Preparation method of 5-hydroxy-3-methyl-2 (5H)-furanone

Abstract

The invention relates to a preparation method of 5-hydroxy-3-methyl-2 (5H)-furanone, which comprises the following steps: (1) diethyl methylmalonate and 2, 2-dimethoxyacetaldehyde react to obtain a compound 1 and a compound 2, and then the compound 1 and the compound 2 are separated; (2) the compound 1 is subjected to a reaction, and 5-hydroxy-3-methyl-2 (5H)-furanone is obtained; and (3) the compound 2 is subjected to a reaction to obtain 5-hydroxy-3-methyl-2 (5H)-furanone, and the sequence of the step (2) and the step (3) is not the same. The preparation method provided by the invention is relatively high in yield, stable in process and relatively simple in post-treatment mode, column chromatography and other operations can be avoided, the used reagents are conventional reagents, the production cost is reduced, the preparation method can be suitable for industrial amplified production, and a technical support is provided for synthesis of strigolactones compounds.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 5-hydroxy-3-methyl-2(5H)-furanone. Background Art

[0002] Strigolactones are a new type of plant hormone secreted by plants that can inhibit plant branching and stimulate the germination of root parasitic weed seeds. More than thirty natural strigolactones have been discovered so far. They all contain a butenolide ring structure connected by an enol ether bond, which is generally called the D-ring, and it is particularly crucial for the function of strigolactones. Orobanche and Striga root parasitic weeds are widely distributed throughout the world. These two types of root parasitic weeds have a wide variety of host plants, and the annual loss of crop production due to their infestation amounts to billions of US dollars. Each Striga and Orobanche plant can produce tens of thousands of seeds, and their germination depends on the stimulation of strigolactones secreted by the roots of host plants. Since the seeds of Striga and Orobanche are tiny, contain little nutrients, and cannot or can only carry out limited photosynthesis by themselves, they will die once they germinate but cannot parasitize on the host plant. Taking advantage of this characteristic, people have proposed a "suicidal germination" strategy to deal with the harm of root parasitic weeds. By applying natural strigolactone analogs, the seeds of Striga and Orobanche weeds are stimulated to germinate in advance, so that they cannot parasitize on the host plant. Eventually, the weed seeds die due to the lack of nutrients from the host plant, thereby achieving the purpose of controlling root parasitic weeds.

[0003] At the same time, in recent years, it has been found that strigolactone compounds can not only stimulate seed germination, but also regulate many aspects of plant growth, such as promoting root growth, inhibiting branching, inhibiting hypocotyl growth, participating in the regulation of sugar and amino acid accumulation in grains, etc., and have great application potential in improving the quality and increasing the yield of crops. As an important synthetic intermediate for the D-ring part of strigolactones and their analogs, the synthesis process of 5-hydroxy-3-methyl-2(5H)-furanone still has many problems, such as low reaction yield, difficult purification, resulting in a relatively high synthesis cost.

[0004] CN119039255A involves a preparation method of 5-hydroxy-3-methyl-2(5H)-furanone: adding 118.6 mmol of methylmalonic acid and 118.6 mmol of glyoxal into a reaction flask containing water, dropping 10 drops of concentrated sulfuric acid, and heating and refluxing at 110 - 115 °C for 10 - 12 h to obtain 5-hydroxy-3-methyl-2(5H)-furanone. The defects of this method include: 1) The generation of impurities cannot be controlled by the synthesis technology; 2) Column chromatography purification is necessary, resulting in too high cost; 3) The yield is low; 4) It is not suitable for industrial scale-up production.

[0005] Therefore, providing a preparation method of 5-hydroxy-3-methyl-2(5H)-furanone with high yield and low cost is of great significance for the synthesis of strigolactone compounds. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a preparation method of 5-hydroxy-3-methyl-2(5H)-furanone. The preparation method provided by the present invention has a relatively high yield, stable process, relatively simple post-treatment method, can avoid operations such as column chromatography, and the reagents used are all conventional reagents, reducing the production cost, and can be applied to industrial scale-up production, providing technical support for the synthesis of strigolactone compounds.

[0007] To achieve this purpose, the present invention adopts the following technical solutions:

[0008] The present invention provides a preparation method of 5-hydroxy-3-methyl-2(5H)-furanone, and the preparation method includes the following steps:

[0009] (1) Diethyl methylmalonate reacts with 2,2-dimethoxyacetaldehyde to obtain Compound 1 and Compound 2, and then Compound 1 and Compound 2 are separated; the reaction formula is as follows:

[0010]

[0011] (2) Compound 1 undergoes a reaction to obtain 5-hydroxy-3-methyl-2(5H)-furanone; the reaction formula is as follows:

[0012]

[0013] (3) Compound 2 undergoes a reaction to obtain 5-hydroxy-3-methyl-2(5H)-furanone; the reaction formula is as follows:

[0014]

[0015] Among them, the order of steps (2) and (3) is not sequential.

[0016] In the present invention, the starting materials diethyl methylmalonate and 2,2-dimethoxyacetaldehyde first undergo a Knoevenagel reaction to obtain Compound 1 and Compound 2, and Compound 2 can obtain Compound 1 through decarboxylation and dehydration reactions; then Compound 1 and Compound 2 respectively undergo reactions to obtain the target product 5-hydroxy-3-methyl-2(5H)-furanone.

[0017] The preparation method provided by the present invention has a relatively high yield, stable process, relatively simple post-treatment method, can avoid operations such as column chromatography, and the reagents used are all conventional reagents, reducing the production cost, and can be applied to industrial scale-up production, providing technical support for the synthesis of strigolactone compounds.

[0018] Preferably, the molar ratio of diethyl methylmalonate to 2,2 - dimethoxyacetaldehyde in step (1) is 1:(1 - 1.5) (for example, it can be 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.), and preferably 1:(1.2 - 1.3).

[0019] Preferably, the reaction in step (1) is carried out in the presence of a solvent.

[0020] Preferably, the solvent includes any one or a combination of at least two of pyridine, toluene, N,N - dimethylformamide, or dimethyl sulfoxide, and preferably pyridine.

[0021] Preferably, the dosage ratio of diethyl methylmalonate to the solvent is 1 g:(5 - 15) mL (for example, it can be 1 g:5 mL, 1 g:8 mL, 1 g:10 mL, 1 g:12 mL, 1 g:14 mL, 1 g:15 mL, etc.), and preferably 1 g:(6 - 10) mL.

[0022] Preferably, the reaction in step (1) is carried out in the presence of an organic base.

[0023] Preferably, the organic base includes any one or a combination of at least two of piperidine, triethylamine, N,N - diisopropylethylamine, or N,N - diisopropylamine, and preferably piperidine.

[0024] Preferably, the molar ratio of diethyl methylmalonate to the organic base is 1:(1 - 2) (for example, it can be 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, etc.), and preferably 1:(1.2 - 1.6).

[0025] Preferably, the temperature of the reaction in step (1) is 80 - 120 °C (for example, it can be 80 °C, 90 °C, 100 °C, 110 °C, 120 °C, etc.), and the reaction time is 10 - 30 h (for example, it can be 10 h, 15 h, 20 h, 25 h, 30 h, etc.).

[0026] Preferably, the temperature of the reaction is 90 - 100 °C, and the reaction time is 16 - 20 h.

[0027] Preferably, the separation method in step (1) includes: extracting the reaction system with the good solvents of compound 1 and compound 2 respectively, and then drying and concentrating to obtain compound 1 and compound 2 respectively.

[0028] Preferably, the good solvent of compound 1 includes petroleum ether and / or toluene.

[0029] Preferably, the good solvent of compound 2 includes ethyl acetate.

[0030] Preferably, the reaction described in step (2) is carried out in the presence of an acid.

[0031] Preferably, the acid includes any one or a combination of at least two of sulfuric acid, hydrochloric acid, trifluoroacetic acid, or polyphosphoric acid, preferably sulfuric acid and / or hydrochloric acid.

[0032] Preferably, the acid exists in the form of an aqueous solution of sulfuric acid and / or hydrochloric acid, or in the anhydrous form of trifluoroacetic acid and / or polyphosphoric acid.

[0033] Preferably, the concentration of the aqueous solution of sulfuric acid and / or hydrochloric acid is 0.2 - 1.2 mol / L (for example, it can be 0.2 mol / L, 0.4 mol / L, 0.6 mol / L, 0.8 mol / L, 1 mol / L, 1.2 mol / L, etc.), preferably 0.5 - 0.8 mol / L.

[0034] Preferably, the dosage ratio of Compound 1 to the aqueous solution of sulfuric acid and / or hydrochloric acid is 1 g:(6 - 15) mL (for example, it can be 1 g:6 mL, 1 g:8 mL, 1 g:10 mL, 1 g:12 mL, 1 g:14 mL, 1 g:15 mL, etc.).

[0035] Preferably, the dosage ratio of Compound 1 to anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid is 1 g:(6 - 15) mL (for example, it can be 1 g:6 mL, 1 g:8 mL, 1 g:10 mL, 1 g:12 mL, 1 g:14 mL, 1 g:15 mL, etc.), preferably 1 g:(8 - 10) mL.

[0036] Preferably, the temperature of the reaction described in step (2) is 50 - 80 °C (for example, it can be 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, etc.), and the reaction time is 10 - 30 h (for example, it can be 10 h, 15 h, 20 h, 25 h, 30 h, etc.).

[0037] Preferably, the temperature of the reaction is 55 - 65 °C, and the reaction time is 15 - 20 h.

[0038] Preferably, the reaction described in step (2) further includes a post-treatment step.

[0039] Preferably, the post-treatment includes: performing a first extraction on the reaction system, adjusting the aqueous phase to a supersaturated salt solution, and then performing another extraction to obtain 5-hydroxy-3-methyl-2(5H)-furanone.

[0040] Preferably, the solvent used for the first extraction includes petroleum ether.

[0041] Preferably, the solvent used for the re - extraction includes dichloromethane.

[0042] Preferably, the reaction in step (3) is carried out in the presence of an acid.

[0043] Preferably, the acid includes any one or a combination of at least two of sulfuric acid, hydrochloric acid, trifluoroacetic acid or polyphosphoric acid, preferably sulfuric acid and / or hydrochloric acid.

[0044] Preferably, the acid exists in the form of an aqueous solution of sulfuric acid and / or hydrochloric acid, or in the anhydrous form of trifluoroacetic acid and / or polyphosphoric acid.

[0045] Preferably, the concentration of the aqueous solution of sulfuric acid and / or hydrochloric acid is 0.2 - 1.2 mol / L (for example, it can be 0.2 mol / L, 0.4 mol / L, 0.6 mol / L, 0.8 mol / L, 1 mol / L, 1.2 mol / L, etc.), preferably 0.5 - 0.8 mol / L.

[0046] Preferably, the dosage ratio of compound 2 to the aqueous solution of sulfuric acid and / or hydrochloric acid is 1 g:(6 - 15) mL (for example, it can be 1 g:6 mL, 1 g:8 mL, 1 g:10 mL, 1 g:12 mL, 1 g:14 mL, 1 g:15 mL, etc.).

[0047] Preferably, the dosage ratio of compound 2 to anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid is 1 g:(6 - 15) mL (for example, it can be 1 g:6 mL, 1 g:8 mL, 1 g:10 mL, 1 g:12 mL, 1 g:14 mL, 1 g:15 mL, etc.), preferably 1 g:(8 - 10) mL.

[0048] Preferably, the temperature of the reaction in step (3) is 80 - 120 °C (for example, it can be 80 °C, 90 °C, 100 °C, 110 °C, 120 °C, etc.), and the reaction time is 10 - 30 h (for example, it can be 10 h, 15 h, 20 h, 25 h, 30 h, etc.).

[0049] Preferably, the temperature of the reaction is 90 - 110 °C, and the reaction time is 15 - 20 h.

[0050] Preferably, the reaction in step (3) further includes a post - treatment step.

[0051] Preferably, the post - treatment includes: performing a first extraction on the reaction system, adjusting the aqueous phase to a supersaturated salt solution, and then performing a re - extraction to obtain 5 - hydroxy - 3 - methyl - 2(5H) - furanone.

[0052] Preferably, the solvent used for the first extraction includes petroleum ether.

[0053] Preferably, the solvent used for the re - extraction includes dichloromethane.

[0054] Preferably, the reaction systems obtained in step (2) and step (3) are mixed for post - treatment.

[0055] Preferably, the preparation method includes the following steps:

[0056] (1) Diethyl methylmalonate, 2,2 - dimethoxyacetaldehyde, an organic base and a solvent are mixed and reacted at 80 - 120 °C for 10 - 30 h to obtain compound 1 and compound 2, and then compound 1 and compound 2 are separated; the molar ratio of diethyl methylmalonate, 2,2 - dimethoxyacetaldehyde and the organic base is 1:(1 - 1.5):(1 - 2), and the dosage ratio of diethyl methylmalonate and the solvent is 1 g:(5 - 15) mL;

[0057] (2) Compound 1 is mixed with an aqueous solution of sulfuric acid and / or hydrochloric acid at 0.2 - 1.2 mol / L or an aqueous solution of trifluoroacetic anhydride and / or polyphosphoric anhydride at a dosage ratio of 1 g:(6 - 15) mL, or compound 1 is mixed with trifluoroacetic anhydride and / or polyphosphoric anhydride at a dosage ratio of 1 g:(6 - 15) mL, and reacted at 50 - 80 °C for 10 - 30 h to obtain 5 - hydroxy - 3 - methyl - 2(5H) - furanone;

[0058] (3) Compound 2 is mixed with an aqueous solution of sulfuric acid and / or hydrochloric acid at 0.2 - 1.2 mol / L or an aqueous solution of trifluoroacetic anhydride and / or polyphosphoric anhydride at a dosage ratio of 1 g:(6 - 15) mL, or compound 2 is mixed with trifluoroacetic anhydride and / or polyphosphoric anhydride at a dosage ratio of 1 g:(6 - 15) mL, and reacted at 80 - 120 °C for 10 - 30 h to obtain 5 - hydroxy - 3 - methyl - 2(5H) - furanone;

[0059] Among them, the order of step (2) and step (3) is not sequential.

[0060] Compared with the prior art, the present invention has at least the following beneficial effects:

[0061] The preparation method provided by the present invention has a relatively high yield, stable process, relatively simple post - treatment method, can avoid operations such as column chromatography, and the reagents used are all conventional reagents, reducing the production cost, and can be applied to industrial scale - up production, providing technical support for the synthesis of strigolactone - like compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 is the 1 1H - NMR spectrum of the target compound P1 in Example 1.

[0063] Figure 2 is the 13 13C - NMR spectrum of the target compound P1 in Example 1. Detailed implementation manners

[0064] The technical solution of the present invention will be further described below in conjunction with the accompanying drawings and through specific implementation manners. However, the following examples are only simple examples of the present invention and do not represent or limit the scope of the patent protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0065] In the following examples, diethyl methylmalonate is represented by SM1, 2,2-dimethoxyacetaldehyde is represented by SM2, and 5-hydroxy-3-methyl-2(5H)-furanone is represented by P1.

[0066] Example 1

[0067] (1) Weigh the starting materials SM1 (100 g, 574 mmol, 1.0 eq.) and SM2 (71.7 g, 689 mmol, 1.2 eq.), add them to a pyridine (800 mL, 8V) solution, add piperidine (58.7 g, 689 mmol, 1.2 eq.) at 25 °C, heat up to 95 °C and react for 16 hours. After monitoring the reaction to completion by TLC, mainly compound 1 and compound 2 are formed; first add 2 L of petroleum ether and 2 L of water for extraction to obtain the petroleum ether solution of compound 1; then extract the aqueous phase with ethyl acetate to obtain the ethyl acetate solution of compound 2. The extracted organic phases are dried with anhydrous sodium sulfate respectively and concentrated to obtain 84.3 g of colorless oily compound 1 with a yield of 78%; concentrated to obtain 28.7 g of colorless oily compound 2 with a yield of 18%;

[0068] (2) Weigh compound 1 (84 g, 446 mmol, 1.0 eq.) and add it to 680 mL of 0.5 mol / L dilute sulfuric acid aqueous solution, heat to 60 °C and react for 16 hours; weigh compound 2 (28 g, 101 mmol, 1.0 eq.) and add it to 120 mL of 0.5 mol / L dilute sulfuric acid aqueous solution, heat to 100 °C and react for 16 hours; monitor by TLC, the raw materials react completely, and both reactions mainly produce the target compound P1; combine the two reaction solutions for treatment, first extract the reaction solution with petroleum ether to remove a small amount of impurities with low polarity, then adjust the aqueous phase to a supersaturated sodium chloride solution, and then extract with dichloromethane to obtain 55.5 g of pale yellow solid target compound P1 with a yield of 89%.

[0069] Detection data of P1 1 H-NMR and 13 C-NMR are as follows:

[0070] 1 H-NMR (600 MHz, CDCl 3): δ 6.89 (s, 1H), 6.10 (s, 1H), 3.91 (brs, 1H), 1.95 (s, 1H).

[0071] 13 C-NMR (126 MHz, CDCl 3 ): δ 172.8, 144.7, 133.4, 97.0, 10.5.

[0072] 1 The 13 H-NMR spectrum and Figure 1 and Figure 2 are shown as follows.

[0073] Example 2

[0074] (1) Weigh the starting materials SM1 (20 g, 114.8 mmol, 1.0 eq.) and SM2 (13.1 g, 126.3 mmol, 1.1 eq.), add them to a toluene (180 mL, 9V) solution, add piperidine (13.6 g, 160.7 mmol, 1.4 eq.) at 25 °C, heat up to 90 °C and react for 18 hours; after monitoring the reaction to completion by TLC, mainly compound 1 and compound 2 are formed; first add 200 mL of water for extraction to obtain the toluene solution of compound 1; then extract the aqueous phase with ethyl acetate to obtain the ethyl acetate solution of compound 2; dry the extracted organic phases with anhydrous sodium sulfate respectively, and concentrate to obtain 13.2 g of colorless oily compound 1 with a yield of 61%; concentrate to obtain 7.03 g of colorless oily compound 2 with a yield of 22%;

[0075] (2) Weigh compound 1 (12 g, 63.8 mmol, 1.0 eq.) and add it to 180 mL of 0.5 mol / L dilute hydrochloric acid aqueous solution, heat to 55 °C and react for 18 hours; weigh compound 2 (5 g, 18 mmol, 1.0 eq.) and add it to 30 mL of 0.5 mol / L dilute sulfuric acid aqueous solution, heat to 90 °C and react for 18 hours; monitor by TLC, the raw materials react completely, and both reactions mainly produce the target compound P1; combine and process the two reaction solutions, first extract the reaction solution with petroleum ether to remove a small amount of impurities with low polarity, then adjust the aqueous phase to a supersaturated sodium chloride solution, and then extract with dichloromethane to obtain 8.12 g of pale yellow solid target compound P1 with a yield of 87%.

[0076] Example 3

[0077] (1) Weigh the starting materials SM1 (20 g, 114.8 mmol, 1.0 eq.) and SM2 (15.5 g, 149.2 mmol, 1.3 eq.), add them to a pyridine (200 mL, 10V) solution, add triethylamine (17.4 g, 172.2 mmol, 1.5 eq.) at 25 °C, heat up to 100 °C and react for 20 hours. After monitoring the reaction to completion by TLC, compounds 1 and 2 are mainly formed. First, add 400 mL of petroleum ether and 400 mL of water for extraction to obtain the petroleum ether solution of compound 1. Then extract the aqueous phase with ethyl acetate to obtain the ethyl acetate solution of compound 2. Dry the extracted organic phases with anhydrous sodium sulfate respectively, and concentrate to obtain 11.5 g of colorless oily compound 1 with a yield of 53%; concentrate to obtain 6.39 g of colorless oily compound 2 with a yield of 20%.

[0078] (2) Weigh compound 1 (11 g, 58.4 mmol, 1.0 eq.) and add it to 160 mL of 0.5 mol / L dilute hydrochloric acid aqueous solution, heat to 65 °C and react for 20 hours; weigh compound 2 (5 g, 18 mmol, 1.0 eq.) and add it to 40 mL of polyphosphoric acid, heat to 110 °C and react for 20 hours. Monitor by TLC, the raw materials react completely, and both reactions mainly produce the target compound P1. However, the conversion rate of compound 2 in the polyphosphoric acid solution is lower than that in the dilute hydrochloric acid solution, so they are treated separately. For the reaction in the dilute hydrochloric acid aqueous solution, first extract the reaction solution with petroleum ether to remove a small amount of impurities with low polarity, then adjust the aqueous phase to a supersaturated sodium chloride solution, and then extract with dichloromethane. After concentration, 6.06 g of pale yellow solid target compound P1 is obtained with a yield of 91%. After quenching the reaction of compound 2 with water, extract the reaction solution with petroleum ether to remove a small amount of impurities with low polarity, then adjust the aqueous phase to a supersaturated sodium chloride solution, and then extract with dichloromethane. After concentration, a yellow oily substance is obtained. Purify the yellow oily substance by column chromatography to obtain 0.74 g of target compound P1 with a yield of 36%.

[0079] Example 4

[0080] (1) Weigh the starting materials SM1 (20 g, 114.8 mmol, 1.0 eq.) and SM2 (17.9 g, 172.2 mmol, 1.5 eq.), add them to a pyridine (120 mL, 6V) solution, add piperidine (15.6 g, 183.6 mmol, 1.6 eq.) at 25 °C, heat up to 105 °C and react for 22 hours. After monitoring the reaction to completion by TLC, compounds 1 and 2 are mainly formed. First, add 2 L of petroleum ether and 2 L of water for extraction to obtain the petroleum ether solution of compound 1. Then, extract the aqueous phase with ethyl acetate to obtain the ethyl acetate solution of compound 2. Dry the extracted organic phases with anhydrous sodium sulfate respectively and concentrate to obtain 15.6 g of colorless oily compound 1 with a yield of 72%; concentrate to obtain 6.71 g of colorless oily compound 2 with a yield of 21%.

[0081] (2) Weigh compound 1 (12 g, 63.8 mmol, 1.0 eq.) and add it to 100 mL of trifluoroacetic acid solution, heat to 70 °C and react for 12 hours; weigh compound 2 (6 g, 21.6 mmol, 1.0 eq.) and add it to 100 mL of trifluoroacetic acid solution, heat to 100 °C and react for 24 hours. Monitor by TLC, the raw materials react completely, and the target compound P1 is formed in both reactions, but the conversion rates are different, so they are treated separately. After concentrating the trifluoroacetic acid in the two reactions, yellow oils are obtained respectively. The reaction product of compound 1 is purified by column chromatography to obtain 4.59 g of the target compound P1 with a yield of 63%; the reaction product of compound 2 is purified by column chromatography to obtain 0.35 g of the target compound P1 with a yield of 14%.

[0082] The applicant declares that the above is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by any person skilled in the art within the technical scope disclosed by the present invention fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A method for preparing 5-hydroxy-3-methyl-2(5H)-furanone, characterized in that: The preparation method comprises the following steps: (1) Diethyl methylmalonate and 2,2-dimethoxyacetaldehyde react to obtain compound 1 and compound 2, and then separate compound 1 and compound 2; the reaction formula is as follows: (2) Compound 1 is reacted to obtain 5-hydroxy-3-methyl-2(5H)-furanone; the reaction formula is as follows: (3) Compound 2 is reacted to obtain 5-hydroxy-3-methyl-2(5H)-furanone; the reaction formula is as follows: Among them, the order of step (2) and step (3) is not specific.

2. The preparation method according to claim 1, characterized in that: The molar ratio of diethyl methylmalonate to 2,2-dimethoxyacetaldehyde in step (1) is 1:(1-1.5), preferably 1:(1.2-1.3).

3. The preparation method according to claim 1 or 2, characterized in that: The reaction in step (1) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of pyridine, toluene, N,N-dimethylformamide or dimethyl sulfoxide or a combination of at least two thereof, preferably pyridine; Preferably, the usage ratio of diethyl methylmalonate to the solvent is 1 g:(5-15) mL, preferably 1 g:(6-10) mL.

4. The preparation method according to any one of claims 1 to 3, characterized in that The reaction in step (1) is carried out in the presence of an organic base; Preferably, the organic base comprises any one or a combination of at least two of piperidine, triethylamine, N,N-diisopropylethylamine or N,N-diisopropylamine, preferably piperidine; Preferably, the molar ratio of diethyl methylmalonate to the organic base is 1:(1-2), preferably 1:(1.2-1.6).

5. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature in step (1) is 80-120° C. and the reaction time is 10-30 h. Preferably, the reaction temperature is 90-100°C, and the reaction time is 16-20h; Preferably, the separation method in step (1) comprises: extracting the reaction system with a good solvent for compound 1 and compound 2, respectively, and then drying and concentrating to obtain compound 1 and compound 2, respectively; Preferably, the good solvent of compound 1 includes petroleum ether and / or toluene; Preferably, the good solvent for compound 2 includes ethyl acetate.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The reaction in step (2) is carried out in the presence of an acid; Preferably, the acid comprises any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid or polyphosphoric acid or a combination of at least two thereof, preferably sulfuric acid and / or hydrochloric acid; Preferably, the acid is present in the form of an aqueous solution of sulfuric acid and / or hydrochloric acid, or in the anhydrous form of trifluoroacetic acid and / or polyphosphoric acid; Preferably, the concentration of the aqueous solution of sulfuric acid and / or hydrochloric acid is 0.2-1.2 mol / L, preferably 0.5-0.8 mol / L; Preferably, the dosage ratio of the compound 1 to the aqueous solution of sulfuric acid and / or hydrochloric acid is 1 g: (6-15) mL, preferably 1 g: (8-10) mL; Preferably, the usage ratio of the compound 1 to anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid is 1 g:(6-15) mL, preferably 1 g:(8-10) mL.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The reaction temperature in step (2) is 50-80°C and the reaction time is 10-30h; Preferably, the reaction temperature is 55-65°C, and the reaction time is 15-20h; Preferably, the reaction in step (2) further comprises a post-treatment step; Preferably, the post-treatment comprises: extracting the reaction system for the first time, adjusting the aqueous phase to a supersaturated salt solution, and then extracting again to obtain 5-hydroxy-3-methyl-2(5H)-furanone; Preferably, the solvent used in the first extraction includes petroleum ether; Preferably, the solvent used in the re-extraction comprises dichloromethane.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The reaction in step (3) is carried out in the presence of an acid; Preferably, the acid comprises any one of sulfuric acid, hydrochloric acid, trifluoroacetic acid or polyphosphoric acid or a combination of at least two thereof, preferably sulfuric acid and / or hydrochloric acid; Preferably, the acid is present in the form of an aqueous solution of sulfuric acid and / or hydrochloric acid, or in the anhydrous form of trifluoroacetic acid and / or polyphosphoric acid; Preferably, the concentration of the aqueous solution of sulfuric acid and / or hydrochloric acid is 0.2-1.2 mol / L, preferably 0.5-0.8 mol / L; Preferably, the ratio of the compound 2 to the aqueous solution of sulfuric acid and / or hydrochloric acid is 1 g: (6-15) mL, preferably 1 g: (8-10) mL; Preferably, the usage ratio of the compound 2 to anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid is 1 g:(6-15) mL, preferably 1 g:(8-10) mL.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The reaction temperature in step (3) is 80-120° C. and the reaction time is 10-30 h. Preferably, the reaction temperature is 90-110°C, and the reaction time is 15-20h; Preferably, the reaction in step (3) further comprises a post-treatment step; Preferably, the post-treatment comprises: extracting the reaction system for the first time, adjusting the aqueous phase to a supersaturated salt solution, and then extracting again to obtain 5-hydroxy-3-methyl-2(5H)-furanone; Preferably, the solvent used in the first extraction includes petroleum ether; Preferably, the solvent used in the re-extraction comprises dichloromethane; Preferably, the reaction systems obtained in step (2) and step (3) are mixed for post-treatment.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) mixing diethyl methylmalonate, 2,2-dimethoxyacetaldehyde, an organic base and a solvent, reacting at 80-120° C. for 10-30 hours to obtain compound 1 and compound 2, and then separating compound 1 and compound 2; the molar ratio of diethyl methylmalonate, 2,2-dimethoxyacetaldehyde and the organic base is 1:(1-1.5):(1-2), and the amount ratio of diethyl methylmalonate to the solvent is 1 g:(5-15) mL; (2) Compound 1 is mixed with a 0.2-1.2 mol / L aqueous solution of sulfuric acid and / or hydrochloric acid at a ratio of 1 g: (6-15) mL, or Compound 1 is mixed with anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid at a ratio of 1 g: (6-15) mL, and reacted at 50-80° C. for 10-30 h to obtain 5-hydroxy-3-methyl-2(5H)-furanone; (3) Compound 2 is mixed with a 0.2-1.2 mol / L aqueous solution of sulfuric acid and / or hydrochloric acid at a ratio of 1 g: (6-15) mL, or Compound 2 is mixed with anhydrous trifluoroacetic acid and / or anhydrous polyphosphoric acid at a ratio of 1 g: (6-15) mL, and reacted at 80-120° C. for 10-30 h to obtain 5-hydroxy-3-methyl-2(5H)-furanone; Among them, the order of step (2) and step (3) is not specific.

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