A process for the preparation of 5-methylfurfural and its derivatives

Abstract

The application discloses a preparation method of 5-methyl furfural and derivatives thereof, and belongs to the technical field of preparation of crude drugs. Deionized water, glyoxylic acid and a catalyst are stirred and uniformly mixed, an alkali liquor is used to adjust the pH to 4.5-5.5, then the mixture is added dropwise into a tert-butyl alcohol solution containing 2-methyl furan, and the reaction is carried out under the condition of temperature rising and stirring; the reaction is continued under the condition of temperature dropping and adding sodium hypochlorite solution, and 5-methyl furfural is obtained; the catalyst is obtained by the reaction of pentaerythritol dimethyl ether and (2-aminoethyl) triphenyl phosphonium bromide. The 5-methyl furfural prepared by using the catalyst has high yield and purity, and the 5-methyl furfural derivatives prepared by using 5-methyl furfural as a raw material also have high yield and purity.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredient (API) preparation technology, specifically to a method for preparing 5-methylfurfural and its derivatives. Background Technology

[0002] 5-Methylfurfural is a core pharmaceutical intermediate for the synthesis of active pharmaceutical ingredients (APIs) in polyhexane drugs. Currently, the Vilsmeier-Haack formylation process is a common route for 5-methylfurfural synthesis. However, this route requires halogenated reagents such as phosphorus oxychloride and generates large amounts of difficult-to-treat phosphorus-containing and acidic wastewater, which does not align with the trend towards green synthesis of APIs. To replace traditional polluting processes, existing research attempts to develop novel catalytic systems for 5-methylfurfural preparation. However, using transition metal catalytic systems can easily lead to excessive heavy metal residues in 5-methylfurfural, which can then be carried over into subsequent derivative preparations, increasing the cost of separating and purifying the final active drug component and raising quality control risks. Even when attempting to introduce metal-free small-molecule organic catalysts into the preparation of 5-methylfurfural, technical bottlenecks such as cumbersome catalyst synthesis steps, low mass transfer efficiency in two-phase reaction systems, and unsatisfactory catalytic conversion rates are generally encountered.

[0003] Chinese invention patent CN120794934A discloses a method for preparing 5-methylfurfural using 2-methylfuran. This invention employs a specially formulated solid acid catalyst to replace the traditional phosphorus oxychloride catalyst, eliminating hydrogen chloride and phosphorus-containing wastewater at the source, and uses sulfolane instead of DMF to reduce solvent residue in the product. The solid catalyst is SO4. 2- Modification forms strong Bronsted acid sites (-SO3H), synergistically with Ce 3+ / Ce 4+ Redox reactions inhibit carbon deposition, selectively activate the α-C of 2-methylfuran, and suppress side reactions, thereby improving the selectivity and yield of the target product. Electrochemical neutralization replaces Na₂CO₃ neutralization, eliminating salt residue solid waste and reducing environmental pollution. After the organic phase is dried by molecular sieve to remove water, most of the solvent is removed by rotary evaporation. The remaining crude product is then subjected to centrifugal molecular distillation to effectively remove unreacted raw materials and trace impurities, thus significantly improving product purity. However, the yield of 5-methylfurfural prepared by this method still needs to be improved.

[0004] Therefore, there is an urgent need to develop an efficient, environmentally friendly catalytic system and process route free of heavy metal residues to achieve high-quality green preparation of 5-methylfurfural, thereby providing high-quality and pure precursors for the synthesis of chemical pharmaceutical raw material derivatives. Summary of the Invention

[0005] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing 5-methylfurfural and its derivatives.

[0006] A method for preparing 5-methylfurfural includes the following steps: Deionized water, glyoxylic acid, and catalyst were stirred and mixed thoroughly. The pH was adjusted to 4.5-5.5 using an alkaline solution, and then added dropwise to a tert-butanol solution containing 2-methylfuran. The mixture was heated and stirred to react. After cooling, an aqueous solution of sodium hypochlorite was added, and the reaction was continued by heating to obtain 5-methylfurfural. The reaction equation is as follows: ; The chemical structural formula of the catalyst is as follows: .

[0007] The molar ratio of 2-methylfuran, glyoxylic acid, and catalyst is 1:(1.1-1.2):(0.08-0.1).

[0008] The alkaline solution is either an aqueous solution of NaOH or an aqueous solution of KOH.

[0009] The temperature for the heating and stirring reaction is 25-30℃, and the time is 4-4.5h.

[0010] The temperature for the continued reaction is 25-30℃, and the time is 1.5-2 hours.

[0011] A method for preparing a 5-methylfurfural derivative includes the following steps: S1: 5-Methylfurfural reacts with hydroxylamine hydrochloride in the presence of sodium carbonate to generate 5-methyl-2-furfural oxime; S2: 5-Methyl-2-furfural oxime reacts with N-chlorosuccinimide to generate N-hydroxy-5-methylfuran-2-methyliminoyl chloride; S3: N-hydroxy-5-methylfuran-2-methyliminoyl chloride reacts with 4-propyn-1-morpholine in the presence of an organic base to generate a 5-methylfurfural derivative, and the reaction equation is as follows: .

[0012] The solvent used in step S1 is a mixed solution of deionized water and anhydrous ethanol; the solvent used in step S2 is anhydrous dichloromethane; and the solvent used in step S3 is dichloromethane.

[0013] In step S3, the organic base is triethylamine.

[0014] A catalyst is prepared by the following method: Acetonitrile, (2-aminoethyl)triphenylphosphonium bromide, and triethylamine were stirred and mixed. A solution of dimethyl succinate in acetonitrile was slowly added dropwise. The reaction was carried out at room temperature, and the catalyst was obtained after post-treatment.

[0015] The molar ratio of (2-aminoethyl)triphenylphosphonium bromide to dimethyl squaric acid is 2.05:1.

[0016] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include: The 5-methylfurfural prepared using the catalyst prepared in this invention has a high yield and purity, and the 5-methylfurfural derivatives prepared using 5-methylfurfural as a raw material also have a high yield and purity. Attached Figure Description

[0017] Figure 1 The infrared spectrum of the catalyst prepared in Example 1; Figure 2 The liquid chromatogram of 5-methylfurfural prepared in Example 3; Figure 3 The 1H NMR spectrum of 5-methylfurfural prepared in Example 3; Figure 4 The infrared spectrum of 5-methylfurfural prepared in Example 3; Figure 5 The liquid chromatogram of the 5-methylfurfural derivative prepared in Example 5; Figure 6 The 1H NMR spectrum of the 5-methylfurfural derivative prepared in Example 5; Figure 7 The infrared spectrum of the 5-methylfurfural derivative prepared in Example 5; Figure 8 The graph shows the relationship between the number of catalytic cycles and the yield of 5-methylfurfural. Detailed Implementation

[0018] Example 1: Preparation of Catalyst 400 ml of acetonitrile, 0.205 mol of (2-aminoethyl)triphenylphosphonium bromide, and 0.21 mol of triethylamine were stirred and mixed. 70 ml of an acetonitrile solution containing 0.1 mol of dimethyl squaric acid was slowly added dropwise over 20 min. The reaction was allowed to proceed at room temperature for 12 h, followed by rotary evaporation at 50 °C to constant weight. 300 ml of acetone was slowly added to the crude product, and the mixture was stirred to precipitate. The precipitate was filtered, and the filter cake was washed successively with 80 ml of acetone and 80 ml of ethyl acetate. The precipitate was then dried under vacuum at 40 °C for 12 h to obtain the catalyst. The reaction equation is shown below:

[0019] Its proton NMR spectrum data are as follows: 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.88-7.79 (m, 12H), 7.78-7.69 (m, 6H), 7.66-7.57 (m, 12H), 3.75-3.56 (m, 8H); HRMS(m / z): 345.1279[M-2Br] 2+ .

[0020] Figure 1 The infrared spectrum of the prepared catalyst is shown in the figure. It can be seen from the figure that the product exhibits high activity in the 3300-3400 cm⁻¹ range. -1 A peak of NH stretching vibration appears nearby, at 1680 cm⁻¹. -1 A carbonyl characteristic peak appears nearby, at 3050 cm⁻¹ -1 1480-1430cm -1 and 1100cm -1 The presence of characteristic peaks of aromatic rings and CN in the vicinity confirms the synthesis of the target catalyst.

[0021] Example 2 Preparation of 5-methylfurfural 40 ml of deionized water, 0.11 mol of glyoxylic acid, and 0.008 mol of catalyst (prepared in Example 1) were stirred and mixed. The pH was adjusted to 4.5 using a 4 wt% NaOH aqueous solution. Then, the mixture was added dropwise to 70 ml of a tert-butanol solution containing 0.1 mol of 2-methylfuran (the system temperature was controlled at 25°C during the dropwise addition). The addition was completed in 30 min. The mixture was stirred at 800 rpm at 25°C for 4.5 h (the pH of the system was maintained at 4.5 ± 0.5 using a 4 wt% NaOH aqueous solution during the reaction). After the reaction was completed, the solution was rotary evaporated at 50°C to constant weight, cooled to room temperature, and 300 ml of acetone was slowly added. The mixture was stirred for 30 min to precipitate the catalyst. The catalyst was recovered by filtration, and the filtrate was rotary evaporated at 45°C to constant weight. The solution was then cooled to 0°C, and 80 g of 10 wt% sodium hypochlorite aqueous solution was slowly added dropwise (0.5 mol / L acetate-sodium acetate buffer was used to maintain the pH of the system at 6 ± 0.5 during the dropwise addition). The addition was completed in 1 h, and the temperature was raised to 25°C to continue the reaction for 2 h. After the reaction was completed, 100 ml of 10 wt% sodium sulfite aqueous solution was slowly added for quenching, and 100 ml of saturated sodium chloride solution was added for salting out. The mixture was stirred for 10 min and extracted with ethyl acetate (3 × 80 ml). The organic phases were combined and washed successively with 50 ml of saturated sodium chloride solution and 50 ml of deionized water. The mixture was dried with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 45 °C for 2 h to obtain crude 5-methylfurfural. The crude product was transferred to a round-bottom flask equipped with a short-path distillation head and subjected to vacuum distillation at a vacuum degree of 0.8 kPa. The low-boiling fraction was first collected and discarded at 35-45℃, and then the fraction at 65-75℃ was collected to obtain 5-methylfurfural with a yield of 92.8% and a liquid phase purity of 99.80%.

[0022] Example 3 Preparation of 5-methylfurfural 40 ml of deionized water, 0.11 mol of glyoxylic acid, and 0.009 mol of catalyst (prepared in Example 1) were stirred and mixed. The pH was adjusted to 5 using a 5 wt% NaOH aqueous solution. Then, the mixture was added dropwise to 70 ml of a tert-butanol solution containing 0.1 mol of 2-methylfuran (the system temperature was controlled at 25°C during the dropwise addition). The addition was completed in 30 min, and the mixture was stirred at 800 rpm at 25°C for 4.5 h (the pH of the system was maintained at 5 ± 0.5 using a 5 wt% NaOH aqueous solution during the reaction). After the reaction was completed, the solution was rotary evaporated at 50°C to constant weight, cooled to room temperature, and 300 ml of acetone was slowly added. The mixture was stirred for 30 min to precipitate the catalyst. The catalyst was recovered by filtration, and the filtrate was rotary evaporated at 45°C to constant weight. The solution was then cooled to 0°C, and 80 g of 11 wt% sodium hypochlorite aqueous solution was slowly added dropwise (0.5 mol / L acetate-sodium acetate buffer was used to maintain the pH of the system at 6 ± 0.5 during the dropwise addition). The addition was completed in 1 h, and the temperature was raised to 25°C to continue the reaction for 2 h. After the reaction was completed, 100 ml of 10 wt% sodium sulfite aqueous solution was slowly added for quenching, and 100 ml of saturated sodium chloride solution was added for salting out. The mixture was stirred for 10 min and extracted with ethyl acetate (3 × 80 ml). The organic phases were combined and washed successively with 50 ml of saturated sodium chloride solution and 50 ml of deionized water. The mixture was dried with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 45 °C for 2 h to obtain crude 5-methylfurfural. The crude product was transferred to a round-bottom flask equipped with a short-path distillation head and subjected to vacuum distillation at 0.8 kPa. The low-boiling fraction was first collected and discarded at 35-45 °C, followed by collection of the fraction at 65-75 °C to yield 5-methylfurfural in 93.4% yield with a liquid phase purity of 99.73% (see [reference]). Figure 2 ).

[0023] The 1H NMR spectrum of 5-methylfurfural is shown below. Figure 3 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.60 (s, 1H), 7.14 (d, J = 3.5 Hz, 1H), 6.28 (d, J = 3.5 Hz, 1H), 2.43 (s, 3H).

[0024] Figure 4 The infrared spectrum of the prepared 5-methylfurfural is shown in the figure. As can be seen from the figure, the product has a wavelength range of 1670-1700 cm⁻¹. -1 Characteristic peaks of aldehyde carbonyl groups appear nearby, at 1400 cm⁻¹. -1 and 1520cm -1 A vibrational peak of the C=C double bond in the furan ring appears nearby, at 1200 cm⁻¹. -1 and 1020-1100cm -1 Characteristic peaks of the COC structure in the furan ring appeared nearby, and also at 2920 cm⁻¹. -1 The presence of a methyl CH stretching vibration peak nearby indicates that the obtained 5-methylfurfural product contains aldehyde, methyl, and furan ring structures simultaneously.

[0025] Example 4 Preparation of 5-Methylfurfural 40 ml of deionized water, 0.11 mol of glyoxylic acid, and 0.01 mol of catalyst (prepared in Example 1) were stirred and mixed. The pH was adjusted to 5.5 using a 6 wt% KOH aqueous solution. Then, the mixture was added dropwise to 70 ml of a tert-butanol solution containing 0.1 mol of 2-methylfuran (the system temperature was controlled at 25°C during the dropwise addition). The addition was completed in 30 min, and the mixture was stirred at 800 rpm at 30°C for 4 h (the pH of the system was maintained at 5.5 ± 0.5 using a 6 wt% KOH aqueous solution during the reaction). After the reaction was completed, the solution was rotary evaporated at 50°C to constant weight, cooled to room temperature, and 300 ml of acetone was slowly added. The mixture was stirred for 30 min to precipitate the catalyst. The catalyst was recovered by filtration, and the filtrate was rotary evaporated at 45°C to constant weight. The solution was then cooled to 0°C, and 80 g of 12 wt% sodium hypochlorite aqueous solution was slowly added dropwise (0.5 mol / L acetate-sodium acetate buffer was used to maintain the pH of the system at 6 ± 0.5 during the dropwise addition). The addition was completed in 1 h, and the temperature was raised to 30°C to continue the reaction for 1.5 h. After the reaction was completed, 100 ml of 10 wt% sodium sulfite aqueous solution was slowly added for quenching, and 100 ml of saturated sodium chloride solution was added for salting out. The mixture was stirred for 10 min and extracted with ethyl acetate (3 × 80 ml). The organic phases were combined and washed successively with 50 ml of saturated sodium chloride solution and 50 ml of deionized water. The mixture was dried with 30 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 45 °C for 2 h to obtain crude 5-methylfurfural. The crude product was transferred to a round-bottom flask equipped with a short-path distillation head and subjected to vacuum distillation at a vacuum degree of 0.8 kPa. The low-boiling fraction was first collected and discarded at 35-45℃, and then the fraction at 65-75℃ was collected to obtain 5-methylfurfural with a yield of 92.5% and a liquid phase purity of 99.76%.

[0026] Example 5 Preparation of 5-methylfurfural derivatives S1: 100 ml deionized water, 50 ml anhydrous ethanol, 11 g 5-methylfurfural, 8.34 g hydroxylamine hydrochloride, and 12.72 g sodium carbonate were mixed and heated to 65 °C for 4 h. After naturally cooling to room temperature, 150 ml saturated sodium chloride solution was added for salting out. Extraction was performed using ethyl acetate (2 × 200 ml). The organic phases were combined and washed successively with 80 ml saturated ammonium chloride solution, 80 ml deionized water, and 80 ml saturated sodium chloride solution. The mixture was dried over 40 g anhydrous magnesium sulfate, filtered, and rotary evaporated at 50 °C to constant weight. The mixture was then dried under vacuum at 40 °C for 12 h to obtain 12.11 g of 5-methyl-2-furfural oxime. Its 1H NMR data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 11.29 (s, 1H), 7.57 (s, 1H), 6.68 (d, J = 3.3 Hz, 1H), 6.16 (d, J = 3.3 Hz, 1H), 2.41 (s, 3H); S2: 120 ml of anhydrous dichloromethane and 12 g of 5-methyl-2-furfural oxime were stirred and mixed. 14.09 g of N-chlorosuccinimide and 2 ml of pyridine were added. The mixture was reacted at room temperature for 4 h. 150 ml of dichloromethane was added to dilute the reaction solution. The solution was washed successively with 100 ml of saturated ammonium chloride solution, 100 ml of deionized water, and 100 ml of saturated sodium chloride solution. The solution was dried over 40 g of anhydrous magnesium sulfate, filtered, and rotary evaporated at 30 °C to constant weight to obtain 14.62 g of N-hydroxy-5-methylfuran-2-methylimine amide chloride. Its 1H NMR spectrum data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 11.14 (s, 1H), 6.92 (d, J = 3.4 Hz, 1H), 6.29 (d, J = 3.4 Hz, 1H), 2.42 (s, 3H); S3: Mix 250 ml of dichloromethane, 6.26 g of 4-propynyl-1-morpholine, and 14.5 g of N-hydroxy-5-methylfuran-2-methylimine chloride. Add 11 g of triethylamine and react at room temperature for 10 h. Filter the solution. Wash the filtrate successively with 120 ml of deionized water and 120 ml of saturated sodium chloride solution. Dry the solution with 35 g of anhydrous magnesium sulfate. Filter the solution and rotary evaporate at 30 °C to constant weight. Purify the crude product by silica gel column chromatography (V... 乙酸乙酯 :V 石油醚 =1:1), and by rotary evaporation at 45℃ to constant weight, a 5-methylfurfural derivative with a purity of 99.73% was obtained (see [reference]). Figure 5 Its proton nuclear magnetic resonance spectrum is as follows: Figure 6 As shown, the proton NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ7.01 (s, 1H), 6.89 (d, J = 3.3 Hz, 1H), 6.21 (d, J = 3.3 Hz, 1H), 3.82 (s,2H), 3.64-3.60 (m, 4H), 2.59-2.55 (m, 4H), 2.44 (s, 3H); The overall yield of the above three steps was 90.3%.

[0027] Figure 7 The infrared spectrum of the prepared 5-methylfurfural derivative is shown in the figure. As can be seen from the figure, the product exhibits high activity at 1640 cm⁻¹. -1 The characteristic absorption peak of the isoxazole ring C=N appears nearby, in the range of 1570-1500 cm⁻¹. -1 A heterocyclic framework vibration absorption peak appears nearby, and at 1250 cm⁻¹ -1 and 1110-1030cm -1 Characteristic absorption peaks for COC and CN appear nearby, and also at 2950-2850 cm⁻¹. -1 The presence of an aliphatic CH stretching vibration absorption peak nearby confirms the synthesis of the target 5-methylfurfural derivative.

[0028] Example 6 Catalyst Recovery Experiment The catalyst recovered by filtration in Example 3 was sequentially treated with a deionized water / acetone mixture (V... 去离子水 :V 丙酮 Wash with a 1:3 ratio (2×50ml), wash with anhydrous acetone (2×50ml), and vacuum dry at 50℃ for 12h. Reuse the solution for the preparation of 5-methylfurfural, following the method described in Example 3. Repeat this process 8 times, preparing 5-methylfurfural according to the method in Example 3. Record the yield of 5-methylfurfural for each preparation. The relationship between the number of recycling cycles and the yield of 5-methylfurfural is as follows: Figure 8 As shown.

[0029] from Figure 8 It can be seen that in the reaction of preparing 5-methylfurfural by catalyzing the catalyst after 8 cycles, the yield of 5-methylfurfural was higher than 92%, indicating that the catalyst has excellent cycle stability and reusability.

[0030] Comparative Example 1 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that the catalyst is replaced with an equimolar amount of a catalyst prepared by the following method: The preparation method of the catalyst is basically the same as that in Example 1, except that the amount of (2-aminoethyl)triphenylphosphonium bromide is replaced with 0.105 mol.

[0031] Comparative Example 2 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that the catalyst is replaced with an equimolar amount of a catalyst prepared by the following method: The preparation method of the catalyst is basically the same as that in Example 1, except that dimethyl squaric acid is replaced with an equimolar amount of dimethyl malonate.

[0032] Comparative Example 3 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that the amount of catalyst is replaced with 0.02 mol.

[0033] Comparative Example 4 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that the amount of catalyst is replaced with 0.005 mol.

[0034] Comparative Example 5 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that no catalyst is added.

[0035] Comparative Example 6 The preparation method of 5-methylfurfural is basically the same as that in Example 3, except that the catalyst is replaced with an equimolar amount of tetrabutylphosphine bromide.

[0036] Comparative Example 7 The preparation method of the 5-methylfurfural derivative is basically the same as that in Example 5, except that the dichloromethane in step S3 is replaced with an equal volume of ethyl acetate.

[0037] Comparative Example 8 The preparation method of the 5-methylfurfural derivative is basically the same as that in Example 5, except that sodium carbonate is not added in step S1.

[0038] Comparative Example 9 The preparation method of the 5-methylfurfural derivative is basically the same as that in Example 5, except that triethylamine is not added in step S3.

[0039] The yields and purities of the 5-methylfurfural and its derivatives prepared in the comparative examples are shown in Tables 1 and 2.

[0040] Table 1. Yield and purity data of 5-methylfurfural

[0041] Table 2. Total Yield and Purity Data of 5-Methylfurfural Derivatives

[0042] The catalyst used in this application is a symmetrical bisquaternary phosphonium salt-squamamide catalyst, containing both a quadrangular amide double NH hydrogen bond donor structure and a triphenylphosphine cation structure. The quadrangular amide group can activate the carbonyl group in glyoxylic acid through double hydrogen bonding, improving the electrophilic reactivity of glyoxylic acid with 2-methylfuran. The triphenylphosphine cation exhibits strong ion association and organic phase affinity, improving the contact efficiency of glyoxylic acid, 2-methylfuran, and the catalyst in the water / tert-butanol system, increasing the selectivity of 2-methylfuran, and reducing side reactions such as acid-catalyzed polymerization. Simultaneously, the catalyst is recovered before oxidation to avoid its destruction in the sodium hypochlorite oxidation system, reducing the impact of catalyst residue on the subsequent oxidation selectivity. During the oxidation stage, the selectivity of 5-methylfurfural is improved by the low-temperature dropwise addition of sodium hypochlorite, while suppressing side reactions such as furan cyclization and ring-opening. Therefore, the obtained 5-methylfurfural exhibits high yield and purity.

[0043] In the preparation of 5-methylfurfural derivatives, this application describes a process where 5-methylfurfural first reacts with hydroxylamine hydrochloride to form 5-methyl-2-furfural oxime, which is then chlorinated with N-chlorosuccinimide to form N-hydroxy-5-methylfuran-2-methyliminoyl chloride. Finally, the 5-methylfurfural derivative is generated under the action of triethylamine. The functional group transformations at each step of this route are clearly defined, and byproducts can be effectively removed by washing, salting out, drying, and column chromatography. Consequently, the obtained 5-methylfurfural derivative exhibits high yield and purity.

[0044] The catalyst used in Comparative Example 1 was an asymmetric monosubstituted quaternary phosphonium salt-squamamide catalyst. The number of NH hydrogen bond donors and triphenylphosphine cation sites was reduced, the carbonyl activation was weakened, and the contact efficiency of glyoxylic acid, 2-methylfuran and catalyst in the water / tert-butanol system decreased, resulting in a decrease in the yield and purity of 5-methylfurfural.

[0045] The change of reaction solvent in Comparative Example 7 resulted in a decrease in the yield and purity of the product. This is because dichloromethane, as an inert polar aprotic solvent, provides a solvation environment for the reactive intermediate generated in situ in step S3, effectively maintaining its concentration and stabilizing its transition state. In contrast, ethyl acetate exhibits a significantly different polarity distribution and solvation ability compared to dichloromethane. Furthermore, the ester group oxygen atom in its structure readily engages in weak competitive coordination interference with highly reactive electron-deficient intermediates. The altered solvent environment weakens the stabilizing effect on nitrile oxides, leading to its own side reactions before effective cycloaddition with alkynes. This not only wastes key reactants but also increases impurities in the reaction system, ultimately resulting in a decrease in the yield and purity of the derivative.

[0046] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing 5-methylfurfural, characterized in that, Includes the following steps: Deionized water, glyoxylic acid, and catalyst were stirred and mixed. The pH was adjusted to 4.5-5.5 using an alkaline solution. The mixture was then added dropwise to a tert-butanol solution containing 2-methylfuran. The mixture was heated and stirred to react. The mixture was then cooled, and an aqueous solution of sodium hypochlorite was added. The reaction was continued by heating to obtain 5-methylfurfural. The chemical structural formula of the catalyst is as follows: 。 2. The method for preparing 5-methylfurfural according to claim 1, characterized in that, The molar ratio of 2-methylfuran, glyoxylic acid, and catalyst is 1:(1.1-1.2):(0.08-0.1).

3. The method for preparing 5-methylfurfural according to claim 1, characterized in that, The alkaline solution is either an aqueous solution of NaOH or an aqueous solution of KOH.

4. The method for preparing 5-methylfurfural according to claim 1, characterized in that, The temperature for the heating and stirring reaction is 25-30℃, and the time is 4-4.5h.

5. The method for preparing 5-methylfurfural according to claim 1, characterized in that, The temperature for the continued reaction is 25-30℃, and the time is 1.5-2 hours.

6. A method for preparing a 5-methylfurfural derivative, characterized in that, Includes the following steps: S1: 5-Methylfurfural reacts with hydroxylamine hydrochloride in the presence of sodium carbonate to generate 5-methyl-2-furfural oxime; S2: 5-Methyl-2-furfural oxime reacts with N-chlorosuccinimide to generate N-hydroxy-5-methylfuran-2-methyliminoyl chloride; S3: N-hydroxy-5-methylfuran-2-methyliminoyl chloride reacts with 4-propynyl-1-morpholine under the action of an organic base to generate a 5-methylfurfural derivative.

7. The method for preparing a 5-methylfurfural derivative according to claim 6, characterized in that, The solvent used in step S1 is a mixed solution of deionized water and anhydrous ethanol; the solvent used in step S2 is anhydrous dichloromethane; and the solvent used in step S3 is dichloromethane.

8. The method for preparing a 5-methylfurfural derivative according to claim 6, characterized in that, In step S3, the organic base is triethylamine.

9. A catalyst, characterized in that, Prepared by the following method: Acetonitrile, (2-aminoethyl)triphenylphosphonium bromide, and triethylamine were stirred and mixed. A solution of dimethyl succinate in acetonitrile was slowly added dropwise. The reaction was carried out at room temperature, and the catalyst was obtained after post-treatment.

10. A catalyst according to claim 9, characterized in that, The molar ratio of (2-aminoethyl)triphenylphosphonium bromide to dimethyl squaric acid is 2.05:1.

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