Synthesis method of triticonazole

Abstract

The invention belongs to the technical field of organic synthesis of pesticides, and discloses a synthesis method of triticonazole. The synthesis method of triticonazole comprises the following steps: taking cyclopentanone and p-chlorobenzaldehyde, and adding a catalyst for reaction to obtain an intermediate S-01; taking the intermediate S-01 and a methylation reagent, and reacting under an alkaline condition to obtain an intermediate S-02; and taking the intermediate S-02, 1, 2, 4-triazole and an oxidizing agent, and reacting under an alkaline condition to obtain triticonazole. According to the synthesis method of the triticonazole, the synthesis period of the triticonazole is remarkably shortened, the used raw materials are easy to obtain, the reaction steps are simple, the yield is high, the synthesized triticonazole is high in purity, a large amount of strong acid and strong alkali are not needed in the reaction, and the synthesis method is an efficient, environment-friendly and easy-to-control green synthesis method.

Description

Technical Field

[0001] The invention relates to the technical field of pesticide organic synthesis, and in particular to a method for synthesizing trichlorfonazole. Background Art

[0002] Trichlorfonazole (trade names: Alios, Charter, Flite, Legat, Premis, Real) is a triazole fungicide developed and manufactured by the former Rhone-Poulenc company. It inhibits C-14 demethylase, a key enzyme in sterol biosynthesis in pathogens, effectively interfering with the synthesis and function of bacterial cell membranes, leading to bacterial death or growth inhibition, ultimately achieving disease control. Trichlorfonazole is primarily used as a seed treatment agent, but can also be applied as a foliar spray. It is suitable for a variety of crops, including cereals (such as wheat, barley, and corn), legumes (such as soybeans, peas, and lentils), and fruit trees (such as apples, pears, and peaches). Within the recommended dosage range for crop safety, trichlorfonazole is safe and harmless to crops. It controls a wide range of diseases, including powdery mildew, rust, black stain, and net blotch caused by pathogens such as Fusarium, Puccinia, Pyricularia, Ustilago, Tilletia, Erysiphe, Pyricularia, Septoria, and Cylindrospermum. These diseases are very common in crops and can seriously impact crop yield and quality. Trichlorfonazole can effectively control these diseases and improve crop yield and quality.

[0003] However, in the existing synthesis method of trichlorfonazole, dimethyl adipate is usually used as a raw material, and a series of reactions such as Claisen condensation, methylation, decarboxylation, condensation, and oxidation are performed to obtain the target compound trichlorfonazole (see the reaction flow diagram). Figure 1 ), but its synthesis steps are cumbersome, and a large amount of strong acid and strong base are required in the reaction, which is contrary to the current development trend of green chemistry.

[0004] Therefore, it is urgent to develop a more efficient, stable, green, environmentally friendly and easy-to-control method for synthesizing trichlorfonazole. Summary of the Invention

[0005] The object of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing trichlorfonazole.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] In a first aspect, the present invention provides a method for synthesizing trichlorfonazole, comprising the following steps:

[0008] (1) Cyclopentanone and p-chlorobenzaldehyde are reacted with a catalyst to obtain an intermediate S-01 as shown in formula (I):

[0009]

[0010] (2) The intermediate S-01 and a methylating agent are reacted under alkaline conditions to obtain the intermediate S-02 shown in formula (II):

[0011]

[0012] (3) Take the intermediate S-02, 1,2,4-triazole and an oxidant and react them under alkaline conditions to obtain trichlorfonazole as shown in formula (III):

[0013]

[0014] In the synthesis method of triticonazole, a catalyst is used to directly react cyclopentanone with p-chlorobenzaldehyde to obtain an intermediate S-01, the intermediate S-01 reacts with methyl bromide under alkaline conditions to obtain an intermediate S-02, and the intermediate S-02, 1,2,4-triazole and an oxidant react under alkaline conditions to obtain the target product triticonazole. The method synthesizes the target product triticonazole through a three-step reaction, significantly shortens the synthesis cycle of triticonazole, and has readily available raw materials, simple reaction steps, high yield, and high purity of the synthesized triticonazole. Furthermore, a large amount of strong acid or strong base is not required in the reaction, and the method is a more efficient, environmentally friendly and easy-to-control green synthesis method.

[0015] As a preferred embodiment of the method for synthesizing trichlorfonazole of the present invention, in step (1), the catalyst is an amino acid catalyst; the amino acid catalyst is at least one of (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine, 4-hydroxyproline, L-proline, D-proline, D,L-proline, D-phenylglycine, (2S)-diphenylprolinol, and S-2-pyrrolidine-1-methylpiperidine.

[0016] The amino acid catalyst of the present invention is a catalyst with biomimetic catalytic performance derived from an amino acid skeleton. In step (1), cyclopentanone reacts with the secondary amine portion of the amino acid catalyst to form an enamine intermediate, which then attacks the aldehyde group, and further undergoes a condensation reaction to obtain the intermediate S-01. The balance between the rigidity and flexibility of the amino acid skeleton helps to regulate the efficiency and selectivity of the reaction. In addition, the reaction conditions in step (1) are mild, and there is no need to use a large amount of harmful reagents such as strong acids and strong bases, thereby further reducing the negative impact on the environment.

[0017] Preferably, the amino acid catalyst is (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine.

[0018] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (1), the molar ratio of cyclopentanone, p-chlorobenzaldehyde and catalyst is (1-10):1:(0.1-0.5).

[0019] Preferably, the molar ratio of cyclopentanone, p-chlorobenzaldehyde and catalyst is 7:1:0.2.

[0020] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (1), a solvent is further included, and the solvent is at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol, water, dimethyl sulfoxide, and tetrahydrofuran.

[0021] Preferably, the solvent is ethanol.

[0022] Preferably, the mass ratio of the solvent to the cyclopentanone is (3-15):1.

[0023] Further preferably, the mass ratio of the solvent to the cyclopentanone is 5:1.

[0024] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (1), the reaction temperature is 10° C. to 60° C., and the reaction time is 10 h to 96 h.

[0025] Preferably, in step (1), the reaction temperature is 50° C. to 55° C., and the reaction time is 10 h to 24 h.

[0026] As a preferred embodiment of the method for synthesizing trichlorfonazole of the present invention, in step (2), the methylating agent is at least one of methyl bromide, methyl iodide, methyl chloride, dimethyl sulfate, and dimethyl carbonate.

[0027] Preferably, in step (2), the methylating agent is methyl bromide.

[0028] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (2), the alkaline condition is achieved by adding a base; the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and pyridine.

[0029] Preferably, in step (2), the base is sodium methoxide.

[0030] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (2), the molar ratio of the intermediate S-01, the base and the methylating agent is 1:(1-2):(2-4.5).

[0031] Preferably, in step (2), the molar ratio of the intermediate S-01, the base and the methylating agent is 1:1.2:2.2.

[0032] As a preferred embodiment of the method for synthesizing trichlorfonazole of the present invention, in step (2), a solvent is further included, and the solvent is at least one of toluene, ethyl acetate, dichloromethane, dichloroethane, and ether.

[0033] Preferably, the solvent is toluene.

[0034] Preferably, the mass ratio of the solvent to the intermediate S-01 is (3-20):1.

[0035] Further preferably, the mass ratio of the solvent to the p-chlorobenzaldehyde is 8:1.

[0036] As a preferred embodiment of the method for synthesizing triticonazole of the present invention, in step (2), the reaction temperature is -5°C to 50°C, and the reaction time is 1 hour to 10 hours.

[0037] Preferably, in step (2), the reaction temperature is 0°C to 25°C, and the reaction time is 1h to 2h.

[0038] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (3), the alkaline condition is achieved by adding a base; the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium tert-butoxide, and potassium tert-butoxide.

[0039] Preferably, in step (3), the base is potassium tert-butoxide.

[0040] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (3), the molar ratio of the intermediate S-02, 1,2,4-triazole, base and oxidant is 1:(1-2):(1-2.5):(1-4).

[0041] Preferably, in step (3), the molar ratio of the intermediate S-02, 1,2,4-triazole, base and oxidant is 1:1.1:1.5:1.5.

[0042] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (3), the oxidant is at least one of trimethylsulfonium iodide, trimethylsulfonium iodide, trimethylcorbium bromide, trimethylsulfonium sulfate, and trimethylsulfonium bromide.

[0043] Preferably, in step (3), the oxidant is trimethylsulfoxide iodide.

[0044] As a preferred embodiment of the synthesis method of trichlorfonazole of the present invention, in step (3), a solvent is further included, and the solvent is at least one of toluene, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0045] Preferably, the solvent is N-methylpyrrolidone.

[0046] Preferably, the mass ratio of the solvent to the intermediate S-02 is (3-20):1.

[0047] Further preferably, the mass ratio of the solvent to the intermediate S-02 is 5:1.

[0048] As a preferred embodiment of the method for synthesizing triticonazole of the present invention, in step (3), the reaction temperature is 20° C. to 150° C., and the reaction time is 6 h to 24 h.

[0049] Preferably, in step (3), the reaction temperature is 60° C. to 115° C., and the reaction time is 6 h to 12 h.

[0050] Compared with the prior art, the present invention has the following beneficial effects: first, the preparation method of triticonazole of the present invention significantly shortens the synthesis cycle of triticonazole, and the raw materials used are easy to obtain, the reaction steps are simple, and a large amount of strong acid and strong base are not required in the reaction, so it is a more efficient, environmentally friendly and easy-to-control green synthesis method with potential industrial production value. Secondly, the triticonazole prepared by the preparation method of the present invention has a high yield and high purity, and can be used as a bactericide to prevent and control diseases such as powdery mildew, rust, black smell, net blotch, etc. caused by various pathogens such as Fusarium (mildew), Puccinia, Pyricularia, Ustilago, Tilletia, Powdery Mildew, Pyricularia teres, Septoria, and Septoria in the process of crop growth, thereby improving the yield and quality of crops. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is a schematic diagram of the reaction process of trichlorfonazole, the background technology of the present invention;

[0052] Figure 2 Is the structural formula of trichlorfonazole of the present invention;

[0053] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate S-02 in Example 1 of the present invention;

[0054] Figure 4 The figure is the hydrogen nuclear magnetic resonance spectrum of trichlorfonazole in Example 1 of the present invention. DETAILED DESCRIPTION

[0055] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. Those skilled in the art should understand that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0056] The following is an elaboration with reference to specific embodiments to illustrate the practical effects of the present invention.

[0057] Unless otherwise specified, the experimental methods used in the examples are conventional methods; the materials, reagents, equipment, etc. used are all commercially available unless otherwise specified.

[0058] The raw materials used in the following examples and comparative examples are described below, but are not limited to these materials:

[0059] (2S)-2-[Diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine, CAS number: 848821-58-9, purchased from Anaiji Chemical, purity 95%, enantiomeric excess (ee): 99%;

[0060] (2S)-diphenylprolinol, CAS number: 112068-01-6, purchased from Anaiji (A040234), purity 98%, enantiomeric excess (ee): 98%;

[0061] (S)-α,α-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether, CAS number: 848821-61-4, purchased from Anaiji (D070452), purity 97%, enantiomeric excess (ee): 99%;

[0062] S-2-Pyrrolidine-1-methylpiperidine, CAS No.: 65921-41-7, was purchased from Bidex Pharmaceuticals (BD265314) with a purity of 95% and an enantiomeric excess (ee): 98%.

[0063] Example 1: Synthesis of trichlorfonazole

[0064] (1) 14.1 g (0.10 mol) of p-chlorobenzaldehyde, 6.5 g (0.02 mol) of catalyst (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine, 16.8 g (0.70 mol) of cyclopentanone, and 84 g of ethanol were added to a reaction flask and stirred at 50°C for 18 hours. After the reaction was completed, the organic phase was concentrated, 100 mL of n-hexane was added, and the mixture was stirred at low temperature for 1 hour and then filtered to obtain 18.9 g of the intermediate compound S-01 with a yield of 92%. The obtained product was directly used for the next step of synthesis.

[0065] The reaction route is as follows:

[0066]

[0067] (2) To a reaction flask, 10.3 g of intermediate compound S-01 (0.05 mol), 82.4 g of toluene, and 8.3 g of sodium methoxide (0.15 mol) were added and stirred at 0°C for 15 minutes. Then, 15.6 g of bromomethane (0.16 mol) was added dropwise. After reacting at 0°C for 2 hours, the mixture was heated to room temperature and stirred for 2 hours. After the reaction, the mixture was washed once with 100 mL of water, once with 50 mL of 1 M hydrochloric acid, and once with 50 mL of saturated brine. The organic phase was concentrated to obtain 6.5 g of intermediate S-02, with a yield of 70%.

[0068] The reaction route is as follows:

[0069]

[0070] The data of the H NMR spectrum of the obtained product S-02 are as follows:

[0071] 1H NMR (400MHz, CDCl3): δ7.49 (d, J = 6.4Hz, 2H), 7.41-7.37 (m, 3H), 2.88 (td, J = 6.0Hz, 2.0Hz, 2H), 1.88 (t, J = 6.0Hz, 2H), 1.15 (s, 6H).

[0072] (3) 11.7 g of the intermediate compound S-02 (0.05 mol), 58.5 g of N-methylpyrrolidone, 3.8 g of 1,2,4-triazole (0.06 mol), and 8.4 g of potassium tert-butoxide (0.08 mol) were added to the reaction flask, and the temperature was raised to 80 ° C. under stirring. 17.6 g of trimethylsulfoxide iodide (0.08 mol) was added to the reactor in batches. After the addition was completed, the temperature was raised to 110 ° C. and stirred for reaction. After the reaction was completed, the mixture was concentrated under reduced pressure, cooled, added toluene, washed with water twice, cooled and crystallized, and filtered to obtain 11.4 g of the target compound trichlorfonazole (S-03) (0.036 mol) with a yield of 71%.

[0073] The reaction route is as follows:

[0074]

[0075] The data of the hydrogen nuclear magnetic resonance spectrum of the obtained product trichlorfonazole are as follows:

[0076] 1H NMR (400MHz, CDCl3): δ8.14(s,1H),7.81(s,1H),7.22(d,J=6.0Hz,2H),7.03(d,J=6.0Hz,2H),5.59 (s,1H),4.37-4.33(m,1H),4.23-4.20(m,1H),2.62(m,2H),1.74(m,2H),1.13(s,3H),0.88(s,3H).

[0077] Example 2: Synthesis of trichlorfonazole

[0078] The only difference between the synthesis method of trichlorfonazole described in this embodiment and that in Example 1 is that the catalyst used in step (1) is 25.3 g (0.10 mol) of (2S)-diphenylprolinol, and 17.5 g of the target compound intermediate S-01 is obtained with a yield of 85%.

[0079] Example 3: Synthesis of trichlorfonazole

[0080] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the catalyst used in step (1) is 59.7 g (0.10 mol) of (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether, and 14.2 g of the target compound intermediate S-01 is obtained with a yield of 69%.

[0081] Example 4: Synthesis of trichlorfonazole

[0082] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the catalyst used in step (1) is 18.2 g (0.10 mol) of S-2-pyrrolidine-1-methylpiperidine, and 15 g of the target compound intermediate S-01 is obtained with a yield of 73%.

[0083] Example 5: Synthesis of trichlorfonazole

[0084] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the molar ratio of cyclopentanone, p-chlorobenzaldehyde and (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 7:1:0.5, and 19.5 g of the target compound intermediate S-01 is obtained with a yield of 95%.

[0085] Example 6: Synthesis of trichlorfonazole

[0086] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the molar ratio of cyclopentanone, p-chlorobenzaldehyde and (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 7:1:0.1, and 15.0 g of the target compound intermediate S-01 is obtained with a yield of 73%.

[0087] Example 7: Synthesis of trichlorfonazole

[0088] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the molar ratio of cyclopentanone, p-chlorobenzaldehyde and (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 10:1:0.2, and 19.0 g of the target compound intermediate S-01 is obtained with a yield of 93%.

[0089] Example 8: Synthesis of trichlorfonazole

[0090] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the molar ratio of cyclopentanone, p-chlorobenzaldehyde and (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 1:1:0.2, and 8.8 g of the target compound intermediate S-01 is obtained with a yield of 43%.

[0091] Example 9: Synthesis of trichlorfonazole

[0092] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the reaction temperature in step (1) is 55° C., and 18.5 g of the target compound intermediate S-01 is obtained with a yield of 90%.

[0093] Example 10: Synthesis of trichlorfonazole

[0094] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the reaction temperature in step (1) is 10° C., and 2.7 g of the target compound intermediate S-01 is obtained with a yield of 13%.

[0095] Example 11: Synthesis of trichlorfonazole

[0096] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that the reaction temperature in step (1) is 60° C., and 18.0 g of the target compound intermediate S-01 is obtained with a yield of 80%.

[0097] Example 12: Synthesis of trichlorfonazole

[0098] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that sodium methoxide in step (2) is replaced by sodium hydroxide, and 1.7 g of the target compound intermediate S-02 is obtained with a yield of 18%.

[0099] Example 13: Synthesis of trichlorfonazole

[0100] The only difference between the synthesis method of trichlorfonazole described in this example and that in Example 1 is that potassium tert-butoxide in step (3) is replaced by sodium hydroxide, and 4.1 g of the target compound trichlorfonazole is obtained with a yield of 26%.

[0101] Comparative Example 1: Synthesis of trichlorfonazole

[0102] The only difference between the synthesis method of trichlorfonazole described in this comparative example and that in Example 1 is that the molar ratio of p-chlorobenzaldehyde to (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 1:0.05, and 13.3 g of the target compound intermediate S-01 is obtained with a yield of 65%.

[0103] Comparative Example 2: Synthesis of trichlorfonazole

[0104] The only difference between the synthesis method of trichlorfonazole described in this comparative example and that in Example 1 is that the molar ratio of p-chlorobenzaldehyde to (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine in step (1) is 1:1, and 13.7 g of the target compound intermediate S-01 is obtained with a yield of 67%.

[0105] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for synthesizing trichlorfon, characterized in that: The following steps are involved: (1) Cyclopentanone and p-chlorobenzaldehyde are reacted with a catalyst to obtain an intermediate S-01 as shown in formula (I): (2) Take the intermediate S-01 and a methylating agent and react under alkaline conditions to obtain an intermediate S-02 as shown in formula (II): (3) Take the intermediate S-02, 1,2,4-triazole and an oxidant, and react under alkaline conditions to obtain trichlorfon azole as shown in formula (III):

2. The synthetic method of trichlorfon as claimed in claim 1, characterized in that, In step (1), the catalyst is an amino acid catalyst; the amino acid catalyst is at least one of (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine, 4-hydroxyproline, L-proline, D-proline, D,L-proline, D-phenylglycine, (2S)-diphenylprolinol, and S-2-pyrrolidine-1-methylpiperidine.

3. The synthetic method of trichlorfon as claimed in claim 2, characterized in that, The amino acid catalyst is (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine.

4. The synthetic method of trichlorfon as claimed in claim 1, characterized in that, In step (1), the molar ratio of cyclopentanone, p-chlorobenzaldehyde and catalyst is (1-10):1:(0.1-0.5).

5. The synthetic method of trichlorfon as claimed in claim 1, characterized in that, In step (1), the reaction temperature is 10°C to 60°C, and the reaction time is 10h to 96h.

6. The method for synthesizing trichlorfon as claimed in claim 5, characterized in that: The reaction temperature is 50°C to 55°C, and the reaction time is 10h to 24h.

7. The method for synthesizing trichlorfon as claimed in claim 1, characterized in that: In step (2), the methylating agent is at least one of methyl bromide, methyl iodide, methyl chloride, dimethyl sulfate, and dimethyl carbonate; the alkaline condition is achieved by adding a base; and the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and pyridine.

8. The method for synthesizing trichlorfon as claimed in claim 1, wherein In step (3), the oxidant is at least one of trimethylsulfonium iodide, trimethylsulfonium iodide, trimethylarsium bromide, trimethylsulfonium sulfate, and trimethylsulfonium bromide; the alkaline condition is achieved by adding a base; and the base is at least one of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, sodium tert-butoxide, and potassium tert-butoxide.

9. The method for synthesizing trichlorfon as claimed in claim 7 or 8, characterized in that: In step (2), the methylating agent is methyl bromide; the base is sodium methoxide; in step (3), the oxidizing agent is trimethyl sulfoxide iodide; and the base is potassium tert-butoxide.

10. The method for synthesizing trichlorfon as claimed in claim 1, characterized in that: In step (2), the reaction temperature is -5°C to 50°C, and the reaction time is 1 h to 10 h; in step (3), the reaction temperature is 20°C to 150°C, and the reaction time is 6 h to 24 h.

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