A process for the preparation of a tetrahydrobenzofuranone oxime derivative

Abstract

The application belongs to the field of organic matter preparation, and particularly relates to a preparation method of tetrahydrobenzofuran ketone oxime derivative. Compound I, compound II and a Lewis acid zinc-based catalyst are mixed in a solvent, and then are reacted at 60-85 DEG C for 1.5-3h. After the reaction is completed, the product is separated. The method has simple steps, is controllable, has high yield, has low requirement on the preparation environment, and realizes high-efficiency synthesis of the tetrahydrobenzofuran ketone oxime derivative.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation, specifically relating to a method for preparing a tetrahydrobenzofuranone oxime derivative. Background Technology

[0002] Tetrahydrobenzofuranone oxime derivatives are a class of compounds containing a tetrahydrobenzofuranone skeleton and an oxime group, playing a vital role in modern chemistry and medicine. They are important structural units in many organic synthesis raw materials, natural product molecules, and biopharmaceutical intermediates. These compounds have great potential for the modification and derivatization of bioactive molecules, and can combine with or modify other bioactive molecules to alter their biological activity and chemical properties.

[0003] β-Nitrostyrene is an important intermediate in organic synthesis. The nitro group in its molecular structure endows it with strong electron-withdrawing properties, polarizing the electron cloud of the olefin double bond and facilitating various reactions such as Michael addition, substitution, and cyclization with nucleophiles or electrophiles. In 1958, Stetter first reported the Michael / cyclization tandem reaction of β-nitroethylene, achieving the efficient synthesis of tetrahydrobenzofuranone oxime derivatives. This method uses β-nitroene and 1,3-cyclohexanedione as starting materials. Under sodium alkoxide catalysis, the reaction does not proceed as a conventional Michael addition to produce the usual addition product, but rather a further cyclization product, tetrahydrobenzofuranone oxime. Traditional methods for synthesizing tetrahydrobenzofuranone oxime derivatives are cumbersome and yield low amounts; therefore, exploring efficient and economical synthetic routes is particularly important. Summary of the Invention

[0004] To address the problems of low product yield, difficult post-processing, and challenging catalyst separation in existing technologies for tetrahydrobenzofuranone oxime derivatives, this invention provides a method for preparing tetrahydrobenzofuranone oxime derivatives with high yield and easy catalyst separation. The technical solution is as follows:

[0005] A method for preparing a tetrahydrobenzofuranone oxime derivative includes the following steps: The general reaction formula is as follows:

[0006]

[0007] In the formula: R 1 It is hydrogen or methyl; R 2 It can be hydrogen or methyl; the reaction is carried out using a Lewis acid-based zinc-based catalyst.

[0008] Furthermore, compound I is one or more of 4-methyl-β-nitrostyrene, 2-methyl-β-nitrostyrene, 3-methyl-β-nitrostyrene, 4-chloro-β-nitrostyrene, 2-bromo-β-nitrostyrene, or β-nitrostyrene.

[0009] Furthermore, compound II is one or more of 1,3-cyclohexanedione, 5-methyl-1,3-cyclohexanedione, or 5,5-dimethyl-1,3-cyclohexanedione.

[0010] Further, the process includes the following steps: mixing compound I, compound II, and a Lewis acidic zinc-based catalyst in a solvent and reacting at 60–85°C for 1.5–3 h; separating the products after the reaction is complete.

[0011] Furthermore, the molar ratio of compound I to compound II is 1:1 to 1.5; the molar ratio of compound I to zinc in the zinc-based catalyst is 1:0.5 to 1.5.

[0012] Furthermore, the solvent includes one or more of dimethyl sulfoxide or N,N-dimethylformamide.

[0013] Furthermore, the preparation of the zinc-based catalyst includes the following steps: modifying the hydroxyl polymer with 4-toluenesulfonyl chloride to obtain a sulfonate polymer; reacting the sulfonate polymer with diethanolamine to obtain a complexing matrix; and loading zinc chloride onto the complexing matrix to obtain the zinc-based catalyst.

[0014] Furthermore, this includes the following steps:

[0015] a. Hydroxypropyl cellulose and 4-toluenesulfonyl chloride were dissolved in an aqueous solution of N,N-dimethylformamide at 0–10 °C and mixed thoroughly; the temperature was raised to 20–30 °C and N-methylmorpholine was added dropwise, maintaining the pH of the system at 7–8, and the reaction was carried out for 4–6 h; excess ethanol was added to precipitate the product, which was then thoroughly washed and dried to obtain sulfonate cellulose;

[0016] b. Mix sulfonate-based cellulose with diethanolamine, heat to 45-65°C and stir until homogeneous, react for 8-12 hours; add excess acetone, separate the product and wash thoroughly, and dry to obtain the complex matrix;

[0017] c. Prepare a methanol solution of zinc chloride; disperse the complex matrix in methanol, add the methanol solution of zinc chloride, reflux for 10-16 h, separate the solid product, wash thoroughly and dry to obtain the zinc-based catalyst.

[0018] Further, in the aqueous solution of N,N-dimethylformamide described in step a, the volume ratio of N,N-dimethylformamide to water is 1 to 3:1; the mass ratio of hydroxypropyl cellulose to 4-toluenesulfonyl chloride is 1:1.2 to 1.8; the mass ratio of N-methylmorpholine to 4-toluenesulfonyl chloride is 1:1.2 to 1.5; and the volume of excess ethanol is 3 to 6 times that of the liquid in the system.

[0019] Furthermore, in step b, the mass ratio of sulfonate-based cellulose to diethanolamine is 1:4 to 6; the volume of excess acetone is 3 to 6 times that of the liquid in the system; and in step c, the mass ratio of the complexing matrix to zinc chloride is 1:0.5 to 0.8.

[0020] By adopting the above scheme, the method of the present invention has the following advantages:

[0021] 1. The preparation method of the present invention can generate the cyclized product tetrahydrobenzofuranone oxime in one step. The steps are simple, controllable and have a high yield. It has low requirements for the preparation environment and solves the problems of poor stability of catalysts such as sodium methoxide and the tendency of excessive alkalinity to cause over-reaction or decomposition of the substrate.

[0022] 2. The preparation method of the present invention has mild conditions, a wide range of applicable substrates, high product yield, and simple and efficient post-processing, providing a more convenient new route for the efficient synthesis of tetrahydrobenzofuranone oxime derivatives.

[0023] 3. The method of this invention utilizes the Lewis acidic activated electrophilic reagent in the prepared catalyst to promote nucleophilic addition and cyclization, resulting in high selectivity for the reaction, few byproducts, and stable yield. The hydroxypropyl cellulose ligand combines with zinc chloride to adsorb the reactants, promoting contact between the reactants and the catalyst, thus catalyzing the reaction.

[0024] 4. The method of the present invention first esterifies hydroxypropyl cellulose with sulfonyl chloride group, and then replaces it with diethanolamine to obtain a complex matrix that can complex with zinc chloride and can fully retain Lewis acidity. Zinc chloride is fixed and loaded on cellulose support. Compared with homogeneous catalysts, it is easier to separate, has less pollution to the product, has high product purity (mostly above 90%), can be reused, and its catalytic performance is not easily decayed.

[0025] 5. The catalyst of the present invention, while possessing Lewis acidity, is designed with the strength and distribution density of acid sites and the morphology of the support, and utilizes the adsorption properties of cellulose to promote the catalytic effect of Michael / cyclization tandem, resulting in strong selectivity for tetrahydrobenzofuranone oxime. Detailed Implementation

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: (1) 1g of hydroxypropyl cellulose and 1.5g of 4-toluenesulfonyl chloride were dissolved in an aqueous solution of N,N-dimethylformamide with a volume ratio of 2:1 under ice bath conditions and mixed evenly; the temperature was raised to 25°C and 1.2g of N-methylmorpholine was slowly added dropwise, maintaining the pH of the system at 7-8, and the reaction was carried out for 5h; 4 times the volume of excess ethanol was added to precipitate the product, the product was dissolved in acetone, and then precipitated with ethanol. The above operation was repeated 3 times and then freeze-dried to obtain sulfonate cellulose.

[0028] (2) Mix 1g of sulfonate cellulose with 5g of diethanolamine, heat to 60℃ and stir evenly, react for 10h; add excess acetone, separate the product, place the separated product in water, add acetone again, repeat the above operation 3 times, freeze dry to obtain the complex matrix.

[0029] (3) Take 0.68g of zinc chloride and prepare a methanol solution of zinc chloride; disperse 1g of the complex matrix in methanol, add the methanol solution of zinc chloride, reflux for 14h, separate the solid product, wash with water and methanol 3 times, and dry under vacuum at 80℃ to obtain the zinc-based catalyst.

[0030] (4) Take 1 mmol of 1,3-cyclohexanedione, 1 mmol of 4-methyl-β-nitrostyrene, and 0.3 g of zinc-based catalyst and place them in dimethyl sulfoxide solvent. React at 80 °C. The reaction is monitored by TLC (petroleum ether: ethyl acetate = 2:1 as the developing solvent). After 1.5 h of reaction, extract and separate the liquid with dichloromethane (10 mL × 2) and water (15 mL). The aqueous phase is recovered by the method in step (3). The organic phase is washed with saturated brine and dried with anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure to obtain a yellow oily substance. Purify the substance by column chromatography (petroleum ether: ethyl acetate = 4:1 as the eluent) to obtain (Z)2-(hydroxyimino)-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one with high purity. Its structural formula is as follows:

[0031]

[0032] The sample was a white solid; yield: 46%; mp: 186.5–188.1℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3254,2953,1695,1630,1389,1362,1166,953,791; 1H NMR(400MHz,(CD3)2CO)δ(ppm):9.49(s,1H),7.14–7.06(m,4H),4.77(s,1H),2.85– 2.76(m,1H),2.75–2.67(m,1H),2.40–2.31(m,2H),2.27(s,3H),2.24–2.11(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):193.2,173.8,157.8,137.4,137.1,129.8(2C),128.4(2C),118.5,46.1,37.5,23.5,22.1,21.0; HR-MS(ESI)calcd.for C 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0946.

[0033] (E)-2-(hydroxyimino)-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0034]

[0035] The sample was a white solid; yield: 46%; mp: 194.3–195.6 °C; R f =0.5(EA:PE=1:2); IR(KBr,cm -1 ):ν3254,3144,2899,1701,1629,1393,1358,1207,1165,1060,1002,803; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.31 (s, 1H), 7.16 (d, J = 8.0Hz, 2H), 7.05 (d, J = 8.0Hz, 2 H),5.03(s,1H),2.82–2.64(m,2H),2.32–2.28(m,2H),2.27(s,3H),2.17–2.12(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):192.7,174.1,166.9,137.2,134.6,129.7(2C),128.9(2C),119.3,45.5,37.5,23.6,22.2,21.0; HR-MS(ESI)calcd.for C 15H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0950.

[0036] Example 2: The difference from Example 1 is as follows:

[0037] Step (4) React 1 mmol of 1,3-cyclohexanedione and 1 mmol of 2-methyl-β-nitrostyrene to obtain (Z)2-(hydroxyimino)-3-(o-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0038]

[0039] The sample was a white solid; yield: 36%; mp: 212.3–214.1℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3263,2882,1700,1652,1633,1464,1395,1182,1166,955,764,732; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.46 (s, 1H), 7.17–7.13 (m, 1H), 7.13–7.05 (m, 2H), 6.98 (dd, J=7.0, 1.8Hz, 1H),5.05(s,1H),2.85–2.78(m,1H),2.77-2.68(m,1H),2.46(s,3H),2.40–2.27(m,2H),2.23–2.16(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):193.1,173.9,157.9,138.4,137.0,131.3,1 27.9,127.8,126.9,118.6,43.2,37.5,23.5,22.2,19.9; HR-MS(ESI)calcd.for C 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0942.

[0040] (E)-2-(hydroxyimino)-3-(o-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; The structural formula is as follows:

[0041]

[0042] The sample was a white solid; yield: 37%; mp: 187.4–189.2 °C; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3245,2892,1709,1634,1392,1181,1059,1005,753; 1 H NMR(400MHz, (CD3)2CO)δ(ppm):9.24(s,1H),7.14–7.10(m,1H),7.10–7.03(m,2H),6.97–6.94(m,1H), 5.18(s,1H),2.86–2.78(m,1H),2.75–2.67(m,1H),2.56(s,3H),2.34–2.20(m,2H),2.19–2.09(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):192.6,173.8,168.0,137.4,136.8,130.7,1 27.5,127.2,126.9,120.4,42.2,37.4,23.5,22.2,20.0; HR-MS(ESI)calcd.for C 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0945.

[0043] Example 3: The difference from Example 1 is as follows:

[0044] Step (4) React 1 mmol of 1,3-cyclohexanedione and 1 mmol of 3-methyl-β-nitrostyrene to obtain (Z)2-(hydroxyimino)-3-(m-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0045]

[0046] The sample was a white solid; yield: 41%; mp: 179.2–181.0℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3254,2949,1692,1632,1390,1364,1181,1061,952,759; 1H NMR (400MHz, (CD3)2CO) δ (ppm): 9.51 (s, 1H), 7.16 (dd, J1=J2=8.2Hz, 1H), 7.03 (dd, J1=8.4, J2=6.6Hz, 3H ),4.77(s,1H),2.86–2.77(m,1H),2.75–2.67(m,1H),2.41–2.30(m,2H),2.28(s,3H),2.22–2.14(m,2H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):193.2,173.9,157.7,140.0,138.6,129.2,12 9.1,128.6,125.6,118.4,46.4,37.5,23.5,22.1,21.4; HR-MS(ESI)calcd.forC 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0940.

[0047] (E)-2-(hydroxyimino)-3-(m-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0048]

[0049] The sample was a white solid; yield: 42%; mp: 183.2–184.5 °C; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3394,2957,1072,1633,1395,1357,1171,1060,999,754; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.33 (s, 1H), 7.17–7.11 (m, 2H), 7.08 (d, J = 7.6Hz, 1H), 7.01 (d, J = 6 .0Hz,1H),5.02(s,1H),2.85–2.75(m,1H),2.74–2.64(m,1H),2.31–2.25(m,5H),2.16–2.08(m,2H); 13 C{ 1H}NMR(100MHz,(CD3)2CO)δ(ppm):192.7,174.0,166.8,138.3,137.5,129.5,12 8.8,128.4,126.0,119.3,45.7,37.4,23.5,22.1,21.4; HR-MS(ESI)calcd.forC 15 H 15 NNaO3[(M+Na) + ]:280.0944; Found:280.0945.

[0050] Example 4: The difference from Example 1 is as follows:

[0051] Step (4) involves reacting 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1 mmol of 2-bromo-β-nitrostyrene to obtain (Z)3-(2-bromophenyl)-2-(hydroxyimino)-6,6-dimethyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0052]

[0053] The sample was a white solid, yield: 45%; mp 161.8–162.5 °C; Rf = 0.4 (EA:PE = 1:2); IR (KBr, cm⁻¹): ν 3291, 2964, 1693, 1654, 1395, 1171, 1026, 963, 745; ¹H NMR (400 MHz, (CD₃)₂CO) δ (ppm): 9.54 (s, ¹H), 7.58 (d, J = 8.0 Hz, ¹H), 7.31 (dd, J 1 = J 2=7.6Hz,1H),7.24–7.14(m,2H),5.33(s,1H),2.71(d,J=18,1H),2.68(d,J=1 8,1H),2.31(d,J=16,1H),2.23(d,J=16,1H),1.22(s,3H),1.19(s,3H); 13C{1 H}NMR(151MHz,(CD3)2CO)δ(ppm):192.4,173.1,156.9,134.0133.8,130.4,1 29.9,129.0,128.7,51.7,46.3,37.0,34.7,28.9,28.6; HR-MS(ESI)calcd.for C16H16BrNNaO3[(M+Na)+]:372.0206; Found:372.0203.

[0054] (E)-3-(2-bromophenyl)-2-(hydroxyimino)-6,6-dimethyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0055]

[0056] White solid, yield: 32%; mp 151.3–153.2℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3274,3150,2869,1707,1652,1635,1394,1236,1180,1030,994,752; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.36 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.28 (dd, J1 = J2 = 7.6Hz, 1H), 7.25–7.17 (m, 1H), 7.13 (dd ,J1=J2=8.0Hz,1H),5.49(s,1H),2.68(d,J=18,1H),2.63(d,J=18,1H),2.23(d,J=16,1H),2.16(d,J=16,1H),1.16(s,2x3H); 13 C{ 1 H}NMR(151MHz,(CD3)2CO)δ(ppm):191.8,173.2,166.6,137.5,133.6,129.4,128.5,110.9,51.6,46.1,37.1,34.7,28.8,28.5; HR-MS(ESI)calcd.for C 16 H 16 BrNNaO3[(M+Na) + ]:372.0206; Found:372.0204.

[0057] Example 5: The difference from Example 1 is as follows:

[0058] Step (4) involves reacting 1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1 mmol of β-nitrostyrene to obtain (Z)2-(hydroxyimino)-6,6-dimethyl-3-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0059]

[0060] The sample was a white solid; yield: 46%; mp: 173.5–176.2℃; Rf =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3246,2955,2889,1702,1620,1400,1163,1148,1032,956,727; 1 H NMR(400MHz,(CD3)2CO)δ(ppm):

[0061] 9.55(s,1H),7.32–7.26(m,2H),7.25–7.20(m,3H),4.85(s,1H),2.78–2.58(m,2H),2.33–2.20(m,2H),1.20(s,3H),1.17(s,3H); 13 C NMR(100MHz,(CD3)2CO)δ(ppm):192.6,172.5,157.9,140.1,129.2(2C),128.5(2C),127.9,117.2,51.8,46.4,37.0,34.7,28.7,28.6; HR-MS(ESI)calcd.for C 16 H 17 NNaO3[(M+Na) + ]:294.1101; Found:294.1104.

[0062] (E)-2-(hydroxyimino)-6,6-dimethyl-3-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0063]

[0064] The sample was a white solid; yield: 29%; mp: 193.0–194.2℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3372,2960,2880,1708,1652,1636,1399,1036,992,746; 1 H NMR(400MHz,(CD3)2CO)δ(ppm):9.36(s,1H),7.32–7.27(m,3H),7.28–7.25(m,1H),7.22–7.17(m ,1H),5.08(s,1H),2.73–2.59(m,2H),2.21(dd,J1=17.8,J2=16.2Hz,2H),1.15(d,J=5.2Hz,6H); 13 C{ 1H}NMR(100MHz,(CD3)2CO)δ(ppm):192.1,172.7,167.0,137.7,129.0(2C),128. 8(2C),127.6,118.1,51.7,45.8,37.0,34.7,28.7,28.5; HR-MS(ESI)calcd.for C 16 H 17 NNaO3[(M+Na) + ]:294.1101; Found:294.1102.

[0065] Example 6: The difference from Example 1 is as follows:

[0066] Step (4) React 1 mmol of 5-methyl-1,3-cyclohexanedione and 1 mmol of 4-methyl-β-nitrostyrene to obtain (Z)2-(hydroxyimino)-6-methyl-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one. Its structural formula is as follows:

[0067]

[0068] The sample was a white solid; yield: 41%; mp: 180.0–181.9℃; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3270,2956,2923,1691,1633,1389,1168,1022,948,893; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.52 (d, J = 4.4Hz, 1H), 7.13–7.08 (m, 4H), 4.80–4.75 (m, 1H), 2.87–2.74 (m, 1H), 2.62–2.5 4(m,1H),2.51–2.40(m,1H),2.38–2.30(m,1H),2.27(d,J=2.0Hz,3H),2.25–2.10(m,1H),1.17(dd,J1=6.4,J2=3.6Hz,3H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):192.9,173.1,158.0,137.3,137.0,129.8,128.4,118.0,46.2,46.0,31.2,30.6,29.8,21.1,21.0; HR-MS(ESI)calcd.for C 16 H 17NNaO3[(M+Na) + ]:294.1101; Found:294.1098.

[0069] (E)-2-(hydroxyimino)-6-methyl-3-(p-tolyl)-3,5,6,7-tetrahydrobenzofuran-4(2H)-one; its structural formula is as follows:

[0070]

[0071] The sample was a white solid; yield: 37%; mp: 165.4–167.2 °C; R f =0.4(EA:PE=1:2); IR(KBr,cm -1 ):ν3269,2960,2907,1709,1645,1634,1392,1197,1044,1023,999,798; 1 H NMR (400MHz, (CD3)2CO) δ (ppm): 9.33 (d, J = 8.0Hz, 1H), 7.17 (m, 2H), 7.07 (d, J = 2.4Hz, 1H), 7.05 (d, J = 3.2Hz, 1H), 5.01 ( s,1H),2.87–2.72(m,1H),2.60–2.36(m,2H),2.34–2.27(m,1H),2.26(s,3H),2.15–2.07(m,1H),1.14(d,J=6.4Hz,3H); 13 C{ 1 H}NMR(100MHz,(CD3)2CO)δ(ppm):192.3,173.7,167.0,137.1,134.6,129.6,128.8,119.1,45.7,45.3,31.4,30.3,21.0,20.9; HR-MS(ESI)calcd.for C 16 H 17 NNaO3[(M+Na) + ]:294.1101; Found:294.1100.

[0072] Example 7: The difference from Example 1 is as follows:

[0073] Step (4) was carried out at 60°C for 3 hours. The yields of the samples obtained were 27% and 35%.

[0074] Example 8: The difference from Example 1 is as follows:

[0075] Step (4) involved reacting with 0.15 g of zinc-based catalyst at 80 °C for 3 h. The yields of the samples obtained were 28% and 22%.

[0076] Example 9: The difference from Example 1 is as follows:

[0077] Step (4) used 0.45 g of zinc-based catalyst. The yields of the obtained samples were 47% and 46%.

[0078] Example 10: The difference from Example 1 is as follows:

[0079] Step (4) used 1.5 mmol of 4-methyl-β-nitrostyrene. The sample yields were 46% and 46%.

[0080] Comparative Example 1: The difference from Example 1 is that:

[0081] Step (4) was carried out at 40°C for 4 hours. The yield was 0.

[0082] Comparative Example 2: The difference from Example 1 is that:

[0083] Step (4) uses dichloromethane as a solvent and refluxes for 4 hours. The yield is 0.

[0084] Comparative Example 3: The difference from Example 1 is that:

[0085] Step (4) used aluminum chloride as a catalyst and reacted at 60°C for 24 hours. The yields were 10% and 11%.

[0086] Comparing Examples 1 to 6, it can be seen that the method of the present invention can be applied to the preparation of various tetrahydrobenzofuranone oxime derivatives, with high and stable product yields, indicating that the method of the present invention has a wide range of applications and is easy to implement.

[0087] Comparing Examples 1, 7-10, and the comparative examples, it can be seen that the catalyst has a significant impact on the product yield in the method of the present invention. In Example 8, reducing the amount of catalyst resulted in a yield of 28%, while in Comparative Example 3, which directly replaced the catalyst with aluminum chloride without reducing the amount, the yield was only 10%. This indicates that the catalyst used in the present invention has special catalytic properties for the preparation of tetrahydrobenzofuranone oxime derivatives, and the catalytic efficiency of other Lewis acids is less than one-quarter that of the catalyst of the present invention. The reaction temperature of the catalyst in the present invention significantly affects the yield. When the reaction temperature of Comparative Example 1 was reduced from 80°C to 40°C, the reaction yield dropped directly from 46% to 0. The reaction solvent also has a significant impact on the product yield. Using dimethyl sulfoxide as the reaction solvent yielded a variety of products as in Examples 1-6 with stable yields, while in Comparative Example 2, using dichloromethane as the reaction solvent resulted in a product yield of 0, indicating that dichloromethane cannot be used for the preparation of tetrahydrobenzofuranone oxime derivatives.

[0088] For those skilled in the art, various other corresponding changes and modifications can be made based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of this invention.

Claims

1. A method for preparing a tetrahydrobenzofuranone oxime derivative, characterized in that, The general reaction formula is as follows: In the formula: R 1 It is hydrogen or methyl; R 2 The molecule is hydrogen or methyl; compound I is one or more of 4-methyl-β-nitrostyrene, 2-methyl-β-nitrostyrene, 3-methyl-β-nitrostyrene, 4-chloro-β-nitrostyrene, 2-bromo-β-nitrostyrene, or β-nitrostyrene; the reaction is carried out using a Lewis acidic zinc-based catalyst; The preparation of the zinc-based catalyst includes the following steps: a. Hydroxypropyl cellulose and 4-toluenesulfonyl chloride were dissolved in an aqueous solution of N,N-dimethylformamide at 0-10℃ and mixed thoroughly; the temperature was raised to 20-30℃ and N-methylmorpholine was added dropwise, maintaining the pH of the system at 7-8, and the reaction was carried out for 4-6 hours; excess ethanol was added to precipitate the product, which was then thoroughly washed and dried to obtain sulfonate cellulose; b. Mix sulfonate-based cellulose with diethanolamine, heat to 45-65°C and stir until homogeneous, react for 8-12 hours; add excess acetone, separate the product and wash thoroughly, dry to obtain the complex matrix; c. Prepare a methanol solution of zinc chloride; disperse the complex matrix in methanol, add the methanol solution of zinc chloride, reflux for 10-16 h, separate the solid product, wash thoroughly and dry to obtain the zinc-based catalyst.

2. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 1, characterized in that, Compound II is one or more of 1,3-cyclohexanedione, 5-methyl-1,3-cyclohexanedione, or 5,5-dimethyl-1,3-cyclohexanedione.

3. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 1, characterized in that, Includes the following steps: Compound I, compound II, and a Lewis acid zinc-based catalyst were mixed in a solvent and reacted at 60–85 °C for 1.5–3 h; the products were separated after the reaction was complete.

4. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 3, characterized in that, The molar ratio of compound I to compound II is 1:1 to 1.5; the molar ratio of compound I to zinc in the zinc-based catalyst is 1:0.5 to 1.

5.

5. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 3, characterized in that, The solvent is one or both of dimethyl sulfoxide or N,N-dimethylformamide.

6. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 1, characterized in that, In the aqueous solution of N,N-dimethylformamide described in step a, the volume ratio of N,N-dimethylformamide to water is 1~3:1; the mass ratio of hydroxypropyl cellulose to 4-toluenesulfonyl chloride is 1:1.2~1.8; the mass ratio of N-methylmorpholine to 4-toluenesulfonyl chloride is 1:1.2~1.5; and the volume of excess ethanol is 3~6 times that of the liquid in the system.

7. The method for preparing the tetrahydrobenzofuranone oxime derivative according to claim 1, characterized in that, In step b, the mass ratio of sulfonate-based cellulose to diethanolamine is 1:4~6; the volume of excess acetone is 3~6 times that of the liquid in the system; in step c, the mass ratio of the complexing matrix to zinc chloride is 1:0.5~0.8.

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