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

5-substituted-2-(4-substituted phenyl)benzoxazole derivatives and preparation method and application thereof Download PDF

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CN102070549A
CN102070549A CN 201110021056 CN201110021056A CN102070549A CN 102070549 A CN102070549 A CN 102070549A CN 201110021056 CN201110021056 CN 201110021056 CN 201110021056 A CN201110021056 A CN 201110021056A CN 102070549 A CN102070549 A CN 102070549A
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刘新泳
李震宇
展鹏
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Shandong University
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Abstract

The invention provides 5-substituted-2-(4-substituted phenyl)benzoxazole derivatives. A general structural formula thereof is as follows: when A is Ar, wherein R1 is H, F, Cl, Br, I, NO2, OMe or Me; R2 is H, F, Cl, Br, I, NO2, OMe or Me; R3 is H, F, Cl, Br, I, NO2, NH2, Me, Et, i-Pr, t-But or OMe; R4 is H, F, Cl, Br, I, NO2, OMe or Me; R5 is H, F, Cl, Br, I, NO2, OMe or Me; and R6 is H, F, Cl, Br, I, NO2, OMe or Me. When A is R, A is methyl, ethyl, propyl, chloromethyl, bromomethyl, 2-chloroethyl or 2-bromoethyl. The invention also relates to a method for preparing the compounds and application of the compounds when taken as an influenza virus inhibitor.

Description

5-substituted-2- (4-substituted phenyl) benzoxazole derivative and preparation method and application thereof
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
Influenza, called influenza for short, is a respiratory disease caused by influenza virus, has the characteristics of wide epidemic range, strong infectivity, high morbidity and the like, and has higher death rate in children, old people and high risk groups. Influenza virus belongs to the family of orthomyxoviridae, is spherical or filamentous, and is a negative-helix single-stranded segmented RNA virus (see Zhang Qiang et al, progress in anti-influenza virus drug research, pharmacy bulletin, 2010, 45(3), 289 and 299). Influenza viruses are classified into a (a), B and C (C)3 types according to antigenic properties of virion Nucleoprotein (NP) and Membrane Protein (MP) and genetic properties thereof, wherein the a and B types of influenza viruses are mainly associated with human diseases, and human influenza viruses currently circulating worldwide are mainly H1N1 subtype, H3N2 subtype and B type. Anti-influenza drugs currently in common use include two classes: m2 receptor blockers and Neuraminidase (NA) inhibitors. The former mainly inhibits the integration of virus genes into host cells through inhibiting the M2 ion channel of the virus, and can take effect by prophylactic administration or administration within 48h of virus infection, but the former has no effect on influenza B virus and is easy to generate wide virus resistance, so the drugs are not recommended to be used for treating influenza. The neuraminidase inhibitor is effective to influenza A and influenza B viruses and has good safety, and is an anti-influenza medicament recommended to many countries at present (see Zha et al, in vitro anti-influenza virus activity evaluation of clinical commonly used Chinese patent medicines, pharmacy bulletin, 2010, 45(3), 408-containing material 412). However, because the existing drugs are widely applied clinically, influenza viruses are mutated, and different degrees of drug resistance are generated to the drugs, so that the development of novel and highly drug-resistant influenza virus inhibitors is one of the main directions of the research of anti-influenza virus drugs at present.
The invention synthesizes a series of 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives, and discovers an A-type influenza virus inhibitor with good activity and novel structure by screening anti-influenza virus activity, and has important significance for discovering novel anti-influenza virus medicaments with broad spectrum, high efficiency and independent intellectual property rights.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a 5-substituted-2- (4-substituted phenyl) benzoxazole derivative and a preparation method and application thereof.
The technical scheme of the invention is as follows:
1, 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives
The 5-substituted-2- (4-substituted phenyl) benzoxazole derivative has the following structural general formula:
Figure BSA00000421505900011
when A is Ar, the reaction is carried out,
Figure BSA00000421505900012
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.
The synthetic route of the 2.5-substituted-2- (4-substituted phenyl) benzoxazole derivative is as follows:
Figure BSA00000421505900021
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.
Wherein A is the same as in the above-mentioned derivatives.
Preparation of 3, 5-substituted-2- (4-substituted phenyl) benzoxazole derivative 7
Taking p-nitrobenzoic acid 1 as a starting material, refluxing in thionyl chloride to obtain p-nitrobenzoyl chloride 2, acylating the p-nitrobenzoyl chloride 2 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 parent 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-7v, wherein the specific structure is as follows:
TABLE 1 structural formulas of target compounds 7a-7v
Figure BSA00000421505900022
Figure BSA00000421505900031
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.
The preparation method comprises the following specific steps:
(1) preparation of intermediate 5-nitro-2- (4-nitrobenzene) benzoxazole 5
6.68g of p-nitrobenzoic acid and 30mL of thionyl chloride were added to a 250mL round-bottomed flask, refluxed for 2 hours at 80 ℃, and evaporated under reduced pressure to remove the solvent to obtain p-nitrobenzoyl chloride, then 3.08g of 2-amino-4-nitrophenol and 4.04g of triethylamine were dissolved in 50mL of dioxane, added dropwise to the acid chloride in an ice bath, and after completion of the addition, reacted at 100 ℃ for 2 hours, and the progress of the reaction was monitored 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 ℃; recrystallizing N, N-dimethylformamide-ethanol to obtain a diacylation intermediate 4-nitro-2- (4-nitrobenzamide) phenyl-4-nitrobenzoate 4 which is yellow needle crystal;
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 reaction progress. After 4 hours, the reaction is finished, and the intermediate 5-nitro-2- (4-nitrobenzene) benzoxazole is obtained by cooling, suction filtration and N, N-dimethylformamide-ethanol recrystallization, and is white floccule;
(2) preparation of intermediate 5-amino-2- (4-aminophenyl) benzoxazole 6
To a 250mL round bottom flask were added 0.89g of 5-nitro-2- (4-nitrophenyl) benzoxazole 5 and 30mL of N, N-dimethylformamide, heated to dissolve all, followed by addition of 0.09g of 10% palladium on carbon, air purged, stirred under hydrogen atmosphere for 24 hours and reaction progress monitored by TLC. After the reaction is finished, adding a large amount of water, separating out light pink needle-like substances, performing suction filtration, and recrystallizing with methanol to obtain 60.55g of parent nucleus 5-amino-2- (4-aminobenzene) benzoxazole;
(3) preparation of 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives
To a 50mL round bottom flask, 0.0025mol of substituted benzoic acid and 30mL of thionyl chloride were added, refluxed at 80 ℃ for 2 hours, and the solvent was distilled off under reduced pressure to obtain substituted benzoyl chloride, which was then dissolved in 10mL of dry N, N-dimethylformamide. 5g of amino-2- (4-aminophenyl) benzoxazole 6 and 0.25g of triethylamine were dissolved in 20mL of dry N, N-dimethylformamide, and the mixture was added dropwise to the acid chloride in an ice bath, followed by reaction at room temperature and monitoring of the progress of the reaction 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 compounds 7a-7 v.
The target compound is preferably one of the compounds having the structural formulae 7a to 7v listed in table 1.
More preferred compounds of the subject are: n- (4- (5- (3, 4-dimethoxybenzamido) benzoxazol-2-yl) phenyl) -3, 4-dimethoxybenzamide 7h and N- (4- (5-acetamidobenzoxazol-2-yl) phenyl) acetamide 7 t.
4.5-substituted-2- (4-substituted phenyl) benzoxazole derivative pharmaceutical composition
A pharmaceutical composition for resisting influenza A virus comprises the above 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives and medicinal adjuvants, and is made into different dosage forms.
Application of 5, 5-substituted-2- (4-substituted phenyl) benzoxazole derivatives
The 5-substituted-2- (4-substituted phenyl) benzoxazole derivative can be used as an influenza virus inhibitor. In particular to a preparation of anti-influenza virus medicine as an influenza A virus inhibitor.
The invention provides a 5-substituted-2- (4-substituted phenyl) benzoxazole derivative with a brand-new structure, a preparation method thereof, an anti-influenza virus activity screening result thereof and a first application thereof in the field of antivirus. Experiments prove that the 5-substituted-2- (4-substituted phenyl) benzoxazole derivative can be applied as an influenza A virus inhibitor. In particular to a preparation of anti-influenza virus medicine as an influenza A virus inhibitor.
The specific implementation mode is as follows:
the invention is further illustrated by the following examples, all of which are numbered as in Table 1. The percentages are not specifically indicated and are all mass percentages, and the raw materials used are not specifically indicated and are all commercially available.
Example 1: preparation method of intermediate 5-nitro-2- (4-nitrobenzene) benzoxazole 5
6.68g of p-nitrobenzoic acid and 30mL of thionyl chloride were added to a 250mL round-bottomed flask, refluxed for 2 hours at 80 ℃, and evaporated under reduced pressure to remove the solvent to obtain p-nitrobenzoyl chloride, then 3.08g of 2-amino-4-nitrophenol and 4.04g of triethylamine were dissolved in 50mL of dioxane, added dropwise to the acid chloride in an ice bath, and after completion of the addition, reacted at 100 ℃ for 2 hours, and the progress of the reaction was monitored 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 ℃; recrystallizing the N, N-dimethylformamide-ethanol to obtain a diacylated intermediate 4-nitro-2- (4-nitrobenzamide) phenyl-4-nitrobenzoate 4 which is yellow needle crystal, 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 reaction progress. After 4 hours, the reaction was completed, and the reaction mixture was cooled, filtered, and recrystallized from N, N-dimethylformamide-ethanol to obtain 50.13g of an intermediate 5-nitro-2- (4-nitrobenzene) benzoxazole as a white floccule, with a yield of 76.02%, mp: 261-262 ℃;
product spectral analysis data:
1H-NMR(DMSO-d6)δ：8.78(d，1H，J＝1.8Hz，Ar-H)，8.47-8.50(m，4H，Ar-H)，8.41-8.43(dd，1H，J1＝1.8Hz，J2＝9.0Hz，Ar-H)，8.13(d，1H，J＝9.0Hz，Ar-H)；EI-MS：m/z 286.4(M+1).C13H7N3O5(285.04).
example 2: preparation method of intermediate 5-amino-2- (4-aminophenyl) benzoxazole 6
To a 250mL round bottom flask was added 0.89g of 5-nitro-2- (4-nitrophenyl) benzoxazole 5 and 30mL of ln, N-dimethylformamide, heated to dissolve all, followed by the addition of 0.09g of 10% palladium on carbon, air purged, stirred under hydrogen atmosphere for 24 hours and the progress of the reaction monitored by TLC. After the reaction is finished, adding a large amount of water, separating out light pink needle-like substances, performing suction filtration, and recrystallizing with methanol to obtain 60.55g of parent nucleus 5-amino-2- (4-aminobenzene) benzoxazole; yield 81.48%, mp: 230 ℃ and 231 ℃.
Product spectral analysis data
1H-NMR(DMSO-d6)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，NH2)，4.98(s，2H，NH2)；EI-MS：m/z 226.0(M+1).C13H11N3O(225.09).
Example 3: preparation of 5-substituted-2- (4-substituted phenyl) benzoxazole derivative 7
To a 50mL round bottom flask, 0.0025mol of substituted benzoic acid and 30mL of thionyl chloride were added, refluxed at 80 ℃ for 2 hours, and the solvent was distilled off under reduced pressure to obtain substituted benzoyl chloride, which was then dissolved in 10mL of dry N, N-dimethylformamide. 5g of amino-2- (4-aminophenyl) benzoxazole 6 and 0.25g of triethylamine were dissolved in 20mL of dry N, N-dimethylformamide, and the mixture was added dropwise to the acid chloride in an ice bath, followed by reaction at room temperature and monitoring of the progress of the reaction 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 ℃; recrystallization from N, N-dimethylformamide-ethanol gave the title compound 7a in 61.06% yield, mp: is > 300 ℃.
Product spectral analysis data:
1H-NMR(DMSO-d6，ppm)δ：10.92(s，1H，N-H)，10.76(s，1H，N-H)，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(vNH)，1664(υC＝O)，1598，1499，1479(υC＝C)，1525，1347(vNO2)，1320，1172(υC-N)；EI-MS：m/z 524.2(M+1).C27H17N5O7(523.11).
other target products were prepared from various substituted acid chlorides and intermediate 6, respectively, using the methods described above, with the following results:
preparing a compound 7b, wherein the substituted acyl chloride is p-fluorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900051
white needles, yield 57.45%, mp: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.63(s，1H，N-H)，10.46(s，1H，N-H)，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(vNH)，1654(υC＝O)，1534，1506，1412(υC＝C)，1327，1142(υC-N)；EI-MS：m/z 470.5(M+1).C27H17F2N3O3(469.12).
Preparing a compound 7c, wherein the substituted acyl chloride is p-chlorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900061
off-white powder, yield: 61.63%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.68(s，1H，N-H)，10.51(s，1H，N-H)，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(vAr-H)，1647(υC＝O)，1594，1526，1485，1410(υC＝C)，1321，1175(υC-N)；EI-MS：m/z502.2(M+1).C27H17Cl2N3O3(501.06).
Preparing a compound 7d, wherein the substituted acyl chloride is p-bromobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900062
light yellow needle crystal, yield: 47.38%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.67(s，1H，N-H)，10.50(s，1H，N-H)，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(vNH)，1647(υC＝O)，1590，1526，1502，1482(υC＝C)，1325，1174(υC-N)；EI-MS：m/z 590.1(M+1).C27H17Br2N3O3(588.96).
Preparing a compound 7e, wherein the substituted acyl chloride is p-iodobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900063
off-white needle crystals, yield: 52.47%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.64(s，1H，N-H)，10.48(s，1H，N-H)，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(vNH)，1656(υC＝O)，1605，1531，1493(υC＝C)，1324，1173(υC-N)；EI-MS：m/z 686.4(M+1).C27H17I2N3O3(684.94).
Preparing a compound 7f, wherein the substituted acyl chloride is p-methoxybenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900071
off-white needle crystals, yield: 60.67%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.50(s，1H，N-H)，10.31(s，1H，N-H)，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＝9.0Hz，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，-CH3)；IR(KBr，cm-1)：3295(vNH)，2932，2837(υCH(CH3))，1648(υC＝O)，1605，1505，1478(υC＝C)，1315，1176(υC-N)；EI-MS：m/z 494.5(M+1).C29H23N3O5(493.16).
Preparation of 7g of the compound, the substituted acid chloride being 3, 4-dichlorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900072
white needle crystal, yield: 57.45%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.73(s，1H，N-H)，10.58(s，1H，N-H)，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(vNH)，1645(υC＝O)，1595，1526，1500(υC＝C)，1320，1177(υC-N)；EI-MS：m/z 572.1(M+1).C27H15Cl4N3O3(571.24)
Preparing a compound for 7h, wherein the substituted acyl chloride is 3, 4-dimethoxy benzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900073
white needle crystal, yield: 47.45%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.42(s，1H，N-H)，10.26(s，1H，N-H)，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＝9.0Hz，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，OCH3)；IR(KBr，cm-1)：3277(vNH)，2934，2837(υCH)，1647(υC＝O)，1599，1506(υC＝C)，1315，1176(υC-N)；EI-MS：m/z 554.5(M+1).C31H27N3O7(553.18).
Preparing a compound 7i, wherein the substituted acyl chloride is 2-nitro-4-chlorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900074
light yellow needle crystal, yield: 49.36%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：11.10(s，1H，N-H)，10.92(s，1H，N-H)，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(vNH)，1654(υC＝O)，1534，1350(vNO2)，1350，1173(υC-N)；EI-MS：m/z 592.2(M+1).C27H15Cl2N5O7(591.03).
To prepare a compound 7j, the substituted acyl chloride is benzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900081
white needle crystal, yield: 64.02%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.63(s，1H，N-H)，10.45(s，1H，N-H)，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)，7.72-7.79(m，6H，Ar-H)；IR(KBr，cm-1)：3262(vNH)，1653(υC＝O)，1533，1493，1410(υC＝C)，1325，1176(υC-N)；EI-MS：m/z 434.6(M+1).C27H19N3O3(433.14).
Preparing a compound 7k, wherein the substituted acyl chloride is p-aminobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900082
light brown needle crystal, yield: 43.58%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.12(s，1H，N-H)，9.46(s，1H，N-H)，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(vNH)，1653(υC＝O)，1604，1508，1408(υC＝C)，1314，1179(υC-N)；EI-MS：m/z 464.5(M+1).C27H21N5O3(463.16)
Preparing a compound 7l, wherein the substituted acyl chloride is p-methylbenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900083
white needle crystal, yield: 67.16%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.57(s，1H，N-H)，10.39(s，1H，N-H)，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-CH3)；IR(KBr，cm-1)：3282(vNH)，2919(υCH)，1654(υC＝O)，1592，1500，1478(υC＝C)，1321，1165(υC-N)；EI-MS：m/z 462.4(M+1).C29H23N3O3(461.17).
Preparing a compound 7m, wherein the substituted acyl chloride is p-tert-butylbenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900091
white needle crystal, yield: 56.64%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.55(s，1H，N-H)，10.37(s，1H，N-H)，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＝8.4Hz，Ar-H)，7.75(s，2H，Ar-H)，7.58(t，4H，Ar-H)，1.34(s，18H，CH3)；IR(KBr，cm-1)：3304(vNH)，2961，2868(υCH(CH3))，1638(υC＝O)，1592，1500，1479(υC＝C)，1318，1167(υC-N)；EI-MS：m/z 546.5(M+1).C35H35N3O3(545.27).
Preparing a compound 7n, wherein the substituted acyl chloride is p-propylbenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900092
white needle crystal, yield: 62.98%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.54(s，1H，N-H)，10.36(s，1H，N-H)，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＝7.8Hz，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，CH3)；IR(KBr，cm-1)：3309(vNH)，2957，2929，2870(υCH)，1652(υC＝O)，1526，1500，1479(υC＝C)，1318，1179(υC-N)；EI-MS：m/z 518.5(M+1).C33H31N3O3(517.24).
To prepare a compound 7o, the substituted acyl chloride is m-fluorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900093
white needle crystal, yield: 63.78%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.68(s，1H，N-H)，10.51(s，1H，N-H)，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(vNH)，1656(υC＝O)，1587，1531，1482(υC＝C)，1323，1179(υC-N)；EI-MS：m/z 470.5(M+1).C27H17F2N3O3(469.12).
Preparing a compound 7p, wherein the substituted acyl chloride is m-chlorobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900101
white needle crystal, yield: 42.89%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.70(s，1H，N-H)，10.54(s，1H，N-H)，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(vNH)，1651(υC＝O)，1596，1524，1501(υC＝C)，1324，1178(υC-N)；EI-MS：m/z 502.2(M+1).C27H17Cl2N3O3(501.06).
Preparing a compound 7q, wherein the substituted acyl chloride is m-methyl benzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900102
white needle crystal, yield: 67.16%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.57(s，1H，N-H)，10.40(s，1H，N-H)，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-CH3)；IR(KBr，cm-1)：3276(vNH)，2918，2860(υCH)，1694(υC＝O)，1603，1530，1501，1478(υC＝C)，1320，1178(υC-N)；EI-MS：m/z 462.4(M+1).C29H23N3O3(461.17).
Preparing a compound 7r, wherein the substituted acyl chloride is m-nitrobenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
yellow needle crystal, yield: 39.94%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.90(s，1H，N-H)，10.77(s，1H，N-H)，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(vNH)，1667(υC＝O)，1596，1499，1479(υC＝C)，1525，1348(vNO2)，1323，1172(υC-N)；EI-MS：m/z 524.2(M+1).C27H17N5O7(523.11).
Preparing a compound 7s, wherein the substituted acyl chloride is o-methoxybenzoyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900111
white needle crystal, yield: 52.16%. m.p.: is > 300 ℃.1H-NMR(DMSO-d6，ppm)δ：10.50(s，1H，N-H)，10.31(s，1H，N-H)，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＝9.0Hz，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，OCH3)；IR(KBr，cm-1)：3342(vNH)，2944，2840(υCH)，1665(υC＝O)，1596，1533，1502，1482(υC＝C)，1316，1163(υC-N)；EI-MS：m/z494.5(M+1).C29H23N3O5(493.16).
Preparing a compound 7t, wherein the substituted acyl chloride is acetyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900112
white needle crystal, yield: 79.26%. m.p.: 280 ℃ and 281 ℃.1H-NMR(DMSO-d6，ppm)δ：10.32(s，1H，N-H)，10.12(s，1H，N-H)，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，COCH3)，2.08(s，3H，COCH3)；IR(KBr，cm-1)：3302(vNH)，1666(υC＝O)，1600，1532，1500，1481(υC＝C)，1315，1176(υC-N)；EI-MS：m/z 310.1(M+1).C17H15N3O3(309.11).
Preparing a compound 7u, wherein the substituted acyl chloride is 2-chloroacetyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900113
white needle crystal, yield: 82.36%. m.p.: 293 and 295 ℃.1H-NMR(DMSO-d6，ppm)δ：10.69(s，1H，N-H)，10.50(s，1H，N-H)，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，J1＝1.8Hz，J2＝8.4Hz，Ar-H)，4.31(s，4H，COCH2Cl)；IR(KBr，cm-1)：3278(vNH)，2948(υCH)，1673(υC＝O)，1602，1534，1500，1480(υC＝C)，1338，1178(υC-N)；EI-MS：m/z 378.4(M+1).C17H13Cl2N3O3(377.03).
Preparing a compound 7v, wherein the substituted acyl chloride is 2-chloropropionyl chloride,
the intermediate 6 is 5-amino-2- (4-aminophenyl) benzoxazole,
Figure BSA00000421505900114
white needle crystal, yield: 83.44%. m.p.: 296 ℃ and 298 ℃.1H-NMR(DMSO-d6，ppm)δ：10.71(s，1H，N-H)，10.53(s，1H，N-H)，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，J2＝6.6Hz，CH3)；IR(KBr，cm-1)：3273(vNH)，2981，2931(υCH)，1666(υC＝O)，1600，1538，1499(υC＝C)，1251，1198(υC-N)；EI-MS：m/z 406.5(M+1).C19H17Cl2N3O3(405.06).
Example 4: in vitro anti-influenza virus activity assay for target compounds
(see: Vanderlinden E, et al. J Virol.2010, 84 (9): 4277-88., (Naesens L, et al. antiviral Res.2009, 82 (1): 89-94.)
Principle of testing
Viruses are obligate intracellular parasitic microorganisms of simple structure and non-cellular morphology, and must replicate and proliferate in susceptible live animals, chick embryos or cells. Animals, chicken embryos or cells can therefore be used for virus culture and antiviral testing of drugs. The antiviral test effect of the medicine can be judged by observing the change of the pH value of the cell culture solution, the virus cytopathic effect (CPE), the change of the virus titer (PFU), the change of the mRNA level of the virus genome, the change of the corresponding indexes such as chick embryo allantoic fluid or animal serum and the like.
Titration principle of virus CCID 50: many viruses infect cells cultured in vitro, often causing morphological changes such as cell shrinkage, lysis, and cell swelling, which are called viral pathogenic effects (CPE), and can be directly observed by microscopy or identified and judged by staining. The extent of CPE is indirectly reflective of the virulence of the virus and therefore this characteristic can be used to determine the virulence of the virus. The amount of virus required to cause cytopathic effects in half of the wells or tubes of a cell culture plate is defined as the 50% cell infection index (CCID) of the virus50). In antiviral tests for pharmaceutical agents, a viral infection level of 100 CCID50 is commonly used. The test uses 50CCID50The amount of virus infection of (a).
Test material
(1) influenza A/H1N1(strain A/Puerto Rico/8/34), A/H3N2(strain A/HK/7/87), and influenza B (strain B/HK/5/72): provided by the institute of microbiology and immunology, Rega institute of Leuven university, belgium.
(2) MDCK cells: dog kidney epithelial cells (MDCK, Madin Darby Canine Kidney cells), by Belgium Leuven university Rega institute of microorganisms and immunology institute provide.
(3) MTS: 3- (4, 5-Dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazol, purchased from Sigma, USA.
(4) Sample treatment: the samples were dissolved in DMSO to give appropriate concentrations just before use, and diluted 5-fold with double distilled water, each at 5 dilutions.
(5) Positive control drug: tamiflu (Oseltamivir phosphate), Ribavirin (Ribavirin), Amantadine (Amantadine), and Rimantadine (Rimantadine)
Test method
Cytopathic effect method (CPE)
Inoculating the virus stock into 9-10 day old chick embryos, infecting for 48h, collecting allantoic fluid, and titrating in MDCK cells. MDCK cells are suspended in infected media (Ultra-MDCK)
Figure BSA00000421505900121
) In (1). Then transferred to 96-well plates, each containing 7500 cells, and incubated at 35 ℃ for 20 hours. The serial dilutions of test compound and virus were then added to the medium (multiplicity of infection: 50CCID50 per well corresponds to 0.0003 plaque forming units per well) and incubation continued at 35 ℃. After 72 hours of infection, virus-induced cytopathic effect (CPE) was recorded by microscopic observation, and the effective concentration of the drug (EC) that inhibited 50% of CPE production was calculated according to the Reed-Muench method50)。
The Reed-Muench formula is: CCID50Greater than 50% infectedThe logarithm of the reciprocal of the dilution + the distance ratio x the logarithm of the dilution factor; distance ratio ═ (percentage of infection above 50% — 50%)/(percentage of infection above 50% — percentage of infection below 50%)
MTS method:
the activity results were further confirmed by formazan-based MTS cell activity assays. And (3) discarding the culture solution supernatant when the virus control group cell CPE is 75-100%, adding 50 mu L of culture solution containing 5 g.L MTS into each hole, continuously culturing for 2-3 h, then discarding the MTS supernatant, adding 100 mu L of DMSO into each hole, uniformly mixing for 5min, and then measuring the absorbance A value at the wavelength of 570nm by using an enzyme labeling instrument. The inhibition rate of the drug to the virus is calculated according to the following formula:
percent virus inhibition (drug treatment group A mean-virus control group A mean)/(cell control group A mean-virus control group A mean) x 100%), and the concentration of compound (EC) for protecting 50% of influenza virus infected cells from lesions was calculated by Probit regression method of SPSS (statistical software) or Reed-Muench method in combination with the results of cytotoxicity test50) And the Concentration of Compound (CC) that causes lesions in 50% of uninfected viral cells50)。
Example 5: test for anti-influenza Virus Activity of Compounds of interest (MDCK cells)
The original data of the inhibitory activity and toxicity of the substituted benzoxazole derivatives on influenza A viruses (H1N1 and H3N2 subtypes) and influenza B viruses are shown in Table 2.
Figure BSA00000421505900131
TABLE 2 benzoxazole derivatives against influenza virus activity and toxicity
Figure BSA00000421505900132
Figure BSA00000421505900141
aEC50: the concentration of compound that inhibits 50% of the virus-induced cell-mutating effects or that protects 50% of the cells infected with influenza virus from cytopathic effects was determined by cytopathic effects (CPE) and MTS methods, respectively.
bCC50: the concentration at which 50% of cells not infected with influenza virus were diseased was measured by the MTS method.
The activity data are the average of the results of both CPE and MTS activity methods.
SI＝CC50/EC50。
The 22 synthesized benzoxazole derivatives were screened for activity against influenza a virus (subtypes H1N1 and H3N 2) and influenza B virus, and the activity and toxicity data are listed in table 2, with tamiflu (oseltamivir phosphate, Oseltamivircarboxylate), Ribavirin (Ribavirin), Amantadine (Amantadine), and Rimantadine (Rimantadine) as positive control drugs.
As can be seen from table 2, some of the target compounds showed better inhibitory activity against influenza a virus, but no inhibitory activity against influenza B virus. Wherein the compound 7H has the highest inhibitory activity on influenza A virus and has activity (EC) against H1N1 subtype5096.64 μ M, SI > 2) is higher than the activity (EC) of amantadine, a positive control drug50141.75 μ M); activity against subtype H3N2 (EC)5047.87 μ M, SI > 4), higher than the activity (EC) of the positive control drug tamiflu5060 μ M, SI > 4). Secondly, compound 7t, active EC against subtype H1N1 and H3N250218.23 μ M (SI > 1) and 83.41 μ M (SI > 4), respectively, were less active than the positive control drug.

Claims (9)

  1. The 5-substituted-2- (4-substituted phenyl) benzoxazole derivative has the following structural general formula:
    Figure FSA00000421505800011
    when A is Ar, the reaction is carried out,
    Figure FSA00000421505800012
    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:
    Figure FSA00000421505800013
    Figure FSA00000421505800021
  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:
    Figure FSA00000421505800022
    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.
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Cited By (5)

* Cited by examiner, † Cited by third party
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CN108586374A (en) * 2018-01-12 2018-09-28 浙江鼎龙科技有限公司 The preparation method of 2- phenyl benzoxazoles class compounds
CN110283137A (en) * 2019-06-13 2019-09-27 爱斯特（成都）生物制药股份有限公司 A kind of preparation method of 2- (4- bromophenyl) -1,3- benzoxazoles
CN110577500A (en) * 2019-10-01 2019-12-17 常州市阳光药业有限公司 Preparation method of 2- (aminophenyl) -5-aminobenzoxazole
KR102191497B1 (en) * 2019-09-05 2020-12-15 계명대학교 산학협력단 Pharmaceutical composition for preventing or treating influenza virus infection comprising heterocycle compounds
CN113150276A (en) * 2021-03-10 2021-07-23 张宝德 Preparation method of polyimide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《REGISTRY》 20060824 STN Columbus rn:294656-34-1,313537-70-1,313554-23-3,423128-03-4,423128-05-6,423128-08-9,423128-10-3,423128-12-5,904278-74-6 294656-34-1,313537-70-1,313554-23-3,423128-03-4,423128-05-6,423128-08-9,423128-10-3,423128-12-5,904278-74-6 1-3 , 2 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586374A (en) * 2018-01-12 2018-09-28 浙江鼎龙科技有限公司 The preparation method of 2- phenyl benzoxazoles class compounds
CN108586374B (en) * 2018-01-12 2021-01-05 浙江鼎龙科技有限公司 Preparation method of 2-phenylbenzoxazole compound
CN110283137A (en) * 2019-06-13 2019-09-27 爱斯特（成都）生物制药股份有限公司 A kind of preparation method of 2- (4- bromophenyl) -1,3- benzoxazoles
KR102191497B1 (en) * 2019-09-05 2020-12-15 계명대학교 산학협력단 Pharmaceutical composition for preventing or treating influenza virus infection comprising heterocycle compounds
CN110577500A (en) * 2019-10-01 2019-12-17 常州市阳光药业有限公司 Preparation method of 2- (aminophenyl) -5-aminobenzoxazole
CN113150276A (en) * 2021-03-10 2021-07-23 张宝德 Preparation method of polyimide

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