2-methyl-5-trifluoromethyl furan and preparation method thereof

Abstract

The invention belongs to the technical field of preparation of organic chemicals, and particularly relates to 2-methyl-5-trifluoromethyl furan and a preparation method thereof. The preparation method comprises the following steps: adding a solvent into trifluoroacetone, adding alkali under an ice bath condition, adding 1-chloro-2-methyl ethylene oxide, reacting at room temperature, adding acid, reacting at 40-60 DEG C to complete a dehydration reaction, then adding alkali for aromatization, continuing to complete an aromatization reaction, adding water to extract a reaction system, taking an organic phase, filtering, washing and drying to obtain the 1-chloro-2-methyl ethylene oxide. And rectifying to obtain the 2-methyl-5-trifluoromethyl furan. According to the 2-methyl-5-trifluoromethyl furan and the preparation method thereof provided by the invention, the reaction conditions are mild, the steps are simple, and the prepared 2-methyl-5-trifluoromethyl furan is high in yield and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical preparation technology, specifically relating to 2-methyl-5-trifluoromethylfuran and its preparation method. Background Technology

[0002] 2-Methyl-5-trifluoromethylfuran Furan is an important class of fluorine-containing five-membered heterocyclic compounds with the molecular formula C6H5F3O. This compound has a furan ring as its core skeleton, simultaneously connecting two key functional groups: methyl and trifluoromethyl. It has significant application value in pharmaceutical intermediates, fine chemicals, functional materials, and agrochemicals.

[0003] The furan ring is a fundamental structural unit in many bioactive molecules and functional materials. The introduction of a trifluoromethyl group can significantly improve the lipophilicity, metabolic stability, and acid-base solubility of compounds, while also regulating the electronic effects and steric hindrance of the molecule. Therefore, 2-methyl-5-trifluoromethylfuran is often used as a core structural segment to construct drug molecules with therapeutic potential, highly efficient agrochemicals, and novel organic functional materials. Furthermore, this compound has abundant reactive sites, allowing for further derivatization to prepare a variety of high-value-added downstream products, demonstrating broad application prospects in organic synthesis and industrial production.

[0004] Currently, there is no publicly available method for the direct preparation of 2-methyl-5-trifluoromethylfuran. The disclosed related processes are all for the preparation of its derivatives or structural analogs, which cannot efficiently obtain the target product.

[0005] Patent CN115353499A discloses a method for synthesizing 2-halomethyl-5-trifluoromethylfuran, and patent CN119977918A discloses a process for preparing 2-bromomethyl-5-trifluoromethylfuran from acetoacetate and halotrifluoroacetone under the action of alkaline substances and catalysts. Both methods introduce halogen atoms at the methyl site, rather than directly preparing 2-methyl-5-trifluoromethylfuran. To obtain the target product, additional dehalogenation and reduction reactions are required, which is not only cumbersome and results in low overall yield, but also presents problems such as difficulty in separation and purification and high production costs, making industrial-scale production difficult.

[0006] Patent CN110272400A discloses a method for synthesizing 2-trifluoromethyl substituted furan compounds and their derivatives. This process constructs a furan ring through a tandem cyclization reaction of propargyl alcohol and trifluoroacetyl compound. However, the structure of the prepared product is significantly different from that of 2-methyl-5-trifluoromethyl furan, and the target compound cannot be obtained directly. Furthermore, it has drawbacks such as limited substrate range and difficulty in controlling reaction selectivity, making it unsuitable for the large-scale preparation of 2-methyl-5-trifluoromethyl furan.

[0007] Therefore, there is a lack of efficient, mild, and industrially feasible direct preparation methods for 2-methyl-5-trifluoromethylfuran in the existing technology. The reported derivative preparation processes have drawbacks such as lengthy steps, low yield, and high cost. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a 2-methyl-5-trifluoromethylfuran and its preparation method. The reaction conditions are mild and the steps are simple. The 2-methyl-5-trifluoromethylfuran prepared has a high yield and is suitable for industrial production.

[0009] The preparation method of 2-methyl-5-trifluoromethylfuran according to the present invention includes the following steps: (1) Add solvent to trifluoroacetone and add alkali under ice bath conditions to complete the deprotonation reaction; (2) Add 1-chloro-2-methylethylene oxide to the reaction system of step (1) and react at room temperature; (3) Add an acid solution to the reaction system of step (2), react at 40~60℃, then add a base to continue the reaction; (4) Post-processing: Extract the reaction system, take the organic phase, and distill to obtain 2-methyl-5-trifluoromethylfuran.

[0010] The trifluoroacetone is a byproduct of hexafluoroisopropanol produced during the production process, with a purity greater than 99%; the 1-chloro-2-methylethylene oxide has a purity greater than 99%.

[0011] In step (1), the solvent is one of toluene, chlorobenzene, p-xylene, m-xylene, or o-xylene.

[0012] The alkali in step (1) is one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide; the molar ratio of the alkali to trifluoroacetone is 1.0~1.2:1.

[0013] The alkali in step (3) is one of pyridine, triethylamine, sodium carbonate, or potassium carbonate; the alkali is added to adjust the pH to 8-9.

[0014] The acid mentioned in step (3) is one of hydrochloric acid, sulfuric acid, or methanesulfonic acid; the molar ratio of trifluoroacetone to acid (acid in moles of pure substance) is 1:1.2~1.35. The mass concentration of the acid solution is 10~20%.

[0015] The 1-chloro-2-methyl ethylene oxide in step (2) is first dissolved in the solvent type described in step (1) and then added dropwise at 25~40°C.

[0016] In step (4), water is used as the extraction solvent. After extraction, there is also an organic phase drying step, in which anhydrous sodium sulfate is used as the drying reagent.

[0017] The molar ratio of 1-chloro-2-methylethylene oxide to trifluoroacetone is 1.0~1.05:1.

[0018] The target product, 2-methyl-5-trifluoromethylfuran, has a purity of not less than 99.8% and a yield of not less than 85%.

[0019] Preferably, step (1) involves deprotonating trifluoroacetone under the action of an alkali, with an ice bath temperature of 0-5°C and a reaction time of 0.5-1h; the molar ratio of the deprotonating alkali to trifluoroacetone is 1.0-1.2:1, any ratio is acceptable, including 1.0:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1 and any intermediate ratio within this range; the specific operation is to add the selected solvent to trifluoroacetone, cool it to 0-5°C in an ice bath, slowly add the selected deprotonating alkali, and stir until the reaction is complete.

[0020] Preferably, step (2) involves the carbanion attacking the sterically hindered side of the chloroethylene oxide molecule to open the ring, the hydroxyl group in the molecule undergoes nucleophilic addition to the carbonyl group, and a hemiacetal intermediate is formed. The reaction temperature is 25~40℃, any temperature is acceptable, including 25℃, 30℃, 35℃, 40℃ and any intermediate temperature within this range; the reaction time is 4~6h; the specific operation is to dissolve 1-chloro-2-methylethylene oxide in the same selected solvent (toluene, chlorobenzene, p-xylene, m-xylene, o-xylene), and slowly add it dropwise to the reaction system of step (1) at 25~40℃. After the dropwise addition is completed, continue stirring until the reaction is complete to form a hemiacetal intermediate.

[0021] Preferably, the reaction temperature in step (3) is 40~60℃, any temperature is acceptable, including 40℃, 45℃, 50℃, 55℃, 60℃ and any intermediate temperature within this range, the reaction time is 2~4h, and the reaction continues for 1~2h after adjusting the pH, the molar ratio of trifluoroacetone to acid is 1:1.2~1.35, any ratio is acceptable, including 1:1.2, 1:1.25, 1:1.3, 1:1.35 and any intermediate ratio within this range.

[0022] Preferably, the post-processing step is to add water as an extractant to the reaction system, stir thoroughly, allow it to stand and separate into layers, and take the organic phase; if the extraction is insufficient in one step, multiple extractions can be performed, and all organic phases are combined; anhydrous sodium sulfate is added to the combined organic phase, and the mixture is stirred and dried for 1 to 2 hours until the organic phase is free of water; the dried organic phase is then subjected to distillation at -0.08 to -0.095 MPa, and the corresponding fractions are collected to obtain the final product 2-methyl-5-trifluoromethylfuran.

[0023] This invention employs a one-pot, three-step cascade reaction: trifluoroacetone → (base) deprotonation → (epoxide ring opening) → (acid) dehydration / (base) aromatization → target furan. This route offers high atom economy, utilizing 1-chloro-2-methylethylene oxide to simultaneously provide the carbon skeleton and chlorine atoms as leaving groups to promote the cascade aromatization reaction, and directly constructing the furan ring with oxygen atoms.

[0024] The reaction mechanism of the preparation method of the present invention is as follows: .

[0025] Compared with the prior art, the beneficial effects of the present invention are: (1) The present invention uses 1-chloro-2-methyl ethylene oxide, trifluoroacetone, acid and base as raw materials, and successively undergoes base ring opening, nucleophilic addition, dehydration, aromatization, extraction, drying and distillation to obtain the final product 2-methyl-5-trifluoromethyl furan. There is no need to separate intermediate products, the steps are simple and the reaction efficiency is high. It solves the problems of long steps and low total yield in the preparation of similar compounds in the prior art, greatly reduces the difficulty of separation and purification and production cost, and is more suitable for industrial-scale production. (2) The reaction conditions of this invention are mild, and no high temperature and high pressure are required throughout the process. No dangerous strong bases or heavy metal catalysts are required. The operation is safe and there are few by-products in the reaction process. It has high conversion rate, good yield and the solvent can be reused. (3) The raw material cost advantage of this invention is significant. Trifluoroacetone is a by-product of the production process of hexafluoroisopropanol. It is readily available and inexpensive. 1-Chloro-2-methyl ethylene oxide is a commercially available conventional high-purity product that does not require special synthesis, which further reduces the total production cost. Attached Figure Description

[0026] Figure 1 The ¹H NMR spectrum of 2-methyl-5-trifluoromethylfuran prepared in Example 2.

[0027] Figure 2 The GC spectrum of 2-methyl-5-trifluoromethylfuran prepared in Example 2 is shown. Detailed Implementation

[0028] The present invention will be further described in detail below with reference to specific embodiments.

[0029] The trifluoroacetone used in the following examples can be derived from commercially available products or byproducts in the production of hexafluoroisopropanol, with a purity greater than 99%; 1-chloro-2-methylethylene oxide has a purity >99%; the others are all commercially available conventional products that meet the specifications described in this invention.

[0030] Example 1 The preparation method of 2-methyl-5-trifluoromethylfuran according to the present invention includes the following steps: (1) Add 30 mmol of trifluoroacetone dissolved in 200 mL of toluene to a 500 mL round-bottom flask, cool to 0-5 °C in an ice bath, slowly add 30.0 mmol of sodium hydroxide under a nitrogen atmosphere, and stir the reaction for 0.5 h. (2) Dissolve 30.5 mmol of 1-chloro-2-methyl ethylene oxide in 100 mL of toluene and slowly add it dropwise to the reaction system of step (1) at 25 °C. After the addition is complete, continue to stir the reaction at 25 °C for 6 h. (3) Add 36 mmol of 10 wt% hydrochloric acid to the reaction system of step (2), heat to 40°C, stir for 4 h, then slowly add pyridine, stir to adjust the pH value to 8~9, and continue to stir for 2 h at 40°C. (4) Post-processing: Add 200 mL of water to the reaction to extract and remove excess salt. After stirring thoroughly, let it stand to separate into layers and take the organic phase. Add anhydrous sodium sulfate to the organic phase and stir to dry for 1 h. Filter to remove anhydrous sodium sulfate, distill the organic phase at -0.08 MPa, collect the fraction of the target product, and obtain the final product 2-methyl-5-trifluoromethylfuran.

[0031] Product testing: Purity 99.89%, yield 85%.

[0032] Example 2 The preparation method of 2-methyl-5-trifluoromethylfuran according to the present invention includes the following steps: (1) Add 30 mmol of trifluoroacetone dissolved in 200 mL of chlorobenzene to a 500 mL round-bottom flask, cool to 0-5 °C in an ice bath, slowly add 36.0 mmol of potassium tert-butoxide, and stir the reaction for 1 h. (2) Dissolve 30.5 mmol of 1-chloro-2-methyl ethylene oxide in 100 mL of chlorobenzene and slowly add it dropwise to the reaction system of step (1) at 40 °C. After the addition is complete, continue to stir the reaction at 40 °C for 4 h. (3) Dehydration and aromatization: Add 40.5 mmol of 20 wt% sulfuric acid to the reaction system of step (2), heat to 60 °C, stir for 2 h, then slowly add triethylamine, stir to adjust the pH value to 8~9, and continue to stir for 1 h at 60 °C; (4) Add 150 mL of water to the reaction system, stir thoroughly and let stand to separate the layers, take the organic phase; combine the organic phases and add anhydrous sodium sulfate, stir and dry for 2 h; filter to remove anhydrous sodium sulfate, distill the organic phase at -0.08 MPa, collect the fraction of the target product, and obtain the final product 2-methyl-5-trifluoromethylfuran.

[0033] Product testing: Purity 99.92%, yield 87%.

[0034] The ¹H NMR spectrum of the prepared 2-methyl-5-trifluoromethylfuran product is shown below. Figure 1 As shown. Detection was performed using gas chromatography, as... Figure 2 As shown, the purity of the product was determined using the external standard method.

[0035] Example 3 The preparation method of 2-methyl-5-trifluoromethylfuran according to the present invention includes the following steps: (1) Add 30 mmol of trifluoroacetone dissolved in 200 mL of p-xylene to a 500 mL round-bottom flask, cool to 0-5 °C in an ice bath, slowly add 33.0 mmol of potassium hydroxide, and stir the reaction for 0.8 h. (2) Dissolve 30.5 mmol of 1-chloro-2-methyl ethylene oxide in 100 mL of p-xylene and slowly add it dropwise to the reaction system of step (1) at 30 °C. After the addition is complete, continue to stir the reaction at 30 °C for 5 h. (3) Add 39 mmol of methanesulfonic acid to the reaction system of step (2), heat to 50°C, stir for 3 h, then slowly add sodium carbonate, stir to adjust the pH value to 8~9, and continue to stir at 50°C for 1.5 h. (4) Add 150 mL of water to the reaction system, stir thoroughly and let stand to separate the layers, take the organic phase; add anhydrous sodium sulfate, stir and dry for 1.5 h; filter to remove anhydrous sodium sulfate, distill the organic phase at -0.095 MPa, collect the fraction of the target product, and obtain the final product 2-methyl-5-trifluoromethylfuran.

[0036] Product testing: Purity 99.85%, yield 86%.

[0037] Example 4 The preparation method of 2-methyl-5-trifluoromethylfuran according to the present invention includes the following steps: (1) Add 30 mmol of trifluoroacetone dissolved in 200 mL of o-xylene to a 500 mL round-bottom flask, cool to 0-5 °C in an ice bath, slowly add 31.5 mmol of sodium tert-butoxide, and stir the reaction for 0.6 h. (2) Dissolve 30.5 mmol of 1-chloro-2-methyl ethylene oxide in 100 mL of o-xylene and slowly add it dropwise to the reaction system of step (1) at 35 °C. After the addition is complete, continue to stir the reaction at 35 °C for 4.5 h. (3) Add 37.5 mmol of 15 wt% hydrochloric acid to the reaction system of step (2), heat to 45°C, stir for 3.5 h, then slowly add potassium carbonate, stir to adjust the pH value to 8~9, and continue to stir for 1.2 h at 45°C. (4) Add 150 mL of water to the reaction system, stir thoroughly and let stand to separate the layers, take the organic phase; combine the organic phases and add anhydrous sodium sulfate, stir and dry for 1.2 h; filter to remove anhydrous sodium sulfate, distill the organic phase at -0.095 MPa, collect the fraction of the target product, and obtain the final product 2-methyl-5-trifluoromethylfuran.

[0038] Product testing: Purity 99.88%, yield 85.5%.

Claims

1. A method for preparing 2-methyl-5-trifluoromethylfuran, characterized in that, Includes the following steps: (1) Add solvent to trifluoroacetone and add alkali under ice bath conditions; (2) Add 1-chloro-2-methylethylene oxide to the reaction system of step (1) and react at room temperature; (3) Add an acid solution to the reaction system of step (2), react at 40~60℃, then add an alkali and continue the reaction to obtain a reaction solution; (4) Extract the reaction solution, take the organic phase, and distill to obtain 2-methyl-5-trifluoromethylfuran.

2. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: The trifluoroacetone is a byproduct of hexafluoroisopropanol produced during the production process, with a purity greater than 99%; the 1-chloro-2-methylethylene oxide has a purity greater than 99%.

3. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: The solvent in step (1) is one of toluene, chlorobenzene, p-xylene, m-xylene, or o-xylene.

4. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 3, characterized in that: The alkali in step (1) is one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, or sodium tert-butoxide; the molar ratio of the alkali to trifluoroacetone is 1.0~1.2:

1.

5. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: The alkali in step (3) is one of pyridine, triethylamine, sodium carbonate, or potassium carbonate; the alkali is added to adjust the pH to 8-9.

6. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 5, characterized in that: The acid in step (3) is one of hydrochloric acid, sulfuric acid, or methanesulfonic acid; the molar ratio of trifluoroacetone to pure acid is 1:1.2~1.

35.

7. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: The mass concentration of the acid solution in step (3) is 10~20%.

8. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: The 1-chloro-2-methyl ethylene oxide in step (2) is first dissolved in the solvent type described in step (1) and then added dropwise at 25~40°C.

9. The method for preparing 2-methyl-5-trifluoromethylfuran according to claim 1, characterized in that: In step (4), water is used as the extractant. After phase separation, the organic phase is taken and dried.

10. A method for preparing 2-methyl-5-trifluoromethylfuran according to any one of claims 1 to 9, characterized in that: The purity of the 2-methyl-5-trifluoromethylfuran product is not less than 99.8%, and the yield is not less than 85%.

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