H)-ketone (b). The whole synthesis method is simple, efficient and mild, meanwhile, residues of transition metal and the like are avoided, and the method has the advantages of being environmentally friendly and the like; visible light and bromine free radicals are utilized for concerted catalysis cascade reaction, and the advantages of atom economy, step economy, high chemical selectivity and the like are achieved; the heterocyclic molecules with high added value are obtained from simple and easily available raw materials, and the synthesis cost is lower. The pyrrolo [1, 2-a] quinoxaline-4 (5H)-ketone compound prepared by the invention has certain anti-tumor activity and can be applied to preparation of medicines for treating tumors.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis and pharmaceutical technology, and in particular to a synthesis method and application of a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound. Background Art

[0002] Pyrrolo[1,2-a]quinoxaline-4(5H)-one and its derivatives are widely used in drug research and development. This class of compounds has a wide range of biological and pharmaceutical activities and performs well in protein inhibitors. Fig.32 Shown are the chemical structures of some drugs or drug precursors containing a pyrrolo[1,2-a]quinoxaline-4(5H)-one structure.

[0003] like Fig.33 As shown, the existing routes for synthesizing pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds are mainly the following:

[0004] (1) Ma's group disclosed a copper-catalyzed coupling of pyrrole-2-carboxylates with 2-halotrifluoroacetanilide and subsequent hydrolysis and condensation to synthesize pyrroloquinoxalone; (2) Hu and co-workers reported that 2-pyrrolylbenzoic acid reacted with organic azides under the catalysis of 4-dimethylaminopyridine (DMAP) at 110°C to undergo Curtius rearrangement and cyclization to generate pyrrolo[1,2-a]quinoxaline-4(5H)- Ketone; (3) Wu's group developed a palladium-catalyzed cascade carbonyl cyclization reaction of 2-pyrrolyl iodobenzene and NaN3 using benzene-1,3,5-tricarboxylic acid phenyl ester as the CO source; (4) The current mainstream strategy mainly relies on the use of various active carbonyl candidates (including triphosgene, phenyl isocyanate, dioxazolone, CO or CO2) to insert a CO unit into 2-pyrrolylaniline to generate pyrrolo[1,2-a]quinoxaline-4(5H)-one.

[0005] However, the above-mentioned synthesis methods of pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds usually have the problems of harsh reaction conditions, the use of transition metal catalysts, cumbersome synthesis of starting materials, potential safety hazards such as the use of explosive azides, toxic CO and triphosgene, large amounts of by-products and waste, and a relatively narrow reaction range, which limits their application in the synthesis of pharmaceutically active molecules. Summary of the invention

[0006] In view of this, the purpose of the present invention is to provide a method for synthesizing pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds, so as to at least solve the problems existing in the existing methods for synthesizing pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds, such as the use of transition metal catalysts, large amounts of by-products and waste generated, difficulty in obtaining starting materials, and potential safety hazards.

[0007] The present invention solves the above technical problems by the following technical means:

[0008] The present invention provides a method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound. The method comprises the following steps: using a photocatalyst, a hydrogen transfer catalyst and an acidic additive under visible light irradiation to synthesize a quinoxaline-2(1H)-one N=C sp 2 The hydrogen atom transfer of the -H bond initiates the addition and cyclization of the nucleophilic imine radical to the electron-deficient α-cyano-α and β-unsaturated ketone to prepare pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds. The general reaction formula is as follows:

[0009]

[0010] Among them, R 1 is selected from alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl or substituted aryl, R 2 is selected from monosubstituted, disubstituted halogen, alkyl or phenyl, Ar 1 is selected from phenyl or substituted aryl, Ar 2 is selected from substituted aryl or heteroaryl.

[0011] Furthermore, the R 1 is selected from methyl, allyl, 2-hydroxyethyl, 4-chlorophenyl, 3-fluorobenzyl; said R 2 is selected from hydrogen, 7,8-difluoro, 7,8-dimethyl, phenyl; said Ar 1 is selected from phenyl, 2-methoxyphenyl, 4-(trifluoromethyl)phenyl, 4-(phenylthio)phenyl, 4-(tert-butyl)phenyl; the Ar 2 is selected from phenyl or thienyl.

[0012] Furthermore, the photocatalyst is an organic photocatalyst Mes-Acr + ClO4 - .

[0013] Furthermore, the hydrogen transfer catalyst is N-bromosuccinimide.

[0014] Furthermore, the acidic additive is selected from at least one of trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and phenylphosphite, preferably trifluoroacetic acid.

[0015] Furthermore, the synthesis method is as follows: quinoxaline ketone compound a, unsaturated ketone compound b, hydrogen transfer catalyst, photocatalyst and dehydrating agent MgSO4 are added to a dry container filled with a mixed solvent and mixed, the dry container is evacuated and backfilled with nitrogen, the mixture in the dry container is protected by nitrogen, and then placed in an irradiation device of a blue light-emitting diode for blue light irradiation, stirred and reacted at room temperature for 40 to 50 hours, and the crude product obtained by the reaction is purified by column chromatography to obtain a product pyrrolo[1,2-a]quinoxaline-4(5H)-one compound.

[0016] Furthermore, the molar ratio of the compound a, the compound b, the hydrogen transfer catalyst and the photocatalyst is 1:1-2:0.2-0.6:0.01-0.05.

[0017] Furthermore, the visible light irradiation is blue light irradiation, the power of the blue light emitting diode in the blue light irradiation is 8 to 12 W, and the wavelength of the blue light is preferably 430 nm to 460 nm.

[0018] Furthermore, the mixed solvent is a mixture of trifluoroacetic acid and ethyl acetate in a volume ratio of 3.2 / 10.

[0019] The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of the present invention uses cheap and easy-to-synthesize quinoxaline ketone and α-cyano-α, β-unsaturated ketone as starting materials, and reacts with NBS as a hydrogen transfer catalyst and acid to obtain a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound. sp 2 -H bond hydrogen atom transfer, triggering the nucleophilic imine radical to electron-deficient α-cyano-α and β-unsaturated ketone addition and cyclization, can be efficient and high yield pyrrolo [1,2-a] quinoxaline-4 (5H) -one derivatives. The whole synthesis method is simple, efficient, mild, economical, while avoiding the transition metal residue, with the characteristics of green environmental protection; using visible light and bromine radical synergistic catalysis tandem reaction, with the advantages of atom economy and step economy and high chemical selectivity; starting from simple and readily available raw materials to obtain high value-added heterocyclic molecules, the synthesis cost is low.

[0020] The pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds synthesized by the synthesis method of the present invention have important potential drug activity and are core skeletons of anti-tumor drug candidates and medical research analogs. The pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds prepared by the present invention have certain anti-tumor activity, and some compounds have excellent anti-tumor activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a general reaction formula related to a method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of the present invention;

[0022] Figure 2 It is the X-ray single crystal diffraction crystal structure of compound 2 and compound 3;

[0023] Figure 3 is a reaction mechanism associated with the synthesis method of the present invention;

[0024] Figure 4 It is an organic photocatalyst Mes-Acr + ClO4 - The structural formula of

[0025] Figure 5 and Figure 6 It is 5-methyl-4-oxo-1,3-diphenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0026] Figure 7 and Figure 8 It is 3-(2-methoxyphenyl)-5-methyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0027] Fig. 9 , Fig.10 and Fig.11 It is 5-methyl-4-oxo-1-phenyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR, 19 F NMR and 13 C NMR;

[0028] Fig.12 and Fig.13 It is 5-methyl-4-oxo-1-phenyl-3-(4-(phenylthio)phenyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0029] Fig.14 , Fig.15 and Fig.16 It is 3-(4-(tert-butyl)phenyl)-7,8-difluoro-5-methyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile1 H NMR, 19 F NMR and 13 C NMR;

[0030] Fig.17 and Fig.18 It is 3-(4-(tert-butyl)phenyl)-5,7,8-trimethyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0031] Fig.19 and Fig. 20 It is 3-(4-(tert-butyl)phenyl)-5-methyl-4-oxo-1-phenyl-4,5-dihydrobenzo[g]pyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0032] Fig.21 , Fig. 22 and Fig.23 It is 3-(4-(tert-butyl)phenyl)-5-(3-fluorobenzyl)-7,8-dimethyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR, 19 F NMR and 13 C NMR;

[0033] Fig.24 and Fig.25 It is 3-(4-(tert-butyl)phenyl)-5-methyl-4-oxo-1-(thien-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0034] Fig.26 and Fig. 27 It is 5-allyl-3-(4-(tert-butyl)phenyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0035] Fig.28 and Fig.29 It is 3-(4-(tert-butyl)phenyl)-5-(2-hydroxyethyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0036] Fig.30 and Fig.31 It is 3-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile 1 H NMR and 13 C NMR;

[0037] Fig.32 It is a chemical structure of a portion of a drug or a drug precursor containing a pyrrolo[1,2-a]quinoxaline-4(5H)-one structure;

[0038] Fig.33 It is the existing route map for the synthesis of pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0040] In the embodiments of the present application, words such as "exemplary" or "for example" are used to indicate examples, illustrations or descriptions. Any embodiment or design described as "exemplary" or "for example" in the embodiments of the present application should not be interpreted as being more preferred or more advantageous than other embodiments or designs. Specifically, the use of words such as "exemplary" or "for example" is intended to present related concepts in a specific way.

[0041] The English letters in the present invention are interpreted as follows:

[0042] HAT: hydrogen atom transfer; NBS: N-bromosuccinimide; TFA: trifluoroacetic acid; EA: ethyl acetate; BDE: bond dissociation energy; TsOH: p-toluenesulfonic acid; PhPO2H: phenylphosphinate.

[0043] Hydrogen atom transfer is one of the most attractive methods for CH bond activation, which can rapidly assemble CH coupling compounds with atom and step economy. However, when there are multiple potential hydrogen donors and acceptors, the efficiency and selectivity of organic molecular HAT often pose challenges to control. How to achieve site-selective CH bond activation efficiently and controllably is crucial for the highly specific and selective functionalization of drugs. Among them, the synergistic catalysis of visible light and hydrogen atom transfer provides great opportunities for selective CH functionalization, which can achieve chemical transformations that cannot be achieved by traditional methods. Various heteroatom radicals such as S, N, O and halogen-centered radicals can be used as effective HAT reagents. Among them, halogen radicals, especially bromine radicals, have attracted much attention due to their availability and high reactivity. Compared with chlorine, bromine anions are more easily oxidized, and the generated bromine radicals have weaker hydrogen evolution ability than chlorine radicals. This makes bromine radicals have milder initiation conditions and superior HAT selectivity. Recent advances in utilizing bromine radicals as HAT catalysts are mainly based on the photoactivation of in situ formed metal bromine intermediates, and the substrates are limited to activated alkanes (such as tertiary alkyl, benzyl, α-acyl, α-oxo, α-amino, and allylic C sp 3 -H bonds) and aldehydes (Scheme A) because their C-H bond dissociation energies (BDE) are close to the H-Br bonding energy (87 kcal mol -1 ).

[0044] However, for imine-type substrates such as quinoxalinone N=C sp 2 -H bond, there is no reported case of HAT catalytic activation, which is the limitation of the current method of synthesizing substrates through HAT catalytic activation. + ClO4 - (The structural formula is shown in Figure 4 ) as an electron transfer catalyst and NBS as a HAT catalyst, a site-selective cross-coupling / cyclization reaction of quinoxaline-2(1H)-one with α-cyano-α,β-unsaturated ketone was developed in a metal-free manner. sp 2 It starts with the transfer of a -H bond hydrogen atom, triggering the subsequent addition and cyclization of the nucleophilic iminium radical to the electron-deficient α-cyano-α,β-unsaturated ketone, and ultimately ideally assembling a series of valuable pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds.

[0045] The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds of the present invention has the following general reaction formula: Figure 1 As shown. Among them, R 1is selected from alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl or substituted aryl, R 2 is selected from monosubstituted, disubstituted halogen, alkyl or phenyl, Ar 1 is selected from phenyl or substituted aryl, Ar 2 is selected from substituted aryl or heteroaryl. Figure 1 The acid in the mixture is an acidic additive, and the acidic additive is selected from at least one of trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and phenylphosphite, preferably trifluoroacetic acid. Specifically, the method for synthesizing pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds of the present invention comprises the following steps:

[0046] A quinoxaline ketone compound a, an unsaturated ketone compound b, a HAT catalyst, a visible light catalyst and a dehydrating agent MgSO4 are added to a dry container filled with 1 ml of a trifluoroacetic acid / ethyl acetate mixed solvent in a volume ratio of 3.2 / 10 and mixed, the dry container is evacuated and backfilled with nitrogen to protect the mixture in the dry container with nitrogen, and then placed in an irradiation device of a blue light emitting diode for blue light irradiation, stirred and reacted at room temperature for 40 to 50 hours, and the crude product obtained by the reaction is purified by column chromatography to obtain a product pyrrolo[1,2-a]quinoxaline-4(5H)-one compound.

[0047] Among them, the molar ratio of quinoxalinone compound a, compound b, hydrogen transfer catalyst and visible light catalyst is 1:1-2:0.2-0.6:0.01-0.05, and the molar ratio of quinoxalinone compound a, compound b, hydrogen transfer catalyst and visible light catalyst is preferably 1:1.5:0.2:0.01. The power of the blue light-emitting diode in blue light irradiation is 8-12W, preferably 10W, and the wavelength is preferably 430nm-460nm, more preferably 454nm.

[0048] Please refer to the reaction mechanism Figure 3 , using the synthesis method of the above technical solution, the catalytic amount of NBS (BDE = 58.0 kcal / mol) can directly undergo N-Br bond homolysis by visible light photolysis (470 nm blue photon energy = 60.7 kcal / mol), thereby obtaining bromine free radicals to start the entire catalysis, while the bromine free radicals required to maintain the entire catalytic cycle are achieved by photocatalytic single-electron oxidation of bromine anions. Excited photocatalyst Mes-Acr + ClO4 - (The structural formula is shown in Figure 4 ) is a strong oxidant that can achieve single-electron oxidation of bromine anions to generate bromine radicals. The transient bromine radical is responsible for site-selective oxidation from the N=C sp 2-H bond to generate iminium radical I and release HBr. The generated nucleophilic iminium radical I will preferentially add to the electron-deficient α-cyano-α,β-unsaturated ketone b to form an electrophilic radical adduct II, which is then reduced by the reduced photosensitizer [Mes-Acr+]· and protonated to generate the enol intermediate III. The generated enol III coexists with its resonance form IV through the mutual conversion of imine-enamine. After the protonation process, intermediate IV is converted to V, and then undergoes an intramolecular nucleophilic addition reaction to generate intermediate VI. Finally, intermediate VI can also undergo aromatization reaction and release product 1 through dehydration and deprotonation.

[0049] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0050] Examples 1-12 all adopt the following synthesis method, except that the compound a and compound b and the product in each example are different. The specific synthesis method is as follows:

[0051] Quinoxalinone compound a (0.2 mmol, 1 equivalent) was added to a dry glass bottle equipped with a magnetic stirring bar and a nitrogen inlet. The glass bottle was previously charged with NBS (0.04 mmol, 0.4 equivalent; 14 mg), compound b (0.3 mmol, 1.5 equivalent), Mes-Acr + ClO4 - (0.002 mmol, 2 mol%, 2.6 mg) and MgSO4 (80 mg) in TFA / EA=3.2 / 10 (v / v) (1 ml), the mixture in the glass bottle was purged with nitrogen by evacuating the glass bottle three times and backfilling with nitrogen for nitrogen protection, and then placed in an irradiation device equipped with a 10 W blue light emitting diode (LED) for blue light irradiation (with a wavelength of 454 nm), and the reaction was stirred at room temperature for 48 hours. The crude product obtained by the reaction was purified by column chromatography (silica gel, EtOAc:n-Hexane=1:10~1:3) to obtain pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds 1-12.

[0052] Example 1

[0053] The compound synthesized in this example is 5-methyl-4-oxo-1,3-diphenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. 1 is methyl, R 2 is hydrogen, Ar 1 Phenyl, Ar 2The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 1 is a colorless oil with a yield of 80%. 1 H NMR and 13 C NMR Figure 5 and 6 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0054] 1 H NMR (400MHz, CDCl3) δ7.65 (dd, J=8.2, 1.2Hz, 2H), 7.59 (s, 5H), 7.53–7.39 (m, 4H), 7.3 2(d,J=4.0Hz,2H),7.17(d,J=8.4Hz,1H),6.87(dt,J=8.6,4.4Hz,1H),3.61(s,3H)ppm; 13 C NMR (100MHz, CDCl3) δ155.1,138.4,132.5,131.5,131.1,130.5,130.4,130.0,129.7,129.6,1 28.5,128.0,127.1,123.7,122.3,119.8,118.5,115.8,115.0,101.4,28.9ppm; HRMS(ESI)m / z calcd for C 25 H 18 N3O + (M+H) + 376.1444, found m / z 376.1445.

[0055] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 1 of this example is inferred to be as follows:

[0056]

[0057] Example 2

[0058] The compound synthesized in this example is 3-(2-methoxyphenyl)-5-methyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. 1 is methyl, R 2 is hydrogen, Ar 1 is 2-methoxyphenyl, Ar 2The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above. The synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 2 is a yellow solid with a yield of 82%. The product structure of the X-ray single crystal diffraction is as follows: Figure 2 As shown, its CCDC number is 2387273. The pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 2 of this example 1 H NMR and 13 C NMR Figure 7 and 8 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0059] 1 H NMR (400MHz, CDCl3) δ7.58(s,5H),7.48–7.37(m,2H),7.29(d,J=4.1Hz,2H),7.17(d,J=8.4Hz ,1H),7.06(dd,J=14.9,7.8Hz,2H),6.85(dt,J=8.6,4.5Hz,1H),3.85(s,3H),3.58(s,3H)ppm; 13 C NMR (100MHz, CDCl3) δ157.1,154.9,137.9,132.2,131.6,130.3,130.2,130.2,129.8,129.5,128.6,126 .8,123.9,122.1,120.6,120.4,120.3,118.4,115.7,114.9,111.1,102.4,55.6,28.7ppm; HRMS(ESI)m / z calcd for C 26 H 20 N3O2 + (M+H) + 406.1550, found m / z 406.1556.

[0060] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 2 of this example is inferred to be as follows:

[0061]

[0062] Example 3

[0063] The compound synthesized in this example is 5-methyl-4-oxo-1-phenyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R2 is hydrogen, Ar 1 is 4-(trifluoromethyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above. The synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 3 is a yellow solid with a yield of 77%. The product structure of the X-ray single crystal diffraction is as follows: Figure 2 As shown, its CCDC number is 2387274. The pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 3 of this example 1 H NMR, 19 F NMR and 13 C NMR Fig. 9 , 10 As shown in Figure 11, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0064] 1 H NMR (400MHz, CDCl3) δ7.76(q,J=8.4Hz,4H),7.67–7.53(m,5H),7.35(d,J=4.0Hz,2H),7.20(d,J=8.5Hz,1H),7.01–6.78(m,1H),3.63(s,3H)ppm; 13 C NMR (100MHz, CDCl3) δ154.9,138.7,134.9,131.4,130.8,130.7,129.7,129.7,129.7,129.1,129.0,1 27.4,126.3(q,J=276.3Hz),124.9(q,J=3.7Hz).123.5,122.5,120.1,118.5,115.9,114.6,101.3ppm; 19 F NMR(376MHz, CDCl3)δ-62.6(s)ppm; HRMS(ESI)m / z calcd forC 26 H 17 F3N3O + (M+H) + 444.1318, found m / z 444.1323.

[0065] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 3 of this example is inferred to be as follows:

[0066]

[0067] Example 4

[0068] The compound synthesized in this example is 5-methyl-4-oxo-1-phenyl-3-(4-(phenylthio)phenyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R 2 is hydrogen, Ar 1 is 4-(phenylthio)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 4 is a yellow solid with a yield of 76%. 1 H NMR and 13 C NMR Fig.12 and 13 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0069] 1 H NMR (400MHz, CDCl3) δ7.66–7.54(m,7H),7.51–7.45(m,2H),7.39–7.34(m,4H),7.31(dd ,J=9.8,5.4Hz,3H),7.16(d,J=8.4Hz,1H),6.87(dt,J=8.6,4.4Hz,1H),3.61(s,3H)ppm; 13 C NMR (100MHz, CDCl3) δ155.1,138.6,137.2,134.5,132.4,131.6,131.5,131.1,130.5,129.9,129.7,129. 6,129.4,129.1,127.6,127.2,123.6,122.3,119.8,118.5,115.8,114.9,101.3,28.9ppm; HRMS(ESI)m / z calcd for C 31 H 22 N3OS + (M+H) + 484.1478, found m / z 484.1475.

[0070] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 4 of this example is inferred to be as follows:

[0071]

[0072] Example 5

[0073] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-7,8-difluoro-5-methyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R 2 is 7,8-difluoro, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 5 is a yellow solid with a yield of 73%. 1 H NMR, 19 F NMR and 13 C NMR Fig.14 , 15 As shown in Figure 16, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0074] 1 H NMR (400MHz, CDCl3) δ7.63 (q, J=5.0Hz, 3H), 7.57 (dd, J=10.3, 5.1Hz, 4H), 7.50 (d, J=8.4Hz, 2 H),7.12(dd,J=11.4,7.2Hz,1H),6.96(dd,J=11.8,7.6Hz,1H),3.57(s,3H),1.37(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ154.7, 151.6, 146.4 (ddd, J = 259.0, 247.6, 13.5Hz), 138.5, 133.1, 131.0, 130.0, 129.9, 129.7, 129 .2,129.0,128.9–128.6(m),127.5,119.1,114.7,108.0(d,J=24.9Hz),104.8(d,J=23.1Hz),101.8,34.8,31.3,29.3ppm; 19 F NMR (376MHz, CDCl3) δ-135.81 (ddd, J=23.0, 11.4, 7.7Hz), -141.30 (ddd, J=23.1, 11.9, 7.3Hz) ppm; HRMS (ESI) m / z calcd for C 29 H 24 F2N3O + (M+H) +468.1882, found m / z 468.1888.

[0075] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 5 of this example is inferred to be as follows:

[0076]

[0077] Example 6

[0078] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5,7,8-trimethyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R 2 is 7,8-dimethyl, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 6 is a yellow solid with a yield of 70%. 1 H NMR and 13 C NMR Fig.17 and 18 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0079] 1 H NMR(400MHz, CDCl3)δ7.59(dt,J=10.3,4.1Hz,7H),7.53–7.41(m,2H),7.05( s,1H),6.83(s,1H),3.59(s,3H),2.29(s,3H),1.93(s,3H),1.37(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ155.2,151.09,137.9,135.8,132.3,130.6,130.3,130.3,130.0,129.8,129.4,129.3,129. 2,128.5,128.2,124.9,121.4,119.6,119.4,116.5,115.4,100.8,34.7,31.4,28.8,19.9,19.4ppm; HRMS(ESI)m / z calcd for C 31 H 30 N3O + (M+H)+ 460.2383, found m / z 460.2389.

[0080] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 6 of this example is inferred to be as follows:

[0081]

[0082] Example 7

[0083] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5-methyl-4-oxo-1-phenyl-4,5-dihydrobenzo[g]pyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R 2 Phenyl, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 7 is a yellow solid with a yield of 76%. 1 H NMR and 13 C NMR Fig.19 and 20 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0084] 1 H NMR(400MHz, CDCl3)7.80(d,J=8.2Hz,1H),7.72–7.57(m,8H),7.55–7.42(m, 4H),7.39–7.28(m,1H),7.25(d,J=8.3Hz,1H),3.70(s,3H),1.38(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ155.1,151.4,139.4,133.3,131.4,130.6,130.5,130.1,130.0,129.8,129.7,128.1,127.9, 127.7,127.2,126.9,125.8,125.0,123.3,119.5,117.1,115.1,112.1,101.4,34.8,31.4,29.1ppm; HRMS(ESI)m / z calcd for C 33 H 28 N3O + (M+H)+ 482.2227, found m / z 482.2223.

[0085] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 7 of this example is inferred to be as follows:

[0086]

[0087] Example 8

[0088] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5-(3-fluorobenzyl)-7,8-dimethyl-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is 3-fluorobenzyl, R 2 is 7,8-dimethyl, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 8 is a yellow solid with a yield of 80%. 1 H NMR, 19 FNMR and 13 C NMR Fig.21 , 22 As shown in Figure 23, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0089] 1 H NMR(400MHz, CDCl3) δ7.65(dd,J=10.8,4.1Hz,2H),7.61(d,J=6.3Hz,5H),7.52–7.45(m,2H),7.38–7.19( m,1H),7.04(d,J=7.5Hz,1H),6.98–6.81(m,4H),5.43(s,2H),2.13(s,3H),1.88(s,3H),1.36(s,9H)ppm; 13C NMR (100MHz, CDCl3) δ164.4,162.0,155.3,151.2,138.9,138.9,138.3,135.9,132.9,131.0,130.5,130.4,130.4,130.3,130.1,129.8,129.4,1 28.2,128.0,125.0,122.1,122.1,121.6,119.6,119.1,117.1,115.3,11 4.5,114.3,113.6,113.4,101.1,44.8,34.8,31.5,31.4,19.9,19.4ppm; 19 F NMR(376MHz, CDCl3)δ-100.90–-125.26(m)ppm; HRMS(ESI)m / z calcd for C 37 H 33 F3O + (M+H) + 554.2602, found m / z 554.2607.

[0090] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 8 of this example is inferred to be as follows:

[0091]

[0092] Example 9

[0093] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5-methyl-4-oxo-1-(thiophen-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is methyl, R 2 is hydrogen, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 9 is a yellow solid with a yield of 74%. 1 H NMR and 13 C NMR Fig.24 and 25 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0094] 1H NMR (400MHz, CDCl3) δ7.68(dd,J=5.1,1.1Hz,1H),7.59(d,J=8.5Hz,2H),7.49(d,J=8.5Hz,2H),7.41(dd,J=3.6,1.1Hz,1H) ,7.34(dd,J=7.8,1.4Hz,2H),7.28(dd,J=5.1,3.6Hz,2H),6.95(ddd,J=8.6,6.6,2.1Hz,1H),3.62(s,3H),1.37(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ154.9,151.3,132.5,131.4,131.1,130.6,130.2,130.0,129.6,128.3,127.8, 127.3,125.0,123.7,122.5,120.3,118.1,115.7,114.7,103.4,34.8,31.4,28.9ppm; HRMS(ESI)m / z calcd for C 27 H 24 N3OS + (M+H) + 438.1635, found m / z 438.1638.

[0095] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 9 of this example is inferred to be as follows:

[0096]

[0097] Example 10

[0098] The compound synthesized in this example is 5-allyl-3-(4-(tert-butyl)phenyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is allyl, R 2 is hydrogen, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 10 is a yellow solid with a yield of 85%. 1 H NMR and 13 C NMR Fig.26 and 27As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0099] 1 H NMR (400MHz, CDCl3) δ7.65–7.57(m,7H),7.49(d,J=8.3Hz,2H),7.32–7.23(m,2H),7.17(d,J=8.4Hz,1H),6.92–6 .71(m,1H),5.93(ddd,J=22.1,10.2,4.9Hz,1H),5.24(t,J=14.2Hz,2H),4.86(d,J=4.6Hz,2H),1.36(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ154.8,151.2,138.5,132.7,131.7,130.6,130.4,130.1,130.1,129.7,129.6,127.9, 126.9,125.0,123.7,122.2,119.4,118.6,117.5,116.5,115.2,101.6,44.1,34.7,31.4ppm; HRMS(ESI)m / z calcd for C 31 H 28 N3O + (M+H) + 458.2227, found m / z 458.2229.

[0100] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 10 of this example is inferred to be as follows:

[0101]

[0102] Embodiment 11

[0103] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5-(2-hydroxyethyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is 2-hydroxyethyl, R 2 is hydrogen, Ar 1 is 4-(tert-butyl)phenyl, Ar 2 The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 11 is a white solid with a yield of 51%. 1H NMR and 13 C NMR Fig.28 and 29 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0104] 1 H NMR (400MHz, CDCl3) δ7.66–7.54(m,7H),7.54–7.46(m,2H),7.41(d,J=7.6Hz,1H),7.33–7.24(m,1H),7.18(dd,J =8.5,1.1Hz,1H),7.08–6.74(m,1H),4.44(t,J=5.6Hz,2H),4.02(t,J=5.6Hz,2H),2.76(s,1H),1.37(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ156.3,151.3,138.7,132.7,130.7,130.5,130.0,129.7,129.6,127.8 ,127.0,125.0,123.8,122.4,119.2,118.8,115.9,115.1,101.7,60.8,44.5,34.7,31.3ppm; 1 HRMS(ESI)m / zcalcd for C 30 H 28 N3O2 + (M+H) + 462.2176, found m / z 462.2175.

[0105] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 11 of this example is inferred to be as follows:

[0106]

[0107] Example 12

[0108] The compound synthesized in this example is 3-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carbonitrile. In this example, R 1 is 4-chlorophenyl, R 2 is hydrogen, Ar 1 is 4-(tert-butyl)phenyl, Ar 2The synthesis method of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound of this embodiment is as described above, and the synthesized pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 12 is a yellow solid with a yield of 71%. 1 H NMR and 13 C NMR Fig.30 and 31 As shown, the characterization data such as nuclear magnetic resonance and high-resolution mass spectrometry are as follows:

[0109] 1 H NMR (400MHz, CDCl3) δ7.69–7.58(m,7H),7.54(d,J=8.6Hz,2H),7.44(d,J=8.4Hz,2H),7.28(d,J=8.7Hz,2H),7 .18(dd,J=8.5,1.0Hz,1H),7.14–7.04(m,1H),6.93–6.76(m,1H),6.65(dd,J=8.3,1.1Hz,1H),1.32(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ154.9,151.3,139.1,135.2,134.7,133.5,132.2,130.8,130.5,130.5,130.0,129.8, 129.6,127.5,126.7,125.0,123.5,122.6,119.4,118.5,117.4,115.0,101.8,34.6,31.3ppm; HRMS(ESI)m / z calcd for C 34 H 27 ClN3O + (M+H) + 528.1837, found m / z 528.1843.

[0110] Based on the above characterization data, the structure of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compound 12 of this example is inferred to be as follows:

[0111]

[0112] The anti-tumor activity of the pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds synthesized in Example 1-12 was tested. Specifically, human colon cancer cells HCT116, prostate cancer cells DU145 and pancreatic cancer cells BxpC3 were selected. These cell lines were purchased from the American Type Culture Collection (ATCC). HCT116 was cultured in McCoy's 5A medium, DU145 was cultured in DMEM medium, and BxpC3 was cultured in RPMI1640 medium. All culture media were supplemented with 10% fetal bovine serum (FBS) to provide growth factors required for cell growth, and the cell culture conditions were a constant temperature incubator at 37°C and 5% CO2. The culture steps are as follows:

[0113] (1) Tumor cells in the logarithmic growth phase were digested with trypsin and resuspended in complete medium. The cell concentration was measured using a cell counter and the cells were diluted to 3×10 4 Pieces / mL;

[0114] (2) Inoculate 100 μL of cell suspension in each well of a 96-well plate and incubate overnight in a cell culture incubator;

[0115] (3) Compounds 1-12 were diluted to 20 μM with the complete culture medium of the corresponding cells, and 100 μL of the compound dilution was added to each well of a 96-well plate to make the final concentration of the compound 10 μM. Each compound was added to 3 replicates, and the control group was DMSO with the same volume as the compound. The cells were returned to the cell culture incubator and cultured for 72 hours;

[0116] (4) The inhibitory effect of compounds 1-12 on the survival ability of various tumor cells was detected by MTT assay. After the tumor cells were treated with the compounds for 72 hours, 20 μL of 5 mg / mL MTT solution was added to each well and incubated at 37°C for another 4 hours;

[0117] (5) Discard the cell culture medium, add 150 μL DMSO to dissolve the cells, and measure the OD value at 570 nm (OD570) using a microplate reader;

[0118] (6) Data processing: relative survival rate was calculated based on OD570 of the compound-treated group and the control-treated group. Cell survival rate = OD570 化合物 / OD570 DMSO .

[0119] Experimental results: The effects of 10 μM compound 1-12 on the growth ability of colon cancer cells, prostate cancer cell lines, and pancreatic cancer cell lines are shown in Table 1.

[0120] Table 1

[0121]

[0122] The data in Table 1 show that pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds can inhibit or kill tumor cells, have anti-tumor activity, and can be used as anti-tumor drugs for the treatment of colon cancer, prostate cancer, and pancreatic cancer.

[0123] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should be included in the scope of the claims of the present invention. The techniques, shapes, and structural parts not described in detail in the present invention are all well-known technologies.

Claims

1. A method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound, characterized in that: The synthesis method comprises the following steps: using a photocatalyst, a hydrogen transfer catalyst and an acidic additive under visible light irradiation to synthesize a quinoxaline-2(1H)-one N=C sp 2 The hydrogen atom transfer of the -H bond initiates the addition and cyclization of the nucleophilic imine radical to the electron-deficient α-cyano-α and β-unsaturated ketone to prepare pyrrolo[1,2-a]quinoxaline-4(5H)-one compounds. The general reaction formula is as follows: Among them, R 1 is selected from alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl or substituted aryl, R 2 is selected from monosubstituted, disubstituted halogen, alkyl or phenyl, Ar 1 is selected from phenyl or substituted aryl, Ar 2 is selected from substituted aryl or heteroaryl.

2. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 1, characterized in that: The R 1 Selected from methyl, allyl, 2-hydroxyethyl, 4-chlorophenyl, 3-fluorobenzyl; The R 2 Selected from hydrogen, 7,8-difluoro, 7,8-dimethyl, phenyl; The Ar 1 Selected from phenyl, 2-methoxyphenyl, 4-(trifluoromethyl)phenyl, 4-(phenylthio)phenyl, 4-(tert-butyl)phenyl; The Ar 2 is selected from phenyl or thienyl.

3. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 1, characterized in that: The photocatalyst is an organic photocatalyst Mes-Acr + ClO4 - .

4. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 1, characterized in that: The hydrogen transfer catalyst is N-bromosuccinimide.

5. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 1, characterized in that: The acidic additive is selected from at least one of trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and phenylphosphite.

6. A method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to any one of claims 1 to 5, characterized in that: The synthesis method is as follows: A quinoxaline ketone compound a, an unsaturated ketone compound b, a hydrogen transfer catalyst, a photocatalyst and a dehydrating agent MgSO4 are added to a dry container filled with a mixed solvent and mixed, the dry container is evacuated and backfilled with nitrogen, the mixture in the dry container is protected by nitrogen, and then placed in an irradiation device of a blue light emitting diode for blue light irradiation, stirred and reacted at room temperature for 40 to 50 hours, and the crude product obtained by the reaction is purified by column chromatography to obtain a product pyrrolo[1,2-a]quinoxaline-4(5H)-one compound.

7. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 6, characterized in that: The molar ratio of the compound a, the compound b, the hydrogen transfer catalyst and the photocatalyst is 1:1-2:0.2-0.6:0.01-0.

05.

8. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 6, characterized in that: The visible light irradiation is blue light irradiation, the power of the blue light emitting diode in the blue light irradiation is 8 to 12 W, and the wavelength of the blue light is preferably 430 nm to 460 nm.

9. The method for synthesizing a pyrrolo[1,2-a]quinoxaline-4(5H)-one compound according to claim 6, characterized in that: The mixed solvent is trifluoroacetic acid and ethyl acetate mixed in a volume ratio of 3.2 / 10.

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