A method of electrocatalytic synthesis of benzimidazoisoquinoline analogs

Abstract

The application relates to a preparation method of a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, which comprises the following steps: mixing 1-allyl-2-phenyl-1H-benzo[d]imidazole compounds, sodium trifluoromethylsulfinate, an acid and a solvent to perform an electrolysis reaction, so as to obtain the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative. The method has the advantages of simple steps, low cost and no metal catalyst, and can play an important role in the research field of benzoimidazoisoquinoline derivatives.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative. BACKGROUND

[0002] Trifluoromethyl has unique beneficial effects in enhancing chemical and metabolic stability, bioavailability, and interaction with organisms, and has recently become a very useful tool in the fields of medicine and agrochemistry.

[0003] Polycyclic fused 5,6-dihydrobenzo[4,5]imidazo[2,1a]isoquinoline, as a branch of benzimidazole compounds, is the structural core of various biologically active products. For example, 5-methyl-5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline-8,11-dione has specific cytotoxicity to two kinds of cancer cells (HeLa and DU145); 5-methyl-5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline-10-amine can treat diseases by voltage-dependent regulation of potassium ion flux; and polycyclic lactam 5,6-dihydrobenzo[4,5]imidazo[2,1a]isoquinoline can be used for treating hemoglobinopathies such as beta thalassemia and sickle cell anemia.

[0004] The traditional synthesis method of 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline includes two-step synthesis from benzimidazole and palladium acetate, copper acetate, potassium carbonate, and tert-butyl acid via an intermediate phenethyl benzimidazole. However, this route has the disadvantages of requiring multi-step conversion, using expensive reagents, and requiring metal catalysis.

[0005] Therefore, it is of great significance to combine trifluoromethyl and polycyclic fused 5,6-dihydrobenzo[4,5]imidazo[2,1a]isoquinoline as benzimidazole compounds to provide a synthesis method of trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline analogs, which is simple in steps, low in cost, easy to operate, and free of metal participation. SUMMARY

[0006] Based on this, the present application provides a preparation method of trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, which is simple in steps, low in cost, and free of metal catalyst participation.

[0007] The technical solution of the present application to solve the above technical problems is as follows.

[0008] A preparation method of a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, comprising the following steps:

[0009] Electrolysis of a compound of formula I, sodium trifluoromethylsulfinic acid, an acid and a solvent to obtain a compound of formula II; the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative is shown in formula II;

[0010]

[0011] wherein X is selected from hydrogen or nitrogen; when X is hydrogen, m is an integer from 1 to 4, and n is an integer from 1 to 5; when X is nitrogen, m is an integer from 1 to 4, and n is an integer from 1 to 4;

[0012] R 1 are each independently selected from hydrogen, alkyl or halogen;

[0013] R 2 are each independently selected from hydrogen, alkyl, alkoxy, halogen or trifluoromethyl;

[0014] R 3 are each independently selected from hydrogen, methyl.

[0015] In some embodiments of the method of preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, R 1 are each independently selected from hydrogen, methyl, ethyl, fluorine, chlorine or bromine.

[0016] In some embodiments of the method of preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, R 2 are each independently selected from hydrogen, methyl, ethyl, methoxy, fluorine, chlorine or bromine.

[0017] In some embodiments of the method of preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the anode used in the electrolysis reaction is selected from graphite felt, graphite rod or RVC, and the cathode used in the electrolysis reaction is selected from graphite felt, platinum sheet, iron sheet or nickel sheet.

[0018] In some embodiments of the method of preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the current used in the electrolysis reaction is 2 to 4 mA.

[0019] In some embodiments of the method of preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the solvent is selected from one of dichloromethane, dichloroethane, acetonitrile; or

[0020] the solvent is a mixture of one of 1,4-dioxane, acetonitrile, ethanol, methanol, hexafluoroisopropanol and water.

[0021] In some embodiments of the method for preparing the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the acid is at least one selected from trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.

[0022] In some embodiments of the method for preparing the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the acid is at least one selected from trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.

[0023] In some embodiments of the method for preparing the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the acid is at least one selected from trifluoroacetic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.

[0024] In some embodiments of the method for preparing the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the temperature of the electrolysis reaction is 70-90℃ and the time is 4-7h.

[0025] The method for preparing the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative (compound shown in formula II) directly obtains the compound from 1-allyl-2-phenyl-1H-benzo[d]imidazole compound (compound shown in formula I), sodium trifluoromethylsulfinic acid and acid through a four-component electrolysis reaction, the raw materials are easy to obtain, no metal catalyst is needed, and the cost is low and economical and green. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the specific embodiments or prior art description will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0027] Figure 1 The nuclear magnetic hydrogen spectrum of the compound of formula I-1;

[0028] Figure 2 The nuclear magnetic carbon spectrum of the compound of formula I-1;

[0029] Figure 3 The nuclear magnetic hydrogen spectrum of the compound of formula II-1;

[0030] Figure 4 The nuclear magnetic hydrogen spectrum of the compound of formula II-1;

[0031] Figure 5 The nuclear magnetic hydrogen spectrum of the compound of formula II-13;

[0032] Figure 6 The nuclear magnetic hydrogen spectrum of the compound of formula II-13. DETAILED DESCRIPTION

[0033] The technical solutions of the present application are further described in detail below in conjunction with specific examples. The present application can be realized in many different forms and is not limited to the embodiments described herein. It should be understood that the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0035] In the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise explicitly and specifically limited.

[0036] The weight of the related components mentioned in the specification of the embodiments of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of each component. Therefore, as long as the content of the related components in the specification of the embodiments of the present application is enlarged or reduced in proportion, it is within the scope disclosed in the specification of the embodiments of the present application. Specifically, the weight described in the specification of the embodiments of the present application can be μg, mg, g, kg, etc. mass units commonly known in the chemical industry.

[0037] One embodiment of the present application provides a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, whose structural formula is shown as formula II:

[0038]

[0039] wherein X is selected from hydrogen or nitrogen; when X is hydrogen, m is any integer from 1 to 4, and n is any integer from 1 to 5; when X is nitrogen, m is any integer from 1 to 4, and n is any integer from 1 to 4;

[0040] R 1 are each independently selected from hydrogen, alkyl, or halogen;

[0041] R 2 are each independently selected from hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl;

[0042] R 3 are each independently selected from hydrogen, methyl.

[0043] One embodiment of the present application provides a preparation method of a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, comprising the following steps:

[0044] The compound of formula I, sodium trifluoromethylsulfinic acid, an acid and a solvent are mixed to perform an electrolysis reaction to obtain a compound of formula II; the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative is shown in formula II;

[0045]

[0046] wherein X is selected from hydrogen or nitrogen; when X is hydrogen, m is any integer from 1 to 4, and n is any integer from 1 to 5; when X is nitrogen, m is any integer from 1 to 4, and n is any integer from 1 to 4;

[0047] R 1 are each independently selected from hydrogen, alkyl or halogen;

[0048] R 2 are each independently selected from hydrogen, alkyl, alkoxy, halogen or trifluoromethyl;

[0049] R 3 are each independently selected from hydrogen, methyl.

[0050] The compound of formula II is directly obtained from 1-allyl-2-phenyl-1H-benzo[d]imidazole (the compound shown in formula I), sodium trifluoromethylsulfinic acid and an acid through a four-component electrolysis reaction, the raw materials are easy to obtain, no metal catalyst is needed, and the cost is low and economical and green.

[0051] In some examples, in the preparation method of the compound of formula II, R 1 are each independently selected from hydrogen, methyl, ethyl, fluorine, chlorine or bromine. Further, R 1 are each independently selected from hydrogen, methyl or chlorine.

[0052] In some examples, in the preparation method of the compound of formula II, R 2 are each independently selected from hydrogen, methyl, ethyl, methoxy, fluorine, chlorine or bromine.

[0053] In some examples, in the preparation method of the trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, the positive electrode used in the electrolysis reaction is selected from graphite felt, graphite rod or RVC, and the negative electrode used in the electrolysis reaction is selected from platinum sheet, iron sheet or nickel sheet. Alternatively, the positive electrode used in the electrolysis reaction is selected from graphite felt, graphite rod or RVC, and the negative electrode used in the electrolysis reaction is selected from graphite felt or platinum sheet.

[0054] Preferably, the positive electrode used in the electrolysis reaction is graphite felt, and the negative electrode is platinum sheet.

[0055] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the current of the electrolysis reaction is 2-4 mA. Further, the current of the electrolysis reaction is 2.5-4 mA. Preferably, the current of the electrolysis reaction is 3 mA.

[0056] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the solvent is selected from one of dichloromethane, dichloroethane, acetonitrile; or, the solvent is selected from a mixture of one of 1,4-dioxane, acetonitrile, ethanol, methanol, hexafluoroisopropanol and water. Alternatively, the solvent is selected from a mixture of one of 1,4-dioxane, acetonitrile, ethanol, methanol, hexafluoroisopropanol and water. Preferably, the solvent is a mixture of acetonitrile and water. Further, the volume ratio of acetonitrile to water is 1:1.

[0057] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the acid is selected from at least one of trifluoroacetic acid, formic acid, acetic acid and triflic acid. Preferably, the acid is triflic acid.

[0058] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the equivalent ratio of the acid to the compound of formula I is (1- 35):1. Further, the equivalent ratio of the acid to the compound of formula I is (20-35):1. Preferably, the equivalent ratio of the acid to the compound of formula I is 30:1.

[0059] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the equivalent ratio of sodium trifluoromethylsulfinate to the compound of formula I is (2-4):1. Further, the equivalent ratio of sodium trifluoromethylsulfinate to the compound of formula I is (3-4):1. Preferably, the equivalent ratio of sodium trifluoromethylsulfinate to the compound of formula I is 3:1.

[0060] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, the temperature of the electrolysis reaction is 70-90°C and the time is 4-7h. Further, the temperature of the electrolysis reaction is 80-90°C and the time is 6-7h. Preferably, the temperature of the electrolysis reaction is 80°C and the time is 6h.

[0061] In some examples, the method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivative, an electrolyte can be further added in the electrolysis reaction.

[0062] In some of the examples, the method of preparing trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivatives, the electrolyte is selected from at least one of NH4Br, LiClO4, TBAB, TBAI, Bu4NBF4, Et4NBF4, Me4NBF4, NH4I, NH4PF6, Bu4NPF6, Et4NPF6, Me4NPF6, Bu4NF. Further, the electrolyte is selected from NH4Br or TBAB. DETAILED DESCRIPTION

[0064] The following examples illustrate the method of preparing trifluoromethylbenzo[4,5]imidazo[2,1- a]isoquinoline derivatives according to the present application, it being understood that the method of preparing trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivatives according to the present application is not limited to the following examples.

[0065] The 1-allyl-2-phenyl-1H-benzo[d]imidazole used in the following examples was synthesized according to the following procedure:

[0066]

[0067] Substituted benzoic acid (10 mmol) and substituted 1,2-phenylenediamine (10 mmol) were added to a flask containing polyphosphoric acid (PPA) (28 g) and a magnetic stirrer, and the mixture was heated at 150-180 °C (oil bath) for 10 h. The reaction mixture was poured into crushed ice and the pH was adjusted to 7-8 with aqueous NH3(60-70%) while stirring. The precipitate was filtered and washed to yield the crude product.

[0068] Substituted benzaldehyde (10 mmol) was added to a 40 mL flask, followed by NaHSO3(110 mmol), and the mixture was heated under stirring to the reflux temperature in an oil bath, then substituted 1,2-phenylenediamine (10 mmol) was quickly added. After a certain time, the reaction was quenched with ice water and stirring was continued for 30 min, then the system was extracted to obtain the solid compound, which was washed with deionized water three times to obtain the crude product.

[0069] The resulting benzimidazole (8 mmol) and dry DMF (20 mL) were added to a flask connected to an argon balloon, then the solution was cooled to 0 °C. NaH (640.0 mg, 60 wt%, 16 mmol) was added portionwise to the cooled system, and after stirring at 0 °C for 30 min, allyl bromide (1.935 g, 16 mmol) C was added to the reaction solution at 0 °C, and the reaction was maintained at room temperature for 4 h while stirring. After that, the solution was poured into ice water and extracted as usual. The crude mixture was subjected to flash column chromatography on silica gel using ethyl acetate / petroleum ether (v / v, 1:10) as eluent to obtain the target precursor (60-85% yield).

[0070] wherein the compound of formula I-1 has the following structure:

[0071]

[0072] The 1H NMR spectrum of the compound of formula I-1 is shown in Figure 1 The 13C NMR spectrum of the compound of formula I-1 is shown in Figure 2

[0073] Example 1

[0074] (1) 1-allyl-2-phenyl-1H-benzo[d]imidazole (compound of formula I-1) and sodium trifluoromethylsulfinic acid, sodium trifluoromethylsulfinic acid to synthesize 5-(2,2,2-trifluoroethyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline

[0075] Specifically comprising the following steps:

[0076] A three-necked flask equipped with a graphite rod anode and a platinum sheet cathode was charged with 1-allyl-2-phenyl-1H-benzo[d]imidazole (0.1 mmol), sodium trifluoromethylsulfinic acid (0.3 mmol) and solvent successively, and was refluxed at 80°C. The reaction was carried out under a constant current of 3 mA for 4 hours. The reaction system was treated with ethyl acetate and water, and the organic phase was evaporated under reduced pressure. The obtained product was subjected to flash column chromatography (petroleum ether / ethyl acetate, 4:1) to obtain the target product. The structure of the target product is shown in formula II-1. The 1H NMR spectrum is shown in Figure 3 The 13C NMR spectrum is shown in Figure 4

[0077]

[0078] The separation yields of different solvents are shown in Table 1:

[0079] Table 1

[0080] Group Solvent % Yield 1 H2O / Dioxane (1 :1) 8 2 H2O / CH3CN (1 :1) 12 3 H2O / EtOH (1 :1) 4 4 H2O / CH3OH (1 :1) 6 5 H2O / HFIP (1 :1) 5 6 CH3OH Trace 7 EtOH Trace 8 Dioxane Trace 9 DCE 7 10 DCM 7 11 CH3CN 8 12 H2O / CH3CN (3:1) 8 13 H2O / CH3CN (1 :3) 7 14 H2O / CH3CN (1 :1) 15 15 H2O / CH3CN (1 :1) 14

[0081] (2) The same procedure as (1) was used, except that an electrolyte (0.01 mmol) was added. The separation yields of different electrolytes are shown in Table 2:

[0082] Table 2

[0083] Group Electrolyte % Yield 1 [NH4Br] 15 2 LiClO4 8 3 TBAB 18 4 TBAI 7 5 Bu4NBF4 5 6 Et4NBF4 6 7 Me4NBF4 6 8 [NH4I] 7 9 NH4PF6 8 10 Bu4NPF6 6 11 Et4NPF6 7 12 Me4NPF6 5 13 Bu4NF 3

[0084] (3) The same procedure as (2) was used, wherein the electrolyte was TBAB. In addition, an acid was added (the equivalent ratio of acid to compound of formula I was 1:1). The separation yields of different acids are shown in Table 3:

[0085] Table 3 ​​

[0086] Group Acid % Yield 1 / 18 2 CH3COOH 20 3 HCOOH 18 4 CF3COOH 21 5 CF3SO3H 23

[0087] (4) Using the same procedure as (3), the acid is CF3SO3H, the only difference is the ratio of equivalents of acid to compound of formula I, the isolated yields are shown in Table 4:

[0088] Table 4

[0089]

[0090]

[0091] (5) Using the same procedure as (4), the ratio of equivalents of acid to compound of formula I is 30:1, the only difference is the electrode, the isolated yields for the different electrodes are shown in Table 5:

[0092] Table 5

[0093] Group Positive (+) | Negative (-) % Yield 1 Graphite rod | Pt 43 2 RVC | Pt 32 3 Graphite felt | Pt 48 4 Pt | Pt Trace 5 Graphite felt | Graphite felt 28 6 Graphite felt | Fe 14 7 Graphite felt | Ni 23

[0094] (6) Using the same procedure as (5), the electrode is graphite felt | Pt, the only difference is the ratio of equivalents of sodium trifluoromethylsulfinate to compound of formula I, the isolated yields are shown in Table 6:

[0095] Table 6

[0096]

[0097] (7) Using the same procedure as (5), the electrode is graphite felt | Pt, the only difference is the temperature of the electrolysis reaction, the isolated yields are shown in Table 7:

[0098] Table 7

[0099] Group Electrolysis temperature % Yield 1 70 36 2 80 48 3 90 43

[0100] (8) Using the same procedure as (5), the electrode is graphite felt | Pt, the only difference is the current of the electrolysis reaction, the isolated yields are shown in Table 8:

[0101] Table 8

[0102] Group Current (mA) % Yield 1 2 32 2 2.5 41 3 3 48 4 4 50 5 None 0

[0103] (9) Using the same procedure as (5), the electrode is graphite felt | Pt, the only difference is the time of the electrolysis reaction, the isolated yields are shown in Table 9:

[0104] Table 9

[0105] Group Time (h) % Yield 1 4 48 2 5 59 3 6 80 4 7 80

[0106] (10) The same procedure as (9) was used, except that the electrolysis reaction time was 6 h, and the difference was that no electrolyte was added, and the separation yield was 80%.

[0107] (11) The same procedure as (9) was used, except that the electrolysis reaction time was 6 h, and the difference was that the electrolysis reaction was carried out under a nitrogen atmosphere, and the separation yield was 43%.

[0108] The preferred experimental conditions were obtained by (1) to (11) of Example 1, as follows:

[0109] Into a three-necked flask equipped with a graphite felt anode and a platinum plate cathode, 1-allyl-2-phenyl-1H-benzo[d]imidazole (0.1 mmol), sodium trifluoromethylsulfinate (0.3 mmol), trifluoromethanesulfonic acid (3 mmol), acetonitrile and water (1:1, 4 mL) were added successively, and the reaction was carried out at 80 °C under reflux for 6 h under a constant current of 3 mA. The reaction system was treated with ethyl acetate and water, and the organic phase was evaporated under reduced pressure. The obtained product was subjected to flash column chromatography (petroleum ether / ethyl acetate, 4:1) to obtain the target product, and the calculated separation yield was 80%;

[0110]

[0111] Oily liquid. 1 HNMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.51 (s, 3H), 7.30-7.22 (m, 2H), 4.61 (d, J = 13.1 Hz, 1H), 4.33 (d, J = 12.9 Hz, 1H), 3.76 (s, 1H), 2.50 (s, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 148.3, 144.0, 137.2, 135.4, 130.8, 129.1, 128.7, 127.2 (d, 1 J C-F(CF3) = 276 Hz), 126.1, 125.6, 123.0, 122.6, 119.6, 110.5, 44.3, 37.0 (q, 2 J C-F(CF3) = 27 Hz), 32.6 (d, 3 J C-F(CF3) = 2 Hz). 19 FNMR (376 MHz, DMSO-d6) δ -61.5.

[0112] Example 2

[0113] The synthesis of the compound shown in formula II-2, using 1-allyl-2-(4- ethylphenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions being the same as in Example 1, the obtained product was subjected to flash column chromatography (petroleum ether / ethyl acetate / ammonia, 100:20:1) to obtain the target product, and the separation yield was calculated to be 83%;

[0114]

[0115] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.20 (d, J = 7.9 Hz, 1H), 7.85-7.82 (m, 1H), 7.38-7.35 (m, 1H), 7.32-7.28 (m, 1H), 7.17 (s, 1H), 4.54 (dd, J = 12.8, 1.6 Hz, 1H), 4.23 (dd, J = 12.8, 4.0 Hz, 1H), 3.59-3.56 (m, 1H), 2.43 (s, 3H), 2.40-2.29 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 148.6, 144.0, 141.3, 136.4, 134.9, 129.6, 128.3, 126.2 (d, 1 JC-F(CF3) = 272.5 Hz), 126.1, 123.0, 122.7, 119.8, 109.0, 43.6, 37.5 (q, 2 J C-F(CF3) = 27.8 Hz), 33.4 (d, 3 J C-F(CF3) = 2.8 Hz), 21.6. 19 FNMR (376 MHz, CDC13) δ -63.6.

[0116] Example 3

[0117] The synthesis of the compound shown in formula II-3, using 1-allyl-2-(4- ethylphenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions being the same as in Example 1, the yield was 87%;

[0118]

[0119] Oily liquid. 1HNMR (400 MHz, CDC13) δ 8.22 (d, J = 7.9 Hz, 1H), 7.84-7.82 (m, 1H), 7.37-7.35 (m, 1H), 7.33-7.29 (m, 3H), 7.18 (s, 1H), 4.54 (d, J = 12.9 Hz, 1H), 4.23 (dd, J = 12.8, 3.6 Hz, 1H), 3.60-3.58 (m, 1H), 2.72 (q, J = 7.6 Hz, 2H), 2.43-2.25 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H). 13 CNMR (101 MHz, CDC13) δ 148.6, 147.6, 144.0, 136.5, 134.9, 128.4, 127.1, 126.21 (q, 1 J C-F(CF3) = 276.1 Hz), 126.20, 123.3, 122.9, 122.7, 119.8, 109.0, 43.7, 37.5 (q, 2 J C-F(CF3) = 27.7 Hz), 33.45 (d, 3 J C-F(CF3) = 2.5 Hz), 28.95, 15.31. 19 FNMR (376 MHz, CDC13) δ -63.5.

[0120] Example 4

[0121] Synthesis of compound shown in Formula II-4, using 1-allyl-2-(4- methoxyphenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H- benzo[d]imidazole in Example 1, and other reaction conditions are the same as in Example 1, yield 81%;

[0122]

[0123] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.26 (d, J = 8.6 Hz, 1H), 7.83-7.80 (m, 1H), 7.36-7.34 (m,, 1H), 7.31-7.27 (m,, 2H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 4.52 (dd, J = 12.8, 1.6 Hz, 1H), 4.22 (dd, J = 12.8, 3.6 Hz, 1H), 3.89 (s, 3H), 3.58-3.56 (m, 1H), 2.44-2.22 (m, 2H). 13CNMR (101 MHz, CDC13) δ 161.6, 148.6, 143.9, 138.3, 134.8, 128.0, 126.2 (d, 1 J C-F(CF3) = 276.2 Hz), 122.7, 119.5, 118.5, 114.1, 113.4, 108.8, 55.5, 43.6, 37.4 (q, 2 J C-F(CF3) = 27.8 Hz), 33.7 (d, 3 J C-F(CF3) = 2.6 Hz). 19 FNMR (376 MHz, CDC13) δ -63.5.

[0124] Example 5

[0125] The compound of formula II-5 was synthesized using 1-allyl-2-(4- fluorophenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions were the same as in Example 1, with a yield of 75%;

[0126]

[0127] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.36-8.32 (m, 1H), 7.86-7.85 (m, 1H), 7.38-7.33 (m, 3H), 7.23-7.18 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 4.28 (d, J = 12.6 Hz, 1H), 3.64 (s, 1H), 2.47-2.30 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 163.9 (d, 1 J C-F = 250.6 Hz), 147.6, 144.0, 138.7 (d, 3 J C-F = 7.9 Hz), 134.8, 128.5 (d, 3 J C-F = 8.8 Hz), 126.0 (q, 1 J C-F(CF3) = 276 Hz), 123.2, 122.9, 122.3 (d, 4 J C-F = 3.1 Hz), 119.9, 116.2 (d, 2 J C-F= 21.8 Hz), 114.8 (d, 2 J C-F = 22.6 Hz), 109.0, 43.6, 37.3 (q, 2 J C-F(CF3) = 28.1 Hz), 33.4. 19 FNMR (376 MHz, CDC13) δ -63.5, -108.2.

[0128] Example 6

[0129] The synthesis of the compound shown in Formula II-6, using 1-allyl-2-(4- (trifluoromethyl)phenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H- benzo[d]imidazole in Example 1, and otherwise following the same reaction conditions as in Example 1, gave a yield of 71 %;

[0130]

[0131] White solid, m.p. 101-102 °C. 1 HNMR (400 MHz, CDC13) δ 8.44 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.42-7.34 (m, 3H), 4.60 (d, J = 13.1 Hz, 1H), 4.30 (d, J = 13.0 Hz, 1H), 3.72 (s, 1H), 2.47-2.28 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 146.7, 144.0, 136.7, 134.9, 132.3 (q, 2 J C-F(CF3,Ar) = 32.6 Hz), 129.6, 129.2, 126.6, 125.9 (q, 1 J C-F(CF3) = 276 Hz), 125.7 (q, 3 J C-F(CF3,Ar) = 3.8 Hz), 124.8 (q, 3 J C-F(CF3,Ar) = 3.6 Hz), 123.9, 123.6 (q, 1 J C-F(CF3,Ar) = 270.9 Hz), 123.3, 120.3, 109.3, 43.6, 37.3 (q, 2 J C-F(CF3) = 28.1 Hz), 33.4 (d, 3 J C-F(CF3) = 2.3 Hz). 19FNMR (376 MHz, CDC13) δ -62.8, -63.4.

[0132] Example 7

[0133] Synthesis of compound of formula II-7, using 1-allyl-2-(o-tolyl)-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in example 1, and other reaction conditions as in example 1, the product was purified by flash column chromatography (petroleum ether / dichloromethane, 1:6) to give the target product in 81% yield;

[0134]

[0135] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 7.30-7.87 (m, 1H), 7.38-7.36 (m, 1H), 7.35-7.30 (m, 4H), 7.20-7.18 (m, 1H), 4.54 (dd, J = 12.8, 1.6 Hz, 1H), 4.22 (dd, J = 13.2, 3.6 Hz, 1H), 3.60-3.54 (m, 1H), 2.97 (s), 2.26-2.16 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 148.4, 143.9, 139.1, 137.8, 134.1, 131.8, 129.8, 126.2 (q, 1 J C-F(CF3) = 276 Hz), 125.5, 124.5, 123.1, 122.4, 120.2, 108.8, 43.2, 37.1 (q, 2 J C-F(CF3) = 27.7 Hz), 34.5 (d, 3 J C-F(CF3) = 2.7 Hz), 22.5. 19 FNMR (376 MHz, CDC13) δ -63.6.

[0136] Example 8

[0137] Synthesis of compound of formula II-8, using 1-allyl-2-(2-methoxyphenyl)-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in example 1, and other reaction conditions as in example 7, yield 60%;

[0138]

[0139] Oily liquid. 1HNMR (400 MHz, CDC13) δ 7.92 (dd, J = 7.2, 2.4 Hz, 1H), 7.43-7.39 (m, 1H), 7.36-7.28 (m, 3H), 7.08-7.03 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 4.53 (dd, J = 13.2, 2.0 Hz, 1H), 4.22 (dd, J = 12.8, 3.6 Hz, 1H), 4.08 (s, 3H), 3.60-3.53 (m, 1H), 2.25-2.18 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 158.2, 146.1, 144.0, 139.2, 133.5, 131.5, 126.1 (q, 1 J C-F(CF3) = 276 Hz), 123.2, 122.4, 120.6, 119.9, 114.8, 111.6, 108.5, 56.4, 43.2 (d, 4 J C-F(CF3) = 1.0 Hz), 36.9 (q, 2 J C-F(CF3) = 27.8 Hz), 34.4 (d, 3 J C-F(CF3) = 2.6 Hz). 19 FNMR (376 MHz, CDC13) δ -63.60.

[0140] Example 9

[0141] The compound of formula II-9 was synthesized using 1-allyl-2-(2- chlorophenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H- benzo[d]imidazole in Example 1, and other reaction conditions were the same as in Example 1, with a yield of 73%;

[0142]

[0143] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 7.98-7.95 (m, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.39-7.34 (m, 3H), 7.34-7.28 (m, 2H), 4.55 (dd, J = 13.2, 2.0 Hz, 1H), 4.26 (dd, J = 13.2, 3.2 Hz, 1H), 3.63-3.58 (m, 1H), 2.23-2.13 (m, 2H). 13CNMR (101 MHz, CDC13) δ 145.5, 143.7, 139.5, 134.0, 133.3, 131.8, 130.6, 126.6, 126.0 (d, 1 J C-F(CF3) = 278 Hz), 124.2, 123.9, 122.8, 120.9, 108.8, 43.15, 36.8 (q, 2 J C-F(CF3) = 28 Hz), 34.7 (d, 3 J C-F(CF3) = 2.6 Hz). 19 FNMR (376 MHz, CDC13) δ -63.5.

[0144] Example 10

[0145] The compound of formula II-10 was synthesized using 1-allyl-2-(2- bromophenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions were the same as those in Example 7, with a yield of 76%;

[0146]

[0147] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 7.98-7.95 (m, 1H), 7.77 (dd, J = 8.0, 1.2 Hz, 1H), 7.37-7.36 (m, 2H), 7.34-7.30 (m, 2H), 7.28-7.24 (m, 1H), 4.55 (dd, J = 13.2, 2.0 Hz, 1H), 4.26 (dd, J = 12.8, 3.6 Hz, 1H), 3.61-3.56 (m, 1H), 2.21-2.11 (m, 1H). 13 CNMR (101 MHz, CDC13) δ 145.5, 143.7, 139.5, 134.0, 133.3, 131.8, 130.6, 126.6, 126.0 (d, 1 J C-F(CF3) = 278 Hz), 124.2, 123.9, 122.8, 120.9, 108.8, 43.15, 36.8 (q, 2 J C-F(CF3) = 28 Hz), 34.7 (d, 3 J C-F(CF3) = 2.6 Hz). 19 FNMR (376 MHz, CDC13) δ -63.5.

[0148] Example 11

[0149] Synthesis of compounds of Formula II-11-1 and II-11-2, using 1-allyl-2-(3- bromophenyl)-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and otherwise as in Example 1, gave the target product and its isomer in 39% and 33% yield, respectively, after flash column chromatography (petroleum ether / ethyl acetate, 5:1).

[0150]

[0151] Formula II-11-1, oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.49 (d, J = 2.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.58 (dd, J = 8.4, 2.4 Hz, 1H), 7.41-7.31 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 4.55 (dd, J = 13.2, 2.4 Hz, 1H), 4.27 (dd, J = 13.2, 4.0 Hz, 1H), 3.65-3.60 (m, 1H), 2.43-2.24 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 146.9, 143.9, 134.9, 134.8, 133.6, 129.4, 129.0, 127.6, 126.0 (d, 1 J C-F(CF3) = 276 Hz), 123.6, 123.2, 122.8, 120.2, 109.2, 43.69, 37.4 (q, 2 J C-F(CF3) = 28 Hz), 33.0 (d, 3 J C-F(CF3) = 2.5 Hz). 19 FNMR (376 MHz, CDC13) δ -63.5.

[0152] Formula II-11-2, oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.32 (d, J = 8.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.69 (dd, J = 8.0, 1.0 Hz, 1H), 7.43-7.39 (m, 1H), 7.38-7.31 (m, 3H), 4.72 (d, J = 13.3 Hz, 1H), 4.20 (dd, J = 13.2, 4.0 Hz, 1H), 4.10 (d, J = 10.7 Hz, 1H), 2.34-2.19 (m, 2H). 13CNMR (101 MHz, CDC13) δ 147.3, 144.1, 135.5, 134.8, 134.7, 130.0, 128.1, 126.0 (q, 1 J C-F(CF3) = 276.3 Hz), 125.4, 123.6, 123.4, 123.1, 120.1, 109.3, 42.3 (d, 4 J C-F(CF3) = 1.7 Hz), 34.5 (q, 2 J C-F(CF3) = 28.1 Hz), 33.19 (d, 3 J C-F(CF3) = 2.6 Hz). 19 FNMR (376 MHz, CDC13) δ -63.3.

[0153] Example 12

[0154] Synthesis of compound shown in formula II-12, using 1-allyl-2-(pyridin-3-yl)-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions are the same as Example 7, yield 63%;1H NMR is shown in Figure 5 , and13C NMR is shown in Figure 6 .

[0155]

[0156] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.64 (dd, J = 4.8, 1.6 Hz, 1H), 8.57 (dd, J = 7.6, 1.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.31 (m, 2H), 4.62 (dd, J = 12.8, 5.6 Hz, 1H), 4.36 (dd, J = 12.8, 7.6 Hz, 1H), 3.89-3.82 (m, 1H), 3.22-3.19 (m, 1H), 2.45-2.36 (m, 1H). 13 CNMR (101 MHz, CDC13) δ 154.4, 150.6, 147.0, 144.1, 134.6, 126.7 (d, 1 J C-F(CF3) = 275.6 Hz), 123.7, 123.6, 123.1, 122.4, 120.0, 109.4, 43.8, 35.3 (d, 3 J C-F(CF3) = 2.5 Hz), 34.4 (q,2 J C-F(CF3) = 28.7 Hz). 19 FNMR (376 MHz, CDC13) δ -63.3.

[0157] Example 13

[0158] Synthesis of compound of formula II-13, using 1-allyl-2-(2,4-dimethylphenyl)-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions are the same as Example 11, yield 78%;

[0159]

[0160] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 7.87-7.83 (m, 1H), 7.37-7.32 (m, 1H), 7.30-7.26 (m, 2H), 7.12 (s, 1H), 7.00 (s, 1H), 4.51 (dd, J = 12.8, 1.6 Hz, 1H), 4.17 (dd, J = 12.8, 3.2 Hz, 1H), 3.56-3.45 (m, 1H), 2.93 (s, 3H), 2.37 (s, 3H), 2.26-2.14 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 148.7, 143.9, 140.1, 139.0, 137.9, 134.1, 132.5, 126.1, 122.9, 122.3, 121.8, 120.0, 108.7, 43.2 (d, 4 J C-F(CF3) = 1.0 Hz), 37.1 (q, 2 J C-F(CF3) = 27.6 Hz), 34.5 (d, 3 J C-F(CF3) = 2.6 Hz), 22.4, 21.3. 19 FNMR (376 MHz, CDC13) δ -63.62.

[0161] Example 14

[0162] Synthesis of compound of formula II-14, using 1-allyl-2-(2,4-dichlorophenyl)-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions are the same as Example 7, yield 67%;

[0163]

[0164] White solid, mp 194-195℃. 1 HNMR (400MHz, CDCl3) δ7.96-7.93(m,1H),7.57(d,J=2.0Hz,1H),7.36-7.35(m,2H),7.34-7.28(m,2H ),4.55(dd,J=13.2,1.6Hz,1H),4.25(dd,J=13.2,3.2Hz,1H),3.60-3.56(m,1H),2.24-2.15(m,2H). 13 CNMR (101MHz, CDCl3) δ144.7,143.7,140.5,135.7,134.2,133.9,131.5,126.8,125.8(d, 1 J C-F(CF3) =276Hz),124.1,123.0,122.9,121.0,108.9,43.0,36.6(q, 2 J C-F(CF3) =28.3Hz), 34.68(d, 3 J C-F(CF3) =2.6Hz). 19 FNMR (376MHz, CDCl3) δ -63.5.

[0165] Example 15

[0166] The compound shown in Formula II-15 was synthesized by replacing 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1 with 1-allyl-2-phenyl-1H-benzo[d]imidazole, with all other reaction conditions being the same as in Example 1. The product was obtained by rapid column chromatography (petroleum ether / ethyl acetate / acetic acid, 96:24:1) to give the target product in 64% yield.

[0167]

[0168] White solid, mp 200-201℃. 1 HNMR (400MHz, CDCl3) δ8.22(d,J=8.4Hz,1H),7.85-7.83(m,1H),7.61(d,J=8.4Hz,1H),7.43-7. 40(m,1H),7.38-7.34(m,2H),4.73(d,J=12.2Hz,1H),4.19(d,J=12.4Hz,2H),2.35-2.22(m,2H). 13CNMR (101 MHz, CDC13) δ 146.8, 144.1, 135.8, 135.4, 134.8, 131.5, 130.6, 126.2, 125.9 (d, 1 J C-F(CF3) = 276.3 Hz), 125.2, 123.8, 123.30, 120.1, 109.3, 42.4, 34.5 (q, 2 J C-F(CF3) = 28.5 Hz), 31.53 (d, 3 J C-F(CF3) = 1.9 Hz). 19 FNMR (376 MHz, CDC13) δ -63.4.

[0169] Example 16

[0170] The compound of formula II-16 was synthesized by replacing 1-allyl-2-phenyl- lH-benzo[d]imidazole in Example 1 with 1-allyl-4-methyl-2-phenyl-lH-benzo[d]imidazole, and other reaction conditions were the same as those in Example 11, with a yield of 79%.

[0171]

[0172] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.37-8.35 (m, 1H), 7.50-7.42 (m, 2H), 7.35-7.33 (m, 1H), 7.22-7.19 (m, 2H), 7.12-7.08 (m, 1H), 4.52 (dd, J = 13.2, 2.0 Hz, 1H), 4.25 (dd, J = 12.8, 4.0 Hz, 1H), 3.63-3.59 (m, 1H), 2.74 (s, 3H), 2.41-2.23 (m, 2H). 13 CNMR (101 MHz, CDC13) δ

[0173] 147.6, 143.3, 136.3, 134.5, 130.6, 130.1, 128.7, 127.7, 126.3, 126.2 (q, 1 J C-F(CF3) = 276.1 Hz), 126.1, 123.2, 122.1, 106.5, 43.8 (d, 4 J C-F(CF3) = 1.1 Hz), 37.4 (q, 2 J C-F(CF3) = 27.8 Hz), 33.42 (d, 3 J C-F(CF3)= 2.5 Hz), 16.8. 19 FNMR (376 MHz, CDC13) δ -63.5.

[0174] Example 17

[0175] The synthesis of the compound shown in Formula II-17, using 1-allyl-7-methyl-2- phenyl-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and otherwise following the same reaction conditions as in Example 11, gave a yield of 71 %;

[0176]

[0177] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.33-8.31 (m, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.50-7.43 (m, 2H), 7.37-7.34 (m, 1H), 7.21-7.15 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 5.08 (dd, J = 12.8, 2.0 Hz, 1H), 4.44 (dd, J = 13.2, 4.0 Hz, 1H), 3.62-3.58 (m, 1H), 2.72 (s, 3H), 2.57-2.43 (m, 1H), 2.39-2.21 (m, 1H). 13 CNMR (101 MHz, CDC13) δ 144.1, 136.1, 133.6, 130.7, 128.8, 127.3, 126.23, 126.21 (q, 1 J C-F(CF3) = 278.2 Hz), 125.7, 122.7, 121.0, 118.0, 45.7, 37.2 (q, 2 J C-F(CF3) = 28 Hz), 33.6 (d, 3 J C-F(CF3) = 2.5 Hz), 18.7. 19 FNMR (376 MHz, CDC13) δ -63.6.

[0178] Example 18

[0179] The synthesis of the compound shown in Formula II-18, using 1-allyl-5,6-dimethyl-2- phenyl-1H-benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and otherwise following the same reaction conditions as in Example 2, gave a yield of 82 %;

[0180]

[0181] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.29-8.27 (m, 1H), 7.60 (s, 1H), 7.48-7.41 (m, 2H), 7.35-7.33 (m, 1H), 7.14 (s, 1H), 4.49 (dd, J = 12.8, 2.0 Hz, 1H), 4.22 (dd, J = 12.8, 4.0 Hz, 1H), 3.67-3.54 (m, 1H), 2.41 (s, 3H), 2.40 (s, 3H), 2.36-2.23 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 147.5, 142.5, 136.1, 133.4, 132.5, 131.8, 130.4, 128.7, 127.7, 126.2 (d, 1 J C-F(CF3) = 276 Hz), 126.1, 125.9, 119.9, 109.3, 43.63, 37.5 (q, 2 J C-F(CF3) = 27.7 Hz), 33.4 (d, 3 J C-F(CF3) = 2.4 Hz), 20.63, 20.40. 19 FNMR (376 MHz, CDC13) δ -63.6.

[0182] Example 19

[0183] The compound of formula II-19 was synthesized by replacing 1-allyl-2-phenyl-1H- benzo[d]imidazole in Example 1 with 1-allyl-5,6-dichloro-2-phenyl-1H-benzo[d]imidazole, and other reaction conditions were the same as in Example 2, with a yield of 77%;

[0184]

[0185] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.27-8.24 (m, 1H), 7.88 (s, 1H), 7.51-7.48 (m, 2H), 7.46 (s, 1H), 7.39-7.36 (m, 1H), 4.46 (dd, J = 13.2, 2.4 Hz, 1H), 4.25 (dd, J = 12.8, 4.0 Hz, 1H), 3.68-3.63 (m, 1H), 2.41-2.23 (m, 2H). 13CNMR (101 MHz, CDC13) δ 150.1, 143.3, 136.3, 134.1, 131.5, 129.0, 127.8, 127.2, 126.9, 126.4, 126.0 (d, 1 J C-F(CF3) = 276 Hz), 125.1, 121.0, 110.4, 43.9, 37.5 (q, 2 J C-F(CF3) = 27.9 Hz), 33.2 (d, 3 J C-F(CF3) = 2.5 Hz). 19 FNMR (376 MHz, CDC13) δ -63.4.

[0186] Example 20

[0187] The compound of formula II-20 was synthesized using 1-(2-methylallyl)-2-phenyl-1H- benzo[d]imidazole instead of 1-allyl-2-phenyl-1H-benzo[d]imidazole in Example 1, and other reaction conditions were the same as in Example 1, with a yield of 71%.

[0188]

[0189] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.37-8.35 (m, 1H), 7.86-7.83 (m, 1H), 7.50-7.45 (m, 3H), 7.40-7.36 (m, 1H), 7.33-7.29 (m, 2H), 4.47 (d, J = 12.9 Hz, 1H), 3.98 (d, J = 12.9 Hz, 1H), 2.41-2.26 (m, 2H), 1.74 (s, 3H). 13 CNMR (101 MHz, CDC13) δ 148.4, 143.8, 140.7, 134.6, 130.9, 128.4, 126.3, 126.0 (d, 1 J C-F(CF3) = 277.2 Hz), 125.2, 124.8, 123.1, 122.8, 119.9, 109.1, 49.42, 41.6 (q, 2 J C-F(CF3) = 26.9 Hz), 36.3 (d, 3 J C-F(CF3) = 1.3 Hz), 22.6. 19 FNMR (376 MHz, CDC13) δ -59.7.

[0190] Example 21

[0191] The synthesis of the compound shown in Formula II-21, using sodium difluoromethylsulfinate instead of sodium trifluoromethylsulfinate in Example 1, and otherwise the same reaction conditions as in Example 11, gave a yield of 53%.

[0192]

[0193] Oily liquid. 1 HNMR (400 MHz, CDC13) δ 8.34-8.32 (m, 1H), 7.86-7.84 (m, 1H), 7.52-7.43 (m, 2H), 7.39-7.29 (m, 4H), 5.79 (tdd, J = 56.2, 5.3, 3.1 Hz, 1H), 4.46 (dd, J = 12.4, 2.0 Hz, 1H), 4.30 (dd, J = 12.4, 3.6 Hz, 1H), 3.59-3.57 (m, 1H), 2.21-2.09 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 148.2, 143.8, 136.6, 134.8, 130.6, 128.6, 127.8, 126.3, 125.8, 123.1, 122.8, 119.9, 115.9 (t, 1 J C-F(CF2) = 238.1 Hz), 109.0, 44.8, 37.8 (t, 2 J C-F(CF2) = 20.9 Hz), 33.2 (t, 3 J C-F(CF2) = 5.1 Hz). 19 FNMR (376 MHz, CDC13) δ -115.2 - -118.1 (m).

[0194] Each technical feature in the above-described embodiments can be combined arbitrarily, and for the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described, however, as long as the combinations of the technical features do not contradict each other, they should be considered within the scope of the present specification.

[0195] The above-mentioned embodiments only express several implementation manners of the present application, facilitate concrete and detailed understanding of the technical solutions of the present application, but cannot be understood as a limitation on the patent protection scope of the present application. It should be noted that, for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. It should be understood that, on the basis of the technical solutions provided by the present application, the technical solutions obtained by logical analysis, reasoning or limited experiments by the skilled person in the art all belong to the protection scope of the appended claims of the present application. Therefore, the protection scope of the present application patent should be subject to the content of the appended claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A method for preparing a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, characterized in that, Includes the following steps: An electrolytic reaction is carried out by mixing a compound of formula I, sodium trifluoromethylsulfinate, an acid, and a solvent. The positive electrode used in the reaction is selected from graphite felt, graphite rod, and RVC, and the negative electrode is selected from graphite felt, platinum sheet, iron sheet, or nickel sheet. The solvent is selected from dichloromethane, dichloroethane, and acetonitrile, or a mixed solution of 1,4-dioxane, acetonitrile, ethanol, methanol, and hexafluoroisopropanol with water. The acid is selected from at least one of trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid, to obtain a trifluoromethylbenzo[4,5]imidazo[2,1-a]isoquinoline derivative, as shown in formula II: Where X is selected from carbon or nitrogen: when X is carbon, m is any integer from 1 to 4 and n is any integer from 1 to 5; when X is nitrogen, m is any integer from 1 to 4 and n is any integer from 1 to 4. R 1 Each is independently selected from hydrogen, alkyl, or halogen; R 2 Each is independently selected from hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl; R 3 Each is independently selected from hydrogen and methyl.

2. The preparation method according to claim 1, characterized in that, R 1 Each of the following is independently selected from methyl, ethyl, fluorine, chlorine, or bromine.

3. The preparation method according to claim 1, characterized in that, R 2 Each is independently selected from methyl, ethyl, methoxy, fluorine, chlorine, or bromine.

4. The preparation method according to any one of claims 1 to 3, characterized in that... The current for the electrolysis reaction is 2-4 mA.

5. The preparation method according to any one of claims 1 to 3, characterized in that, The equivalent ratio of the acid to the compound of formula I is (1-35):

1.

6. The preparation method according to any one of claims 1 to 3, characterized in that, The equivalent ratio of sodium trifluoromethyl sulfinate to the compound of formula I is (2-4):

1.

7. The preparation method according to any one of claims 1 to 3, characterized in that, The electrolysis reaction is carried out at a temperature of 70–90°C for 4–7 hours.

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