A (2-nitromethyl) aryl carboxylate compound and application thereof

Abstract

This invention discloses a (2-nitromethyl)aryl carbamate compound and its applications. The general structural formula of the (2-nitromethyl)aryl carbamate compound is shown in Formula I. Isoquinolone compounds can be obtained by a one-pot reaction of the (2-nitromethyl)aryl carbamate compound with a substituted cyclic imine under the action of an additive, involving "nitroMannich-lactamization-nitro elimination". The preparation method of this isoquinolone compound has mild reaction conditions, high product yield, good reproducibility, simple operation, easy process scale-up, and economical and readily available raw materials, overcoming the conditions of previous synthetic routes that required strong bases or transition metal catalysis. This method can be used to prepare a series of biologically active alkaloids such as berberine or cinnamidine containing isoquinolone structures, significantly improving the overall product yield and making it more suitable for industrial-scale preparation, thus possessing high application value.

Description

Technical Field

[0001] This invention relates to a (2-nitromethyl)aryl carbamate compound and its applications, belonging to the field of isoquinolone compound synthesis technology. Background Technology

[0002] Isoquinolones, as important heterocyclic skeletons, are widely found in various active natural products and drugs, such as berberine, santonin, and indonotecan. The difficulty in synthesizing these important compounds lies in the construction of the isoquinolone skeleton. Currently, the synthetic methods of isoquinolone skeletons reported in the literature mostly involve transition metal-catalyzed coupling reactions, which expose limitations such as high cost and insufficient substrate breadth (see: Progress in the chemical synthesis of natural drug berberine, Organic Chemistry, 2021, 41(6): 2217-2227, Collective Syntheses of 8-Oxoprotoberberines via Sequential In(OTf)3-Catalyzed Cyclization and Pd(OAc)2-Catalyzed Heck Coupling J.Org.Chem.2023, 88, 11, 7179 and Isoquinolone Syntheses by Annulation Protocols, Catalysts 2021, 11(5), 620). Therefore, developing efficient methods for constructing isoquinolones and applying them to the synthesis of active molecules with different isoquinolone skeletons is of great significance for new drug discovery. Summary of the Invention

[0003] Objectives of the Invention: To address the shortcomings of existing methods for preparing isoquinolone compounds, such as poor operability, low efficiency, and demanding conditions, the first objective of this invention is to provide a (2-nitromethyl)aryl carbamate compound. The second objective is to provide the application of this (2-nitromethyl)aryl carbamate compound in the preparation of isoquinolone compounds. The third objective is to provide a method for preparing isoquinolone compounds using this (2-nitromethyl)aryl carbamate compound.

[0004] Technical solution: The present invention relates to a (2-nitromethyl)aryl carbamate compound, the general structural formula of which is shown below:

[0005]

[0006] Wherein, R1 is any alkyl group, and Ar2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle, or a substituted aromatic heterocycle.

[0007] Furthermore, R1 is derived from methyl, ethyl, or isopropyl.

[0008] Furthermore, aromatic heterocycles include, but are not limited to, pyridine rings, pyridazines, or pyrimidines.

[0009] Furthermore, the substituents of the substituted aromatic heterocycles are alkyl, alkoxy, amino, or halogen.

[0010] Furthermore, the substitution forms of the substituted benzene ring and the substituted aromatic heterocycle are both monosubstituted or polysubstituted.

[0011] Furthermore, multiple substitutions can be di-substituted, tri-substituted, or tetra-substituted.

[0012] Furthermore, the halogens are F, Cl, Br, or I.

[0013] Furthermore, (2-nitromethyl)aryl carbamates are derived from the following compounds:

[0014]

[0015] A method for preparing the (2-nitromethyl)aryl carbamate compound of the present invention includes the following steps:

[0016]

[0017] Wherein, Ar2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle, or a substituted aromatic heterocycle; R1 is any alkyl group, including but not limited to methyl, ethyl, or isopropyl; and X is a halogen such as fluorine, chlorine, bromine, or iodine.

[0018] Furthermore, Route 1 targets aryl compounds with Ar2 as the benzene ring skeleton by substituting benzyl halide compounds with silver nitrite or sodium nitrite in a solvent to obtain corresponding (2-nitromethyl)aryl carbamate compounds. The solvent includes ether compounds, tetrahydrofuran, or 1,4-dioxane, preferably diethyl ether; the reaction temperature is 20–80 °C.

[0019] Furthermore, Route 2 targets Ar2 as a nitrogen-containing heterocyclic skeleton, and obtains the corresponding (2-nitromethyl)aryl carbamate compounds by aryl nucleophilic substitution of nitromethane under basic conditions; the preferred base is DBU, NaH, or sodium (bis(trimethylsilylamino)); the solvent is an ether compound, tetrahydrofuran, 1,4-dioxane, or an amide compound, and the reaction temperature is 20–80 °C.

[0020] Furthermore, the amide compound is N,N-dimethylformamide or N,N-dimethylacetamide, preferably N,N-dimethylformamide.

[0021] The application of the (2-nitromethyl)aryl carbamate compounds described in this invention in the preparation of isoquinolone compounds.

[0022] This invention also includes a method for preparing isoquinolone compounds, which are obtained by a one-pot reaction of a substituted cyclic imine with the (2-nitromethyl) aryl carbamate compound described in this invention under the action of an additive, involving "nitroMannich-lactamization-nitro elimination". The synthetic route is shown below:

[0023]

[0024] Wherein, R1 is any alkyl group, Ar1 is a benzene ring, a substituted benzene ring, an indole, or an aromatic ring skeleton of a substituted indole; and Ar2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle, or a substituted aromatic heterocycle.

[0025] Furthermore, the isoquinolone compounds are berberine compounds or santaline compounds containing an isoquinolone structure.

[0026] Furthermore, berberine compounds include oxoberberine, oxoberberine, oxoberberine, or their structural analogs.

[0027] Furthermore, the compounds are Naucelfine, Angustidine, or Norketoyobyrine or their structural analogs.

[0028] Furthermore, the structural formulas of Nauclefine, Angustidine, and Norketoyobyrine are shown below:

[0029]

[0030] Furthermore, the substituted cyclic imines are derived from the following compounds:

[0031]

[0032] Furthermore, the solvent used in the reaction is one of dichloromethane, dichloroethane, methanol, ethanol, N,N-dimethylformamide, or dimethyl sulfoxide.

[0033] Furthermore, the additive is one of potassium acetate, sodium acetate, ammonium acetate, sodium benzoate, sodium carbonate, sodium bicarbonate, triethylamine, acetic acid, benzoic acid, p-toluenesulfonic acid, or pyridine salt of p-toluenesulfonic acid.

[0034] Furthermore, the molar ratio of the substituted cyclic imine, (2-nitromethyl) aryl carboxylate, and additives is 1:1 to 2:1 to 5.

[0035] Furthermore, the reaction temperature is 30–120°C.

[0036] Furthermore, the reaction solvent is N,N-dimethylformamide, the additive is potassium acetate, ammonium acetate, or sodium bicarbonate, and the reaction temperature is 80–120°C.

[0037] This invention creatively introduces a nitro group as a directing group, and efficiently obtains the isoquinolone skeleton in a one-pot manner through a cascade reaction of "nitro Mannich-lactamization-nitro elimination", thereby providing a convenient and efficient method for preparing isoquinolone compounds.

[0038] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0039] (1) The raw materials involved in the preparation method of isoquinolone compounds of the present invention are economical and readily available, the reaction conditions are mild, the product yield is high, the reproducibility is good, the operation is simple, and the process is easy to scale up, overcoming the conditions of using strong bases or transition metal catalysis in previous synthetic routes.

[0040] (2) The isoquinolone synthesis method developed in this invention improves the convenience, applicability, profitability and economy of the preparation method of the target product oxoberberine and cinnamic acid compounds. The route is significantly shortened and no transition metals are involved.

[0041] (3) The method for preparing isoquinolone compounds of the present invention can be used to prepare a series of alkaloids with significant biological activity, such as berberine or cinnamidine containing isoquinolone structures. It can significantly improve the overall product yield, is more suitable for industrial-scale preparation, and has high application value. Attached Figure Description

[0042] Figure 1 The image shows the 1H NMR spectrum of compound 1.

[0043] Figure 2 The image shows the 1H NMR spectrum of compound 2.

[0044] Figure 3 The image shows the 1H NMR spectrum of compound 3.

[0045] Figure 4 The 1H NMR spectrum of compound 4;

[0046] Figure 5 The image shows the 1H NMR spectrum of compound 5.

[0047] Figure 6 The 1H NMR spectrum of compound 6;

[0048] Figure 7 The 1H NMR spectrum of compound 7;

[0049] Figure 8 The 1H NMR spectrum of compound 8;

[0050] Figure 9 The 1H NMR spectrum of compound 9;

[0051] Figure 10 The 1H NMR spectrum of compound 10;

[0052] Figure 11 This is the 1H NMR spectrum of compound 11. Detailed Implementation

[0053] The technical solution of the present invention will be further described below.

[0054] Example 1

[0055] Preparation of (2-nitromethyl)aryl carbamate compounds:

[0056] 1. Preparation of Compound 1

[0057] The preparation route is shown below:

[0058]

[0059] Under argon protection, in a dry two-necked flask, 2.00 g of AgNO2 was dissolved in 20 mL of anhydrous diethyl ether. The flask was covered with aluminum foil to protect it from light, and stirred at room temperature for 15 minutes. After cooling to 0°C, 1.87 g of methyl 2-bromomethylbenzoate was dissolved in 8 mL of anhydrous diethyl ether and added dropwise to the AgNO2 diethyl ether solution. The mixture was stirred at 0°C for 1 hour and then heated to 35°C and refluxed for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a white solid crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain a white solid (compound 1).

[0060] Compound 1 was analyzed by 1H NMR spectroscopy, such as... Figure 1 As shown, the results data are as follows: 1 H NMR (300MHz, Chloroform-d) δ8.15 (dd, J=7.6, 1.7Hz, 1H), 7.67–7.50 (m, 2H), 7.39 (dd, J=7.3, 1.5Hz, 1H), 5.85 (s, 2H), 3.90 (s, 3H).

[0061] Compound 1 was analyzed by LC-MS, and the LC-MS value was 196.1 [M+H]. + .

[0062] The structure of compound 1, based on the above analysis, is shown below:

[0063]

[0064] 2. Preparation of Compound 2

[0065] The preparation route is shown below:

[0066]

[0067] Under argon protection, in a dry two-necked flask, 2.00 g of AgNO2 was dissolved in 20 mL of anhydrous diethyl ether. The flask was covered with aluminum foil to protect it from light, and stirred at room temperature for 15 minutes. After cooling to 0°C, 2.44 g of methyl 6-(chloromethyl)-2,3-dimethoxybenzoate was dissolved in 8 mL of anhydrous diethyl ether and added dropwise to the AgNO2 diethyl ether solution. The mixture was stirred at 0°C for 1 hour and then heated to 35°C and refluxed for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a white solid crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1) to obtain a white solid (compound 2).

[0068] Compound 2 was analyzed by 1H NMR spectroscopy, such as... Figure 2 As shown, the results data are as follows: 1 H NMR (300MHz, Chloroform-d) δ7.15 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 5.46 (s, 2H), 3.93 (s, 3H), 3.90 (d, J = 3.8 Hz, 6H).

[0069] Compound 2 was analyzed by LC-M, LC-MS 256.1 [M+H] + 278.1 [M+Na] + .

[0070] The structure of compound 2, based on the above analysis, is shown below:

[0071]

[0072] 3. Preparation of Compound 3

[0073] The preparation route is shown below:

[0074]

[0075] Under argon protection, in a dry two-necked flask, 2.00 g of AgNO2 was dissolved in 20 mL of anhydrous diethyl ether. The flask was covered with aluminum foil to protect it from light, and stirred at room temperature for 15 minutes. After cooling to 0°C, 2.28 g of methyl 5-(chloromethyl)benzo[d][1,3]dioxane-4-carboxylic acid was dissolved in 8 mL of anhydrous diethyl ether and added dropwise to the AgNO2 diethyl ether solution. The mixture was stirred at 0°C for 1 hour and then heated to 35°C and refluxed for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a white solid crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1) to obtain a white solid (compound 3).

[0076] Compound 3 was analyzed by 1H NMR spectroscopy, such as... Figure 3 As shown, the results data are as follows: 1 H NMR (300MHz, Chloroform-d) δ6.95 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.14 (s, 2H), 5.68 (s, 2H), 3.90 (s, 3H).

[0077] Compound 3 was analyzed by LC-MS (240.0 M + H). + .

[0078] The structure of compound 3, as analyzed above, is shown below:

[0079]

[0080] 4. Preparation of Compound 4

[0081] The preparation route is shown below:

[0082]

[0083] Under argon protection, 350 mg of NaH was added to a dry two-necked flask. After replacing the air with argon, 15 mL of anhydrous DMF was added to form a suspension. 0.5 mL of CH3NO2 solution was added dropwise at 0°C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, 1 g of methyl 4-chloronicotinic acid was dissolved in 5 mL of anhydrous DMF and added dropwise to the suspension. After the addition was complete, the mixture was heated to 80°C and stirred for 2 hours. After the reaction of the raw materials was complete, three times the volume of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was then extracted 2-3 times with five times the volume of ethyl acetate. The organic phases were combined and washed 2-3 times with saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily substance (compound 4).

[0084] Compound 4 was analyzed by 1H NMR spectroscopy, such as... Figure 4 As shown, the results data are as follows: 1 H NMR (400MHz, Chloroform-d) δ9.33 (d, J = 0.7Hz, 1H), 8.86 (d, J = 5.0Hz, 1H), 7.32 (dd, J = 5.0, 0.6Hz, 1H), 5.89 (s, 2H), 3.96 (s, 3H).

[0085] Compound 4 was analyzed by LC-MS, 197.1 μm [M+H]. + .

[0086] The structure of compound 4, based on the above analysis, is shown below:

[0087]

[0088] 5. Preparation of Compound 5

[0089] The preparation route is shown below:

[0090]

[0091] Under argon protection, 324 mg of NaH was added to a dry two-necked flask. After replacing the air with argon, 15 mL of anhydrous DMF was added to form a suspension. 0.43 mL of CH3NO2 solution was added dropwise at 0°C. After the addition was complete, the mixture was heated to room temperature and stirred for 1 hour. Then, 1 g of 4-chloro-6-methylnicotinic acid methyl ester was dissolved in 5 mL of anhydrous DMF and added dropwise to the suspension. After the addition was complete, the mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, three volumes of saturated ammonium chloride aqueous solution were added to quench the reaction. The mixture was then extracted 2-3 times with five volumes of ethyl acetate. The organic phases were combined and washed 2-3 times with saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily substance (compound 5).

[0092] Compound 5 was analyzed by 1H NMR spectroscopy, such as... Figure 5 As shown, the results data are as follows: 1 H NMR (300MHz, Chloroform-d) δ9.20(s,1H),7.16(s,1H),5.85(s,2H),3.93(s,3H),2.67(s,3H).

[0093] Compound 5 was analyzed by LC-MS (211.1 M + H). + .

[0094] The structure of compound 5, as analyzed above, is shown below:

[0095]

[0096] Example 2

[0097] Preparation of isoquinolone compounds:

[0098] 1. Preparation of 8-oxoberberine (compound 6)

[0099] The preparation route is shown below:

[0100]

[0101] Under argon protection, 255 mg of fragment A (compound 2) and 175 mg of fragment B (commercially available 7,8-dihydro-[1,3]dioxo[4,5-g]isoquinoline, CAS NO: 6882-28-6) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. The air was replaced with nitrogen, and the mixture was heated to 80 °C for 12–16 hours. After the reaction was complete, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 6).

[0102] Compound 6 was analyzed by 1H NMR spectroscopy, such as... Figure 6 As shown, the results data are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.51(d,J=8.7Hz,1H),7.47(s,1H),7.40(d,J=8.7Hz,1H),7.09(s,1H) ,6.91(s,1H),6.06(s,2H),4.17–4.05(m,2H),3.86(s,3H),3.76(s,3H),2.86(t,J=6.1Hz,2H).

[0103] Compound 6 was analyzed by LC-MS, and the LC-MS value was 374.1 [M+Na]. + .

[0104] The structure of compound 6, based on the above analysis, is shown below:

[0105]

[0106] 2. Preparation of 8-oxoberberine (compound 7)

[0107] The preparation route is shown below:

[0108]

[0109] Under argon protection, 255 mg of fragment A (compound 2) and 191 mg of fragment C (commercially available 6,7-dimethoxy-3,4-dihydroisoquinoline, CAS NO: 3382-18-1) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. The air was replaced with nitrogen, and the mixture was heated to 80 °C for 12–16 hours. After the reactants had completely reacted, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 7).

[0110] Compound 7 was analyzed by 1H NMR spectroscopy, such as... Figure 7 As shown, the results data are as follows: 1 H NMR(400MHz,DMSO-d6)δ7.54(d,J=8.8Hz,1H),7.47–7.39(m,2H),7.16(s,1H),6.94(s ,1H),4.20–4.07(m,2H),3.85(s,6H),3.82(s,3H),3.79(s,3H),2.90(t,J=6.2Hz,2H).

[0111] Compound 7 was analyzed by LC-MS, and the LC-MS value was 368.1 [M+H]. + .

[0112] The structure of compound 7, as analyzed above, is shown below:

[0113]

[0114] 3. Preparation of berberine (compound 8) represented by 8-oxygen.

[0115] The preparation route is shown below:

[0116]

[0117] Under argon protection, 239 mg of fragment D (compound 3) and 191 mg of fragment C (commercially available 6,7-dimethoxy-3,4-dihydroisoquinoline, CAS NO: 3382-18-1) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. The air was replaced with nitrogen, and the mixture was heated to 80 °C for 12–16 hours. After the reactants had completely reacted, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 8).

[0118] Compound 8 was analyzed by 1H NMR spectroscopy, such as... Figure 8 As shown, the results data are as follows: 1H NMR (400MHz, DMSO-d6) δ7.41 (s, 1H), 7.35 (d, J = 8.2Hz, 1H), 7.23–7.14 (m, 2H), 6.94 (s, 1H) ), 6.20 (s, 2H), 4.16–4.06 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 2.89 (dd, J = 7.1, 5.1Hz, 2H).

[0119] Compound 8 was analyzed by LC-MS (352.1 M + H). + .

[0120] The structure of compound 8, as analyzed above, is shown below:

[0121]

[0122] 4. Preparation of Nauclefine (Compound 9)

[0123] The preparation route is shown below:

[0124]

[0125] Under argon protection, 196 mg of fragment E (compound 4) and 170 mg of fragment F (commercially available 4,9-dihydro-3H-pyrido(3,4-B)indole, CAS NO:4894-26-2) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. After purging the air with nitrogen, the mixture was heated to 80 °C and reacted for 12–16 hours. After the reactants were completely reacted, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 9).

[0126] Compound 9 was analyzed by 1H NMR spectroscopy, such as... Figure 9 As shown, the results data are as follows: 1 H NMR (400MHz, DMSO-d6) δ12.12–11.91(m,1H),9.32(s,1H),8.66(d,J=5.5Hz,1H),7.63(d,J=7.9Hz,1H),7.49( dd,J=19.4,6.8Hz,2H),7.26(t,J=7.6Hz,1H),7.13–7.06(m,2H),4.41(t,J=6.7Hz,2H),3.13(t,J=6.7Hz,2H).

[0127] Compound 9 was analyzed by LC-MS, 288.1 [M+H]. + .

[0128] The structure of compound 9, as analyzed above, is shown below:

[0129]

[0130] 5. Preparation of Angustidine (Compound 10)

[0131] The preparation route is shown below:

[0132]

[0133] Under argon protection, 210 mg of fragment G (compound 5) and 170 mg of fragment F (commercially available 4,9-dihydro-3H-pyrido(3,4-B)indole, CAS NO: 4894-26-2) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. After purging the air with nitrogen, the mixture was heated to 80 °C and reacted for 12–16 hours. After the reaction of the starting materials was complete, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 10).

[0134] Compound 10 was analyzed by proton NMR spectroscopy, such as... Figure 10 As shown, the results data are as follows: 1 H NMR (300MHz, DMSO-d6) δ11.82(s,1H),9.20(s,1H),7.62(d,J=7.9Hz,1H),7.45(d,J=8.2Hz,1H),7.35(s,1H),7.25(ddd,J=8. 2,7.0,1.2Hz,1H),7.08(ddd,J=7.9,7.0,1.0Hz,1H),6.93(s,1H),4.37(t,J=6.6Hz,2H),3.10(t,J=6.7Hz,2H),2.57(s,3H).

[0135] Compound 10 was analyzed by LC-MS (302.1 M + H). + .

[0136] The structure of compound 10, as analyzed above, is shown below:

[0137]

[0138] 6. Preparation of Norketoyobyrine (compound 11)

[0139] The preparation route is shown below:

[0140]

[0141] Under argon protection, 195 mg of fragment H (compound 1) and 170 mg of fragment F (commercially available 4,9-dihydro-3H-pyrido(3,4-B)indole, CAS NO: 4894-26-2) were added to a dry two-necked flask. After dissolving in 4 mL of anhydrous DMF, 115 mg of ammonium acetate was added. The air was replaced with nitrogen, and the mixture was heated to 80 °C for 12–16 hours. After the reaction was complete, the solvent was directly evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (compound 11).

[0142] Compound 11 was analyzed by 1H NMR spectroscopy, such as... Figure 11 As shown, the results data are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.24(d,J=8.0Hz,1H),7.71(td,J=7.5,7.0,1.4Hz,1H),7.62(dd,J=13.2,7 .9Hz,2H),7.53–7.37(m,2H),7.27–7.16(m,1H),7.14–7.01(m,2H),4.41(t,J=6.6Hz,2H),3.10(t,J=6.6Hz,2H).

[0143] Compound 11 was analyzed by LC-MS, 287.1 [M+H]. + .

[0144] The structure of compound 11, as analyzed above, is shown below:

[0145]

Claims

1. A (2-nitromethyl)aryl formate compound, characterized by, The structural general formula of the (2-nitromethyl) aryl formate compound is shown as follows: , specifically selected from the following compounds: 。 2. A process for the preparation of isoquinolones, characterized in that, from a substituted cyclic imine and the (2-nitromethyl)aryl carboxylate compound of claim 1 or by one-pot reaction of "nitro Mannich-lactamization-nitro elimination" in the presence of an additive ammonium acetate, the synthetic route is shown as follows: 。 3. The method for preparing the isoquinolone compound according to claim 2, characterized in that, The solvent used in the reaction is one of dichloromethane, dichloroethane, methanol, ethanol, N, N-dimethylformamide or dimethyl sulfoxide.

4. The method for preparing the isoquinolone compound according to claim 2, characterized in that, The molar ratio of the substituted cyclic imine and the (2-nitromethyl) aryl formate and the additive is 1:1~2:1~5, and the reaction temperature is 30~120℃.

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