A method for synthesizing ethyl 2-furanpropionate

Abstract

The application discloses a synthesis method of 2-furanpropionic acid ethyl ester, and belongs to the technical field of synthesis of spices and pharmaceutical intermediates. Furfuryl alcohol and methylsulfonyl chloride are reacted to obtain a methyl sulfonate intermediate, then the methyl sulfonate intermediate is subjected to a bromination reaction to obtain 2-bromomethyl furan; under the action of a strong base, the 2-bromomethyl furan is reacted with ethyl acetate to obtain a product 2-furanpropionic acid ethyl ester. The synthesis method of 2-furanpropionic acid ethyl ester provided by the application is economical in reagents, mild in reaction conditions, safe in reaction process, high in reaction yield (up to 94%) and high in product purity (up to 99%), and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of fragrance and pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing ethyl 2-furanopropionate. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Ethyl 2-furanopropionate (CAS: 10031-90-0) is an important food flavoring agent, currently mainly used in the food flavoring industry. Ethyl 2-furanopropionate is a colorless liquid that gradually turns pale yellow upon exposure to air, possessing a chamomile-like, fruity aroma.

[0004] The current synthetic method for ethyl 2-furanpropionate mainly uses furfural as a raw material, reacting with phosphorus ylide via a Witting reaction to obtain furan-substituted ethyl acrylate, followed by reduction and hydrogenation with Pd / C-H2 (US7737149 B2, Organic Letters, 2020, 22, 5223-5228). This route has the following problems: 1. The Witting reagent is expensive, increasing production costs. 2. The large molecular weight triphenylphosphine oxide produced in the reaction is removed as waste, which does not conform to the principle of atom economy, and the presence of a large amount of triphenylphosphine oxide increases the difficulty of post-processing and product purification. 3. The Pd / C used in the reduction process is expensive, which is not conducive to cost control, and the use of flammable and explosive hydrogen as a reducing agent also increases the safety hazards in the production process. 4. The yield is low (24%-74%). Therefore, a safe, simple, inexpensive, and high-yield method for synthesizing ethyl 2-furanpropionate urgently needs to be developed. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing ethyl 2-furanopropionate. The synthesis method provided by the present invention has fewer reaction steps, uses economical and inexpensive reagents, has mild reaction conditions, and produces products with high purity, making it suitable for industrial production.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] The first aspect of the present invention provides a method for synthesizing ethyl 2-furanopropionate, characterized by comprising the following steps:

[0008] S1. Furfuryl alcohol and methanesulfonyl chloride are reacted to obtain a methanesulfonate intermediate, and then the methanesulfonate intermediate is brominated to obtain 2-bromomethylfuran;

[0009] S2. Under the action of a strong base, 2-bromomethylfuran reacts with ethyl acetate to give the product ethyl 2-furanpropionate.

[0010] Preferably, in S1, at low temperature, in an organic solvent, in the presence of triethylamine, methanesulfonyl chloride is added to furfuryl alcohol, and the reaction is rapidly stirred to obtain a methanesulfonate intermediate.

[0011] Further preferred methods involve rapid stirring at 20-30°C for 3-5 hours.

[0012] More preferably, the low temperature is -5~5℃.

[0013] Preferably, the brominating agent used in the bromination reaction is one of potassium bromide, sodium bromide, and lithium bromide.

[0014] Preferably, the reaction solvent for the bromination reaction is a polar solvent, and preferably, the polar solvent includes acetone, alcohol or DMF.

[0015] Preferably, the molar mass ratio of the brominating agent used in the furfuryl alcohol, methanesulfonyl chloride and bromination reaction is 1:1:1~3.

[0016] Preferably, in S2, a strong base is added to ethyl acetate at low temperature, followed by the slow addition of 2-bromomethylfuran to carry out the reaction.

[0017] More preferably, the reaction is carried out at a temperature of 20-30°C for 10-15 hours.

[0018] Preferably, the strong base is one of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0019] The beneficial effects of this invention are as follows:

[0020] This invention provides a method for synthesizing ethyl 2-furanopropionate, comprising: reacting furfuryl alcohol and methanesulfonyl chloride to obtain a methanesulfonate intermediate, then subjecting the methanesulfonate intermediate to a bromination reaction to obtain 2-bromomethylfuran; and reacting 2-bromomethylfuran with ethyl acetate under strong alkali conditions to obtain the product ethyl 2-furanopropionate. The method for synthesizing ethyl 2-furanopropionate provided by this invention uses inexpensive and economical reagents, operates under mild reaction conditions, is safe in the reaction process, achieves high reaction yield (up to 77%), and produces a high product purity (up to 99%), making it suitable for industrial production. Attached Figure Description

[0021] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0022] Figure 1The 1H NMR spectrum of ethyl 2-furanopropionate prepared in Example 1 of this invention. Detailed Implementation

[0023] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0024] In a first aspect, the present invention provides a method for synthesizing ethyl 2-furanopropionate, comprising the following steps:

[0025] S1. Furfuryl alcohol and methanesulfonyl chloride are reacted to obtain a methanesulfonate intermediate, and then the methanesulfonate intermediate is brominated to obtain 2-bromomethylfuran;

[0026] S2. Under the action of a strong base, 2-bromomethylfuran reacts with ethyl acetate to give the product ethyl 2-furanpropionate.

[0027] In some embodiments of the present invention, in S1, at low temperature, in an organic solvent, in the presence of triethylamine, methanesulfonyl chloride is added to furfuryl alcohol, and the reaction is rapidly stirred to obtain a methanesulfonate intermediate.

[0028] In some embodiments of the present invention, the low temperature is -5 to 5°C. In some embodiments, the low temperature is -5°C, -5°C, -3°C, 0°C, 1°C, 2°C, or 5°C, etc. Preferably, in some embodiments, the low temperature is 0°C.

[0029] In some embodiments of the present invention, the organic solvent includes, but is not limited to, dichloromethane. The present invention does not impose any particular limitation on the source of the organic solvent used; it can be commercially available.

[0030] In some embodiments of the present invention, rapid stirring is performed at room temperature for 3-5 hours. In some embodiments, the stirring time can be selected as 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, etc. Further, the room temperature refers to 20-30°C. In some embodiments, the room temperature is 20°C, 22°C, 23°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, etc. In some embodiments, rapid stirring at 25°C for 4 hours can be selected.

[0031] In some embodiments of the present invention, after the reaction of furfuryl alcohol and methanesulfonyl chloride is completed, cold water is added to the reaction system, the mixture is extracted and separated, the obtained organic phase is dried, and the organic solvent is removed by vacuum concentration to obtain the methanesulfonate intermediate.

[0032] In some embodiments of the present invention, the methanesulfonate intermediate and the brominating agent are heated under reflux in a reaction solvent. After the reaction is complete, the organic solvent is removed, the mixture is extracted and separated, and the organic phase is removed to obtain 2-bromomethylfuran.

[0033] In some embodiments of the present invention, the brominating agent used in the bromination reaction is one of potassium bromide, sodium bromide, and lithium bromide, preferably lithium bromide. The present invention does not impose any special restrictions on the source of the brominating agent used, and it can be commercially available.

[0034] In some embodiments of the present invention, the reaction solvent for the bromination reaction is a polar solvent, preferably including but not limited to acetone, alcohol, or DMF. In some embodiments, the reaction solvent for the bromination reaction is acetone. The present invention does not impose any special restrictions on the source of the reaction solvent, and it can be commercially available.

[0035] In some embodiments of the present invention, the molar ratio of the brominating agent used in the reaction of furfuryl alcohol, methanesulfonyl chloride, and bromination is 1:1:1 to 3. In some embodiments, the molar ratio of the brominating agent used in the reaction of furfuryl alcohol, methanesulfonyl chloride, and bromination is 1:1:2.0.

[0036] In some embodiments of the present invention, in S2, a strong base is added to ethyl acetate at low temperature, and then 2-bromomethylfuran is slowly added to carry out the reaction.

[0037] In some embodiments of the present invention, the reaction is carried out at a temperature of 20-30°C for a time of 10-15 hours. In some embodiments, the reaction temperature is 20°C, 22°C, 23°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C. In some embodiments, the reaction time is 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours.

[0038] In some embodiments of the present invention, the strong base is one of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. In some embodiments, the strong base is potassium tert-butoxide. The present invention does not impose any particular limitation on the source of the brominating agent used, and it can be commercially available.

[0039] In some embodiments of the present invention, after the reaction of 2-bromomethylfuran and ethyl acetate is complete, cold water is added to the reaction system, the mixture is extracted and separated, the obtained organic phase is dried, the organic solvent is removed, and crude product ethyl 2-furan propionate is obtained; after the crude product is purified by distillation, ethyl 2-furan propionate is obtained.

[0040] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0041] Example 1

[0042] A method for synthesizing ethyl 2-furanopropionate includes the following steps:

[0043] The synthesis route is as follows:

[0044]

[0045] At 0°C, 700 mL of dichloromethane, 98 g (1.0 mol) of furfuryl alcohol, and 101 g (1.0 mol) of triethylamine were added to a reaction flask. While stirring, 115 g (1.0 mol) of methanesulfonyl chloride was slowly added to the reaction system. After the addition was complete, the mixture was rapidly stirred at 25°C for 4 hours. Once the reaction was complete, 500 mL of cold water was added to the reaction system, and the mixture was extracted and separated. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent, yielding the methanesulfonate intermediate.

[0046] The obtained methanesulfonate intermediate was added to 600 mL of acetone solution, and lithium bromide (174 g, 2.0 mol) was added. The mixture was heated under reflux for 10 h. After the reaction was complete, the acetone was removed by vacuum distillation. 600 mL of dichloromethane and 400 mL of water were added for extraction and separation. The organic phase was removed by vacuum distillation to obtain the crude brominated intermediate.

[0047] Potassium tert-butoxide (112 g, 1.0 mol) was added to 600 mL of ethyl acetate at 0-5 °C. The crude brominated intermediate obtained above was then added slowly in portions. The reaction was carried out at 25 °C for 12 h. After the reaction was complete, 300 mL of ice water was added to the reaction system, and the mixture was extracted and separated. The collected organic phase was subjected to vacuum distillation to remove the solvent. The crude product was subjected to vacuum distillation to collect the fraction at 110-112 °C (17 torr) of 129.3 g, with a purity of 99% and an overall yield of 77%.

[0048] 1 H NMR (500 MHz, CDCl3) δ 7.38 – 7.27 (m, 1H), 6.40 – 6.16 (m, 1H), 6.02 (d, J = 3.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.67– 2.62 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H).

[0049] Example 2

[0050] A method for synthesizing ethyl 2-furanopropionate includes the following steps:

[0051] At 0°C, 700 mL of dichloromethane, 98 g (1.0 mol) of furfuryl alcohol, and 101 g (1.0 mol) of triethylamine were added to a reaction flask. While stirring, 115 g (1.0 mol) of methanesulfonyl chloride was slowly added to the reaction system. After the addition was complete, the mixture was rapidly stirred at 25°C for 4 hours. Once the reaction was complete, 500 mL of cold water was added to the reaction system, and the mixture was extracted and separated. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent, yielding the methanesulfonate intermediate.

[0052] The obtained methanesulfonate intermediate was added to 600 mL of acetone solution, and lithium bromide (174 g, 2.0 mol) was added. The mixture was heated under reflux for 10 h. After the reaction was complete, the acetone was removed by vacuum distillation. 600 mL of dichloromethane and 400 mL of water were added for extraction and separation. The organic phase was removed by vacuum distillation to obtain the crude brominated intermediate.

[0053] Sodium methoxide (54 g, 1.0 mol) was added to 600 mL of ethyl acetate at 0-5 °C. Then, the crude brominated intermediate obtained above was slowly added in portions. The reaction was carried out at 25 °C for 12 h. After the reaction was complete, 300 mL of ice water was added to the reaction system, and the mixture was extracted and separated. The collected organic phase was subjected to vacuum distillation to remove the solvent. The crude product was subjected to vacuum distillation to collect the fraction (17 torr) at 110-112 °C, which was 87.4 g with a purity of 93% and an overall yield of 52%.

[0054] Example 3

[0055] A method for synthesizing ethyl 2-furanopropionate includes the following steps:

[0056] At 0°C, 700 mL of dichloromethane, 98 g (1.0 mol) of furfuryl alcohol, and 101 g (1.0 mol) of triethylamine were added to a reaction flask. While stirring, 115 g (1.0 mol) of methanesulfonyl chloride was slowly added to the reaction system. After the addition was complete, the mixture was rapidly stirred at 25°C for 4 hours. Once the reaction was complete, 500 mL of cold water was added to the reaction system, and the mixture was extracted and separated. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent, yielding the methanesulfonate intermediate.

[0057] The obtained methanesulfonate intermediate was added to 600 mL of acetone solution, and lithium bromide (174 g, 2.0 mol) was added. The mixture was heated under reflux for 10 h. After the reaction was complete, the acetone was removed by vacuum distillation. 600 mL of dichloromethane and 400 mL of water were added for extraction and separation. The organic phase was removed by vacuum distillation to obtain the crude brominated intermediate.

[0058] Sodium tert-butoxide (96 g, 1.0 mol) was added to 600 mL of ethyl acetate at 0–5 °C. The crude brominated intermediate obtained above was then slowly added in portions. The reaction was carried out at 25 °C for 12 h. After the reaction was complete, 300 mL of ice water was added to the reaction system, and the mixture was extracted and separated. The collected organic phase was subjected to vacuum distillation to remove the solvent. The crude product was subjected to vacuum distillation to collect the fraction at 110–112 °C (17 torr) of 109.2 g, with a purity of 95% and an overall yield of 65%.

[0059] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing ethyl 2-furanopropionate, characterized in that, Includes the following steps: S1. Furfuryl alcohol and methanesulfonyl chloride are reacted to obtain a methanesulfonate intermediate, and then the methanesulfonate intermediate is brominated to obtain 2-bromomethylfuran; The molar mass ratio of the brominating agent used in the furfuryl alcohol, methanesulfonyl chloride and bromination reaction is 1:1:1~3; S2. Under the action of a strong base, 2-bromomethylfuran reacts with ethyl acetate to give the product ethyl 2-furanpropionate; wherein, at low temperature, a strong base is added to ethyl acetate, and then 2-bromomethylfuran is slowly added to carry out the reaction; The brominating agent used in the bromination reaction is one of potassium bromide, sodium bromide, and lithium bromide. The strong base is one of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The low temperature is 0-5℃.

2. The synthesis method according to claim 1, characterized in that, In S1, at low temperature, in an organic solvent, in the presence of triethylamine, methanesulfonyl chloride was added to furfuryl alcohol, and the reaction was rapidly stirred to obtain a methanesulfonate intermediate; The low temperature is -5~5℃.

3. The synthesis method as described in claim 2, characterized in that, Stir rapidly at 20-30℃ for 3-5 hours.

4. The synthesis method according to claim 1, characterized in that, The reaction solvent for the bromination reaction is a polar solvent.

5. The synthesis method as described in claim 4, characterized in that, The polar solvent includes acetone, alcohol, or DMF.

6. The synthesis method according to claim 1, characterized in that, In S2, the reaction temperature is 20~30℃ and the reaction time is 10~15 h.

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