Synthetic method of efficient polysubstituted pyrrolo [2, 1-a] isoquinoline compound

Abstract

The invention relates to a synthetic method of an efficient polysubstituted pyrrolo [2, 1-a] isoquinoline compound, and discloses a method for synthesizing the polysubstituted pyrrolo [2, 1-a] isoquinoline compound by taking a 2-(3, 4-dihydroisoquinoline-2 (1H)-yl) malononitrile compound and 2, 3-dichloro-5, 6-dicyanobenzoquinone as oxidizing agents and substituted isocyano acetate under the action of a catalyst. The method has the advantages of cheap initial raw materials, mild reaction conditions and simple experimental operation, can save the investment of funds and labor force, and provides a simple and efficient preparation method for the polysubstituted pyrrole [2, 1-a] isoquinoline compound.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a highly efficient multi-substituted pyrrolo[2,1-a]isoquinoline compound. Background Art

[0002] Pyrrolo[2,1-a]isoquinoline, whose structure contains two structural units, isoquinoline and pyrrole, is an important class of heterocyclic compounds; it exists in many natural products and pharmaceutically active molecules, exhibits a variety of effective pharmacological activities, and its synthesis method has received extensive attention and development. The present invention creatively adds 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile compounds, substituted isocyanoacetic acid esters, and catalysts to an organic solvent in sequence to synthesize polysubstituted pyrrolo[2,1-a]isoquinoline compounds. The starting raw materials used in the method are cheap, the reaction conditions are mild, the substrate is widely applicable, the experimental operation is simple, and the investment of funds and labor can be saved, providing a simple and efficient preparation method for polysubstituted pyrrolo[2,1-a]isoquinoline compounds. Therefore, the present invention has outstanding practical value, can actively promote the process development of similar products and downstream products, and improve the economic benefits of industrial production. Summary of the invention

[0003] The purpose of the present invention is to overcome the shortcomings of the existing production technology and provide a method for synthesizing polysubstituted pyrrolo[2,1-a]isoquinoline compounds with simple operation and mild reaction conditions.

[0004] The technical scheme of the present invention is: a substrate, a catalyst, and an oxidant are placed in a test tube, a solvent is added, and a polysubstituted pyrrolo[2,1-a]isoquinoline compound is synthesized under argon protection and room temperature conditions. The reaction formula is as follows:

[0005]

[0006] (1)R 1 Selected from nitro, chloro, bromo, fluoro, methyl, methoxy, 1,3-dioxolane, phenyl, naphthalene, thiophene;

[0007] (2)R 2 Selected from methyl carboxylate, ethyl carboxylate, tert-butyl carboxylate, and p-toluenesulfonyl;

[0008] (3) the catalyst is selected from silver carbonate, silver oxide, silver fluoride, silver trifluoromethanesulfonate, etc., preferably silver carbonate;

[0009] (4) The solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile, and 1,2-dichloroethane, preferably 1,4-dioxane;

[0010] (5) The temperature is 0-80°C, the maintenance time is 24-72 hours, preferably room temperature, the maintenance time is 36 hours;

[0011] (6) The molar ratio of each substance in the reactants is: 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile compound: isocyanoacetate: catalyst: base = 1:1.2:0-2:0-2, preferably 1:1.2:1.2:1.2. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] 1. Figure 1 is the preparation reaction formula of compound I1;

[0013] 2. Figure 2 is the preparation reaction formula of compound I2;

[0014] 3. Figure 3 is the preparation reaction formula of compound I3;

[0015] 4. Figure 4 is the preparation reaction formula of compound I4;

[0016] 5. Figure 5 is the preparation reaction formula of compound I5;

[0017] 6. Figure 6 is the preparation reaction formula of compound I6;

[0018] 7. Figure 7 is the preparation reaction formula of compound I7;

[0019] 8. Figure 8 is the preparation reaction formula of compound I8;

[0020] 9. Fig. 9 is the preparation reaction formula of compound I9;

[0021] 10. Fig.10 is the preparation reaction formula of compound I10;

[0022] 11. Fig.11 is the preparation reaction formula of compound I11;

[0023] 12. Fig.12 is the preparation reaction formula of compound I12;

[0024] 13. Fig.13 is the preparation reaction formula of compound I13;

[0025] 14. Fig.14 is the preparation reaction formula of compound I14;

[0026] 15. Fig.15 is the preparation reaction formula of compound I15;

[0027] 16. Fig.16 is the preparation reaction formula of compound I16;

[0028] 17. Fig.17 is the preparation reaction formula of compound I17;

[0029] 18. Fig.18 is the preparation reaction formula of compound I18;

[0030] 19. Fig.19 is the preparation reaction formula of compound I19;

[0031] 20. Fig. 20 This is the preparation reaction formula of compound I20. DETAILED DESCRIPTION

[0032] The present invention is further described below through specific embodiments, but this should not be understood as the scope of the above subject matter described in the present invention is limited to the following embodiments, and all technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0033] Example 1: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A1 and isocyanoacetate substrate B1 as raw materials (reaction formula 1)

[0034]

[0035] A magnetic stirrer, A1 (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was reacted at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and rinsed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain product I1.

[0036] The product testing data are as follows:

[0037] White solid, yield 82%, melting range 158-160℃.

[0038] 1 H NMR (400MHz, CDCl3): δ8.12–8.12(m,1H),7.30–7.27(m,2H),7.24–7.22(m,1H),5.04(s,2H) ,4.35(q,J=7.2Hz,2H), 3.95(t,J=6.8Hz,2H), 3.05(t,J=6.4Hz,2H), 1.36(t,J=7.2Hz,3H).

[0039] 13 C NMR (100MHz, CDCl3): δ164.6,147.2,135.4,133.5,129.0,128.5,127.6,126.7,126.4,113.7,99.0,88.5,60.2,42.5,29.0,14.2.

[0040] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 16 N3O2282.1237; Found:282.1232.

[0041] Example 2: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A2 and isocyanoacetate substrate B1 as raw materials (Reaction Formula 2)

[0042]

[0043] A magnetic stirrer, A2 (0.2 mmol, 48.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the reaction system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I2.

[0044] The product testing data are as follows:

[0045] Bright yellow solid, yield 59%, melting range 223-225℃.

[0046] 1 H NMR (400MHz, CDCl3): δ9.08(s,1H),8.15(d,J=7.8Hz,1H),7.42(d,J=8.0Hz,1H),5.17(s,2H ), 4.40 (q, J = 7.2Hz, 2H), 4.04 (t, J = 6.4Hz, 2H), 3.18 (t, J = 6.4Hz, 2H), 1.37 (t, J = 6.8Hz, 3H).

[0047] 13 C NMR (100MHz, CDCl3): δ164.3,147.5,147.1,140.2,132.6,128.6,127.8,123.6,123.3,113.0,99.9,89.5,60.9,42.1,29.2,14.1.

[0048] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 15 N4O4327.1088;Found:327.1078.

[0049] Implementation Case 3: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A3 and isocyanoacetate substrate B1 as raw materials (Reaction Formula 3)

[0050]

[0051] A magnetic stirrer, A3 (0.2 mmol, 43.0 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I3.

[0052] The product testing data are as follows:

[0053] Bright yellow solid, yield 82%, melting range 175-177°C.

[0054] 1 H NMR (400MHz, CDCl3): δ7.93 (dd, J=10.8, 2.8Hz, 1H), 7.18 (dd, J=8.4, 5.6Hz, 1H), 7.01–6.96 (m, 1H), 5.08(s,2H),4.36(q,J=7.2Hz,2H),3.97–3.94(m,2H),3.02(t,J=6.8Hz,2H),1.38(t,J=7.2Hz,3H).

[0055] 13 C NMR (100MHz, CDCl3): δ164.4, 161.4 (d, J = 241.7Hz), 147.2, 134.2 (d, J = 2.8Hz), 129.1 (d, J = 3.1Hz), 128.8 (d, J = 8.1Hz), 128.0 (d, J = 9.6Hz), 115.7 (d, J = 6.8Hz), 115.5 (d, J = 10.5Hz), 113.4, 99.4, 89.0, 60.4, 42.8, 28.3, 14.1.

[0056] 19 F NMR (376MHz, CDCl3) δ-114.84.

[0057] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 15 FN3O2300.1143; Found:300.1133.

[0058] Example 4: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A4 and isocyanoacetate substrate B1 as raw materials (reaction formula 4)

[0059]

[0060] A magnetic stirrer, A4 (0.2 mmol, 46.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give product I4.

[0061] The product testing data are as follows:

[0062] Bright yellow solid, yield 78%, melting range 133-135°C.

[0063] 1 H NMR (400MHz, CDCl3): δ8.18 (d, J=2.0Hz, 1H), 7.29 (dd, J=8.0, 2.0Hz,

[0064] 1H),7.20(d,J=8.0Hz,1H),5.17(s,2H),4.39(q,J=7.2Hz,2H),3.99(t,J=6.4

[0065] Hz, 2H), 3.05 (t, J = 6.6 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0066] 13 C NMR (100MHz, CDCl3): δ164.4,147.4,133.6,132.5,131.8,128.7,128.6,128.4,127.9,113.3,99.3,89.0,60.4,42.5,28.5,14.1.

[0067] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 15 ClN3O2316.0847; Found:316.0838.

[0068] Implementation Case 5 Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A5 and isocyanoacetate substrate B1 as raw materials (Reaction Formula 5)

[0069]

[0070] A magnetic stirrer, A5 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I5.

[0071] The product testing data are as follows:

[0072] Bright yellow solid, yield 79%, melting range 148-150℃.

[0073] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=2.0Hz,1H),7.39(dd,J=8.0,2.0Hz,1H),7.10(d,J=8.0Hz,1H),5 .13(s,2H),4.35(q,J=7.2Hz,2H),3.96–3.93(m,2H),2.99(t,J=6.4Hz,2H),1.41(t,J=7.2Hz,3H).

[0074] 13 C NMR (100MHz, CDCl3): δ164.5,147.5,133.4,132.3,131.6,131.3,129.0,128.2,120.4,113.4,99.3,89.1,60.4,42.5,28.5,14.2.

[0075] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 15BrN3O2360.0342; Found:360.0328.

[0076] Example 6: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A6 and isocyanoacetate substrate B1 as raw materials (reaction formula 6)

[0077]

[0078] A magnetic stirrer, A6 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I6.

[0079] The product testing data are as follows:

[0080] Bright yellow solid, yield 64%, melting range 149-151°C.

[0081] 1 H NMR (600MHz, CDCl3) δ8.03(d,J=9.0Hz,1H),7.43(dd,J=6.4,1.8Hz,1H),7.40(s,1H),5.03(s ,2H),4.35(q,J=7.2Hz,2H),3.97–3.95(m,2H),3.04(t,J=6.6Hz,2H),1.37(t,J=7.2Hz,3H).

[0082] 13 C NMR (150MHz, DMSO-d6) δ164.1,147.5,136.9,133.7,130.6,130.0,129.3,125.4,121.9,114.0,98.1,88.1,59.9,42.0,27.9,14.2.

[0083] HRMS (ESI-TOF) m / z: [M+H]+ Calcdfor C 16 H 15 BrN3O2360.0342; Found:360.0338.

[0084] Implementation Case 7

[0085] Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A7 and isocyanoacetate substrate B1 as raw materials (reaction formula 7)

[0086]

[0087] A magnetic stirrer, A7 (0.2 mmol, 55.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I7.

[0088] The product testing data are as follows:

[0089] Bright yellow solid, yield 85%, melting range 150-152°C.

[0090] 1 H NMR (400MHz, CDCl3): δ8.05–8.04(m,1H),7.53(dd,J=8.0,0.8Hz,1H),7.16(t,J=8.0Hz,1H),5.0 4(s,2H),4.33(q,J=7.2Hz,2H),3.95–3.93(m,2H),3.20(t,J=6.6Hz,2H),1.34(t,J=7.2Hz,3H).

[0091] 13C NMR (100MHz, CDCl3): δ164.4,147.2,134.3,133.1,133.0,128.3,127.8,127.7,123.3,113.4,99.4,88.8,60.3,42.1,28.6,14.2.

[0092] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 15 BrN3O2360.0342; Found:360.0345.

[0093] Implementation Case 8

[0094] Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A8 and isocyanoacetate substrate B1 as raw materials (reaction formula 8)

[0095]

[0096] A magnetic stirrer, A8 (0.2 mmol, 42.3 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give product I8.

[0097] The product testing data are as follows:

[0098] Bright yellow solid, yield 73%, melting range 158-160℃.

[0099] 1H NMR (400MHz, CDCl3): δ7.92(s,1H),7.11(s,2H),5.07(s,2H),4.35(q,J=7.2Hz,2 H), 3.94–3.91 (m, 2H), 2.99 (t, J = 6.8Hz, 2H), 2.36 (s, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0100] 13 C NMR (100MHz, CDCl3): δ164.7,147.4,136.2,135.5,130.6,129.7,129.1,127.4,126.3,113.7,98.9,88.5,60.1,42.8,28.6,21.2,14.2.

[0101] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 18 N3O2296.1394; Found:296.1389.

[0102] Example 9: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A9 and isocyanoacetate substrate B1 as raw materials (reaction formula 9)

[0103]

[0104] A magnetic stirrer, A9 (0.2 mmol, 45.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give product I9.

[0105] The product testing data are as follows:

[0106] White solid, yield 70%, melting range 137-139℃.

[0107] 1 H NMR (400MHz, CDCl3): δ7.78(d,J=2.4Hz,1H),7.13(d,J=8.4Hz,1H),6.84(dd,J=8.4,2.4Hz,1H),5.04(s,2 H), 4.36 (q, J = 7.2Hz, 2H), 3.93 (t, J = 6.0Hz, 2H), 3.82 (s, 3H), 2.97 (t, J = 6.4Hz, 2H), 1.37 (t, J = 7.2Hz, 3H).

[0108] 13 C NMR (100MHz, CDCl3): δ164.5,158.3,147.1,135.4,128.3,127.2,125.6,114.5,114.4,113.7,99.1,88.7,60.3,55.4,43.0,28.1,14.3.

[0109] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 17 H 18 N3O3312.1343; Found:312.1341.

[0110] Example 10: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A10 and isocyanoacetate substrate B1 as raw materials (reaction formula 10)

[0111]

[0112] A magnetic stirrer, A10 (0.2 mmol, 45.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I10.

[0113] The product testing data are as follows:

[0114] Bright yellow solid, yield 67%, melting range 139-141°C.

[0115] 1 H NMR (400MHz, CDCl3): δ8.11(d,J=8.8Hz,1H),6.81(dd,J=8.8,2.6Hz,1H),6.75(d,J=2.4Hz,1H),5.02(s,2 H), 4.34 (q, J = 7.2Hz, 2H), 3.91 (t, J = 6.4Hz, 2H), 3.83 (s, 3H), 3.01 (t, J = 6.4Hz, 2H), 1.36 (t, J = 7.2Hz, 3H).

[0116] 13 C NMR (100MHz, CDCl3): δ164.6,160.0,147.2,135.9,135.6,130.3,119.3,114.0,113.2,111.8,98.3,87.9,60.1,55.3,42.4,29.3,14.2.

[0117] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 17 H 18 N3O3312.1343;Found:312.1339.

[0118] Example 11: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A11 and isocyanoacetate substrate B1 as raw materials (reaction formula 11):

[0119]

[0120] A magnetic stirrer, A11 (0.2 mmol, 53.2 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain product I11.

[0121] The product testing data are as follows:

[0122] Bright yellow solid, yield 65%, melting range 204-206℃.

[0123] 1 H NMR (400MHz, CDCl3): δ8.31 (s, 1H), 7.33 (s, 1H), 5.12 (s, 2H), 4.37 (q, J = 7.2Hz, 2H), 3.99–3.96 (m, 2H), 3.02 (t, J = 6.4Hz, 2H), 1.40 (t, J = 7.2Hz, 3H).

[0124] 13 C NMR (100MHz, CDCl3): δ164.4,147.4,133.3,132.9,132.5,130.9,130.2,129.23,126.3,113.2,99.5,89.3,60.6,42.4,28.4,14.2.

[0125] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 16 H 14 Cl2N3O2350.0458; Found:350.0441.

[0126] Example 12: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A12 and isocyanoacetate substrate B1 as raw materials (reaction formula 12)

[0127]

[0128] A magnetic stirrer, A12 (0.2 mmol, 51.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I12.

[0129] The product testing data are as follows:

[0130] White solid, yield 41%, melting range 131-133℃.

[0131] 1 H NMR (400MHz, CDCl3): δ7.92(s,1H),6.72(s,1H),4.98(s,2H),4.37(q,J=7.2H z, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.99 (t, J = 6.8Hz, 2H), 1.37 (t, J = 7.2Hz, 3H).

[0132] 13 C NMR (100MHz, CDCl3): δ164.6,149.7,147.4,147.1,136.2,127.0,119.3,113.9,112.4,110.6,98.6,88.2,60.2,56.1,56.0,42.8,28.7,14.5.

[0133] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 18 H 20 N3O4342.1448; Found:342.1441.

[0134] Example 13: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A13 and isocyanoacetate substrate B1 as raw materials (reaction formula 13):

[0135]

[0136] A magnetic stirrer, A13 (0.2 mmol, 48.3 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I13.

[0137] The product testing data are as follows:

[0138] White solid, yield 72%, melting range 210-212℃.

[0139] 1 H NMR (400MHz, CDCl3): δ7.65(s,1H),6.70(s,1H),5.98(s,2H),5.02(s,2H),4.35(q,J=7.2Hz,2H),3.91–3.88(m,2H),3.02–2.83(t,J=6.8Hz 2H), 1.37 (t, J = 7.2Hz, 3H).

[0140] 13 C NMR (100MHz, CDCl3): δ164.6,148.1,147.2,146.4,135.7,128.6,120.2,113.9,109.2,108.0,101.4,98.5,88.1,60.2,42.6,29.2,14.3.

[0141] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 17 H 16 N3O4326.1135; Found:326.1132.

[0142] Example 14: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A14 and isocyanoacetate substrate B1 as raw materials (reaction formula 14):

[0143]

[0144] A magnetic stirrer, A14 (0.2 mmol, 54.7 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I14.

[0145] The product testing data are as follows:

[0146] Bright yellow solid, yield 66%, melting range 181-183°C.

[0147] 1 H NMR (400MHz, CDCl3): δ8.41(d,J=1.6Hz,1H),7.62–7.60(m,2H),7.52(dd,J=7.8,1.8Hz,1H),7.45(t,J=7.2Hz,2H),7.36(t,J=7.2 Hz,1H),7.30(d,J=8.0Hz,1H),5.08(s,2H),4.33(q,J=7.2Hz,2H),4.01–3.97(m,2H),3.08(t,J=6.4Hz,2H),1.22(t,J=7.2Hz,3H).

[0148] 13 C NMR (100MHz, CDCl3): δ164.6,147.3,140.5,139.8,135.4,132.4,128.8,128.0 ,127.5,127.4,126.9,126.8,113.7,99.2,88.7,60.3,42.7,29.6,28.7,14.1.

[0149] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 22 H 20 N3O2358.1550; Found:358.1539.

[0150] Example 15 Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A15 and isocyanoacetate substrate B1 as raw materials (reaction formula 15)

[0151]

[0152] A magnetic stirrer, A15 (0.2 mmol, 49.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I15.

[0153] The product testing data are as follows:

[0154] Brown solid, yield 53%, melting range 183-185℃.

[0155] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=8.8Hz,1H),8.03(d,J=8.2Hz,1H),7.86(d,J=7.6Hz,1H),7.76(d,J=8.8Hz,1H),7.58 –7.50(m,2H),5.07(s,2H),4.37(q,J=7.2Hz,2H),4.05(t,J=6.4Hz,2H),3.48(t,J=6.8Hz,2H),1.36(t,J=7.2Hz,3H).

[0156] 13C NMR (100MHz, CDCl3): δ164.7,147.3,135.8,133.6,130.5,130.2,128.6,126.7 ,126.6,126.2,125.7,124.2,123.5,113.7,99.5,88.5,60.3,42.1,24.2,14.3.

[0157] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 20 H 18 N3O2332.1394; Found:332.1385.

[0158] Example 16: Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A16 and isocyanoacetate substrate B1 as raw materials (reaction formula 16):

[0159]

[0160] A magnetic stirrer, A16 (0.2 mmol, 49.5 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I16.

[0161] The product testing data are as follows:

[0162] Brown solid, yield 51%, melting range 172-174°C.

[0163] 1H NMR (400MHz, CDCl3): δ7.97(d,J=8.2Hz,1H),7.86–7.74(m,2H),7.48–7.34(m,3H),5.07(s, 2H), 4.24 (s, 1H), 3.90 (s, 1H), 3.78 (s, 2H), 3.29 (s, 1H), 3.00 (s, 1H), 0.47 (t, J = 7.2Hz, 3H).

[0164] 13 C NMR (100MHz, CDCl3): δ165.1,146.7,133.9,133.5,132.9,130.1,129.6,128.0, 126.1,125.8,125.5,125.4,124.5,113.8,101.3,88.8,59.9,42.0,30.4,12.8.

[0165] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 20 H 18 N3O2332.1394; Found:332.1384.

[0166] Example 17 Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A17 and isocyanoacetate substrate B1 as raw materials (reaction formula 17)

[0167]

[0168] A magnetic stirrer, A17 (0.2 mmol, 41.1 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B1 (0.24 mmol, 27.1 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I17.

[0169] The product testing data are as follows:

[0170] White solid, yield 43%, melting range 118-120℃.

[0171] 1 H NMR (400MHz, CDCl3): δ7.93(d,J=5.2Hz,1H),7.14(d,J=5.2Hz,1H),5.00(s,2H),4.37 (q, J=7.2Hz, 2H), 4.04 (t, J=7.2Hz, 2H), 3.19 (t, J=7.2Hz, 2H), 1.40 (t, J=7.2Hz, 3H).

[0172] 13 C NMR (100MHz, CDCl3): δ164.3,146.6,136.0,133.8,128.0,127.5,122.2,114.0,98.4,88.2,60.2,43.3,24.0,14.4.

[0173] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 14 H 14 N3O2S288.0801; Found:288.0794.

[0174] Example 18 Using 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile substrate A1 and isocyanoacetate substrate B2 as raw materials (Reaction Formula 18)

[0175]

[0176] A magnetic stirrer, A1 (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B2 (0.24 mmol, 23.8 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I18.

[0177] The product testing data are as follows:

[0178] Brown solid, yield 80%, melting range 137-139°C.

[0179] 1 H NMR (400MHz, CDCl3): δ8.09–8.06(m,1H),7.32–7.22(m,3H),5.03(s,2H),3.97–3.93(m,2H),3.86(s,3H),3.04(t,J=6.4Hz,2H).

[0180] 13 C NMR (100MHz, CDCl3): δ164.9,147.1,135.5,133.5,129.1,128.3,127.6,126.9,126.4,113.6,98.8,88.6,51.1,42.6,29.0.

[0181] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 15 H 14 N3O2268.1081; Found:268.1074.

[0182] Example 19: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A1 and isocyanoacetate substrate B3 as raw materials (Reaction Formula 19):

[0183]

[0184] A magnetic stirrer, A1 (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B3 (0.24 mmol, 33.9 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through celite and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I19.

[0185] The product testing data are as follows:

[0186] Brown solid, yield 79%, melting range 152-154°C.

[0187] 1 H NMR (400MHz, CDCl3): δ8.12–8.10(m,1H),7.30–7.26(m,2H),7.23–7.21(m, 1H), 5.02 (s, 2H), 3.94 (t, J = 6.4Hz, 2H), 3.04 (t, J = 6.4Hz, 2H), 1.58 (s, 9H).

[0188] 13 C NMR (100MHz, CDCl3): δ164.1,147.2,135.2,133.5,128.9,128.8,127.5,126.6,126.5,113.8,100.4,88.5,81.4,42.5,29.1,28.4.

[0189] HRMS (ESI-TOF) m / z: [M+H] + Calcdfor C 18 H 20 N3O2310.1550; Found:310.1543.

[0190] Example 20: Using 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile substrate A1 and isocyanoacetate substrate B4 as raw materials (reaction formula 20)

[0191]

[0192] A magnetic stirrer, A1 (0.2 mmol, 39.4 mg, 1.0 equiv.) and DDQ (0.24 mmol, 54.5 mg, 1.2 equiv.) were added to a pre-dried 10 mL reaction tube and dissolved in acetonitrile (2 mL). The system was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw material was consumed, the reaction system solvent was removed by a rotary evaporator. Then B4 (0.24 mmol, 46.9 mg, 1.2 equiv.), DBU (0.24 mmol, 35.8 μL, 1.2 equiv.), and Ag2CO3 (0.24 mmol, 66.2 mg, 1.2 equiv.) were added and dissolved in 1,4-dioxane (3 mL). The reaction was allowed to react at room temperature for 36 hours. After the reaction was completed, the system was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was collected and concentrated in vacuo using a rotary evaporator. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to give the product I20.

[0193] The product testing data are as follows:

[0194] White solid, yield 15%, melting range 236-238℃.

[0195] 1 H NMR (400MHz, CDCl3): δ8.22–8.20(m,1H),7.80(d,J=8.4Hz,2H),7.29–7.24(m,4H),7.2 0–7.18(m,1H),5.17(s,2H),3.99(t,J=6.4Hz,2H),3.00(t,J=6.8Hz,2H),2.38(s,3H).

[0196] 13 C NMR (100MHz, CDCl3): δ145.5,143.9,140.6,133.9,133.4,129.7,129.6,128.5,127.9,127.3,126.0,125.2,112.9,105.9,89.4,42.9,28.7,21.5.

[0197] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 20 H 18 N3O2S 364.1114; Found:364.1105.

Claims

1. A method for synthesizing a highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compound, characterized in that 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile compounds, 2,3-dichloro-5,6-dicyanobenzoquinone as oxidant, substituted isocyanoacetate, catalyst and base are added to an organic solvent in sequence, and reacted at room temperature to synthesize polysubstituted pyrrolo[2,1-a]isoquinoline compounds. The reaction formula is as follows: Where R 1 Selected from nitro, chloro, bromo, fluoro, methyl, methoxy, 1,3-dioxolane, phenyl, naphthalene, thiophene; R 2 Selected from methyl carboxylate, ethyl carboxylate, tert-butyl carboxylate and p-toluenesulfonyl.

2. A method for synthesizing a highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compound according to claim 1, characterized in that: The catalyst used is selected from silver carbonate, silver oxide, silver fluoride, silver trifluoromethanesulfonate, etc., preferably silver carbonate.

3. A method for synthesizing a highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compound according to claim 1, characterized in that: The solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, acetonitrile and 1,2-dichloroethane, preferably 1,4-dioxane.

4. A method for synthesizing a highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compound according to claim 1, characterized in that: The temperature used is 0°C-80°C, and the maintenance time is 24-72 hours, preferably room temperature, and the maintenance time is 36 hours.

5. A method for synthesizing a highly efficient polysubstituted pyrrolo[2,1-a]isoquinoline compound according to claim 1, characterized in that: The molar ratio of each substance in the reactants is: 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile compound: substituted isocyanoacetate: catalyst: base = 1:1.2:0-2:0-2, preferably 1:1.2:1.2:1.2.

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