Preparation method of (E)-3-(pyrrolo [1, 2-a] quinoxaline-3-yl) acrylate and derivative thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of (E)-3-(pyrrolo [1, 2-a] quinoxaline-3-yl) acrylate and a derivative thereof, which comprises the following steps: taking a pyrrolo [1, 2-a] quinoxaline compound and acrylate as reactants, taking amino acid as a ligand, and carrying out a reaction at the temperature of 60-80 DEG C to obtain the (E)-3-(pyrrolo [1, 2-a] quinoxaline-3-yl) acrylate. The preparation method comprises the following steps: mixing a reactant, a palladium catalyst, silver salt, amino acid and a solvent, performing C-H activation reaction, stirring at 80-120 DEG C for 24-36 hours, cooling reaction liquid to room temperature after the reaction is finished, diluting, quenching, separating and purifying to obtain (E)-3-(pyrrolo [1, 2-a] quinoxaline-3-yl) acrylate and the derivative thereof. Palladium is used as a catalyst, pyrrolo [1, 2-a] quinoxaline and derivatives thereof, acrylic ester, a solvent and an amino acid ligand are added, under the condition, pyrrolo [1, 2-a] quinoxaline and acrylic ester smoothly react to obtain a corresponding pyrrolo [1, 2-a] quinoxaline alkylene product, and the highest yield can reach 82%. A new mode of direct functionalization of specific C-H bonds of aromatic hydrocarbon is established, and an innovative thought is provided for inert bond activation research.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a method for preparing (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives. Background Art

[0002] Pyrrolo[1,2-a]quinoxaline and its derivatives, as nitrogen heterocyclic compounds with unique rigid skeletons and biological activities, have attracted attention in recent years due to their wide application values. In the field of drug research and development, their main skeletons can significantly enhance pharmacological activities through structural modification. At present, it has been reported that they show significant inhibitory effects on disease models such as tumors, diabetes, cancer, tuberculosis, malaria, bacterial infections, and viral infections, demonstrating broad clinical transformation potential. In the field of materials science, the rigid conjugated characteristics of the skeleton endow it with excellent carrier mobility and environmental stability, making it an ideal candidate material for organic field-effect transistors (OFETs), flexible electronic devices, and wearable sensors. At the same time, its energy level structure and high fluorescence quantum yield can not only develop efficient organic light-emitting diodes (OLEDs) and organic solar cells (OPVs), but also promote innovative applications in biomedical fields such as photodetectors, metal ion fluorescence probes, and live cell imaging. In summary, pyrrolo[1,2-a]quinoxaline and its derivatives not only provide a molecular basis for drug design and materials engineering, but also highlight the important theoretical value and practical application requirements for developing new substituted derivatives and precise synthesis strategies.

[0003] In the field of allylic substitution reactions, significant progress has been made in the pre-functionalization strategy based on the β-X (X = N, O, or halogen) elimination mechanism, and the design and application of heteroatom-derived directing groups have been systematically studied. In sharp contrast, the non-directed direct C-H allylation system, although this economical transformation can avoid the pre-functionalization step, generally faces the challenge of insufficient site selectivity control. The Yu research group pioneered the palladium-catalyzed meta-selective C-H alkenylation reaction by introducing a weakly coordinating anchoring heterocycle strategy. So far, the successful cases of non-directed enantioselective C-H alkenylation are still relatively limited. The team first developed a Pd / S,O-based catalytic system and successfully achieved the enantioselective alkenylation of aniline substrates; subsequent studies further extended this system to the precise transformation of indole and tetrahydroquinoline compounds, but in the reaction research, it was still limited to the active sites on the aromatic ring. Summary of the Invention

[0004] In view of the above deficiencies in the background art, the present invention provides a method for preparing (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives. The present invention has developed a direct C-H olefination reaction condition at the C-3 position of pyrrolo[1,2-a]quinoxaline based on a palladium acetate / L-pyroglutamic acid catalytic system. The significant advantage of this reaction system is that no directing group needs to be introduced, and the C-C coupling between allyl ester and the C-3 position of pyrrolo[1,2-a]quinoxaline can be achieved only through the synergistic effect of the catalyst and the ligand. This method provides a novel and efficient strategy for the selective modification of heterocyclic compounds.

[0005] To achieve the above object, the present invention is realized through the following technical solutions:

[0006] A method for preparing (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives, characterized by comprising the following steps:

[0007] Using pyrrolo[1,2-a]quinoxaline compounds and acrylates as reactants, and an amino acid as a ligand, mixing the reactants, palladium catalyst, silver salt, amino acid and solvent, and then carrying out a C-H activation reaction, stirring at 80-120 °C for 24-36 h. After the reaction is completed, cooling the reaction solution to room temperature, diluting, quenching, and then separating and purifying to obtain (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives;

[0008] The reaction general formula of the C-H activation reaction is as follows:

[0009]

[0010] In the formula, R 1 is selected from any one of hydrogen, benzene, 4-methylbenzene, 4-methoxybenzene, 4-fluorobenzene, 4-chlorobenzene, naphthalene, iodine and chlorine; R 2 is selected from any one of Et, t-Bu, n-Bu, Bn, Ph, CH 2 CF 3 , adamantane, L-menthol, borneol, geraniol and fructose propanedione.

[0011] Under a preferred scheme, the palladium catalyst is selected from one or more of palladium acetate, palladium chloride and tetrakis(triphenylphosphine)palladium; the amino acid is L-pyroglutamic acid.

[0012] Under a preferred scheme, the silver salt is selected from one or more of silver carbonate, silver acetate and silver sulfate; the solvent is selected from one or more combinations of dimethyl carbonate, glacial acetic acid and trifluoroacetic acid.

[0013] Under the preferred scheme, the molar ratio of the pyrrolo[1,2-a]quinoxaline compound, acrylate, palladium catalyst, silver salt and amino acid is 1:3:0.2:3:0.4.

[0014] Under the preferred scheme, the cooled reaction solution is diluted with ethyl acetate, and then the reaction solution is quenched with saturated aqueous sodium bicarbonate.

[0015] Under the preferred scheme, the separation and purification include the following steps:

[0016] The organic phase of the reaction solution is extracted several times with an extractant, and the organic phases are combined to obtain an extract;

[0017] The solvent in the extract is removed by rotary evaporation under reduced pressure to obtain a crude product;

[0018] The crude product is purified by flash purification chromatography on silica gel to obtain (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives.

[0019] Under the preferred scheme, the extractant is ethyl acetate.

[0020] Under the preferred scheme, the crude product is purified with a mixed solution of petroleum ether and ethyl acetate as the eluent, and the volume ratio of petroleum ether to ethyl acetate is (5-20):1.

[0021] The beneficial effects of the present invention are as follows:

[0022] 1. In the prior art, the para-selective C-H functionalization reaction in the non-directed mode is only limited to the active sites on the aromatic ring, and the present invention innovatively conducts an olefination reaction on the sites on the nitrogen-containing heterocycle.

[0023] 2. The method for para-selective C-H functionalization reaction in the non-directed mode provided by the present invention not only avoids the need to introduce an additional directing group, but also establishes a new mode for the direct functionalization of specific C-H bonds in aromatic hydrocarbons, providing an innovative idea for the study of inert bond activation.

[0024] 3. In the present invention, palladium is used as a catalyst, and pyrrolo[1,2-a]quinoxaline and its derivatives, acrylate, solvent and amino acid ligand are added. Under these conditions, pyrrolo[1,2-a]quinoxaline reacts smoothly with acrylate to obtain the corresponding pyrrolo[1,2-a]quinoxaline olefination product, and the highest yield can reach 82%. Specific Embodiments

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0026] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. The experimental methods in the embodiments are conventional methods unless otherwise specified. For those conditions not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0027] In the present invention, a method for preparing (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives by using palladium as a catalyst and adding pyrrolo[1,2-a]quinoxaline and acrylate as reactants includes the following steps:

[0028] React pyrrolo[1,2-a]quinoxaline, acrylate, palladium catalyst, silver salt, ligand and solvent in a pressure-resistant tube. Stir the mixture in air at 80-120 °C for hours to carry out the C-H activation reaction. After the reaction is completed, cool it to room temperature. Quench with ethyl acetate and saturated aqueous sodium bicarbonate solution and carry out extraction and liquid separation. Combine the organic phases and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel to obtain the final product (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives.

[0029] Among them, the acrylate is an alkyl acrylate or an aryl acrylate or a drug molecule ester group; the palladium catalyst can be, but is not limited to, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium;

[0030] The silver salt can be, but is not limited to, silver carbonate, silver acetate, silver sulfate; the solvent is a mixture of dimethyl carbonate, glacial acetic acid, or trifluoroacetic acid.

[0031] The reaction general formula of the C-H activation reaction is as follows:

[0032]

[0033] In the formula, R 1 is the substituent at the 1-position on pyrrolo[1,2-a]quinoxaline, selected from the following groups (one of): hydrogen, benzene, 4-methylbenzene, 4-methoxybenzene, 4-fluorobenzene, 4-chlorobenzene, naphthalene, iodine, chlorine;

[0034] R 2is a substituent on the acrylate and is selected from the following groups (one of): Et, t-Bu, n-Bu, Bn, Ph, CH 2 CF 3 , adamantane, L-menthol, borneol, geraniol, fructone.

[0035] The molar ratio of acrylate to pyrrolo[1,2-a]quinoxaline is 3:1.

[0036] The molar ratio of palladium catalyst to pyrrolo[1,2-a]quinoxaline is 0.2:1.

[0037] The molar ratio of silver salt to pyrrolo[1,2-a]quinoxaline is 3:1.

[0038] The molar ratio of base to pyrrolo[1,2-a]quinoxaline is 0.4:1.

[0039] The reactor is heated by a heating plate.

[0040] The reaction temperature is 80 - 120 °C and the time is 24 - 36 h.

[0041] Example 1: Synthesis of Ethyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0042] A preparation method of ethyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and its reaction formula is as follows:

[0043]

[0044] Specifically, it includes the following steps:

[0045] Using pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), ethyl acrylate (66 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3(165.4 mg, 3 equiv), L - pyroglutamic acid (10.4 mg, 40 mol%), and glacial acetic acid (1 mL) were reacted in a pressure - resistant tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate, and 30 mL of saturated aqueous sodium bicarbonate was added to quench and perform extraction and liquid - separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ethyl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate. 43.1 mg of ethyl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate was obtained with a yield of 81%.

[0046] The NMR identification results of ethyl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate are as follows:

[0047] 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 7.98 (d, J = 15.6 Hz, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.81 (d, J = 3.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.46 - 7.41 (m, 1H), 7.04 (d, J = 2.9 Hz, 1H), 6.35 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H);

[0048] 13 C NMR (101 MHz, CDCl 3 ) δ 167.42, 143.37, 136.35, 134.30, 130.40, 128.69, 127.46, 125.98, 125.34, 117.27, 116.61, 115.52, 113.85, 111.93, 60.50, 14.51.

[0049] HRMS (APCI): m / z calcd for C 16 H 14 N 2 O 2 (M + H)+: 267.1128, found: 267.1123.

[0050] Example 2: Synthesis of Ethyl (E)-3-(7-Methylpyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0051] A preparation method of ethyl (E)-3-(7-methylpyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and its reaction formula is as follows:

[0052]

[0053] Specifically, it includes the following steps:

[0054] React 7-methylpyrrolo[1,2-a]quinoxaline (36.4 mg, 0.2 mmol), ethyl acrylate (66 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) in a pressure-resistant tube (10 mL). Stir the mixture in air at 100 °C for 36 hours. After the reaction is completed, cool to room temperature. Dilute the reaction solution with 20 mL of ethyl acetate, add 30 mL of saturated sodium bicarbonate aqueous solution to quench and perform extraction and liquid separation. Add 10 mL of ethyl acetate to the aqueous solution for secondary extraction. Combine the organic phases and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ethyl (E)-3-(7-methylpyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and obtain 31.8 mg of ethyl (E)-3-(7-methylpyrrolo[1,2-a]quinoxalin-3-yl)acrylate, with a yield of 68%.

[0055] The nuclear magnetic resonance identification results of ethyl (E)-3-(7-methylpyrrolo[1,2-a]quinoxalin-3-yl)acrylate are as follows:

[0056] 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.03 (d, J = 15.8 Hz, 1H), 7.85 (d, J = 3.1 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 10.8 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.39 (d, J = 15.7 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H);

[0057] 13 C NMR (101 MHz, CDCl 3 ) δ 167.14, 166.49, 143.19, 133.73, 133.29, 130.63, 129.21, 129.02, 127.91, 126.51, 120.97, 118.35, 116.98, 114.06, 61.13, 60.76, 14.53.

[0058] HRMS (APCI): m / z calcd for C 17 H 16 N 2 O 2 (M + H)+: 281.1285, found: 281.1281.

[0059] Example 3: Synthesis of Ethyl (E)-3-[1-(p-tolyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate

[0060] A method for preparing ethyl (E)-3-[1-(p-tolyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, the reaction formula is as follows:

[0061]

[0062] Specifically, it includes the following steps:

[0063] React 1-(p-tolyl)pyrrolo[1,2-a]quinoxaline (51.7 mg, 0.2 mmol), ethyl acrylate (66 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) in a pressure-resistant tube (10 mL). Stir the mixture in air at 100 °C for 36 hours. After the reaction is completed, cool to room temperature. Dilute the reaction solution with 20 mL of ethyl acetate, add 30 mL of saturated sodium bicarbonate aqueous solution to quench and perform extraction and liquid separation, and add 10 mL of ethyl acetate to the aqueous solution for secondary extraction. Combine the organic phases, and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ethyl (E)-3-[1-(p-tolyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, obtaining 51.3 mg of ethyl (E)-3-[1-(p-tolyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, with a yield of 72%.

[0064] The nuclear magnetic resonance identification results of ethyl (E)-3-[1-(p-tolyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate are as follows:

[0065] 1 H NMR(400MHz,CDCl 3 )δ9.05(s,1H),8.07(d,J=15.8Hz,1H),7.95(d,J=8.1Hz,1H),7.44-7.34(m,4H),7.20-7.13(m,1H),7.04(d,J=8.8Hz,2H),6.94(s,1H),6.38(d,J=15.7Hz,1H),4.29(q,J=7.2Hz,2H),3.91(s,3H),1.35(t,J=7.1Hz,3H);

[0066] 13 C NMR(101MHz,CDCl 3 )δ167.46,160.43,143.47,137.64,134.04,133.77,131.14,130.30,128.84,127.45,126.40,125.63,125.35,116.94,116.60,114.43,114.15,60.54,55.54,14.53.

[0067] HRMS(APCI):m / z calcd for C 23 H 20 N 2 O 2 (M+H)+:357.1598,found:357.1601.

[0068] Example 4: Synthesis of ethyl (E)-3-[1-(4-fluorophenyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate

[0069] A preparation method of ethyl (E)-3-[1-(4-fluorophenyl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, and its reaction formula is as follows:

[0070]

[0071] Specifically, it includes the following steps:

[0072] Using 1-(4-fluorophenyl)pyrrolo[1,2-a]quinoxaline (52.5mg, 0.2mmol), ethyl acrylate (66μL, 0.6mmol), Pd(OAc) 2 (8.6mg, 20mol%), Ag2 CO 3 (165.4 mg, 3 eq), L - pyroglutamic acid (10.4 mg, 40 mol%), and glacial acetic acid (1 mL) were reacted in a pressure - resistant tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate, and 30 mL of saturated aqueous sodium bicarbonate solution was added to quench and perform extraction and liquid separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ethyl (E) - 3 - [1 - (4 - fluorophenyl)pyrrolo[1,2 - a]quinoxalin - 3 - yl]acrylate, and 28.8 mg of ethyl (E) - 3 - [1 - (4 - fluorophenyl)pyrrolo[1,2 - a]quinoxalin - 3 - yl]acrylate was obtained with a yield of 40%.

[0073] The NMR identification results of ethyl (E) - 3 - [1 - (4 - fluorophenyl)pyrrolo[1,2 - a]quinoxalin - 3 - yl]acrylate are as follows:

[0074] 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.07 (d, J = 16.3 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.7, 5.3 Hz, 2H), 7.42 - 7.37 (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.25 - 7.15 (m, 3H), 6.97 (s, 1H), 6.40 (d, J = 15.6 Hz, 1H), 4.29 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H);

[0075] 13 C NMR (101 MHz, CDCl 3 ) δ 167.36, 164.65, 162.17, 143.38, 137.39, 133.78, 132.79, 131.79, 131.71, 130.40, 129.22, 128.63, 127.69, 126.51, 125.92, 117.45, 116.45, 116.38, 116.16, 114.58, 60.65, 14.55;

[0076] 19 F NMR (376 MHz, CDCl 3 ) δ - 111.13.

[0077] HRMS(APCI): m / z calcd for C 22 H 17 FN 2 O 2 (M + H)+: 361.1347, found: 361.1350.

[0078] Example 5: Synthesis of Ethyl (E)-3-[1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate

[0079] A preparation method of ethyl (E)-3-[1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, and the reaction formula is as follows:

[0080]

[0081] Specifically, it includes the following steps:

[0082] React 1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxaline (78.5 mg, 0.2 mmol), ethyl acrylate (66 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) in a pressure-resistant tube (10 mL). Stir the mixture in air at 100 °C for 36 hours. After the reaction is completed, cool to room temperature. Dilute the reaction solution with 20 mL of ethyl acetate, add 30 mL of saturated sodium bicarbonate aqueous solution to quench and perform extraction and liquid separation, add 10 mL of ethyl acetate to the aqueous solution for secondary extraction. Combine the organic phases and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ethyl (E)-3-[1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, and obtain 64.3 mg of ethyl (E)-3-[1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate, with a yield of 82%.

[0083] The nuclear magnetic resonance identification results of ethyl (E)-3-[1-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxalin-3-yl]acrylate are as follows:

[0084] 1 H NMR(400 MHz, CDCl 3)δ9.12(s,1H),8.12(d,J=15.8Hz,1H),8.06(s,1H),8.02 - 7.94(m,3H),7.94 - 7.90(m,1H),7.65 - 7.59(m,2H),7.56(d,J=8.4Hz,1H),7.43 - 7.34(m,2H),7.14 - 7.06(m,2H),6.44(d,J=15.6Hz,1H),4.31(q,J=7.1Hz,2H),1.37(t,J=7.2Hz,3H);

[0085] 13 C NMR(101MHz,CDCl 3 )δ167.44,143.47,133.94,133.43,133.36,130.53,130.25,129.02,128.74,128.65,128.45,128.08,127.65,127.28,127.13,127.02,126.71,125.85,117.33,116.89,114.82,60.63,14.56.

[0086] HRMS(APCI):m / z calcd for C 26 H 20 N 2 O 2 (M + H)+:393.1598,found:393.1601.

[0087] Example 6: Synthesis of Butyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0088] A preparation method of butyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and the reaction formula is as follows:

[0089]

[0090] Specifically, it includes the following steps:

[0091] Using pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), butyl acrylate (86 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3(165.4 mg, 3 eq), L - pyroglutamic acid (10.4 mg, 40 mol%), and glacial acetic acid (1 mL) were reacted in a pressure - resistant tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate, quenched with 30 mL of saturated aqueous sodium bicarbonate solution and subjected to extraction and liquid - separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)butyl acrylate. 35.9 mg of (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)butyl acrylate was obtained with a yield of 61%.

[0092] The NMR identification results of (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)butyl acrylate are as follows:

[0093] 1 H NMR(400 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.08 - 7.97 (m, 2H), 7.91 (d, J = 3.1 Hz, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 2.9 Hz, 1H), 6.41 (d, J = 15.7 Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 1.77 - 1.66 (m, 2H), 1.46 (h, J = 7.4 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H);

[0094] 13 C NMR(101 MHz, CDCl 3 ) δ 167.58, 143.38, 136.26, 134.31, 130.41, 128.87, 127.59, 126.14, 125.41, 117.62, 116.88, 115.75, 113.97, 112.14, 64.52, 31.00, 19.38, 13.92

[0095] HRMS(APCI): m / z calcd for C 18 H 18 N 2 O 2 (M + H)+: 295.1441, found: 295.1444.

[0096] Example 7: Synthesis of phenyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0097] A preparation method of phenyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and the reaction formula is as follows:

[0098]

[0099] Specifically, it includes the following steps:

[0100] React pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), phenyl acrylate (83 μL, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) in a pressure-resistant tube (10 mL). Stir the mixture in air at 100 °C for 36 hours. After the reaction is completed, cool to room temperature. Dilute the reaction solution with 20 mL of ethyl acetate, add 30 mL of saturated sodium bicarbonate aqueous solution to quench and perform extraction and liquid separation, add 10 mL of ethyl acetate to the aqueous solution for secondary extraction. Combine the organic phases, and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product phenyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate. 44.6 mg of phenyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate is obtained, and the yield is 71%.

[0101] The nuclear magnetic resonance identification results of phenyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate are as follows:

[0102] 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.15 (d, J = 15.7 Hz, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 3.1 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.38 - 7.31 (m, 2H), 7.23 - 7.09 (m, 5H), 6.52 (d, J = 15.7 Hz, 1H); 13 C NMR (101 MHz, CDCl 3)δ 165.87, 151.05, 143.27, 136.28, 134.86, 130.45, 129.56, 129.00, 127.51, 126.28, 125.84, 121.83, 117.68, 117.30, 115.96, 115.63, 114.02, 112.31.

[0103] HRMS(APCI): m / z calcd for C 21 H 16 N 2 O 2 (M + H)+: 329.1285, found: 329.1288.

[0104] Example 8: Synthesis of Adamantan-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0105] A preparation method of adamantan-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and the reaction formula is as follows:

[0106]

[0107] Specifically, it includes the following steps:

[0108] React pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), adamantan-1-yl acrylate (123.8 mg, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) in a pressure-resistant tube (10 mL). Stir the mixture in air at 100 °C for 36 hours. After the reaction is completed, cool to room temperature. Dilute the reaction solution with 20 mL of ethyl acetate, add 30 mL of saturated sodium bicarbonate aqueous solution to quench and perform extraction and liquid separation, add 10 mL of ethyl acetate to the aqueous solution for secondary extraction. Combine the organic phases, and remove the solvent by rotary evaporation under reduced pressure. Purify the crude product by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product adamantan-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and obtain 49.8 mg of adamantan-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, with a yield of 67%.

[0109] The nuclear magnetic resonance identification results of adamantan-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate are as follows:

[0110] 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 15.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.59 (t, J = 6.4 Hz, 1H), 7.36 (d, J = 19.4 Hz, 5H), 7.20 (s, 1H), 6.55 (d, J = 15.7 Hz, 1H), 4.43 - 4.37 (m, 2H), 1.45 (d, J = 7.2 Hz, 4H), 0.08 (s, 3H);

[0111] 13 C NMR (101 MHz, CDCl 3 ) δ 166.88, 137.18, 132.91, 130.21, 128.63, 128.04, 126.81, 118.28, 116.67, 113.46, 106.96, 98.16, 89.36, 60.91, 47.82, 14.52, 0.14.

[0112] HRMS (APCI): m / z calcd for C 24 H 24 N 2 O 2 (M + H)+: 373.1911, found: 373.1913.

[0113] Example 9: Synthesis of (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0114] A preparation method of (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and its reaction formula is as follows:

[0115]

[0116] Specifically, it includes the following steps:

[0117] Using pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl acrylate (12.5 mg, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3 (165.4 mg, 3 equivalents), L-pyroglutamic acid (10.4 mg, 40 mol%) and glacial acetic acid (1 mL) were reacted in a pressure tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After completion of the reaction, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate and quenched by adding 30 mL of saturated aqueous sodium bicarbonate solution and subjected to extraction and liquid separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate. 29.3 mg of (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate was obtained with a yield of 39%.

[0118] (1R,3R,4S)-4-isopropyl-3-methylcyclohexyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate was identified by nuclear magnetic resonance as follows:

[0119] 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.08 - 7.98 (m, 2H), 7.91 (d, J = 3.1 Hz, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.12 (d, J = 2.9 Hz, 1H), 6.41 (d, J = 15.7 Hz, 1H), 4.86 (td, J = 10.9, 4.4 Hz, 1H), 2.09 (d, J = 11.4 Hz, 1H), 2.02 - 1.91 (m, 1H), 1.72 (d, J = 11.5 Hz, 2H), 1.60 - 1.51 (m, 1H), 1.50 - 1.43 (m, 1H), 1.16 - 1.04 (m, 2H), 0.96 - 0.91 (m, 7H), 0.82 (d, J = 7.0 Hz, 3H);

[0120] 13 C NMR (101 MHz, CDCl 3)δ167.08,143.39,136.18,134.15,130.34,128.87,127.61,126.14,125.36,117.79,117.39,115.79,113.98,112.16,74.32,47.42,41.27,34.47,31.60,26.55,23.73,22.22,20.94,16.64.

[0121] HRMS(APCI):m / z calcd for C 24 H 28 N 2 O 2 (M+H)+:377.2224,found:377.2227.

[0122] Example 10: Synthesis of ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0123] A method for preparing ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, the reaction formula is as follows:

[0124]

[0125] Specifically, it includes the following steps:

[0126] Using pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl acrylate (188.6 mg, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3(165.4 mg, 3 eq), L-pyroglutamic acid (10.4 mg, 40 mol%), and glacial acetic acid (1 mL) were reacted in a pressure tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After completion of the reaction, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate, quenched with 30 mL of saturated aqueous sodium bicarbonate, and subjected to extraction and liquid separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate. 40.3 mg of ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate was obtained with a yield of 42%.

[0127] The NMR identification results of ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-3a-yl)methyl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate are as follows:

[0128] 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 8.11 (d, J = 15.7 Hz, 1H), 8.00 (d, J = 6.5 Hz, 1H), 7.90 (d, J = 3.1 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.43 (d, J = 15.7 Hz, 1H), 4.63 (d, J = 5.4 Hz, 1H), 4.55 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 2.6 Hz, 1H), 4.29 - 4.22 (m, 2H), 3.94 (d, J = 14.9 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 1.56 (s, 3H), 1.49 (d, J = 16.4 Hz, 6H), 1.35 (s, 3H);

[0129] 13 C NMR (101 MHz, CDCl 3 ) δ 166.78, 143.34, 135.34, 130.49, 128.89, 127.53, 126.17, 125.57, 117.24, 115.84, 113.97, 112.11, 109.28, 108.85, 101.90, 70.92, 70.26, 65.51, 61.42, 60.50, 26.61, 26.07, 25.50, 24.19, 21.17, 14.32.

[0130] HRMS (APCI): m / z calcd for C 26 H 28 N 2 O 7 (M + H)+: 481.1969, found: 481.1974.

[0131] Example 11: Synthesis of (Z)-3,7-dimethylocta-2,6-dien-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate

[0132] A preparation method of (Z)-3,7-dimethylocta-2,6-dien-1-yl (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate, and the reaction formula is as follows:

[0133]

[0134] Specifically, it includes the following steps:

[0135] Using pyrrolo[1,2-a]quinoxaline (33.6 mg, 0.2 mmol), (Z)-3,7-dimethylocta-2,6-dien-1-yl acrylate (125 mg, 0.6 mmol), Pd(OAc) 2 (8.6 mg, 20 mol%), Ag 2 CO 3(165.4 mg, 3 eq), L - pyroglutamic acid (10.4 mg, 40 mol%), and glacial acetic acid (1 mL) were reacted in a pressure - resistant tube (10 mL). The mixture was stirred in air at 100 °C for 36 h. After the reaction was completed, it was cooled to room temperature. The reaction solution was diluted with 20 mL of ethyl acetate, quenched with 30 mL of saturated aqueous sodium bicarbonate solution and subjected to extraction and liquid - separation. 10 mL of ethyl acetate was added to the aqueous solution for secondary extraction. The organic phases were combined and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 10:1) to obtain the final product (Z) - 3,7 - dimethylocta - 2,6 - diene - 1 - yl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate. 28.5 mg of (Z) - 3,7 - dimethylocta - 2,6 - diene - 1 - yl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate was obtained with a yield of 38%.

[0136] The NMR identification results of (Z) - 3,7 - dimethylocta - 2,6 - diene - 1 - yl (E) - 3 - (pyrrolo[1,2 - a]quinoxalin - 3 - yl)acrylate are as follows:

[0137] 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.08 - 8.00 (m, 2H), 7.92 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.14 (s, 1H), 6.42 (d, J = 15.8 Hz, 1H), 5.15 - 5.08 (m, 1H), 4.27 (td, J = 7.3, 4.2 Hz, 2H), 2.10 - 1.94 (m, 2H), 1.82 - 1.74 (m, 1H), 1.68 (s, 3H), 1.62 (s, 3H), 1.23 (d, J = 15.4 Hz, 2H), 0.97 (d, J = 6.5 Hz, 3H);

[0138] 13 C NMR (101 MHz, CDCl 3 ) δ 167.59, 143.49, 136.40, 134.38, 131.50, 130.49, 128.86, 127.64, 126.14, 125.47, 124.76, 116.86, 115.69, 113.98, 112.13, 63.22, 37.19, 35.77, 29.77, 25.87, 25.58, 19.65, 17.82, 0.13.

[0139] HRMS(APCI): m / z calcd for C 24 H 26 N 2 O 2 (M + H)+: 375.2067, found: 375.2066.

[0140] As described above, it is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, should be covered by the protection scope of the present invention.

Claims

1. A method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives, characterized in that: The steps include: Using pyrrolo[1,2-a]quinoxaline compounds and acrylate as reactants and amino acids as ligands, the reactants, palladium catalysts, silver salts, amino acids and solvents are mixed to carry out CH activation reaction, and stirred at 80 to 120° C. for 24 to 36 hours. After the reaction is completed, the reaction solution is cooled to room temperature, diluted, quenched, and then separated and purified to obtain (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives; The general reaction formula of the CH activation reaction is as follows: In the formula, R1 is selected from any one of hydrogen, benzene, 4-methylbenzene, 4-methoxybenzene, 4-fluorobenzene, 4-chlorobenzene, naphthalene, iodine and chlorine; R2 is selected from any one of Et, t-Bu, n-Bu, Bn, Ph, CH2CF3, adamantane, L-menthol, geraniol, geraniol and fructose propanedione.

2. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 1, characterized in that: The palladium catalyst is selected from one or more of palladium acetate, palladium chloride and tetrakis(triphenylphosphine)palladium; and the amino acid is L-pyroglutamic acid.

3. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 1, characterized in that: The silver salt is selected from one or more of silver carbonate, silver acetate and silver sulfate; the solvent is selected from one or more of dimethyl carbonate, glacial acetic acid and trifluoroacetic acid.

4. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 1, characterized in that: The molar ratio of the pyrrolo[1,2-a]quinoxaline compound, acrylate, palladium catalyst, silver salt and amino acid is 1:3:0.2:3:0.

4.

5. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 1, characterized in that: The cooled reaction solution was diluted with ethyl acetate, and then quenched with saturated aqueous sodium bicarbonate solution.

6. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 1, characterized in that: The separation and purification comprises the following steps: Extracting the organic phase of the reaction solution several times with an extractant, combining the organic phases, and obtaining an extract; The solvent in the extract is removed by rotary evaporation under reduced pressure to obtain a crude product; The crude product was purified by flash chromatography on silica gel to give (E)-3-(pyrrolo[1,2-a]quinoxalin-3-yl)acrylate and its derivatives.

7. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 6, characterized in that: The extractant is ethyl acetate.

8. The method for preparing (E)-3-(pyrrolo[1,2-a]quinoxaline-3-yl)acrylate and its derivatives according to claim 6, characterized in that: The crude product is purified using a mixed solution of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of petroleum ether to ethyl acetate is (5-20):1.

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