A method for the synthesis of 2,3-dihydrobenzofurans

Abstract

This invention relates to the field of chemical synthesis technology, specifically to a method for synthesizing 2,3-dihydrobenzofuran. The synthesis method involves adding benzofuran and a catalyst to a high-pressure reactor without adding a solvent, and then conducting a catalytic hydrogenation reaction under pressure and temperature. The 2,3-dihydrobenzofuran synthesis method provided by this invention simplifies the post-processing of the product through solvent-free hydrogenation, improves product quality and yield, and significantly increases production efficiency, providing strong technical support for the mass production of 2,3-dihydrobenzofuran.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for synthesizing 2,3-dihydrobenzofuran. Background Technology

[0002] Ramelteamide, chemically named (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, was approved by the FDA in the United States in September 2005 under the brand name Rozerem. It is used to treat insomnia with difficulty falling asleep and is also effective for chronic and short-term insomnia. Ramelteamide selectively activates melatonin receptors type 1 and type 2 (MT1, MT2), increasing slow-wave sleep (SWS) and rapid eye movement (REW) sleep, thereby reducing insomnia. Ramelteamide is the first non-addictive insomnia treatment drug not listed under special regulations.

[0003] 2,3-Dihydrobenzofuran is an intermediate for ramelteamide and an important raw material for its synthesis. The synthesis of 2,3-dihydrobenzofuran mainly uses benzofuran as a raw material and organic solvents such as methanol as solvents. A catalytic hydrogenation reaction is carried out under pressure and temperature. After the reaction, the mixture is first filtered, and then the oily material obtained from the filter is distilled to remove the solvent, yielding the final product. This production method has drawbacks: the distillation process requires a lot of equipment, the product purity is not high, a small portion of the product is distilled off during the solvent removal process, and the product tends to deteriorate after prolonged distillation. Therefore, existing methods for synthesizing 2,3-dihydrobenzofuran suffer from low overall product yield and poor product quality. Summary of the Invention

[0004] To address the technical problems of low overall product yield and poor product quality in existing methods for synthesizing 2,3-dihydrobenzofuran, this invention provides a method for synthesizing 2,3-dihydrobenzofuran with a product purity of over 99.7% and a product yield of over 99.5%.

[0005] The technical solution of this invention is as follows:

[0006] A method for synthesizing 2,3-dihydrobenzofuran involves adding benzofuran and a catalyst to a high-pressure reactor without adding a solvent, and then pressurizing and heating the reactor to carry out a catalytic hydrogenation reaction.

[0007] Furthermore, the catalytic hydrogenation reaction temperature is 35-50℃.

[0008] Furthermore, the catalytic hydrogenation reaction pressure is 0.4-0.9 MPa.

[0009] Furthermore, the catalyst is Pd / C.

[0010] Furthermore, after the reaction is complete, the product is obtained by pressure filtration.

[0011] Furthermore, the reaction route for the synthesis of 2,3-dihydrobenzofuran is as follows:

[0012] ;

[0013] The specific steps are as follows:

[0014] (1) Add process water, chloroacetic acid, compound A (salicylaldehyde) and liquid alkali to the reaction vessel, heat up to react, adjust the pH to acidic after the reaction is complete, cool down and filter to obtain compound B (2-formylphenoxyacetic acid).

[0015] (2) Compound B was added to the reaction vessel, and sodium acetate was added after heating. Acetic anhydride was added dropwise, and the reaction was kept at the temperature. Compound C (benzofuran) was obtained by distillation.

[0016] (3) Add compound C and catalyst to the autoclave without adding solvent, pressurize and heat to carry out catalytic hydrogenation reaction, and after the reaction is completed, filter to obtain product (compound D, 2,3-dihydrobenzofuran).

[0017] Furthermore, in step (1), the reaction temperature is 95-105℃ and the reaction time is 2-6h.

[0018] Furthermore, in step (2), the heating temperature is 140-150℃ and the reaction time is 2-6h.

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

[0020] The method for synthesizing 2,3-dihydrobenzofuran provided by this invention simplifies the post-processing of the product through solvent-free hydrogenation, improves the product quality and yield, and greatly increases production efficiency, providing strong technical support for the mass production of 2,3-dihydrobenzofuran. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 This is the HPLC chromatogram of the first batch of products in Example 1.

[0023] Figure 2 This is the HPLC chromatogram of the fifth batch of product in Example 1.

[0024] Figure 3This is the HPLC spectrum of the product from Example 2. Detailed Implementation

[0025] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0026] Example 1

[0027] Add 700 kg of benzofuran and 7 kg of 5% Pd / C to a 1000 L autoclave. Under solvent-free conditions, purge with nitrogen, introduce hydrogen, and pressurize and heat to carry out a catalytic hydrogenation reaction. Control the reaction temperature at 35-50 °C and the reaction pressure at 0.4-0.9 MPa. Continue the reaction until no more hydrogen is absorbed. Filter the product 2,3-dihydrobenzofuran.

[0028] The synthesis method of Example 1 was repeated for 7 batches. The purity of each batch of product was tested and the yield was calculated. The results are shown in Tables 1-8 below.

[0029] Table 1. HPLC test results of the first batch of products in Example 1

[0030]

[0031] Table 2 HPLC test results of the second batch of products in Example 1

[0032]

[0033] Table 3. HPLC test results of the third batch of products in Example 1

[0034]

[0035] Table 4. HPLC test results of the fourth batch of products in Example 1

[0036]

[0037] Table 5. HPLC detection results of the 5th batch of products in Example 1

[0038]

[0039] Table 6. HPLC detection results of the 6th batch of products in Example 1

[0040]

[0041] Table 7. HPLC test results of the 7th batch of products in Example 1

[0042]

[0043] Table 8. Yield and Production Rate of Each Batch of Products in Example 1

[0044]

[0045] Comparative Example 1

[0046] Add 800 kg of methanol, 400 kg of benzofuran, and 12 kg of 5% Pd / C to a 2000 L high-pressure reactor. Purge with nitrogen, introduce hydrogen, and pressurize and heat to carry out a catalytic hydrogenation reaction. Control the reaction temperature at 35-50 °C and the reaction pressure at 0.4-0.9 MPa. React until no more hydrogen is absorbed. Filter the material under pressure, and distill to remove solvent to obtain the product 2,3-dihydrobenzofuran.

[0047] The synthesis method of Comparative Example 1 was repeated for 7 batches. The purity of each batch of product was tested and the yield was calculated. The results are shown in Table 9 below.

[0048] Table 9. Purity, Yield, and Quantity of Each Batch of Products in Comparative Example 1

[0049]

[0050] Comparing Example 1 and Comparative Example 1, it can be found that the 2,3-dihydrobenzofuran produced by the solventless hydrogenation synthesis method provided by the present invention has good quality, high overall production efficiency, and high yield. Furthermore, since it does not involve a distillation process, it does not require additional equipment.

[0051] Example 2

[0052] A synthetic method for 2,3-dihydrobenzofuran, the reaction route is as follows:

[0053] ;

[0054] The specific steps are as follows:

[0055] (1) Add 300g of process water, 77.5g of chloroacetic acid, 100g of compound A and 219g of liquid alkali to a three-necked flask, heat to 95-105℃ and keep warm for 4h, adjust the pH to acidic with concentrated hydrochloric acid, cool to 20-30℃ and filter to obtain compound B;

[0056] (2) Add 200g of compound B prepared in step (1) to a three-necked flask, heat to 140-150℃, add 45.6g of sodium acetate, add 170g of acetic anhydride dropwise, keep the reaction at the temperature for 4h, and distill to obtain compound C;

[0057] (3) Add 100g of compound C prepared in step (2) and 1g of catalyst to the autoclave. Do not add solvent. Replace with nitrogen and introduce hydrogen. Pressurize and heat to carry out catalytic hydrogenation reaction. Control the reaction temperature at 35-50℃ and the reaction pressure at 0.4-0.9MPa. React until no more hydrogen is absorbed. Filter to obtain 101.5g of product 2,3-dihydrobenzofuran. HPLC analysis shows that the product purity is 100% and the product yield is 99.8%.

[0058] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for the synthesis of 2,3-dihydrobenzofuran, characterized in that, The reaction route for the synthesis of 2,3-dihydrobenzofuran is as follows: ； The specific steps are as follows: (1) Add process water, chloroacetic acid, salicylaldehyde and liquid alkali to the reaction vessel, heat up to react, adjust the pH to acidic after the reaction is complete, cool down and filter to obtain 2-formylphenoxyacetic acid; (2) Add 2-formylphenoxyacetic acid to the reaction vessel, heat up and add sodium acetate, add acetic anhydride dropwise, keep the reaction at the temperature, and distill to obtain benzofuran; (3) Add benzofuran and catalyst to the autoclave without adding solvent, pressurize and heat to carry out catalytic hydrogenation reaction. The reaction temperature is 35-50℃, the reaction pressure is 0.4-0.9MPa, the catalyst is 5% Pd / C, and the mass of the catalyst is 1g / 100g based on the mass of benzofuran. After the reaction is completed, filter to obtain the product. Product purity > 99.7%, product yield > 99.5%.

2. The method of synthesis of claim 1, wherein, In step (1), the reaction temperature is 95-105℃ and the reaction time is 2-6h.

3. The method of synthesis of claim 1, wherein, In step (2), the heating temperature is 140-150℃ and the reaction time is 2-6h.

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