A trifluoromethyl substituted ethylene diazole and its preparation method and application

Abstract

The invention discloses a trifluoromethyl-substituted ethylene diazole and a preparation method and application thereof, and belongs to the field of organic synthetic chemistry. The trifluoromethyl-substituted ethylene diazole has the following structure: #imgabs0# wherein X is 5-substituted tetrazole, tetrazole, purine, substituted purine, imidazole, substituted imidazole, benzimidazole, substituted benzimidazole, pyrazole, substituted pyrazole, 1,2,3-triazole, 1,2,3-benzotriazole or 1,2,4-triazole, and X is bonded to a fixed group via a nitrogen atom. The invention discloses a series of ethylene diazole compounds with a trifluoromethyl-substituted group, and the trifluoromethyl-substituted ethylene diazole compounds have good antifungal activity and are expected to be developed into a new class of antibacterial drugs.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a trifluoromethyl-substituted vinyldiazole and a preparation method and application thereof. Background Art

[0002] Azoles are an important class of nitrogen-containing heterocycles that are widely found in natural products, synthetic drugs, and functional materials. For example, pyrazole pesticides have the advantages of high efficiency, low toxicity, and diverse structures, and are widely used in many fields such as weed control, insecticide / mite control, and bactericidal control (Chem. Rev. 2021, 121, 1670). Benzimidazole derivatives are widely used in the field of agricultural fungicides, and also have multiple biological activities such as antiviral, anticancer, anti-inflammatory, and antioxidant. Triazole drugs are a new class of antifungal drugs that have been most widely used in clinical practice in recent years. Due to the long-term and large-scale use of azole antifungal drugs in various patients, the problem of fungal resistance has become increasingly prominent. Therefore, it is of great significance to develop new broad-spectrum, high-efficiency, and low-toxic antifungal drugs.

[0003] Integrating multiple azole units into the same molecule is one of the feasible ways to enhance activity and broaden the antibacterial spectrum. For example, the molecular structure of fluconazole contains two 1,2,4-triazole groups. However, existing synthetic methods are mainly limited to the construction of biazole compounds containing two identical azole groups (Org. Lett. 2019, 21, 7639). The methods that can conveniently construct azole groups containing two different structures are still very limited, and usually require multiple steps of reaction to achieve.

[0004] On the other hand, trifluoromethyl (CF3) is an important fluorine-containing group with strong electron-absorbing properties, good lipophilicity and stability. The introduction of trifluoromethyl into small organic molecules can significantly change their physical and chemical properties and biological activities. Studies have shown that the introduction of trifluoromethyl near nitrogen atoms can effectively reduce the alkalinity of small molecules, thereby improving the bioavailability of compounds, and can also improve the stability of alkylamine structures to P450 enzyme oxidation metabolism (Organic Chemistry, 2011, 31, 1785).

[0005] In summary, trifluoromethyl-substituted diazole compounds have good application prospects in the fields of medicine, pesticides, etc., but there are still few related studies on trifluoromethyl-substituted diazole compounds in the prior art. Summary of the invention

[0006] In view of the above problems, the present invention provides a trifluoromethyl-substituted vinyl diazole and a preparation method and application thereof.

[0007] The purpose of the present invention is achieved by the following technical solutions:

[0008] A trifluoromethyl-substituted vinyl diazole having the following structure:

[0009]

[0010] wherein X is 5-substituted tetrazole, tetrazole, purine, substituted purine, imidazole, substituted imidazole, benzimidazole, substituted benzimidazole, pyrazole, substituted pyrazole, 1,2,3-triazole, 1,2,3-benzotriazole or 1,2,4-triazole;

[0011] X is linked to the fixed group via the nitrogen atom.

[0012] In some embodiments of the present invention, the structural formula of the trifluoromethyl-substituted vinylbisoxazole is one of the following structural formulas:

[0013]

[0014] Another aspect of the present invention is to provide a method for preparing the trifluoromethyl-substituted vinyl diazole, comprising the following steps:

[0015] The tetrazolyl trifluoromethyl olefin and the NH-containing nitrogen azole compound corresponding to the X group are reacted in the presence of a base and a solvent and then purified to obtain the product;

[0016] The structural formula of the tetrazolyl trifluoromethyl olefin is The preparation method can be obtained by referring to the literature (Chen, S.-J.; Li, J.-H.; He, Z.-Q.; Chen, G.-S.; Zhuang, Y.-Y.; Chen, C.-P.; Liu, Y.-LN-Trifluoropropylation of Azoles through N-Vinylation and Sequential Hydrogenation. J.Org.Chem.2022, 10.1021 / acs.joc.2c02323).

[0017] In some embodiments of the present invention, the base is at least one of triethylamine, 1,8-diazacyclo[5,4,0]undecene-7 (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), and potassium carbonate; in some preferred embodiments, the base is triethylamine or DBU.

[0018] In some embodiments of the present invention, the solvent is at least one of petroleum ether, n-octane, cyclohexane, ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, chlorobenzene, xylene, toluene, ethanol, chloroform, butanone, and acetone; in some preferred embodiments, the solvent is tetrahydrofuran.

[0019] In some embodiments of the present invention, the molar ratio of the tetrazolyl trifluoromethyl olefin to the azole compound and the base is 1.0:(1.0-2.0):(0.1-2.0); in some preferred embodiments, the molar ratio is 1.0:1.2:2.0.

[0020] In some embodiments of the present invention, the reaction temperature is room temperature or not higher than 50°C, and the reaction time is 24-72h; in some preferred embodiments, the reaction temperature is 50°C, and the reaction time is 24h.

[0021] In some embodiments of the present invention, the purification is carried out by separation through silica gel column chromatography, and the eluent is a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:(1-19).

[0022] The third aspect of the present invention is to provide a use of the trifluoromethyl substituted ethylenediazole in the preparation of antifungal drugs, especially for the preparation of anti-Candida albicans drugs and / or anti-Trichophyton rubrum drugs, and can also be used to prepare anti-rapeseed sclerotinia drugs and / or anti-rice sheath blight drugs.

[0023] The beneficial effects of the present invention are:

[0024] (1) The present invention discloses a series of ethylenediazole compounds having a trifluoromethyl substituent group, wherein the trifluoromethyl substituted ethylenediazole compounds have good antifungal activity and are expected to be developed into a new class of antibacterial drugs;

[0025] (2) The present invention also discloses a method for preparing the trifluoromethyl-substituted ethylene diazole compound, which is the first to use tetrazolyl trifluoromethyl olefin as a Michael acceptor and an NH-containing azole compound as a Michael donor to synthesize the compound through a simple nitrogen-Michael addition reaction. The reaction conditions are mild and no transition metal catalysis is required. The reaction also has a wide range of substrate applicability and is applicable to various types of NH-containing azole compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention is further described using the accompanying drawings, but the embodiments in the accompanying drawings do not constitute any limitation to the present invention. A person skilled in the art can obtain other drawings based on the following drawings without creative work.

[0027] Figure 1 is the H NMR spectrum of compound III-1;

[0028] Figure 2 This is the C NMR spectrum of compound III-1;

[0029] Figure 3 This is the NMR fluorine spectrum of compound III-1. DETAILED DESCRIPTION

[0030] The present invention is further described in conjunction with the following examples.

[0031] Example 1

[0032] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0033] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 5-phenyltetrazolyl II-1 (17.5 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0034]

[0035] After the reaction, the reaction solution was directly separated by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether mixed solvent (v / v=1:19-1:9) to obtain 29 mg of the compound represented by formula III-1 with a yield of 75% as a white solid.

[0036] Analytical data of the compound represented by formula III-1: mp = 110-111 ° C. 1 H NMR (400MHz, CDCl3) δ8.20-8.13(m,2H),8.07-7.99(m,2H),7.52-7.47(m,3H),7.45(dd,J=5. 1,2.0Hz,3H),6.34-6.25(m,1H),5.84(dd,J=14.5,10.0Hz,1H),5.48(dd,J=14.5,3.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.3, 166.0, 131.1, 130.8, 129.0, 129.0, 127.2, 127.0, 126.4, 126.2, 121.6 (q, J = 283.3Hz), 62.9 ( q, J = 33.5Hz), 49.7. 19 F NMR(376MHz, CDCl3)δ-72.3(d,J=6.3Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 17 H 13 F3N8Na + 409.1107; found 409.1108.

[0037] Example 2

[0038] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0039] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 5-benzylmercaptotetrazole II-2 (23.0 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0040]

[0041] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with ethyl acetate / petroleum ether mixed solvent (v / v=1:19) as the eluent, to obtain 33 mg of the compound represented by formula III-2, with a yield of 77%, as a light yellow solid.

[0042] Analytical data of the compound represented by formula III-2: mp = 84-85 ° C. 1 H NMR (400MHz, CDCl3) δ8.21-8.12(m,2H),7.54-7.47(m,3H),7.32-7.19(m,5H),6.19-6.11( m,1H),5.73(dd,J=14.5,10.0Hz,1H),5.37(dd,J=14.5,3.9Hz,1H),4.30(d,J=1.0Hz,2H). 13 C NMR (101MHz, CDCl3) δ166.3, 165.5, 136.0, 131.1, 129.0, 128.9, 128.6, 127.8, 127.2, 126.2, 121.5 (d, J = 283.6Hz), 62.8 (q, J = 33.5Hz), 49.7, 36.3. 19 F NMR(376MHz, CDCl3)δ-72.4(d,J=6.5Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 18 H 15 F3N8NaS + 455.0985; found 455.0982.

[0043] Example 3

[0044] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0045] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), tetrazole II-3 (8.4 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0046]

[0047] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:4-6:4) to obtain 23 mg of the compound represented by formula III-3 with a yield of 74% as a white solid.

[0048] Analytical data of the compound represented by formula III-3: mp = 75-76 ° C. 1 H NMR(400MHz, CDCl3)δ8.58(s,1H),8.22-8.08(m,2H),7.55-7.49(m,3H),6.1 8-6.10(m,1H),5.63(dd,J=14.7,10.4Hz,1H),5.38(dd,J=14.8,4.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.5, 143.5, 131.4, 129.1, 127.2, 125.8, 121.3 (q, J = 283.9Hz), 63.2 (q, J = 33.3Hz), 44.7 (q, J = 2.5Hz). 19 F NMR(376MHz, CDCl3)δ-72.4(d,J=6.1Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 11 H9F3N8Na + 333.0794; found 333.0792.

[0049] Example 4

[0050] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0051] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 6-chloropurine II-4 (18.5 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0052]

[0053] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with ethyl acetate / petroleum ether mixed solvent (v / v=1:4) as the eluent, to obtain 35 mg of the compound represented by formula III-4, with a yield of 89%, as a light yellow solid.

[0054] Analytical data of the compound represented by formula III-4: mp = 145-146 ° C. 1 H NMR(400MHz, CDCl3)δ8.79(s,1H),8.15-8.07(m,2H),7.94(s,1H),7.54-7.47(m,3 H),6.37-6.25(m,1H),5.38(dd,J=14.7,10.5Hz,1H),5.24(dd,J=14.7,4.3Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.4,152.6,151.9,151.4,144.7,131.6,131.3,129.1 ,127.1,125.9,121.6(q,J=283.7Hz),62.2(q,J=32.9Hz),41.8(d,J=2.4Hz). 19 F NMR(376MHz, CDCl3)δ-72.3(d,J=6.2Hz).HRMS(ESI)m / z[M+H] + Calculate for C 15 H 11 ClF3N8 + 395.0742; found 395.0738.

[0055] Example 5

[0056] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0057] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), imidazole II-5 (8.2 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0058]

[0059] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:1) to obtain 16 mg of the compound represented by formula III-5, with a yield of 52%, as a white solid.

[0060] Analytical data of the compound represented by formula III-5: 1 H NMR (400MHz, CDCl3) δ8.18-8.15(m,2H),7.54-7.50(m,3H),7.39(s,1H),6.99(s,1H),6.7 6(s,1H),5.82-5.74(m,1H),5.15(dd,J=15.0,10.6Hz,1H),4.84(dd,J=15.0,3.7Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.2, 137.5, 131.2, 130.8, 129.1, 127.2, 126.1, 121.6 (d, J = 283.5Hz), 118.6, 65.0 (q, J = 32.3Hz), 43.9. 19 FNMR(376MHz, CDCl3)δ-72.4(d,J=6.2Hz).HRMS(ESI)m / z[M+H] + Calculate for C 13 H 12 F3N6 + 309.1070; found 309.1068.

[0061] Example 6

[0062] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0063] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 2-propyl imidazole II-6 (13.0 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 48 hours. The reaction equation is:

[0064]

[0065] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:3) to obtain 19 mg of the compound represented by formula III-6, with a yield of 52%, as a colorless oily liquid.

[0066] Analytical data of the compound represented by formula III-6: 1H NMR (400MHz, CDCl3) δ8.14-8.05(m,2H),7.50-7.40(m,3H),6.79(d,J=1.5Hz,1H),6.48(d,J=1.5Hz,1H),5.65-5.57(m,1H) ,4.97(dd,J=15.2,10.4Hz,1H),4.66(dd,J=15.2,3.5Hz,1H),2.63-2.45(m,2H),1.81-1.62(m,2H),0.92(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.2,148.3,131.2,129.1,128.7,127.1,126.1,121.7(q,J=283.8Hz),118.4,64.8(q,J=32.4Hz),42.8,28.3,21.1,13.9. 19 F NMR(376MHz, CDCl3)δ-72.5(d,J=6.2Hz).HRMS(ESI)m / z[M+H] + Calculate for C 16 H 18 F3N6 + 351.1540; found 351.1538.

[0067] Example 7

[0068] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0069] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 2-methylbenzimidazole II-7 (16.0 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 48 hours. The reaction equation is:

[0070]

[0071] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:4-3:7) to obtain 15 mg of the compound represented by formula III-7 with a yield of 40% as a white solid.

[0072] Analytical data of the compound represented by formula III-7: mp = 105-106 ° C. 1H NMR (400MHz, CDCl3) δ8.16-8.11(m,2H),7.68-7.64(m,1H),7.54-7.48(m,3H),7.28-7.21(m,3 H),5.95-5.87(m,1H),5.24(dd,J=15.6,9.6Hz,1H),4.95(dd,J=15.6,3.6Hz,1H),2.45(s,3H). 13 C NMR (101MHz, CDCl3) δ166.3,151.2,142.6,134.0,131.2,129.1,127.1,126.1,12 3.2,123.0,121.9(q,J=284.8Hz),119.8,108.2,63.2(q,J=32.1Hz),41.9,13.4. 19 F NMR(376MHz, CDCl3)δ-72.3(d,J=6.7Hz).HRMS(ESI)m / z[M+H] + Calculate for C 18 H 16 F3N6 + 373.1383; found 373.1380.

[0073] Example 8

[0074] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0075] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), pyrazole II-8 (8.2 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0076]

[0077] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:19) to obtain 18 mg of the compound represented by formula III-8, with a yield of 58%, as a light yellow solid.

[0078] Analytical data of the compound represented by formula III-8: mp = 105-106 ° C. 1H NMR (400MHz, CDCl3) δ8.20-8.13(m,2H),7.53-7.48(m,4H),7.18(d,J=2.3Hz,1H),6.19-6.1 1(m,1H),6.09(t,J=2.1Hz,1H),5.20(dd,J=14.4,10.3Hz,1H),5.03(dd,J=14.4,3.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ165.8, 141.4, 131.0, 130.6, 129.0, 127.1, 126.4, 121.9 (q, J = 283.1Hz), 106.4, 64.2 (q, J = 32.2Hz), 48.8 (d, J = 2.2Hz). 19 F NMR(376MHz, CDCl3)δ-72.5(d,J=6.8Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 13 H 11 F3N6Na + 331.0889; found 331.0879.

[0079] Example 9

[0080] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0081] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 4-bromopyrazole II-9 (17.6 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0082]

[0083] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:9) to obtain 32 mg of the compound represented by formula III-9 with a yield of 83% as a white solid.

[0084] Analytical data of the compound represented by formula III-9: mp = 85-86 ° C. 1H NMR (400MHz, CDCl3) δ8.21-8.09(m,2H),7.53-7.49(m,3H),7.47(s,1H),7.26(s,1 H),6.17-6.09(m,1H),5.19(dd,J=14.4,10.3Hz,1H),4.98(dd,J=14.4,3.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.0, 142.0, 131.1, 130.7, 129.0, 127.2, 126.3, 121.8 (q, J = 283.4Hz), 94.1, 63.8 (q, J = 32.4Hz), 49.2 (q, J = 2.2Hz). 19 F NMR(376MHz, CDCl3)δ-72.5(d,J=6.3Hz).HRMS(ESI)m / z[M+Na] + calcdfor C 13 H 10 BrF3N6Na + 408.9995; found 408.9987.

[0085] Example 10

[0086] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0087] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 1,2,3-triazole II-10 (8.3 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0088]

[0089] After the reaction, the reaction solution was directly separated by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether mixed solvent (v / v=1:4~1:1) to obtain 26 mg of the compound represented by formula III-10 with a yield of 85% as a white solid.

[0090] Analytical data of the compound represented by formula III-10: mp = 99-100 ° C. 1H NMR (400MHz, CDCl3) δ8.18-8.11(m,2H),7.58(d,J=1.0Hz,1H),7.55-7.48(m,3H),7.39(d,J =1.1Hz,1H),6.19-6.10(m,1H),5.49(dd,J=14.6,10.4Hz,1H),5.37(dd,J=14.6,4.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.2, 134.3, 131.2, 129.1, 127.1, 126.1, 124.8, 121.6 (q, J = 283.3Hz), 64.1 (q, J = 33.0Hz), 46.6 (q, J = 2.4Hz). 19 F NMR(376MHz, CDCl3)δ-72.5(d,J=6.2Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 12 H 10 F3N7Na + 332.0842; found 332.0843.

[0091] Embodiment 11

[0092] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0093] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), benzotriazole II-11 (14.3 mg, 0.12 mmol), tetrahydrofuran (1 mL) and DBU (1.5 mg, 0.01 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0094]

[0095] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography, with the eluent being a mixed solvent of ethyl acetate / petroleum ether (v / v=1:9) to obtain 25 mg of the compound represented by formula III-11 with a yield of 70% as a white solid.

[0096] Analytical data of the compound represented by formula III-11: mp = 80-81 ° C. 1H NMR (400MHz, CDCl3) δ8.12-8.05(m,2H),7.99(dt,J=8.3,1.0Hz,1H),7.50-7.46(m,3H),7.45-7.39(m,2H),7.3 1(ddd,J=8.1,5.5,2.5Hz,1H),6.31-6.23(m,1H),5.73(dd,J=14.8,10.2Hz,1H),5.51(dd,J=14.8,3.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.1,145.7,133.0,131.1,129.0,128.4,127.1,126.1,12 4.5, 121.8 (q, J = 283.8Hz), 120.4, 108.4, 64.0 (q, J = 32.6Hz), 44.9 (q, J = 2.3Hz). 19 F NMR(376MHz, CDCl3)δ-72.3(d,J=6.4Hz).HRMS(ESI)m / z[M+Na] + Calculate for C 16 H 12 F3N7Na + 382.0998; found 382.0995.

[0097] Example 12

[0098] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0099] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 1,2,4-triazole II-12 (8.3 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence. The tube was covered with a stopper and stirred in an oil bath at 50°C for 72 hours. The reaction equation is:

[0100]

[0101] After the reaction, the reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography. The eluent was a mixed solvent of ethyl acetate / petroleum ether (v / v=1:4~1:1) to obtain 25 mg of the compound represented by formula III-12 with a yield of 81% as a white solid.

[0102] Analytical data of the compound represented by formula III-12: mp = 75-77 ° C. 1H NMR (400MHz, CDCl3) δ8.20-8.08(m,2H),7.95(d,J=18.3Hz,2H),7.56-7.46(m,3H ), 6.20-6.12(m,1H),5.36(dd,J=14.4,10.5Hz,1H),5.05(dd,J=14.4,3.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ166.2, 153.3, 144.4, 131.2, 129.0, 127.1, 126.1, 121.6 (q, J = 283.2Hz), 63.3 (q, J = 32.9Hz), 46.3. 19 FNMR(376MHz, CDCl3)δ-72.5(d,J=6.6Hz).HRMS(ESI)m / z[M+H] + Calculate for C 12 H 11 F3N7 + 310.1023; found 310.1022.

[0103] Embodiment 13

[0104] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0105] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 5-phenyltetrazolyl II-1 (17.5 mg, 0.12 mmol), tetrahydrofuran (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred at room temperature for 24 hours. The reaction equation is:

[0106]

[0107] After the reaction, the reaction solution was directly separated by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether mixed solvent (v / v=1:19-1:9) to obtain 20 mg of the compound represented by formula III-1 with a yield of 52% as a white solid.

[0108] Embodiment 14

[0109] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0110] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 5-phenyltetrazolyl II-1 (17.5 mg, 0.12 mmol), acetonitrile (1 mL) and triethylamine (28 μL, 0.2 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0111]

[0112] After the reaction, the reaction solution was directly separated by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether mixed solvent (v / v=1:19-1:9) to obtain 26 mg of the compound represented by formula III-1 with a yield of 67% as a white solid.

[0113] Embodiment 15

[0114] A trifluoromethyl-substituted ethylenediazole, the preparation method of which comprises the following steps:

[0115] Tetrazolyl trifluoromethyl olefin I (24.0 mg, 0.1 mmol), 5-phenyltetrazolyl II-1 (17.5 mg, 0.12 mmol), tetrahydrofuran (1 mL) and potassium carbonate (15.0 mg, 0.11 mmol) were added to the reaction tube in sequence, and the tube was covered with a stopper and stirred in an oil bath at 50°C for 24 hours. The reaction equation is:

[0116]

[0117] After the reaction, the reaction solution was directly separated by silica gel column chromatography, and the eluent was ethyl acetate / petroleum ether mixed solvent (v / v=1:19-1:9) to obtain 23 mg of the compound represented by formula III-1 with a yield of 59% as a white solid.

[0118] Example 16

[0119] In vitro antibacterial test of the trifluoromethyl-substituted ethylenediazole compounds prepared in Examples 1-12:

[0120] Fluconazole was used as the positive control drug, Candida albicans (Y0109) and Trichophyton rubrum were used as experimental fungal strains, and the minimum inhibitory concentration (MIC) of trifluoromethyl-substituted ethylenediazole compounds against the two experimental fungi was determined by 96-well microdilution method according to the standardized antifungal sensitivity test method proposed by the National Committee for Clinical Laboratory Standards (NCCLS) of the United States (National Committee for Clinical Laboratory Standards, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts Approved standard. Document M27-A2, National Committee for Clinical Laboratory Standards, Wayne, PA, 2002). 80 ), i.e., the minimum inhibitory concentration when the growth inhibition rate of the experimental fungi is 80%. The results of the in vitro antibacterial experiment are shown in Table 1;

[0121] Table 1 In vitro antibacterial activity (MIC) of trifluoromethyl substituted ethylene diazole compounds 80 , μg / mL)

[0122]

[0123]

[0124] As can be seen from the data in Table 1, the results of the in vitro antifungal activity test show that most of the trifluoromethyl-substituted ethylenediazole compounds have a certain inhibitory effect on the growth of the fungi involved in this experiment, among which the antibacterial activity of compounds III-5, III-7, and III-11 against Candida albicans Y0109 is equivalent to that of fluconazole; the antibacterial activity of compounds III-3 and III-11 against Trichophyton rubrum is equivalent to that of fluconazole, and the antibacterial activity of compound III-12 against Trichophyton rubrum is slightly better than that of fluconazole, and has the potential for further optimization.

[0125] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A trifluoromethyl-substituted ethylenediazole, It is characterized in that It has the following structure: wherein X is tetrazole, purine, imidazole, benzimidazole, pyrazole, 1,2,3-triazole, 1,2,3-benzotriazole or 1,2,4-triazole; X is bonded to the fixed group via the nitrogen atom.

2. A trifluoromethyl-substituted ethylenediazole, It is characterized in that Its structural formula is one of the following:

3. The method for preparing the trifluoromethyl-substituted vinyl diazole according to claim 1, It is characterized in that The following steps are involved: The tetrazolyl trifluoromethyl olefin and the NH-containing nitrogen azole compound corresponding to the X group are reacted in the presence of a base and a solvent and then purified to obtain the product.

4. The method for preparing the trifluoromethyl-substituted vinyl diazole according to claim 3, It is characterized in that The base is at least one of triethylamine, 1,8-diazacyclo[5,4,0]undecene-7, 1,5-diazabicyclo[4.3.0]-5-nonene, and potassium carbonate.

5. The method for preparing trifluoromethyl-substituted vinyl diazole according to claim 3, It is characterized in that The solvent is at least one of petroleum ether, n-octane, cyclohexane, ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, chlorobenzene, xylene, toluene, ethanol, chloroform, butanone and acetone.

6. The method for preparing the trifluoromethyl-substituted vinyl diazole according to claim 3, It is characterized in that The molar ratio of the tetrazolyl trifluoromethyl olefin to the azole compound and the base is 1.0:(1.0-2.0):(0.1-2.0).

7. The method for preparing trifluoromethyl-substituted vinyl diazole according to claim 3, It is characterized in that The reaction temperature is room temperature or not higher than 50° C., and the reaction time is 24-72 hours.

8. The method for preparing trifluoromethyl-substituted vinyl diazole according to claim 3, It is characterized in that The purification is carried out by separation through silica gel column chromatography, and the eluent is a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:(1-19).

9. Use of the trifluoromethyl-substituted vinyldiazole according to any one of claims 1-2 in the preparation of antifungal drugs.

10. The use according to claim 9, It is characterized in that The antifungal drug is an anti-Candida albicans drug and / or an anti-Trichophyton rubrum drug.

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