(2-nitromethyl) aryl formate compound and application thereof

Abstract

The invention discloses a (2-nitromethyl) aryl formate compound and application thereof, and the structural general formula of the (2-nitromethyl) aryl formate compound is as shown in formula I, the isoquinolone compound can be obtained by carrying out a one-pot reaction of'nitro Mannich-lactamization-nitro elimination 'on a (2-nitromethyl) aryl formate compound and substituted cyclic imine under the action of an additive. The preparation method of the isoquinolone compound is mild in reaction condition, high in product yield, good in reproducibility, simple and convenient to operate, easy in process amplification and economical and easily available in raw materials, and overcomes the condition that a strong base or a transition metal is used for catalysis in a conventional synthesis route. The method can be used for preparing a series of alkaloids containing isoquinolone structures, such as berberine or wingceleine and the like, which have remarkable biological activity, can integrally and remarkably improve the total yield of the product, is more suitable for industrial large-scale preparation, and has higher application value. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a (2-nitromethyl) aryl formate compound and application thereof, belonging to the technical field of synthesis of isoquinolone compounds. Background Art

[0002] As an important heterocyclic skeleton, isoquinolone is widely present in various active natural products and drugs, such as berberine, berberine, indoletecan, etc. The difficulty in the synthesis of such important compounds lies in the construction of the isoquinolone skeleton. The synthesis methods of isoquinolone skeletons reported in the literature currently 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 isoquinolone construction methods and applying them to the synthesis of different active molecules containing isoquinolone skeletons is of great significance for new drug discovery. Summary of the invention

[0003] Purpose of the invention: In view of the shortcomings of the existing methods for preparing isoquinolone compounds, such as poor operability, low preparation efficiency and harsh conditions, the first purpose of the present invention is to provide a (2-nitromethyl)aryl formate compound. The second purpose of the present invention is to provide the use of the (2-nitromethyl)aryl formate compound in the preparation of isoquinolone compounds. The third purpose of the present invention is to provide a method for preparing isoquinolone compounds using the (2-nitromethyl)aryl formate compound.

[0004] Technical solution: The (2-nitromethyl) aryl formate compound of the present invention has a general structural formula as shown below:

[0005]

[0006] Among them, R 1 is any alkyl group, Ar 2 It is a benzene ring, a substituted benzene ring, an aromatic heterocycle or a substituted aromatic heterocycle.

[0007] Furthermore, R 1 Derived from methyl, ethyl or isopropyl.

[0008] Furthermore, the aromatic heterocycle includes but is not limited to pyridine ring, pyridazine or pyrimidine and the like.

[0009] Furthermore, the substituent of the substituted aromatic heterocycle is an alkyl group, an alkoxy group, an amino group or a halogen group.

[0010] Furthermore, the substitution forms of the substituted benzene ring and the substituted aromatic heterocycle are both mono-substituted or poly-substituted.

[0011] Furthermore, the polysubstitution is disubstitution, trisubstitution or tetrasubstitution.

[0012] Furthermore, the halogen is F, Cl, Br or I.

[0013] Further, the (2-nitromethyl)aryl formate compound is taken from the following compounds:

[0014]

[0015] A method for preparing the (2-nitromethyl)aryl formate compounds of the present invention comprises the following steps:

[0016]

[0017] Among them, Ar 2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle or a substituted aromatic heterocycle, R 1 is any alkyl group, including but not limited to methyl, ethyl or isopropyl, etc.; X is halogen fluorine, chlorine, bromine or iodine.

[0018] Furthermore, route 1 targets Ar 2 The aromatic compound having a benzene ring skeleton is substituted by a benzyl halogenated hydrocarbon compound and silver nitrite or sodium nitrite in a solvent to obtain a corresponding (2-nitromethyl) aromatic formate compound, wherein the solvent includes an ether compound, tetrahydrofuran or 1,4-dioxane, preferably diethyl ether; the reaction temperature is 20 to 80°C.

[0019] Furthermore, route 2 targets Ar 2 The invention relates to a nitrogen-containing heterocyclic skeleton, wherein the corresponding (2-nitromethyl) aryl formate compound is obtained by carrying out aromatic nucleophilic substitution with nitromethane under alkaline conditions; the base used is preferably DBU, NaH or (bistrimethylsilylamide) sodium; the solvent is an ether compound, tetrahydrofuran, 1,4-dioxane or an amide compound, and the reaction temperature is 20 to 80°C.

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

[0021] The invention discloses an application of the (2-nitromethyl) aryl formate compounds in the preparation of isoquinolone compounds.

[0022] The present invention also includes a method for preparing an isoquinolone compound, which is obtained by a one-pot reaction of "nitro Mannich-lactamization-nitro elimination" between a substituted cyclic imine and the (2-nitromethyl) aryl formate compound of the present invention under the action of an additive. The synthetic route is as follows:

[0023]

[0024] Among them, R 1 is any alkyl group, Ar 1 is a benzene ring, a substituted benzene ring, an indole or an aromatic ring skeleton of a substituted indole; Ar 2 It is a benzene ring, a substituted benzene ring, an aromatic heterocycle or a substituted aromatic heterocycle.

[0025] Furthermore, the isoquinolone compound is a berberine compound or a berberine compound containing an isoquinolone structure.

[0026] Furthermore, the berberine compound is oxoberberine, oxoberberine, oxygen-representing berberine or a structural analogue thereof.

[0027] Furthermore, the uranine compound is Nauclefine, Angustidine or Norketoyobyrine or a structural analogue thereof.

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

[0029]

[0030] Further, the substituted cyclic imine is taken 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 p-toluenesulfonic acid pyridinium salt.

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

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

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

[0037] The present invention creatively introduces a nitro group as a directing group, and efficiently obtains an isoquinolone skeleton in a one-pot form 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 the 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, thus overcoming the conditions of using strong bases or transition metal catalysis in previous synthetic routes.

[0040] (2) The isoquinolone synthesis method developed in the present invention improves the convenience, applicability, profitability and economy of the preparation method of the target product berberine and berberine compounds as a whole, and the route is significantly shortened without the involvement of transition metals.

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

[0042] Figure 1 is the H NMR spectrum of compound 1;

[0043] Figure 2 is the H NMR spectrum of compound 2;

[0044] Figure 3 is the H NMR spectrum of compound 3;

[0045] Figure 4 is the H NMR spectrum of compound 4;

[0046] Figure 5 is the H NMR spectrum of compound 5;

[0047] Figure 6 is the H NMR spectrum of compound 6;

[0048] Figure 7 is the H NMR spectrum of compound 7;

[0049] Figure 8 is the H NMR spectrum of compound 8;

[0050] Fig. 9 is the H NMR spectrum of compound 9;

[0051] Fig.10 is the H NMR spectrum of compound 10;

[0052] Fig.11 is the H NMR spectrum of compound 11. DETAILED DESCRIPTION

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

[0054] Example 1

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

[0056] 1. Preparation of Compound 1

[0057] The preparation route is as follows:

[0058]

[0059] Under argon protection, 2.00 g AgNO 2 Dissolve in 20 mL of anhydrous ether, cover the flask with tin foil to avoid light, stir at room temperature for 15 minutes, cool to 0 ° C, dissolve 1.87 g of methyl 2-bromomethylbenzoate in 8 ml of anhydrous ether, and add dropwise to the above AgNO 2 After stirring at 0°C for 1 hour, the mixture was heated to 35°C and refluxed for 2 hours. After the reaction of the raw material was complete, it 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] The prepared compound 1 was subjected to H NMR spectrum analysis, as shown in Figure 1 As shown, the result data: 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] The prepared compound 1 was subjected to LC-MS analysis, LC-MS196.1[M+H] + .

[0062] The structure of compound 1 according to the above analysis is shown below:

[0063]

[0064] 2. Preparation of Compound 2

[0065] The preparation route is as follows:

[0066]

[0067] Under argon protection, 2.00 g AgNO 2 Dissolve in 20mL of anhydrous ether, cover the flask with tin foil to avoid light, stir at room temperature for 15 minutes, cool at 0°C, dissolve 2.44g of methyl 6-(chloromethyl)-2,3-dimethoxybenzoate in 8ml of anhydrous ether, add dropwise to the above AgNO2 ether solution, stir at 0°C for 1 hour, then heat to 35°C and reflux for 2 hours. After the reaction of the raw material is complete, filter through diatomaceous earth, wash with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain a white solid crude product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1) to obtain a white solid (compound 2).

[0068] The prepared compound 2 was subjected to H NMR spectrum analysis, as shown in Figure 2 As shown, the result data: 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] The prepared compound 2 was subjected to LC-MS analysis, LC-MS 256.1 [M+H] + ,278.1[M+Na] + .

[0070] The structure of compound 2 according to the above analysis is shown below:

[0071]

[0072] 3. Preparation of Compound 3

[0073] The preparation route is as follows:

[0074]

[0075] Under argon protection, 2.00 g AgNO 2 Dissolve in 20mL of anhydrous ether, cover the flask with tin foil to avoid light, stir at room temperature for 15 minutes, cool to 0°C, dissolve 2.28g of 5-(chloromethyl)benzo[d][1,3]dioxane-4-carboxylic acid methyl ester in 8mL of anhydrous ether, add dropwise to the above AgNO2 ether solution, stir at 0°C for 1 hour, then heat to 35°C and reflux for 2 hours. After the reaction of the raw material is complete, filter through diatomaceous earth, wash with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain a white solid crude product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1) to obtain a white solid (compound 3).

[0076] The prepared compound 3 was subjected to H NMR spectrum analysis, as shown in Figure 3 As shown, the result data: 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] The prepared compound 3 was subjected to LC-MS analysis, LC-MS 240.0 [M+H] + .

[0078] The structure of compound 3 according to the above analysis is shown below:

[0079]

[0080] 4. Preparation of Compound 4

[0081] The preparation route is as follows:

[0082]

[0083] Under argon protection, add 350 mg NaH to a dry two-necked bottle, replace the air with argon, add 15 mL of anhydrous DMF to form a suspension, and add 0.5 mL of CH 3 NO 2After the addition is complete, the mixture is heated to room temperature and stirred for 1 hour. Then, 1 g of methyl 4-chloronicotinate is dissolved in 5 ml of anhydrous DMF and added dropwise to the above suspension. After the addition is complete, the mixture is heated to 80°C and stirred for 2 hours. After the reaction of the raw materials is complete, three times the volume of saturated aqueous ammonium chloride solution is added to quench the reaction, and then five times the volume of ethyl acetate is used for extraction 2-3 times. The organic phases are combined and then washed with saturated aqueous sodium chloride solution 2-3 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude yellow oily product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily product (Compound 4).

[0084] The prepared compound 4 was subjected to H NMR spectrum analysis, as shown in Figure 4 As shown, the result data: 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] The prepared compound 4 was subjected to LC-MS analysis, LC-MS197.1[M+H] + .

[0086] The structure of compound 4 according to the above analysis is shown below:

[0087]

[0088] 5. Preparation of Compound 5

[0089] The preparation route is as follows:

[0090]

[0091] Under argon protection, 324 mg of NaH was added to a dry two-necked bottle. After replacing the air with argon, 15 mL of anhydrous DMF was added to form a suspension. 0.43 mL of CH 3 NO 2 After the addition is complete, the mixture is heated to room temperature and stirred for 1 hour. Then, 1 g of 4-chloro-6-methylnicotinate is dissolved in 5 mL of anhydrous DMF and added dropwise to the above suspension. After the addition is complete, the mixture is heated to 80°C and stirred for 2 hours. After the reaction of the raw materials is complete, three times the volume of saturated aqueous ammonium chloride solution is added to quench the reaction, and then five times the volume of ethyl acetate is used for extraction 2-3 times. The organic phases are combined and then washed with saturated aqueous sodium chloride solution 2-3 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain a yellow oily product (Compound 5).

[0092] The prepared compound 5 was subjected to H NMR spectrum analysis, as shown in FIG. Figure 5 As shown, the result data: 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] The prepared compound 5 was subjected to LC-M analysis, LC-MS 211.1 [M+H] + .

[0094] The structure of compound 5 according to the above analysis 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 as follows:

[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, 4 mL of anhydrous DMF was added to dissolve, and 115 mg of ammonium acetate was added. After replacing the air with nitrogen, the mixture was heated to 80°C and reacted for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 6 was subjected to H NMR spectrum analysis, as shown in Figure 6 As shown, the result data: 1 H NMR (400 MHz, DMSO-d 6 )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,1 H), 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] The prepared compound 6 was subjected to LC-MS analysis, LC-MS 374.1 [M+Na] + .

[0104] The structure of compound 6 from the above analysis is shown below:

[0105]

[0106] 2. Preparation of 8-oxo-raphanine (Compound 7)

[0107] The preparation route is as follows:

[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 bottle, 4 mL of anhydrous DMF was added to dissolve, 115 mg of ammonium acetate was added, the air was replaced with nitrogen, and the reaction was heated to 80 ° C for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 7 was subjected to H NMR spectrum analysis, as shown in Figure 7 As shown, the result data: 1 H NMR (400 MHz, DMSO-d 6 )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] The prepared compound 7 was subjected to LC-MS analysis, LC-MS 368.1 [M+H] + .

[0112] The structure of compound 7 according to the above analysis is shown below:

[0113]

[0114] 3. Preparation of 8-oxo berberine (Compound 8)

[0115] The preparation route is as follows:

[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 bottle, 4 mL of anhydrous DMF was added to dissolve, 115 mg of ammonium acetate was added, the air was replaced with nitrogen, and the reaction was heated to 80 ° C for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 8 was subjected to H NMR spectrum analysis, as shown in Figure 8 As shown, the result data: 1 H NMR (400 MHz, DMSO-d 6 )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] The prepared compound 8 was subjected to LC-M analysis, LC-MS 352.1 [M+H] + .

[0120] The structure of compound 8 according to the above analysis is shown below:

[0121]

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

[0123] The preparation route is as follows:

[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 bottle, 4 mL of anhydrous DMF was added to dissolve, and 115 mg of ammonium acetate was added. After replacing the air with nitrogen, the mixture was heated to 80°C and reacted for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 9 was subjected to H NMR spectrum analysis, as shown in Fig. 9 As shown, the result data: 1H NMR (400 MHz, DMSO-d 6 )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] The prepared compound 9 was subjected to LC-MS analysis, LC-MS 288.1 [M+H] + .

[0128] The structure of compound 9 according to the above analysis is shown below:

[0129]

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

[0131] The preparation route is as follows:

[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 bottle, 4 mL of anhydrous DMF was added to dissolve, and 115 mg of ammonium acetate was added. After replacing the air with nitrogen, the mixture was heated to 80°C and reacted for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 10 was subjected to H NMR spectrum analysis. Fig.10 As shown, the result data: 1 H NMR (300 MHz, DMSO-d 6 )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=8.2,7.0,1.2 Hz,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] The prepared compound 10 was subjected to LC-M analysis, LC-MS 302.1 [M+H] + .

[0136] The structure of compound 10 according to the above analysis is shown below:

[0137]

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

[0139] The preparation route is as follows:

[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, 4 mL of anhydrous DMF was added to dissolve, and 115 mg of ammonium acetate was added. After replacing the air with nitrogen, the mixture was heated to 80°C and reacted for 12 to 16 hours. After the reaction of the raw materials was complete, the solvent was directly dried to obtain a 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] The prepared compound 11 was subjected to H NMR spectrum analysis, as shown in Fig.11 As shown, the result data: 1 H NMR (400 MHz, DMSO-d 6 )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] The prepared compound 11 was subjected to LC-M analysis, LC-MS 287.1 [M+H] + .

[0144] The structure of compound 11 according to the above analysis is shown below:

[0145]

Claims

1. A (2-nitromethyl) aryl formate compound, characterized in that: The general structural formula of the (2-nitromethyl) aryl formate compound is as follows: Wherein, R1 is any alkyl group, and Ar2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle or a substituted aromatic heterocycle.

2. The (2-nitromethyl)aryl formate compound according to claim 1, characterized in that: R1 is selected from methyl, ethyl or isopropyl, the aromatic heterocycle is a pyridine ring, pyridazine or pyrimidine, the substituent of the substituted aromatic heterocycle is an alkyl, alkoxy, amino or halogen, and the substitution forms of the substituted benzene ring and the substituted aromatic heterocycle are both monosubstituted or polysubstituted.

3. The (2-nitromethyl)aryl formate compound according to claim 1, characterized in that: (2-Nitromethyl)aryl formate compounds are derived from the following compounds:

4. Use of the (2-nitromethyl)aryl formate compound according to any one of claims 1 to 3 in the preparation of isoquinolone compounds.

5. A method for preparing an isoquinolone compound, characterized in that: The substituted cyclic imine and the (2-nitromethyl) aryl formate compound according to any one of claims 1 to 3 are subjected to a one-pot reaction of "nitro Mannich-lactamization-nitro elimination" under the action of an additive. The synthesis route is as follows: 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; Ar2 is a benzene ring, a substituted benzene ring, an aromatic heterocycle or a substituted aromatic heterocycle.

6. The method for preparing isoquinolone compounds according to claim 5, characterized in that: Isoquinolone compounds are berberine compounds or berberine compounds containing an isoquinolone structure.

7. The method for preparing isoquinolone compounds according to claim 5, characterized in that: Substituted cyclic imines are derived from the following compounds:

8. The method for preparing isoquinolone compounds according to claim 5, characterized in that: The solvent used in the reaction is one of dichloromethane, dichloroethane, methanol, ethanol, N,N-dimethylformamide or dimethyl sulfoxide.

9. The method for preparing isoquinolone compounds according to claim 5, characterized in that: 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 p-toluenesulfonic acid pyridinium salt.

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

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