CN102070549A - 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives and preparation method and application thereof - Google Patents

Abstract

当A为Ar时，其中，R¹为H、F、Cl、Br、I、NO₂、OMe或Me；R²为H、F、Cl、Br、I、NO₂、OMe或Me；R³为H、F、Cl、Br、I、NO₂、NH₂、Me、Et、i-Pr、t-But或OMe；R⁴为H、F、Cl、Br、I、NO₂、OMe或Me；R⁵为H、F、Cl、Br、I、NO₂、OMe或Me；R⁶为H、F、Cl、Br、I、NO₂、OMe或Me。A为R时，A＝甲基、乙基，丙基、氯甲基、溴甲基、2-氯乙基或2-溴乙基。本发明还涉及该类化合物的制备方法及其作为流感病毒抑制剂的应用。The present invention provides 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives, the general structural formula of which is as follows:

When A is Ar, Wherein, R ¹ is H, F, Cl, Br, I, NO ₂ , OMe or Me; R ² is H, F, Cl, Br, I, NO ₂ , OMe or Me; R ³ is H, F, Cl , Br, I, NO ₂ , NH ₂ , Me, Et, i-Pr, t-But or OMe; R ⁴ is H, F, Cl, Br, I, NO ₂ , OMe or Me; R ⁵ is H, F, Cl, Br, I, _NO2 , OMe or Me; ^R6 is H, F, Cl, Br, I, _NO2 , OMe or Me. When A is R, A=methyl, ethyl, propyl, chloromethyl, bromomethyl, 2-chloroethyl or 2-bromoethyl. The invention also relates to a preparation method of the compound and its application as an influenza virus inhibitor.

Description

5-substituted-2-(4-substituted phenyl)benzoxazole derivatives and their preparation methods and applications

technical field

The invention relates to a derivative and a preparation method thereof, in particular to a 5-substituted-2-(4-substituted phenyl)benzoxazole derivative and a preparation method and application thereof, belonging to the technical field of organic compound synthesis and medical application .

Background technique

Influenza, referred to as influenza, is a respiratory disease caused by influenza virus. It has the characteristics of wide prevalence, strong infectivity, and high morbidity. It has a high mortality rate among children, the elderly, and high-risk groups. Influenza virus belongs to the Orthomyxoviridae family and is spherical or filamentous. It is a negative-helical single-stranded RNA virus (see Zhang Qiang et al., Research Progress in Anti-Influenza Virus Drugs, Acta Pharmaceutica Sinica, 2010, 45(3), 289-299 ). According to the different antigenic characteristics of virion nucleoprotein (NP) and membrane protein (MP) and their genetic characteristics, influenza viruses are divided into three types: A (A), B (B) and C (C), of which A and B Types of influenza viruses are mainly related to human pathogenesis. Currently, the human influenza viruses prevalent in the world are mainly H1N1 subtype, H3N2 subtype and B type. Currently commonly used anti-influenza drugs include two types: M2 receptor blockers and neuraminidase (neuraminidase, NA) inhibitors. The former mainly inhibits the integration of viral genes into host cells by inhibiting the M2 ion channel of the virus. Prophylactic administration or administration within 48 hours of viral infection can take effect, but it is ineffective against influenza B virus and is prone to extensive viral drug resistance , so this type of drug is not recommended for the treatment of influenza. Neuraminidase inhibitors are effective and safe for both influenza viruses A and B, and are currently recommended anti-influenza drugs in many countries (see Zu Mian et al., Evaluation of In Vitro Anti-Influenza Virus Activity of Commonly Used Chinese Proprietary Medicines, Pharmacology Journal, 2010, 45(3), 408-412). However, due to the extensive clinical application of existing drugs, the influenza virus has mutated, resulting in varying degrees of drug resistance to these drugs. One of the main directions of research.

The present invention synthesized a series of 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives, and through anti-influenza virus activity screening, found a class of anti-influenza virus with good activity and novel structure It is of great significance for the discovery of new anti-influenza virus drugs with broad-spectrum high-efficiency and independent intellectual property rights.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides a 5-substituted-2-(4-substituted phenyl)benzoxazole derivative and its preparation method and application.

Technical scheme of the present invention is as follows:

1.5-substituted-2-(4-substituted phenyl)benzoxazole derivatives

The 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives of the present invention have a general structural formula as follows:

When A is Ar,

in,

R ¹ is H, F, Cl, Br, I, NO ₂ , OMe or Me;

R ² is H, F, Cl, Br, I, NO ₂ , OMe or Me;

R ³ is H, F, Cl, Br, I, NO ₂ , NH ₂ , Me, Et, i-Pr, t-But or OMe;

^R4 is H, F, Cl, Br, I, _NO2 , OMe or Me;

R ⁵ is H, F, Cl, Br, I, NO ₂ , OMe or Me;

^R6 is H, F, Cl, Br, I, _NO2 , OMe or Me.

When A is R, A=methyl, ethyl, propyl, chloromethyl, bromomethyl, 2-chloroethyl or 2-bromoethyl.

2. The synthetic route of 2.5-substituted-2-(4-substituted phenyl) benzoxazole derivatives is as follows:

Reagents: (i) thionyl chloride, reflux; (ii) triethylamine, dioxane; (iii) p-toluenesulfonic acid, xylene, 140°C, 8h; (iv) palladium carbon, hydrogen; (v ) triethylamine, N, N-dimethylformamide.

Wherein A is the same as in the above-mentioned derivatives.

3. Preparation of 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives 7

Using p-nitrobenzoic acid 1 as the starting material, reflux in thionyl chloride to obtain p-nitrobenzoyl chloride 2, and then acylate with 2-amino 4-nitrophenol 3 to obtain the bis-acylated intermediate 4- Nitro-2-(4-nitrobenzamide)phenyl-4-nitrobenzoate 4, intermediate 4 was cyclized under the action of p-toluenesulfonic acid and xylene to give 5-nitro-2- (4-Nitrobenzene) benzoxazole 5, compound 5 will reduce the nitro group to amino group under the catalysis of palladium carbon to obtain the mother nucleus 5-amino-2-(4-aminobenzene) benzoxazole 6, the final compound 6 reacts with various substituted benzoyl chlorides or fatty acid chlorides to generate benzoxazole target compounds 7a-7v through acylation reaction, and the specific structures are as follows:

Table 1 Structural formulas of target compounds 7a-7v

The various substituted benzoyl chlorides or fatty acid chlorides mentioned above are: p-nitrobenzoyl chloride, p-fluorobenzoyl chloride, p-chlorobenzoyl chloride, p-bromobenzoyl chloride, p-iodobenzoyl chloride, p-methoxybenzoyl chloride Acyl chloride, 3,4-dichlorobenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 2-nitro-4-chlorobenzoyl chloride, benzoyl chloride, p-aminobenzoyl chloride, p-methylbenzene Formyl chloride, p-tert-butylbenzoyl chloride, p-propylbenzoyl chloride, m-fluorobenzoyl chloride, m-chlorobenzoyl chloride, m-toluoyl chloride, m-nitrobenzoyl chloride, o-methoxybenzoyl chloride Acyl chloride, acetyl chloride, 2-chloroacetyl chloride, 2-chloropropionyl chloride.

Concrete preparation steps are as follows:

(1) Preparation of intermediate 5-nitro-2-(4-nitrobenzene) benzoxazole 5

Add 6.68g of p-nitrobenzoic acid and 30mL of thionyl chloride to a 250mL round bottom flask, reflux at 80°C for 2 hours, evaporate the solvent under reduced pressure to obtain p-nitrobenzoyl chloride, then add 3.08g of 2-amino- 4-Nitrophenol and 4.04g of triethylamine were dissolved in 50ml of dioxane, and were added dropwise to the above-mentioned acid chloride in an ice bath. After the dropwise addition was completed, they were reacted at 100° C. for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, an appropriate amount of water was added, suction filtered, and vacuum-dried at 90°C; (4-nitrobenzamide) phenyl-4-nitrobenzoate 4, yellow needle-like crystals;

Add 0.28g of intermediate 4, 0.2g of p-toluenesulfonic acid and 30mL of xylene into a 100mL round bottom flask, reflux at 140°C, and monitor the reaction progress by TLC. After 4 hours, the reaction was completed, cooled, filtered with suction, and recrystallized from N,N-dimethylformamide-ethanol to obtain 50.13 g of the intermediate 5-nitro-2-(4-nitrophenyl)benzoxazole, which was white floc;

(2) Preparation of intermediate 5-amino-2-(4-aminobenzene) benzoxazole 6

Add 0.89g of 5-nitro-2-(4-nitrophenyl)benzoxazole 5 and 30mL of N,N-dimethylformamide into a 250mL round bottom flask, heat to dissolve them all, then add 10% 0.09 g of palladium carbon, the air was removed, stirred for 24 hours under a hydrogen atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, a large amount of water was added to precipitate pale pink needles, which were suction filtered and recrystallized from methanol to obtain 60.55 g of the mother nucleus 5-amino-2-(4-aminobenzene)benzoxazole;

(3) Preparation of 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives

Add 0.0025mol of substituted benzoic acid and 30mL of thionyl chloride to a 50mL round bottom flask, reflux at 80°C for 2 hours, distill off the solvent under reduced pressure to obtain substituted benzoyl chloride, then dissolve in 10ml of dry N,N- in dimethylformamide. Dissolve 0.23g of 5-amino-2-(4-aminobenzene)benzoxazole 6 and 0.25g of triethylamine in 20mL of dry N,N-dimethylformamide, and add dropwise to Among the above acid chlorides, after the dropwise addition, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After 2 hours of reaction, the solvent was distilled off under reduced pressure, excess water was added, crystals were precipitated, filtered by suction, and dried in vacuum at 90°C; recrystallized from N,N-dimethylformamide-ethanol to obtain target compounds 7a-7v.

The target compound is preferably one of the compounds listed in Table 1 with the structural formula 7a-7v.

The more preferred compound of the target compound is: N-(4-(5-(3,4-dimethoxybenzamido)benzoxazol-2-yl)phenyl)-3,4 - Dimethoxybenzamide 7h and N-(4-(5-acetamidobenzoxazol-2-yl)phenyl)acetamide 7t.

4. The pharmaceutical composition of 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives

An anti-type A influenza virus pharmaceutical composition contains the above-mentioned 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives and pharmaceutical auxiliary materials, and is made into medicines in different dosage forms.

5. Application of 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives

The 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives of the invention can be used as influenza virus inhibitors. Specifically, it is used as a type A influenza virus inhibitor for the preparation of anti-influenza virus drugs.

The present invention provides 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives with brand new structure, their preparation method, their anti-influenza virus activity screening results and their first application in the field of anti-virus. Tests have proved that the 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives of the present invention can be used as type A influenza virus inhibitors. Specifically, it is used as a type A influenza virus inhibitor for the preparation of anti-influenza virus drugs.

Detailed ways:

The present invention will be further described below in conjunction with embodiment, and the numbering of all compounds is identical with table 1. The stated percentages are mass percentages unless otherwise specified, and the raw materials used are commercially available unless otherwise specified.

Embodiment 1: the preparation method of intermediate 5-nitro-2-(4-nitrophenyl) benzoxazole 5

Add 6.68g of p-nitrobenzoic acid and 30mL of thionyl chloride to a 250mL round bottom flask, reflux at 80°C for 2 hours, evaporate the solvent under reduced pressure to obtain p-nitrobenzoyl chloride, then add 3.08g of 2-amino- 4-Nitrophenol and 4.04g of triethylamine were dissolved in 50ml of dioxane, and were added dropwise to the above-mentioned acid chloride in an ice bath. After the dropwise addition was completed, they were reacted at 100° C. for 2 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, an appropriate amount of water was added, suction filtered, and vacuum-dried at 90°C; (4-nitrobenzamide) phenyl-4-nitrobenzoate 4, yellow needle-like crystals, mp: 234-236°C;

Add 0.28g of intermediate 4, 0.2g of p-toluenesulfonic acid and 30mL of xylene into a 100mL round bottom flask, reflux at 140°C, and monitor the reaction progress by TLC. After 4 hours, the reaction was completed, cooled, filtered with suction, and recrystallized from N,N-dimethylformamide-ethanol to obtain 50.13 g of the intermediate 5-nitro-2-(4-nitrophenyl)benzoxazole, which was white Floc, yield 76.02%, mp: 261-262°C;

Product spectral analysis data:

¹ H-NMR (DMSO-d ₆ ) δ: 8.78 (d, 1H, J=1.8Hz, Ar-H), 8.47-8.50 (m, 4H, Ar-H), 8.41-8.43 (dd, 1H, J ₁ = 1.8 Hz, J ₂ = 9.0 Hz, Ar-H), 8.13 (d, 1H, J = 9.0 Hz, Ar-H); EI-MS: m/z 286.4 (M+1).C ₁₃ H ₇ N ₃ O ₅ (285.04).

Embodiment 2: the preparation method of intermediate 5-amino-2-(4-aminobenzene) benzoxazole 6

Add 0.89g of 5-nitro-2-(4-nitrophenyl)benzoxazole 5 and 30mL of N,N-dimethylformamide into a 250mL round bottom flask, heat to dissolve them all, and then add 10% of Palladium carbon 0.09g, the air was removed, stirred for 24 hours under a hydrogen atmosphere, and the reaction progress was monitored by TLC. After the reaction was completed, a large amount of water was added to precipitate light pink needles, which were filtered by suction and recrystallized from methanol to obtain 60.55 g of the mother nucleus 5-amino-2-(4-aminobenzene) benzoxazole; the yield was 81.48%, mp: 230-231°C.

Product spectral analysis data

¹ H-NMR (DMSO-d ₆ ) δ: 7.78 (d, 2H, J=1.8Hz, Ar-H), 7.28 (d, 1H, J=9.0Hz, Ar-H), 6.76 (d, 1H, J=8.4Hz, Ar-H), 6.66 (d, 2H, J=8.4Hz, Ar-H), 6.53-6.55 (dd, 1H, _J1 =1.8Hz, _J2 =9.0Hz, Ar-H) , 5.88 (s, 2H, NH ₂ ), 4.98 (s, 2H, NH ₂ ); EI-MS: m/z 226.0 (M+1). C ₁₃ H ₁₁ N ₃ O (225.09).

Example 3: Preparation of 5-substituted-2-(4-substituted phenyl) benzoxazole derivatives 7

Add 0.0025mol of substituted benzoic acid and 30mL of thionyl chloride to a 50mL round bottom flask, reflux at 80°C for 2 hours, distill off the solvent under reduced pressure to obtain substituted benzoyl chloride, then dissolve in 10ml of dry N,N- in dimethylformamide. Dissolve 0.23g of 5-amino-2-(4-aminobenzene)benzoxazole 6 and 0.25g of triethylamine in 20mL of dry N,N-dimethylformamide, and add dropwise to Among the above acid chlorides, after the dropwise addition, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. After 2 hours of reaction, the solvent was distilled off under reduced pressure, excess water was added, crystals were precipitated, filtered by suction, and dried in vacuum at 90°C; recrystallization from N,N-dimethylformamide-ethanol gave the target compound 7a, the yield was 61.06 %, mp: >300°C.

Product spectral analysis data:

¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.92 (s, 1H, NH), 10.76 (s, 1H, NH), 8.40 (d, 4H, J=7.8Hz, Ar-H), 8.28 ( s, 1H, Ar-H), 8.22-8.24 (m, 6H, Ar-H), 8.06 (d, 2H, J=7.8Hz, Ar-H), 7.79 (d, 1H, J=8.4Hz, Ar -H), 7.75 (d, 1H, J=8.4Hz, Ar-H); IR (KBr, cm ^-1 ): 3309 (v _NH ), 1664 (υ _C=O ), 1598, 1499, 1479 (υ _C=C ), 1525, 1347(v _NO2 ), 1320, 1172(υ _CN ); EI-MS: m/z 524.2(M+1).C ₂₇ H ₁₇ N ₅ O ₇ (523.11).

Using various substituted acid chlorides and intermediate 6 to obtain other target products respectively by the above method, the results are as follows:

To prepare compound 7b, the substituted acid chloride is p-fluorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield 57.45%, mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.63(s, 1H, NH), 10.46(s, 1H, NH), 8.25(s , 1H, Ar-H), 8.21(d, 2H, J=8.4Hz, Ar-H), 8.04-8.09(m, 6H, Ar-H), 7.77(d, 1H, J=9.0Hz, Ar- H), 7.38-7.42 (m, 4H, Ar-H); IR (KBr, cm ^-1 ): 3310 (v _NH ), 1654 (υ _C=O ), 1534, 1506, 1412 (υ _C=C ) , 1327, 1142 (υ _CN ); EI-MS: m/z 470.5 (M+1).C ₂₇ H ₁₇ F ₂ N ₃ O ₃ (469.12).

To prepare compound 7c, the substituted acid chloride is p-chlorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Off-white powder, yield: 61.63%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.68(s, 1H, NH), 10.51(s, 1H, NH), 8.25(s , 1H, Ar-H), 8.21(d, 2H, J=9.0Hz, Ar-H), 8.02-8.05(m, 6H, Ar-H), 7.77(d, 1H, J=9.0Hz, Ar- H), 7.74 (d, 1H, J=9.0Hz, Ar-H), 7.63-7.66 (m, 4H, Ar-H); IR (KBr, cm ^-1 ): 3243 (v _Ar-H ), 1647 (υ _C=O ), 1594, 1526, 1485, 1410 (υ _C=C ), 1321, 1175 (υ _CN ); EI-MS: m/z502.2(M+1).C ₂₇ H ₁₇ C _l2 N ₃ O ₃ (501.06).

To prepare compound 7d, the substituted acid chloride is p-bromobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Pale yellow needles, yield: 47.38%.mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.67(s, 1H, NH), 10.50(s, 1H, NH), 8.26 (s, 1H, Ar-H), 8.21(d, 2H, J=9.0Hz, Ar-H), 8.05(d, 2H, J=9.0Hz, Ar-H), 7.95(d, 4H, J= 8.4Hz, Ar-H), 7.73-7.80 (m, 6H, Ar-H); IR (KBr, cm ^-1 ): 3285 (v _NH ), 1647 (υ _C=O ), 1590, 1526, 1502, 1482 (υ _C=C ), 1325, 1174 (υ _CN ); EI-MS: m/z 590.1 (M+1). C ₂₇ H ₁₇ Br ₂ N ₃ O3 (588.96).

To prepare compound 7e, the substituted acid chloride is p-iodobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Off-white needle crystals, yield: 52.47%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.64 (s, 1H, NH), 10.48 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.21(d, 2H, J=9.0Hz, Ar-H), 8.04(d, 2H, J=9.0Hz, Ar-H), 7.94-7.97(m, 4H, Ar -H), 7.72-7.79 (m, 6H, Ar-H); IR (KBr, cm ^-1 ): 3297, 3202 (v _NH ), 1656 (υ _C=O ), 1605, 1531, 1493 (υ _{C =C} ), 1324, 1173 (υ _CN ); EI-MS: m/z 686.4 (M+1).C ₂₇ H ₁₇ I ₂ N ₃ O ₃ (684.94).

To prepare compound 7f, the substituted acid chloride is p-methoxybenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Off-white needle crystals, yield: 60.67%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.50 (s, 1H, NH), 10.31 (s, 1H, NH), 8.28 ( s, 1H, Ar-H), 8.19 (d, 2H, J=9.0Hz, Ar-H), 7.99 (d, 2H, J=8.4Hz, Ar-H), 7.74 (d, 1H, J=9.0 Hz, Ar-H), 7.64-7.69 (m, 3H, Ar-H), 7.51-7.55 (m, 2H, Ar-H), 7.20 (d, 2H, J=8.4Hz, Ar-H), 7.09 (t, 2H, Ar-H), 3.92 (s, 6H, -CH ₃ ); IR (KBr, cm ^-1 ): 3295 (v _NH ), 2932, 2837 (υ _CH(CH3) ), 1648 (υ _C=O ), 1605, 1505, 1478 (υ _C=C ), 1315, 1176 (υ _CN ); EI-MS: m/z 494.5 (M+1).C ₂₉ H ₂₃ N ₃ O ₅ (493.16) .

Preparation of compound 7g, the substituted acid chloride is 3,4-dichlorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 57.45%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.73 (s, 1H, NH), 10.58 (s, 1H, NH), 8.24- 8.26(m, 3H, Ar-H), 8.22(d, 2H, J=8.4Hz, Ar-H), 8.04(d, 2H, J=9.0Hz, Ar-H), 7.94-7.97(m, 4H , Ar-H), 7.72-7.79 (m, 6H, Ar-H); IR (KBr, cm ^-1 ): 3257 (v _NH ), 1645 (υ _C=O ), 1595, 1526, 1500 (υ _{C =C} ), 1320, 1177 (υ _CN ); EI-MS: m/z 572.1 (M+1).C ₂₇ H ₁₅ C _l4 N ₃ O ₃ (571.24)

To prepare compound 7h, the substituted acid chloride is 3,4-dimethoxybenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 47.45%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.42 (s, 1H, NH), 10.26 (s, 1H, NH), 8.25 ( s, 1H, Ar-H), 8.21 (d, 2H, J=8.4Hz, Ar-H), 8.04 (d, 2H, J=8.4Hz, Ar-H), 7.75 (d, 1H, J=9.0 Hz, Ar-H), 7.72(d, 1H, J=8.4Hz, Ar-H), 7.67(d, 2H, J=7.8Hz, Ar-H), 7.57(s, 2H, Ar-H), 7.12 (t, 2H, Ar-H), 3.86 (s, 12H, OCH ₃ ); IR (KBr, cm ^-1 ): 3277 (v _NH ), 2934, 2837 (υ _CH ), 1647 (υ _C=O ), 1599, 1506 (υ _C=C ), 1315, 1176 (υ _CN ); EI-MS: m/z 554.5 (M+1).C ₃₁ H ₂₇ N ₃ O ₇ (553.18).

To prepare compound 7i, the substituted acid chloride is 2-nitro-4-chlorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Pale yellow needles, yield: 49.36%.mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 11.10(s, 1H, NH), 10.92(s, 1H, NH), 8.31 (d, 2H, J=7.8Hz, Ar-H), 8.23(d, 2H, J=9.0Hz, Ar-H), 8.16(s, 1H, J=7.8Hz, Ar-H), 8.01(t , 2H, Ar-H), 7.89-7.92(m, 4H, Ar-H), 7.79(d, 1H, J=9.0Hz, Ar-H), 7.61(d, 1H, J=9.0Hz, Ar- H); IR (KBr, cm ^-1 ): 3246 (v _NH ), 1654 (υ _C=O ), 1534, 1350 (v _NO2 ), 1350, 1173 (υ _CN ); EI-MS: m/z 592.2 (M+1).C ₂₇ H ₁₅ Cl ₂ N ₅ O ₇ (591.03).

To prepare compound 7j, the substituted acid chloride is benzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 64.02%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.63 (s, 1H, NH), 10.45 (s, 1H, NH), 8.27 ( d, 1H, J=8.4Hz, Ar-H), 8.21(d, 2H, J=9.0Hz, Ar-H), 8.18(d, 1H, J=9.0Hz, Ar-H), 8.06(d, 2H, J=8.4Hz, Ar-H), 8.98-8.00(m, 5H, Ar-H), 7.76(d, 3H, J=3.6Hz, Ar-H), 7.61-7.65(m, 3H, Ar-H) -H), 7.72-7.79 (m, 6H, Ar-H); IR (KBr, cm ^-1 ): 3262 (v _NH ), 1653 (υ _C=O ), 1533, 1493, 1410 (υ _C=C ), 1325, 1176 (υ _CN ); EI-MS: m/z 434.6 (M+1).C ₂₇ H ₁₉ N ₃ O ₃ (433.14).

To prepare compound 7k, the substituted acid chloride is p-aminobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Light brown needles, yield: 43.58%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.12 (s, 1H, NH), 9.46 (s, 1H, NH), 8.22 (s, 1H, Ar-H), 8.14-8.18 (m, 3H, Ar-H), 8.02 (d, 2H, J=9.0Hz, Ar-H), 7.95 (s, 1H, Ar-H), 7.83(d, 1H, J=9.0Hz, Ar-H), 7.74-7.77(m, 5H, Ar-H), 7.70(d, 2H, J=1.8Hz, Ar-H); IR(KBr, cm ^-1 ): 3335, 3221 (v _NH ), 1653 (υ _C=O ), 1604, 1508, 1408 (υ _C=C ), 1314, 1179 (υ _CN ); EI-MS: m/z 464.5 (M +1).C ₂₇ H ₂₁ N ₅ O ₃ (463.16)

To prepare compound 7l, the substituted acid chloride is p-toluoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 67.16%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.57 (s, 1H, NH), 10.39 (s, 1H, NH), 8.27 ( s, 1H, Ar-H), 8.21(d, 2H, J=8.4Hz, Ar-H), 8.05(d, 2H, J=9.0Hz, Ar-H), 7.76-7.81(m, 6H, Ar -H), 7.43-7.46 (m, 4H, Ar-H), 2.51 (s, 6H, Ph-CH ₃ ); IR (KBr, cm ^-1 ): 3282 (v _NH ), 2919 (υ _CH ), 1654 (υ _C=O ), 1592, 1500, 1478 (υ _C=C ), 1321, 1165 (υ _CN ); EI-MS: m/z 462.4 (M+1).C ₂₉ H ₂₃ N ₃ O ₃ (461.17).

To prepare compound 7m, the substituted acid chloride is p-tert-butylbenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 56.64%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.55 (s, 1H, NH), 10.37 (s, 1H, NH), 8.27 ( s, 1H, Ar-H), 8.20(d, 2H, J=9.0Hz, Ar-H), 8.05(d, 2H, J=8.4Hz, Ar-H), 7.92(d, 4H, J=8.4 Hz, Ar-H), 7.75(s, 2H, Ar-H), 7.58(t, 4H, Ar-H), 1.34(s, 18H, CH ₃ ); IR(KBr, cm ^-1 ): 3304( v _NH ), 2961, 2868 (υ _CH(CH3) ), 1638 (υ _C=O ), 1592, 1500, 1479 (υ _C=C ), 1318, 1167 (υ _CN ); EI-MS: m/z 546.5(M+1).C ₃₅ H ₃₅ N ₃ O ₃ (545.27).

Preparation of compound 7n, the substituted acid chloride is p-propylbenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 62.98%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.54 (s, 1H, NH), 10.36 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.20(d, 2H, J=8.4Hz, Ar-H), 8.05(d, 2H, J=8.4Hz, Ar-H), 7.92(d, 4H, J=7.8 Hz, Ar-H), 7.75(s, 2H, Ar-H), 7.38(t, 4H, Ar-H), 2.65(t, 4H, Ar-CH2), 1.62-1.66(m, 4H, _CH2 ), 0.92 (t, 6H, CH ₃ ); IR (KBr, cm ^-1 ): 3309 (v _NH ), 2957, 2929, 2870 (υ _CH ), 1652 (υ _C=O ), 1526, 1500, 1479 (υ _C=C ), 1318, 1179 (υ _CN ); EI-MS: m/z 518.5 (M+1). C ₃₃ H ₃₁ N ₃ O ₃ (517.24).

To prepare compound 7o, the substituted acid chloride is m-fluorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 63.78%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.68 (s, 1H, NH), 10.51 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.22(d, 2H, J=9.0Hz, Ar-H), 8.04-8.06(m, 2H, Ar-H), 7.85(d, 2H, J=7.8Hz, Ar -H), 7.81(d, 2H, J=7.8Hz, Ar-H), 7.78(d, 1H, J=9.0Hz, Ar-H), 7.69(d, 1H, J=9.0Hz, Ar-H ), 7.60-7.65 (m, 2H, Ar-H), 7.46-7.51 (m, 2H, Ar-H); IR (KBr, cm ^-1 ): 3320 (v _NH ), 1656 (υ _C=O ) , 1587, 1531, 1482 (υ _C=C ), 1323, 1179 (υ _CN ); EI-MS: m/z 470.5 (M+1).C ₂₇ H ₁₇ F ₂ N ₃ O ₃ (469.12).

To prepare compound 7p, the substituted acid chloride is m-chlorobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 42.89%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.70 (s, 1H, NH), 10.54 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.22(d, 2H, J=8.4Hz, Ar-H), 8.04-8.06(m, 4H, Ar-H), 7.96(d, 2H, J=7.2Hz, Ar -H), 7.78(d, 1H, J=9.0Hz, Ar-H), 7.74(d, 1H, J=9.0Hz, Ar-H), 7.69(t, 2H, Ar-H), 7.59-7.62 (m, 2H, Ar-H); IR (KBr, cm ^-1 ): 3312 (v _NH ), 1651 (υ _C=O ), 1596, 1524, 1501 (υ _C=C ), 1324, 1178 (υ _CN ); EI-MS: m/z 502.2 (M+1).C ₂₇ H ₁₇ Cl ₂ N ₃ O ₃ (501.06).

To prepare compound 7q, the substituted acid chloride is m-toluoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 67.16%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.57 (s, 1H, NH), 10.40 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.21(d, 2H, J=8.4Hz, Ar-H), 8.05(d, 2H, J=9.0Hz, Ar-H), 7.75-7.81(m, 6H, Ar -H), 7.43-7.46 (m, 4H, Ar-H), 2.51 (s, 6H, Ph-CH ₃ ); IR (KBr, cm ^-1 ): 3276 (v _NH ), 2918, 2860 (υ _CH ), 1694 (υ _C=O ), 1603, 1530, 1501, 1478 (υ _C=C ), 1320, 1178 (υ _CN ); EI-MS: m/z 462.4 (M+1).C ₂₉ H ₂₃ N ₃ O ₃ (461.17).

Preparation of compound 7r, the substituted acid chloride is m-nitrobenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

Yellow needles, yield: 39.94%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.90 (s, 1H, NH), 10.77 (s, 1H, NH), 8.26 ( s, 1H, Ar-H), 8.22(d, 2H, J=9.0Hz, Ar-H), 8.04-8.06(m, 2H, Ar-H), 7.85(d, 2H, J=7.8Hz, Ar -H), 7.81(d, 2H, J=7.8Hz, Ar-H), 7.78(d, 1H, J=9.0Hz, Ar-H), 7.69(d, 1H, J=9.0Hz, Ar-H ), 7.60-7.65 (m, 2H, Ar-H), 7.46-7.51 (m, 2H, Ar-H); IR (KBr, cm ^-1 ): 3307 (v _NH ), 1667 (υ _C=O ) , 1596, 1499, 1479 (υ _C=C ), 1525, 1348 (v _NO2 ), 1323, 1172 (υ _CN ); EI-MS: m/z 524.2 (M+1).C ₂₇ H ₁₇ N ₅ O ₇ (523.11).

To prepare compound 7s, the substituted acid chloride is o-methoxybenzoyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 52.16%. mp: >300°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.50 (s, 1H, NH), 10.31 (s, 1H, NH), 8.28 ( s, 1H, Ar-H), 8.19 (d, 2H, J=9.0Hz, Ar-H), 8.00 (d, 2H, J=8.4Hz, Ar-H), 7.74 (d, 2H, J=9.0 Hz, Ar-H), 7.64-7.70 (m, 3H, Ar-H), 7.51-7.55 (dd, 2H, _J1 = 15.0Hz, _J2 = 8.4Hz, Ar-H), 7.21 (d, 2H , J=8.4Hz, Ar-H), 7.09(t, 2H, Ar-H), 3.92(s, 6H, OCH ₃ ); IR(KBr, cm ^-1 ): 3342(v _NH ), 2944, 2840 (υ _CH ), 1665 (υ _C=O ), 1596, 1533, 1502, 1482 (υ _C=C ), 1316, 1163 (υ _CN ); EI-MS: m/z 494.5 (M+1). C ₂₉ H ₂₃ N ₃ O ₅ (493.16).

To prepare compound 7t, the substituted acid chloride is acetyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 79.26%.mp: 280-281℃. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.32(s, 1H, NH), 10.12(s, 1H, NH), 8.12 (d, 1H, J=9.0Hz, Ar-H), 8.09(s, 1H, Ar-H), 7.81(d, 2H, J=9.0Hz, Ar-H), 7.67(d, 1H, J= 9.0Hz, Ar-H), 7.48(d, 2H, J=9.0Hz, Ar-H), 2.11(s, 3H, COCH ₃ ), 2.08(s, 3H, COCH ₃ ); IR(KBr, cm ^{- 1} ): 3302 (v _NH ), 1666 (υ _C=O ), 1600, 1532, 1500, 1481 (υ _C=C ), 1315, 1176 (υ _CN ); EI-MS: m/z 310.1 (M+ 1). C ₁₇ H ₁₅ N ₃ O ₃ (309.11).

To prepare compound 7u, the substituted acid chloride is 2-chloroacetyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 82.36%.mp: 293-295°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.69(s, 1H, NH), 10.50(s, 1H, NH), 8.17 (d, 2H, J=8.4Hz, Ar-H), 8.10(s, 1H, Ar-H), 7.84(d, 2H, J=9.0Hz, Ar-H), 7.74(d, 1H, J= 8.4Hz, Ar-H), 7.51-7.53 (dd, 1H, J ₁ =1.8Hz, J ₂ =8.4Hz, Ar-H), 4.31 (s, 4H, COCH ₂ Cl); IR (KBr, cm ^{- 1} ): 3278 (v _NH ), 2948 (υ _CH ), 1673 (υ _C=O ), 1602, 1534, 1500, 1480 (υ _C=C ), 1338, 1178 (υ _CN ); EI-MS: m /z 378.4(M+1).C ₁₇ H ₁₃ Cl ₂ N ₃ O ₃ (377.03).

To prepare compound 7v, the substituted acid chloride is 2-chloropropionyl chloride,

Intermediate 6 is 5-amino-2-(4-aminophenyl)benzoxazole,

White needles, yield: 83.44%.mp: 296-298°C. ¹ H-NMR (DMSO-d ₆ , ppm) δ: 10.71(s, 1H, NH), 10.53(s, 1H, NH), 8.18 (d, 2H, J=9.0Hz, Ar-H), 8.13(s, 1H, Ar-H), 7.86(d, 2H, J=8.4Hz, Ar-H), 7.74(d, 1H, J= 9.0Hz, Ar-H), 7.53-7.55 (dd, 1H, _J1 = 1.8Hz, _J2 = 9.0Hz, Ar-H), 4.72 (t, 2H, COCHCl), 1.65 (dd, 6H, _J1 =3.0Hz, J ₂ =6.6Hz, CH ₃ ); IR (KBr, cm ^-1 ): 3273 (v _NH ), 2981, 2931 (υ _CH ), 1666 (υ _C=O ), 1600, 1538, 1499 (υ _C=C ), 1251, 1198 (υ _CN ); EI-MS: m/z 406.5(M+1).C ₁₉ H ₁₇ Cl ₂ N ₃ O ₃ (405.06).

Embodiment 4: In vitro anti-influenza virus activity test of the target compound

(See ① Vanderlinden E, et al. J Virol. 2010, 84 (9): 4277-88. ② Naesens L, et al. Antiviral Res. 2009, 82 (1): 89-94.)

Test Principle

Viruses are a type of obligate intracellular parasitic microorganisms with simple structure and non-cellular form. They must replicate and multiply in susceptible living animals, chicken embryos or cells. Therefore, animals, chicken embryos or cells can be used to carry out virus culture and drug antiviral tests. Drugs can be judged by observing changes in the pH of cell culture fluid, virus cytopathic effect (CPE), virus titer (PFU), changes in viral genome mRNA levels, changes in chicken embryo allantoic fluid or animal serum, etc. Antiviral test effect.

Viral CCID50 titration principle: After most viruses infect cells cultured in vitro, they often cause changes in cell morphology, such as cell shrinkage, lysis, and cell swelling. This change is called viral cytopathic effect (CPE). It can be observed directly through a microscope, and can also be identified and judged by staining. The degree of CPE can indirectly reflect the virulence of the virus, so this feature can be used to measure the virulence of the virus. That is, the amount of virus required to cause lesions in half of the wells of the cell culture plate or in test tubes is defined as the 50% cell culture infectious dose (CCID ₅₀ ) of the virus. In antiviral tests of drugs, a virus infection dose of 100 CCID50 is commonly used. A virus infection dose of ₅₀ CCID50 was used in this test.

test material

(1) Influenza A/H1N1(strain A/Puerto Rico/8/34), A/H3N2(strain A/HK/7/87) and influenza B(strainB/HK/5/72): developed by Rega University of Leuven, Belgium Provided by the Institute of Microbiology and Immunology, Research Institute.

(2) MDCK cells: Madin Darby canine kidney cells (MDCK), provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium.

(3) MTS: 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfonic acid phenyl)-2H-tetraazole Azole was purchased from Sigma, USA.

(4) Sample treatment: the sample was dissolved in DMSO to make an appropriate concentration before use, and diluted 5 times with double distilled water, each with 5 dilutions.

(5) Positive control drug: Tamiflu (Oseltamivir phosphate, Oseltamivir carboxylate), Ribavirin (Ribavirin), Amantadine (Amantadine) and Rimantadine (Rimantadine)

Test Methods

Cytopathic effect method (CPE)

)中。接着转移到96孔板上，每孔含有7500细胞，并在35℃下孵育20小时。然后，将系列稀释的待测化合物和病毒一起加入到培养基中(感染复数：每孔50CCID50相当于每孔0.0003个噬斑形成单位)，在35℃下继续孵育。在感染72小时后，用显微镜进行观察记录病毒诱导的细胞病变效应(CPE)，按Reed-Muench法计算能抑制50％CPE产生的药物有效浓度(EC₅₀)。The virus stock was inoculated into chicken embryos aged 9-10 days, and the allantoic fluid was collected 48 hours after infection, and titrated in MDCK cells. MDCK cells were suspended in infected medium (Ultra-MDCK

)middle. They were then transferred to 96-well plates containing 7500 cells per well and incubated at 35°C for 20 hours. Then, serial dilutions of the test compound and the virus were added to the culture medium (multiplicity of infection: 50 CCID50 per well is equivalent to 0.0003 plaque-forming units per well), and the incubation was continued at 35°C. After 72 hours of infection, observe and record virus-induced cytopathic effect (CPE) with a microscope, and calculate the effective drug concentration (EC ₅₀ ) that can inhibit 50% of CPE production according to the Reed-Muench method.

The Reed-Muench formula is: CCID ₅₀ = logarithm of the reciprocal of the dilution of infection above 50% + distance ratio × logarithm of the dilution factor; distance ratio = (percentage of infection above 50% - 50%)/ (Percent of infections above 50% - Percent of infections below 50%)

MTS method:

The activity results were further confirmed by the formazan-based MTS cell activity assay. The basic steps are the same as above, when the CPE of the cells in the virus control group is 75% to 100%, discard the supernatant of the culture solution, add 50 μl of the culture solution containing 5g·L MTS to each well, continue to cultivate for 2 to 3 hours, discard the supernatant of the MTS, and discard the supernatant of the MTS in each well. Add 100 μl of DMSO, mix for 5 minutes, and measure the absorbance A value at 570 nm wavelength with a microplate reader. Calculate the inhibitory rate of the drug to the virus according to the following formula:

Virus inhibition rate%=(mean value of drug treatment group A-mean value of virus control group A)/(mean value of cell control group A-mean value of virus control group A)×100%, combined with cytotoxicity test results, using the Probit regression of statistical software SPSS The concentration of the compound that protects 50% of influenza virus-infected cells from pathological changes (EC ₅₀ ) and the compound concentration that causes 50% of uninfected virus cells to become pathological (CC ₅₀ ) was calculated by Reed-Muench method.

Embodiment 5: Anti-influenza virus activity experiment of target compound (MDCK cell)

Table 2 shows the original data on the inhibitory activity and toxicity of substituted benzoxazole derivatives against influenza A virus (H1N1 and H3N2 subtypes) and influenza B virus.

Table 2 Anti-influenza virus activity and toxicity of benzoxazole derivatives

^a EC ₅₀ : the concentration of the compound that inhibits 50% of the virus-induced mutagenic effect or the concentration of the compound that protects 50% of cells infected with influenza virus from cytopathic effects, determined by cytopathic effect (cytopathic effect, CPE) and MTS, respectively. method measured.

^b CC ₅₀ : the concentration that makes 50% of cells not infected with influenza virus pathological, measured by MTS method.

The activity data is the average of the results of the two activity methods of CPE and MTS.

SI = CC ₅₀ /EC ₅₀ .

The 22 synthetic benzoxazole derivatives were screened against influenza A virus (H1N1 and H3N2 subtypes) and influenza B virus activity, and the activity and toxicity data are listed in Table 2, with Tamiflu (phosphate Oseltamivir, Oseltamivircarboxylate), ribavirin (Ribavirin), amantadine (Amantadine) and rimantadine (Rimantadine) were used as positive control drugs.

It can be seen from Table 2 that some target compounds exhibit good inhibitory activity against influenza A virus, but have no inhibitory activity against influenza B virus. Among them, compound 7h has the highest inhibitory activity against influenza A virus, and the activity against H1N1 subtype (EC ₅₀ =96.64 μM, SI>2) is higher than that of the positive control drug amantadine (EC ₅₀ =141.75 μM); anti-H3N2 The activity of the subtype (EC ₅₀ =47.87 μM, SI>4) was higher than that of the positive control drug Tamiflu (EC ₅₀ =60 μM, SI>4). Followed by compound 7t, the activity EC ₅₀ against H1N1 and H3N2 subtypes was 218.23 μM (SI>1) and 83.41 μM (SI>4), respectively, both of which were lower than the activity of the positive control drug.

Claims (9)

1. The 5-substituted-2- (4-substituted phenyl) benzoxazole derivative has the following structural general formula:

   

   when A is Ar, the reaction is carried out,

   

   wherein,

   R¹is H, F, Cl, Br, I, NO₂OMe or Me;

   R²is H, F, Cl, Br, I, NO₂OMe or Me;

   R³is H, F, Cl, Br, I, NO₂、NH₂Me, Et, i-Pr, t-But or OMe;

   R⁴is H, F, Cl, Br, I, NO₂OMe or Me;

   R⁵is H, F, Cl, Br, I, NO₂OMe or Me;

   R⁶is H, F, Cl, Br, I, NO₂OMe or Me;

   and when A is R, A is methyl, ethyl, propyl, chloromethyl, bromomethyl, 2-chloroethyl or 2-bromoethyl.
2. 2. The compound of claim 1, wherein the compound is one of the following structures 7a-7 v:

   

   
3. 3. the compound of claim 2, characterized by being one of the following: n- (4- (5- (3, 4-dimethoxybenzamido) benzoxazol-2-yl) phenyl) -3, 4-dimethoxybenzamide or N- (4- (5-acetamidobenzoxazol-2-yl) phenyl) acetamide.
4. 4. A process for producing a 5-substituted-2- (4-substituted phenyl) benzoxazole derivative according to claim 1, characterized by comprising:

   the synthetic route is as follows:

   

   reagent: (i) refluxing with thionyl chloride; (ii) triethylamine, dioxane; (iii) p-toluenesulfonic acid, dimethylbenzene, at 140 ℃ for 8 hours; (iv) palladium on carbon, hydrogen; (v) triethylamine, N-dimethylformamide;

   the preparation method comprises the following steps: taking p-nitrobenzoic acid (1) as an initial raw material, refluxing in thionyl chloride to obtain p-nitrobenzoyl chloride (2), acylating the p-nitrobenzoyl chloride with 2-amino-4-nitrophenol (3) to obtain a diacylated intermediate 4-nitro-2- (4-nitrobenzamide) phenyl-4-nitrobenzoate (4), cyclizing the intermediate (4) under the action of p-toluenesulfonic acid and xylene to obtain 5-nitro-2- (4-nitrobenzene) benzoxazole (5), reducing nitro of the compound (5) into amino under the catalysis of palladium carbon to obtain a mother nucleus 5-amino-2- (4-aminobenzene) benzoxazole (6), and finally carrying out acylation reaction on the compound (6) and various substituted benzoyl chlorides or fatty acyl chlorides to generate benzoxazole target compounds (7a-7 v);

   the various substituted benzoyl chlorides or fatty acid chlorides mentioned above are: p-nitrobenzoyl chloride, p-fluorobenzoyl chloride, p-chlorobenzoyl chloride, p-bromobenzoyl chloride, p-iodobenzoyl chloride, p-methoxybenzoyl chloride, 3, 4-dichlorobenzoyl chloride, 3, 4-dimethoxybenzoyl chloride, 2-nitro-4-chlorobenzoyl chloride, benzoyl chloride, p-aminobenzoyl chloride, p-methylbenzoyl chloride, p-tert-butylbenzoyl chloride, p-propylbenzoyl chloride, m-fluorobenzoyl chloride, m-chlorobenzoyl chloride, m-methylbenzoyl chloride, m-nitrobenzoyl chloride, o-methoxybenzoyl chloride, acetyl chloride, 2-chloroacetyl chloride, 2-chloropropionyl chloride.
5. 5. The process for producing 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives according to claim 4, characterized in that the intermediate 5-nitro-2- (4-nitrophenyl) benzoxazole (5) is produced as follows:

   adding 6.68g of p-nitrobenzoic acid and 30mL of thionyl chloride into a 250mL round-bottom flask, refluxing for 2 hours at 80 ℃, evaporating the solvent under reduced pressure to obtain p-nitrobenzoyl chloride, dissolving 3.08g of 2-amino-4-nitrophenol and 4.04g of triethylamine into 50mL of dioxane, dropwise adding the mixture into the acyl chloride in an ice bath, reacting for 2 hours at 100 ℃ after dropwise adding, and monitoring the reaction process by TLC; after the reaction is finished, evaporating the solvent under reduced pressure, adding a proper amount of water, performing suction filtration, and performing vacuum drying at 90 ℃; recrystallization from N, N-dimethylformamide-ethanol gave the diacylated intermediate 4-nitro-2- (4-nitrobenzamide) phenyl-4-nitrobenzoate (4) as yellow needle crystals, mp: 234 ℃ and 236 ℃;

   to a 100mL round bottom flask was added 0.28g of intermediate (4), 0.2g of p-toluenesulfonic acid and 30mL of xylene, refluxed at 140 ℃ and monitored by TLC for the progress of the reaction; after 4 hours, the reaction was completed, and the reaction mixture was cooled, filtered, and recrystallized from N, N-dimethylformamide-ethanol to obtain 0.13g of an intermediate 5-nitro-2- (4-nitrobenzene) benzoxazole (5) as a white floc, with a yield of 76.02%, mp: 261 ℃ and 262 ℃.
6. 6. The process for producing 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives according to claim 4, characterized in that the intermediate 5-amino-2- (4-aminophenyl) benzoxazole (6) is produced as follows:

   adding 0.89g of 5-nitro-2- (4-nitrobenzene) benzoxazole (5) and 30mL of N, N-dimethylformamide into a 250mL round-bottom flask, heating to completely dissolve the 5-nitro-2- (4-nitrobenzene) benzoxazole, then adding 0.09g of 10% palladium carbon, pumping out air, stirring for 24 hours in a hydrogen environment, and monitoring the reaction progress by TLC; after the reaction is finished, a large amount of water is added to precipitate a light pink needle-like substance, the solution is subjected to suction filtration and methanol recrystallization to obtain 0.55g of mother nucleus 5-amino-2- (4-aminobenzene) benzoxazole (6), the yield is 81.48%, and the mp: 230 ℃ and 231 ℃.
7. 7. The process for producing a 5-substituted-2- (4-substituted phenyl) benzoxazole derivative according to claim 4, characterized in that the 5-substituted-2- (4-substituted phenyl) benzoxazole derivative is produced by the following method:

   adding 0.0025mol of substituted benzoic acid and 30mL of thionyl chloride into a 50mL round-bottom flask, refluxing for 2 hours at 80 ℃, evaporating the solvent under reduced pressure to obtain substituted benzoyl chloride, and dissolving the substituted benzoyl chloride in 10mL of dry N, N-dimethylformamide; dissolving 5g of amino-2- (4-aminobenzene) benzoxazole (6) and 0.25g of triethylamine in 20mL of dry N, N-dimethylformamide, dropwise adding the mixture into the acyl chloride in an ice bath, reacting at room temperature after dropwise adding, and monitoring the reaction process by TLC; after the reaction is finished for 2 hours, the solvent is evaporated under reduced pressure, excessive water is added, crystals are separated out, and the mixture is filtered by suction and dried in vacuum at the temperature of 90 ℃; and recrystallizing the N, N-dimethylformamide-ethanol to obtain the target compound (7a-7 v).
8. 8. Use of the 5-substituted-2- (4-substituted phenyl) benzoxazole derivative according to claim 1 for the preparation of a medicament for an influenza virus inhibitor.
9. 9. A pharmaceutical composition for resisting influenza virus, which is characterized in that the 5-substituted-2- (4-substituted phenyl) benzoxazole derivative of claim 1 and pharmaceutical excipients are used for preparing pharmaceutical preparations with different dosage forms.