A green and efficient preparation method and application of hydantoin molecular derivatives

Abstract

The present invention discloses a green and efficient method for preparing hydantoin molecular derivatives, comprising the following steps: S1, placing compound 1, compound 2, a solvent, and a base in a reaction flask for reaction according to the following reaction formula: #imgabs0#. The present invention develops a cascade nucleophilic / aza-Michael addition reaction of N-alkoxy β-oxo-acrylamide with isocyanate under Lewis base catalysis, obtaining various highly functionalized hydantoin derivatives with yields of 80-98% under mild reaction conditions. This method is characterized by low catalyst loading (1 mol%), high atom economy, simple operation, a wide substrate range, a short reaction time, and exhibits certain bactericidal activity.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a preparation method and application of a green and efficient hydantoin molecular derivative. Background Art

[0002] Hydantoin derivatives exhibit a wide range of pharmacological and biological activities, including anti-inflammatory, anticancer, antibacterial, anti-HIV, anticonvulsant, and antiplatelet activities. Furthermore, clinically approved drugs such as phenytoin and methenytoin as anticonvulsants, nitrofurantoin as a muscle relaxant, and nilutamide as an androgen receptor antagonist, as well as the clinical candidate drugs GLGP-0492, BMS-587101, and BMS-564929, are representative examples of hydantoin-containing compounds.

[0003] Classic synthetic pathways, including the Bucherer-Bergs reaction, the Biltz reaction, and the Urech or Read reaction, have been widely used in the synthesis of hydantoins. Beyond these well-established transformations, various alternative processes have been reported over the years, including direct functionalization of the hydantoin core, C–H α-amination of esters, transition-metal-catalyzed synthetic approaches, gene-promoted [3+2] cyclizations involving α-halogenated hydroxyl compounds, and other reactions. Despite significant progress, these approaches suffer from several drawbacks, such as the need for metal catalysts or toxic reagents, harsh reaction conditions, and poor atom economy. Therefore, the development of new and efficient methods to access valuable hydantoin backbones remains highly desirable. Over the past few years, nucleophilic addition-initiated domino reactions, metal-catalyzed functionalization-promoted cyclizations, and free radical cascade reactions have been extensively explored to construct structurally diverse nitrogen-containing heterocyclic molecules. In particular, in the case of N-alkoxyacrylamides, the nucleophilicity of the amide nitrogen atom is enhanced through an α-effect, which favors the first step of nucleophilic attack. On the one hand, N-alkoxyacrylamide (R = H, alkyl or aryl) is often used as 1,4-N,C β -synthesized to perform [4+2] cyclization. Comesse and Chen groups independently reported the reaction of N-alkoxyacrylamide and activated olefins through

[0004] A formal [4+2] cyclization of the Aza-Michael / Michael addition process. In 2020, Sun and co-workers demonstrated an asymmetric Aza-Michael / Michael addition cascade reaction of 3-methyleneindolinone with α,β-substituted N-alkoxyacrylamides. On the other hand, β-ester-based N-alkoxyacrylamides (known as fumaric acid amides) are more suitable as 1,3-N,C-synthetic compounds for [3+2] cycloaddition reactions. In 2012, Hamada and co-workers described a protocol for the synthesis of chiral γ-lactams via an organocatalytic cascade aza-Michael / Michael reaction of fumaric acid amides with β-unsaturated aldehydes. More recently, Sun's group developed a base-controlled dearomatization [3+2] cyclization reaction between 3-nitroindole and fumaric acid amides using dearomatization and aromatization strategies. However, to our knowledge, these studies were limited to the construction of γ- or δ-lactam scaffolds, and the synthetic potential of acrylamides remains to be further explored. On the basis of the above research background, as a continuation of our research on the heterocyclic chemistry of N-alkoxy α-halohydroxy compounds, we envision that N-alkoxy acrylamides will smoothly undergo cascade nucleophilic / aza-Michael addition reactions with isocyanates to provide a series of highly functionalized hydantoin derivatives. Summary of the Invention

[0005] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a green and efficient preparation method and application of hydantoin molecular derivatives.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A green and efficient method for preparing a hydantoin molecular derivative comprises the following steps:

[0008] S1. Compound 1, compound 2, solvent, and base are placed in a reaction flask for reaction. The reaction formula is as follows:

[0009]

[0010] Among them, R 1 is phenyl, polysubstituted or monosubstituted phenyl, alkyl, thiophene and naphthyl; R 2 is alkyl or benzyl; R 3 is benzyl, alkyl, or ester; R 4 are halogen, alkyl, and benzyl groups at different positions on the benzene ring;

[0011] S2: The reaction flask was stirred at room temperature and detected by TLC. After the reaction was completed, purification was performed to obtain the target compound 3.

[0012] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.1.

[0013] Preferably, the solvent is acetonitrile.

[0014] Preferably, the base is triethylamine, and the amount of the triethylamine is 10 mmol%.

[0015] Preferably, the purification method is column chromatography.

[0016] A green and efficient hydantoin derivative is used to inhibit peanut brown spot pathogen. The compound 3 has the following structure:

[0017]

[0018] A green and efficient hydantoin molecular derivative is used to inhibit apple ring rot pathogen. The compound 3 has the following structure:

[0019]

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention develops a cascade nucleophilic / aza-Michael addition reaction of N-alkoxy β-oxo-acrylamide with isocyanate under Lewis base catalysis, and obtains various highly functionalized hydantoin derivatives with a yield of 80-98% under mild reaction conditions. The method is characterized by low catalyst loading (1 mol%), high atom economy, simple operation, a wide substrate range, short reaction time, and exhibits certain bactericidal activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The table is a statistical table of the bactericidal activity results of the products of the present invention (in vitro test (50 μg / mL), inhibition rate ± standard deviation (%)). DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0024] Example 1:

[0025] The preparation reaction formula of compound 3aa is as follows:

[0026]

[0027] The synthesis steps of compound 3aa are as follows: to a stirred solution of β-oxyacrylamide 1a (0.20 mmol) and isocyanate 2a (0.22 mmol) in anhydrous CH3CN (2.0 mL), Et3N (0.01 equivalent) was added; the reaction mixture was then stirred at room temperature and monitored by TLC; after completion of the reaction, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE / EtOAc = 3:1 or 1:1) to obtain 3aa as a white solid in 98% yield.

[0028] The NMR data and characteristic data of compound 3aa are as follows: 1 H NMR (500MHz, CDCl3) δ7.80–7.74(m,2H),7.55(t,J=7.4Hz,1H),7.40(t,J=7.8Hz,2H),7.19(d,J=8.5Hz,2H),7.14(d,J= 8.3Hz, 2H), 4.86 (t, J = 3.9Hz, 1H), 4.16 (s, 3H), 3.60 (dd, J = 18.3, 4.3Hz, 1H), 3.53 (dd, J = 18.3, 3.6Hz, 1H), 2.29 (s, 3H).

[0029] 13 C NMR (126MHz, CDCl3) δ194.83,166.75,151.38,136.48,135.69,133.84,131.88,130.15,128.72,127.99,123.18,64.95,54.94,36.28,20.94.

[0030] Example 2:

[0031] The preparation reaction formula of compound 3ba is as follows:

[0032]

[0033] The synthesis steps of compound 3ba are as follows: to a stirred solution of β-oxyacrylamide 1b (0.20 mmol) and isocyanate 2a (0.22 mmol) in anhydrous CH3CN (2.0 mL), Et3N (0.01 equivalent) was added; the reaction mixture was then stirred at room temperature and monitored by TLC; after completion of the reaction, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE / EtOAc = 3:1 or 1:1) to obtain 3ba as a white solid in 98% yield.

[0034] The NMR data and characteristic data of compound 3ba are as follows:

[0035] 1H NMR (500MHz, CDCl3) δ7.59(d,J=8.2Hz,2H),7.12(dd,J=8.4,2.1Hz,4H),7.06(d,J=8.3Hz,2H),4.77(t,J=3. 9Hz, 1H), 4.09 (s, 3H), 3.51 (dd, J = 18.3, 4.3Hz, 1H), 3.42 (dd, J = 18.2, 3.5Hz, 1H), 2.30 (s, 3H), 2.22 (s, 3H).

[0036] 13 C NMR (126MHz, CDCl3) δ194.36,166.83,151.40,144.84,136.43,133.25,13 1.91,130.12,129.39,128.11,123.20,64.93,54.98,36.16,21.69,20.94.

[0037] Example 3:

[0038] The preparation reaction formula of compound 3ca is as follows

[0039]

[0040] The synthesis steps of compound 3ca are as follows: to a stirred solution of β-oxyacrylamide 1c (0.20 mmol) and isocyanate 2a (0.22 mmol) in anhydrous CH3CN (2.0 mL), Et3N (0.01 equiv) was added; the reaction mixture was then stirred at room temperature and monitored by TLC; after completion of the reaction, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE / EtOAc = 3:1 or 1:1) to afford 3ca as a white solid in 95% yield.

[0041] The NMR data and characteristic data of compound 3ca are as follows:

[0042] 1 H NMR (500MHz, CDCl3) δ7.71–7.65(m,2H),7.12(d,J=8.5Hz,2H),7.07(d,J=8.4Hz,2H),6.79(d,J=8.9Hz,2H),4.77( t,J=3.9Hz,1H),4.09(s,3H),3.77(s,3H),3.48(dd,J=18.1,4.3Hz,1H),3.40(dd,J=18.1,3.5Hz,1H),2.23(s,3H).

[0043] 13C NMR (126MHz, CDCl3) δ193.08,166.89,164.04,151.41,136.40,131.94,13 0.35,130.11,128.78,123.20,113.86,64.93,55.54,55.03,35.93,20.94.

[0044] Example 4:

[0045] The preparation reaction formula of compound 3da is as follows:

[0046]

[0047] The synthesis steps of compound 3da are as follows: to a stirred solution of β-oxoacrylamide 1d (0.20 mmol) and isocyanate 2a (0.22 mmol) in anhydrous CH3CN (2.0 mL) was added Et3N (0.01 equivalent); the reaction mixture was then stirred at room temperature and monitored by TLC; after completion of the reaction, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE / EtOAc = 3:1 or 1:1) to afford 3da as a white solid in 97% yield.

[0048] The NMR data and characteristic data of compound 3da are as follows:

[0049] 1 H NMR (500MHz, CDCl3) δ7.75–7.69(m,2H),7.11(d,J=8.4Hz,2H),7.06(d,J=8.4Hz,2H),6.99(t,J=8.5Hz,2H), 4.78(t,J=3.9Hz,1H), 4.07(s,3H), 3.49(dd,J=18.2,4.3Hz,1H), 3.41(dd,J=18.2,3.5Hz,1H), 2.21(s,3H).

[0050] 13 C NMR (126MHz, CDCl3) δ193.31, 166.70, 166.12 (d, J = 256.4Hz), 151.35, 136.52, 132.13 (d, J = 2.9Hz) ,131.84,130.73(d,J=9.5Hz),130.15,123.15,115.91(d,J=22.1Hz),64.96,54.91,36.14,20.93.

[0051] Example 5:

[0052] The preparation reaction formula of compound 3ea is as follows:

[0053]

[0054] The synthesis steps of compound 3ea are similar to those in Example 1, except that compound 1a is replaced by compound 1e. Compound 3ea is a white solid with a yield of 92%.

[0055] The NMR data and characteristic data of compound 3ea are as follows:

[0056] 1 H NMR (500MHz, CDCl3) δ7.72–7.68(m,2H),7.40–7.35(m,2H),7.20–7.12(m,4H),4.86(t,J=3.9 Hz, 1H), 4.15 (s, 3H), 3.56 (dd, J = 18.2, 4.3Hz, 1H), 3.48 (dd, J = 18.2, 3.6Hz, 1H), 2.30 (s, 3H).

[0057] 13 C NMR (126MHz, CDCl3) δ193.70,166.61,151.30,140.45,136.59,133.98,131.80,130.18,129.38,129.08,123.16,64.98,54.89,36.22,20.94.

[0058] Example 6:

[0059] The preparation reaction formula of compound 3fa is as follows:

[0060]

[0061] The synthesis steps of compound 3fa are similar to those in Example 1, except that compound 1a is replaced by compound 1f. Compound 3fa is a white solid with a yield of 98%.

[0062] The NMR data and characteristic data of compound 3fa are as follows:

[0063] 1 H NMR(500MHz, CDCl3)δ7.63(d,J=8.6Hz,2H),7.55(d,J=8.6Hz,2H),7.20–7.12(m,4H),4.85(t,J= 3.9Hz, 1H), 4.16 (s, 3H), 3.55 (dd, J = 18.2, 4.3Hz, 1H), 3.48 (dd, J = 18.2, 3.6Hz, 1H), 2.30 (s, 3H).

[0064] 13C NMR (126MHz, CDCl3) δ193.90,166.59,151.29,136.61,134.37,132.08,131.78,130.19,129.45,129.22,123.17,64.98,54.88,36.21,20.95.

[0065] Example 7:

[0066] The preparation reaction formula of compound 3ga is as follows:

[0067]

[0068] The synthesis steps of compound 3ga are similar to those in Example 1, except that compound 1a is replaced by compound 1g. Compound 3ga is a white solid with a yield of 94%.

[0069] The NMR data and characteristic data of compound 3ga are as follows:

[0070] 1 H NMR (500MHz, CDCl3) δ7.55(d,J=4.9Hz,1H),7.44(d,J=3.7Hz,1H),7.12(d,J=8.2Hz,2H),7.06(d,J=8.2Hz,2H),6.97(t,J =4.2Hz, 1H), 4.76 (t, J = 3.8Hz, 1H), 4.05 (s, 3H), 3.46 (dd, J = 17.9, 4.3Hz, 1H), 3.40 (dd, J = 17.9, 3.4Hz, 1H), 2.22 (s, 3H).

[0071] 13 C NMR (126MHz, CDCl3) δ187.47,166.44,151.23,142.51,136.48,134.75,132.62,131.84,130.12,128.25,123.18,64.98,54.97,36.80,20.94.

[0072] Example 8:

[0073] The preparation reaction formula of compound 3ha is as follows:

[0074]

[0075] The synthesis steps of compound 3ha are similar to those of Example 1, except that compound 1a is replaced by compound 1h. Compound 3ha is a white solid with a yield of 98%.

[0076] The NMR data and characteristic data of compound 3ha are as follows:

[0077] 1 H NMR (500MHz, CDCl3) δ8.31(d,J=8.0Hz,1H),7.88(d,J=8.2Hz,1H),7.78–7.73(m,1H),7.50–7.42(m,3H),7.33–7.27(m,1H),7.17(d,J=8.4 Hz, 2H), 7.08 (d, J = 8.2Hz, 2H), 4.84 (t, J = 4.0Hz, 1H), 4.11 (s, 3H), 3.61 (dd, J = 18.2, 4.3Hz, 1H), 3.55 (dd, J = 18.2, 3.7Hz, 1H), 2.23 (s, 3H).

[0078] 13 C NMR (126MHz, CDCl3) δ198.65,166.79,151.39,136.63,134.11,133.85,133.58,131.90,130.23 ,129.89,128.46,128.35,127.96,126.75,125.47,124.16,123.42,65.02,55.40,39.56,20.96.

[0079] Example 9:

[0080] The preparation reaction formula of compound 3ia is as follows

[0081]

[0082] The synthesis steps of compound 3ia are similar to those in Example 1, except that compound 1a is replaced by compound 1i. Compound 3ia is a white solid with a yield of 83%.

[0083] The NMR data and characteristic data of compound 3ia are as follows:

[0084] 1 H NMR (500MHz, CDCl3) δ7.68 (dd, J=8.0, 1.7Hz, 1H), 7.45 (ddd, J=8.9, 7.4, 1.7Hz, 1H), 7.17–7.09 (m ,4H),7.01–6.96(m,2H),3.99(s,3H),3.07(d,J=16.9Hz,1H),3.00(d,J=16.9Hz,1H),2.27(s,3H).

[0085] 13C NMR (126MHz, CDCl3) δ187.26,162.93,157.90,150.38,139.71,136.66,130.39,12 8.84,128.55,126.44,122.81,119.82,117.53,88.36,65.88,40.98,29.71,21.17.

[0086] Example 10:

[0087] The preparation reaction formula of compound 3ja is as follows:

[0088]

[0089] The synthesis steps of compound 3ja are similar to those in Example 1, except that compound 1a is replaced by compound 1j. Compound 3ja is a white solid with a yield of 90%.

[0090] The NMR data and characteristic data of compound 3ja are as follows:

[0091] 1 H NMR (500MHz, CDCl3) δ7.14–7.07 (m, 4H), 4.66 (dd, J = 4.3, 3.6Hz, 1H), 4.05 (s, 3H), 3. 11(dd,J=18.3,4.5Hz,1H),2.93(dd,J=18.3,3.4Hz,1H),2.26(s,3H),0.84(s,9H).

[0092] 13 C NMR (126MHz, CDCl3) δ210.76,166.87,151.22,136.26,131.80,129.99,122.92,64.91,54.66,44.00,34.75,25.92,20.95.

[0093] Example 11:

[0094] The preparation reaction formula of compound 3bb is as follows:

[0095]

[0096] The synthesis steps of compound 3bb are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2b. Compound 3bb is a white solid with a yield of 92%.

[0097] The NMR data and characteristic data of compound 3bb are as follows:

[0098] 1H NMR(500MHz, CDCl3) δ7.60(d,J=8.1Hz,2H),7.11(dd,J=15.5,6.3Hz,4H),6.78(d,J=8.9Hz,2H),4.71 (t,J=3.8Hz,1H),4.09(s,3H),3.69(s,3H),3.44(d,J=4.1Hz,1H),3.42(d,J=3.7Hz,1H),2.31(s,3H).

[0099] 13 C NMR (126MHz, CDCl3) δ194.39,166.94,158.27,151.66,144.87,133.26,12 9.41,128.10,127.09,125.64,114.83,64.94,55.60,55.49,36.23,21.70.

[0100] Example 12:

[0101] The preparation reaction formula of compound 3bc is as follows:

[0102]

[0103] The synthesis steps of compound 3bc are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2c. Compound 3bc is a white solid with a yield of 96%.

[0104] The NMR data and characteristic data of compound 3bc are as follows:

[0105] 1 H NMR (500MHz, CDCl3) δ7.67(d,J=8.1Hz,2H),7.30–7.26(m,2H),7.20(d,J=8.0Hz,2H),7.03(t,J=8.5Hz,2H), 4.85(t,J=3.8Hz,1H), 4.16(s,3H), 3.56(dd,J=18.3,4.1Hz,1H), 3.51(dd,J=18.3,3.6Hz,1H), 2.38(s,3H).

[0106] 13C NMR (126MHz, CDCl3) δ194.33,166.61,160.76(d,J=247.0Hz),151.51,145.06,133.10,130.51(d,J =3.0Hz), 129.46, 128.09, 125.34 (d, J = 8.6Hz), 116.47 (d, J = 22.8Hz), 64.99, 55.21, 36.13, 21.69.

[0107] Example 13:

[0108] The preparation reaction formula of compound 3bd is as follows:

[0109]

[0110] The synthesis steps of compound 3bd are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2d. Compound 3bd is a white solid with a yield of 98%.

[0111] The NMR data and characteristic data of compound 3bd are as follows:

[0112] 1 H NMR (500MHz, CDCl3) δ7.60(d,J=8.1Hz,2H),7.23(q,J=8.9Hz,4H),7.14(d,J=8.0Hz,2H),4.8 0(t,J=3.7Hz,1H),4.09(s,3H),3.53(dd,J=18.3,4.2Hz,1H),3.49–3.42(m,1H),2.31(s,3H).

[0113] 13 C NMR (126MHz, CDCl3) δ194.18,166.38,151.24,145.12,133.22,133.04,131.79,129.67,129.48,128.11,123.97,65.01,54.67,36.07,21.71.

[0114] Example 14:

[0115] The preparation reaction formula of compound 3be is as follows

[0116]

[0117] The synthesis steps of compound 3be are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2e. Compound 3be is a white solid with a yield of 90%.

[0118] The NMR data and characteristic data of compound 3be are as follows:

[0119] 1 H NMR (500MHz, CDCl3) δ7.71–7.63(m,4H),7.58–7.53(m,2H),7.22(d,J=8.1Hz,2H),4.96(t,J=3. 8Hz, 1H), 4.16 (s, 3H), 3.69 (dd, J = 18.3, 4.3Hz, 1H), 3.59 (dd, J = 18.3, 3.3Hz, 1H), 2.39 (s, 3H).

[0120] 13 C NMR (126MHz, CDCl3) δ193.93,165.71,150.96,145.41,139.02,133.54,132 .83,129.56,128.14,121.32,118.16,108.90,65.09,53.95,36.02,21.73.

[0121] Example 15:

[0122] The preparation reaction formula of compound 3bf is as follows

[0123]

[0124] The synthesis steps of compound 3bf are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2f. Compound 3bf is a colorless oil with a yield of 93%.

[0125] The NMR data and characteristic data of compound 3bf are as follows:

[0126] 1 H NMR(500MHz, CDCl3)δ7.70–7.62(m,3H),7.57(d,J=8.1Hz,1H),7.50–7.39(m,2H),7.19(d,J=8.1Hz,2H),4 .95(t,J=3.8Hz,1H),4.16(s,3H),3.62(dd,J=18.3,4.1Hz,1H),3.57(dd,J=18.3,3.6Hz,1H),2.36(s,3H).

[0127] 13C NMR (126MHz, CDCl3) δ194.20,166.18,151.27,145.17,135.47,132.98,131.95(q,J=32.8Hz),130.16,129.47, 128.12, 125.50, 123.47 (q, J = 272.8Hz), 122.67 (q, J = 3.6Hz), 119.00 (q, J = 3.8Hz), 65.03, 54.49, 36.04, 21.68.

[0128] Example 16:

[0129] The preparation reaction formula of compound 3bg is as follows:

[0130]

[0131] The synthesis steps of compound 3bg are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2g. Compound 3bg is a colorless oil with a yield of 93%.

[0132] The NMR data and characteristic data of compound 3bg are as follows:

[0133] 1 H NMR(500MHz, CDCl3)δ7.60(d,J=7.0Hz,2H),7.37(d,J=8.0Hz,1H),7.21–7.17(m,1H),7.12(dd,J=17.5,5.7Hz,4H) ,4.86(dd,J=3.7,2.6Hz,1H),4.10(d,J=1.6Hz,3H),3.51–3.43(m,1H),3.27(dd,J=18.4,2.4Hz,1H),2.31(s,3H).

[0134] 13 C NMR (126MHz, CDCl3) δ194.47,167.16,152.00,144.98,133.14,132.74,131.68 ,130.93,130.68,130.11,129.47,128.07,128.03,65.01,55.97,36.60,21.72.

[0135] Example 17:

[0136] The preparation reaction formula of compound 3bh is as follows:

[0137]

[0138] The synthesis steps of compound 3bh are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2h. Compound 3bh is a white solid with a yield of 87%.

[0139] The NMR data and characteristic data of compound 3bh are as follows:

[0140] 1 H NMR (500MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.22(d,J=8.0Hz,2H),4.29(t,J=4.1Hz,1H),4.01(s,3H),3.66(dd,J=18.2,4.1Hz,1H),3. 60–3.52(m,1H),3.42(dd,J=18.2,4.1Hz,1H),2.36(s,3H),1.75–1.60(m,5H),1.35–1.25(m,1H),1.25–1.13(m,3H),1.05–0.95(m,1H).

[0141] 13 C NMR (126MHz, CDCl3) δ194.37,167.66,152.68,144.93,133.47,129.59,128.17,64.79,53.86,52.80,38.65,31.59,30.44,25.80,25.16,21.74.

[0142] Example 18:

[0143] The preparation reaction formula of compound 3bi is as follows:

[0144]

[0145] The synthesis steps of compound 3bi are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2i. Compound 3bi is a white solid with a yield of 80%.

[0146] The NMR data and characteristic data of compound 3bi are as follows:

[0147] 1 H NMR (500MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.21(s,2H),4.30(dd,J=5.2,2.6Hz,1H),3.98( s, 3H), 3.71 (dd, J = 18.0, 5.3Hz, 1H), 3.46 (dd, J = 18.0, 2.6Hz, 1H), 2.35 (s, 3H), 1.35 (s, 9H).

[0148] 13 C NMR (126MHz, CDCl3) δ194.45,167.34,153.14,144.84,133.73,129.55,128.16,64.52,56.26,53.49,40.05,28.57,21.72.

[0149] Example 19:

[0150] The preparation reaction formula of compound 3bj is as follows:

[0151]

[0152] The synthesis steps of compound 3bj are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2j. Compound 3bj is a white solid with a yield of 85%.

[0153] The NMR data and characteristic data of compound 3bj are as follows:

[0154] 1 H NMR (500MHz, CDCl3) δ7.57(d,J=8.2Hz,2H),7.18–7.10(m,6H),7.10–7.04(m,1H),4.57(d,J=15.4Hz,1H),4.29(d,J=15.4 Hz,1H),4.21(dd,J=5.2,3.4Hz,1H),4.03(s,3H),3.40(dd,J=18.2,3.4Hz,1H),3.23(dd,J=18.2,5.2Hz,1H),2.33(s,3H).

[0155] 13 C NMR (126MHz, CDCl3) δ194.38,167.44,153.41,144.84,135.55,133.10,12 9.35,128.90,128.11,128.08,128.06,65.02,53.91,45.79,37.43,21.73.

[0156] Example 20:

[0157] The preparation reaction formula of compound 3bk is as follows:

[0158]

[0159] The synthesis steps of compound 3bk are similar to those in Example 1, except that compound 1a is replaced by compound 1b, and compound 2a is replaced by compound 2k. Compound 3bk is a white solid with a yield of 80%.

[0160] The NMR data and characteristic data of compound 3bk are as follows:

[0161] 1 H NMR (500MHz, CDCl3) δ7.59(d,J=8.2Hz,2H),7.19(dd,J=12.3,3.5Hz,1H),7.13(d,J=8.1Hz,2H),7.05(dd,J=7.8,1.6Hz,1H),6.84(d,J=7.9Hz,1H),6 .78(td,J=7.7,0.9Hz,1H),4.78(t,J=4.0Hz,1H),4.10(s,3H),3.70(s,3H ), 3.39 (dd, J = 18.2, 4.2Hz, 1H), 3.28 (dd, J = 18.2, 3.9Hz, 1H), 2.31 (s, 3H).

[0162] 13 C NMR (126MHz, CDCl3) δ194.51,167.73,155.36,152.29,144.65,133.43,130.02,12 9.82,129.37,128.03,122.49,121.19,111.91,64.87,56.09,55.69,36.63,21.69.

[0163] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

[0164] Effect experiment example:

[0165] Considering the potential biological activity of the products, chlorothalonil and carbendazim were used as comparison agents. Some target compounds were tested for fungicidal activity using the mycelial growth rate method. In vitro fungicidal activity was tested against common plant fungi, including cucumber wilt disease, peanut brown spot (Cercospora arachidicola), apple ring spot (Physalospora piricola), wheat stripe blight (Rhizotonia cerealis), corn leaf spot (Bipolaris maydis), watermelon anthrax (Colletotrichum orbiculare), and rice seedling rot (Gibberella fujikuroi).

[0166] The experimental results are as shown in the attached manual. Figure 1 As shown, the results showed that at a concentration of 50 μg / mL, 3ag and 3ah showed inhibitory activity comparable to that of chlorothalonil against peanut brown spot pathogen, and 3ai showed inhibitory activity comparable to that of chlorothalonil and carbendazim against apple ring rot pathogen.

[0167] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of the present invention.

Claims

1. A green and efficient method for preparing a hydantoin molecular derivative, characterized in that: The following steps are involved: S1. Compound 1, compound 2a, a solvent, and a base are placed in a reaction flask for reaction, or compound 1b, compound 2, a solvent, and a base are placed in a reaction flask for reaction. The reaction formula is as follows: Among them, R 1 is phenyl, alkyl, thiophene and naphthyl; R 2 is alkyl or benzyl; R 3 is benzyl, alkyl, or ester; R 4 is 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 2-chlorophenyl, cyclohexyl, tert-butyl, benzyl, 2-methoxyphenyl; S2: stirring the reaction flask at room temperature, detecting by TLC, and after completion of the reaction, purifying to obtain the target compound; The base is triethylamine.

2. The method for preparing a green and efficient hydantoin molecular derivative according to claim 1, characterized in that: The molar ratio of compound 1 to compound 2a is 1:1.1; The molar ratio of compound 1b to compound 2 is 1:1.

1.

3. The method for preparing a green and efficient hydantoin molecular derivative according to claim 1, characterized in that: The solvent is acetonitrile.

4. The method for preparing a green and efficient hydantoin molecular derivative according to claim 1, characterized in that: The amount of triethylamine was 10 mmol%.

5. The method for preparing a green and efficient hydantoin molecular derivative according to claim 1, characterized in that: The purification method is column chromatography.

6. Use of a hydantoin derivative in inhibiting peanut brown spot pathogen, wherein the hydantoin derivative has the following structure: 、 。 7. Use of a hydantoin derivative in inhibiting apple ring rot pathogen, wherein the hydantoin derivative has the following structure: 。

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