Preparation method of 1, 4-benzodioxane-6-formaldehyde

Abstract

The invention discloses a preparation method of 1, 4-benzodioxane-6-formaldehyde, which comprises the following steps: 1, 4-benzodioxane-6-formaldehyde is used as a raw material; the method takes 3, 4-dihydroxy benzaldehyde as an initial raw material, and comprises the following steps: uniformly mixing 3, 4-dihydroxy benzaldehyde with ethylene glycol or ethylene oxide under the protection of nitrogen and in the presence of a condensing agent and a solvent, then slowly adding diethyl azodicarboxylate at 0-5 DEG C, keeping the temperature for 30-40 minutes, then heating to 25-30 DEG C, keeping the temperature overnight, and reacting; or in the presence of a condensing agent and a solvent, slowly dropwise adding a tert-butyl alcohol solution of ethylene glycol dimethanesulfonate at the temperature of 25-35 DEG C, keeping the temperature for 30-60 minutes, then heating to 85-90 DEG C, keeping the temperature overnight, and reacting to obtain a 1, 4-benzodioxane-6-formaldehyde product. Compared with the existing process, the preparation method disclosed by the invention has the advantages of low comprehensive cost of used raw materials, reduced use of catalysts, easiness in operation, high yield, high purity and suitability for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical organic synthesis, and specifically relates to a method for preparing 1,4-benzodioxane-6-carboxaldehyde. Background Art

[0002] 1,4-Benzodioxane-6-carbaldehyde is an organic compound, mainly used as an intermediate in organic synthesis and pharmaceutical chemistry. The aldehyde group in 1,4-Benzodioxane-6-carbaldehyde can be converted into the corresponding hydroxyl group under the action of a reducing agent, and into the corresponding benzoic acid product under the action of an oxidizing agent. It can be used to synthesize pesticide molecules and bioactive molecules, as well as compounds with specific structures, such as tetrahydroisoquinolinone, benzofuran analogs and other compounds. 1,4-Benzodioxane-6-carbaldehyde can also be used as a potential inhibitor of CAMP-specific type IV phosphodiesterase.

[0003] In the prior art, 3,4-dihydroxybenzaldehyde is often used as a raw material to react with 1,2-dibromoethane or 1,2-dichloroethane to synthesize 1,4-benzodioxane-6-carboxaldehyde. However, the yield of this synthetic route is low and the reaction time is long. Therefore, it is an urgent problem for those skilled in the art to study a new method for preparing 1,4-benzodioxane-6-carboxaldehyde that can improve the yield and purity of the product and reduce the cost. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for preparing 1,4-benzodioxane-6-carboxaldehyde. The preparation method of the present invention not only has low comprehensive cost, but also has high yield and purity, is easy to operate, and is suitable for industrial production.

[0005] To achieve the above objectives, the present invention provides the following technical solutions:

[0006] A method for preparing 1,4-benzodioxane-6-carboxaldehyde, the method using 3,4-dihydroxybenzaldehyde as a starting material comprises:

[0007] Mix evenly with ethylene glycol or ethylene oxide under nitrogen protection and in the presence of a condensing agent and a solvent, then slowly add diethyl azodicarboxylate at 0-5°C and keep warm for 30-40 minutes, then heat to 25-30°C and keep warm overnight to react, to obtain 1,4-benzodioxane-6-carboxaldehyde product;

[0008] Alternatively, in the presence of a condensing agent and a solvent, a tert-butyl alcohol solution of ethylene glycol dimethanesulfonate is slowly added dropwise at 25-35° C. and kept warm for 30-60 minutes, and then the temperature is raised to 85-90° C. and kept warm overnight to react to obtain 1,4-benzodioxane-6-carboxaldehyde product.

[0009] Preferably, the solvent comprises sodium hydroxide solution, potassium hydroxide solution or tetrahydrofuran.

[0010] Preferably, the condensing agent is triphenylphosphine or an ammonium bromide compound; more preferably, the ammonium bromide compound is tetrabutylammonium bromide.

[0011] Preferably, the molar ratio of the 3,4-dihydroxybenzaldehyde to ethylene glycol, ethylene oxide or ethylene glycol dimethanesulfonate is 1:(1-1.1).

[0012] Preferably, the molar ratio of the 3,4-dihydroxybenzaldehyde to the condensing agent is 1:(0.05-3).

[0013] Preferably, the method further comprises purification of the product.

[0014] Preferably, the purification step is: recover under reduced pressure to a paste, add 5% dilute hydrochloric acid to pulp, cool 0-5°C, filter, vacuum dry the crude product, add ethyl acetate (1V), n-hexane (5V) and 5% activated carbon, heat up and reflux for 1-1.5h, filter hot, cool the filtrate by 0-5°C, filter and dry; or recover under reduced pressure to 1 / 2 volume, add water, cool 0-5°C, filter, vacuum dry the crude product, add ethyl acetate (1V), n-hexane (5V) and 5% activated carbon, heat up and reflux for 1.5h, filter hot, cool the filtrate by 0-5°C, filter and dry.

[0015] The beneficial effects of the present invention are:

[0016] The raw material selection of the present invention is not single. Different raw materials are selected, and different condensing agents are used, so the process is also different. From the perspective of comprehensive cost, ethylene oxide has the lowest cost.

[0017] Compared with the existing process, the preparation method of the invention has lower comprehensive cost of raw materials, reduces the use of catalysts, is easy to operate, has high yield and purity, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the H NMR spectrum of 1,4-benzodioxane-6-carbaldehyde prepared in Example. DETAILED DESCRIPTION

[0019] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0020] Unless otherwise defined, technical or scientific terms used in the present disclosure shall have the common meanings understood by one of ordinary skill in the art to which the present invention belongs.

[0021] Example 1

[0022]

[0023] To a 1000mL four-necked bottle, add ethylene glycol (29.05g, 0.468mol, 1.10equiv.), triphenylphosphine (270.05g, 1.03mol, 2.42equiv.), 3,4-dihydroxybenzaldehyde (58.70g, 0.425mol) and tetrahydrofuran (350mL, 6V), nitrogen protection, refrigeration cooling to 0-5℃, slowly add diethyl azodicarboxylate (157.8mL, 1.03mol, 2.42equiv.), add at an internal temperature of 0-5℃ for about 40min, keep warm for 30min. Heat to 25-30℃ and keep warm overnight for reaction. The mixture was recovered under reduced pressure to a paste state, 400 mL of 5% dilute hydrochloric acid was added for pulping, the temperature was lowered by 0-5°C, suction filtered, the crude product was vacuum dried, ethyl acetate (1V), n-hexane (5V) and 5% activated carbon were added, the temperature was raised to reflux and kept warm for 1.5 h, hot filtered, the filtrate was cooled by 0-5°C, suction filtered and dried to obtain the product 1,4-benzodioxane-6-carboxaldehyde (53.02 g, yield 76%, purity 99.3% (HPLC).

[0024] 1 H NMR (500MHz, CDCl3) results are as follows Figure 1 Shown: δ9.83(d,J=2.9Hz,1H),7.47–7.33(m,2H),6.99(dd,J=8.7,3.0Hz,1H),4.32(ddd,J=8.1,5.5,3.0Hz,4H).

[0025] Example 2

[0026]

[0027] In a 1000mL four-necked bottle, add 3,4-dihydroxybenzaldehyde (79.28g, 0.574mol), tetrabutylammonium bromide (TBAB, 11.10g, 6%) and 60% sodium hydroxide solution (317mL, 4V), raise the temperature to 85-90℃, and keep it warm for 30min. Cool down to 25-35℃ in a water bath, add ethylene glycol dimethanesulfonate (137.80g, 1.10equiv.) in tert-butyl alcohol (400mL, 5V) dropwise, the internal temperature is 25-35℃, add it all in about 1.0h, keep it warm for 1.0h, raise the temperature to 85-90℃ and keep it warm overnight to react. The mixture was recovered to 1 / 2 volume under reduced pressure, 400 mL of water was added, the temperature was lowered by 0-5°C, suction filtered, the crude product was vacuum dried, ethyl acetate (1V), n-hexane (5V) and 5% activated carbon were added, the temperature was raised to reflux and kept warm for 1.5 h, hot filtered, the filtrate was cooled by 0-5°C, suction filtered and dried to obtain the product 1,4-benzodioxane-6-carbaldehyde (77.27 g, yield 82%, purity 99.6% (HPLC).

[0028] 1 H NMR (500MHz, CDCl3) δ9.83 (d, J = 2.9 Hz, 1H), 7.47–7.33 (m, 2H), 6.99 (dd, J = 8.7, 3.0 Hz, 1H), 4.32 (ddd, J = 8.1, 5.5, 3.0 Hz, 4H).

[0029] Example 3

[0030]

[0031] Add 3,4-dihydroxybenzaldehyde (58.70 g, 0.425 mol) and tetrahydrofuran (350 mL, 6V) to a 1000 mL four-necked bottle, protect with nitrogen, cool to 10-15°C in a cold water bath, slowly pass ethylene oxide (18.72 g, 0.425 mol) into the reaction system, pass it through in about 30 minutes, and keep it warm for 3.0 hours; add triphenylphosphine (135.02 g, 0.515 mol, 1.21 equiv.), cool it down to 0-5°C, slowly add diethyl azodicarboxylate (78.9 mL, 0.515 mol, 1.21 equiv.), add it at an internal temperature of 0-5°C for about 40 minutes, and keep it warm for 30 minutes. Heat to 25-30°C and keep it warm overnight for reaction. The mixture was recovered under reduced pressure to a paste state, and 400 mL of 5% dilute hydrochloric acid was added for pulping. The temperature was lowered by 0-5°C, and suction was taken to filter. The crude product was vacuum dried. Ethyl acetate (1V), n-hexane (5V) and 5% activated carbon were added, and the temperature was raised to reflux for 1.5 h. The mixture was hot filtered, and the filtrate was cooled by 0-5°C, suction was taken to filter, and dried to obtain the product 1,4-benzodioxane-6-carbaldehyde (61.40 g, yield 88%, purity 99.5% (HPLC)).

[0032] 1 H NMR (500MHz, CDCl3) δ9.83 (d, J = 2.9 Hz, 1H), 7.47–7.33 (m, 2H), 6.99 (dd, J = 8.7, 3.0 Hz, 1H), 4.32 (ddd, J = 8.1, 5.5, 3.0 Hz, 4H).

[0033] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 1,4-benzodioxane-6-carbaldehyde, characterized in that: The method uses 3,4-dihydroxybenzaldehyde as a starting material and comprises: Mix evenly with ethylene glycol or ethylene oxide under nitrogen protection and in the presence of a condensing agent and a solvent, then slowly add diethyl azodicarboxylate at 0-5°C and keep warm for 30-40 minutes, then heat to 25-30°C and keep warm overnight to react, to obtain 1,4-benzodioxane-6-carboxaldehyde product; Alternatively, in the presence of a condensing agent and a solvent, a tert-butyl alcohol solution of ethylene glycol dimethanesulfonate is slowly added dropwise at 25-35° C. and kept warm for 30-60 minutes, and then the temperature is raised to 85-90° C. and kept warm overnight to react to obtain 1,4-benzodioxane-6-carboxaldehyde product.

2. The preparation method according to claim 1, characterized in that: The condensing agent is triphenylphosphine or an ammonium bromide compound; more preferably, the ammonium bromide compound is tetrabutylammonium bromide.

3. The preparation method according to claim 1, characterized in that: The solvent includes sodium hydroxide solution, potassium hydroxide solution or tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 3,4-dihydroxybenzaldehyde to ethylene glycol, ethylene oxide or ethylene glycol dimethanesulfonate is 1:(1-1.1).

5. The preparation method according to claim 1, characterized in that: The molar ratio of the 3,4-dihydroxybenzaldehyde to the condensation agent is 1:(0.05-3).

6. The preparation method according to claim 1, characterized in that: The ratio of diethyl azodicarboxylate to the condensation agent is 1:

1.

7. The preparation method according to claim 1, characterized in that: The method also includes purification of the product.

8. The preparation method according to claim 7, characterized in that: The purification step is: recovering under reduced pressure to a paste, adding 5% dilute hydrochloric acid to pulp, cooling 0-5°C, filtering, vacuum drying the crude product, adding ethyl acetate (1V), n-hexane (5V) and 5% activated carbon, heating and reflux for 1-1.5h, hot filtering, cooling the filtrate by 0-5°C, filtering and drying; or recovering under reduced pressure to 1 / 2 volume, adding water, cooling 0-5°C, filtering, vacuum drying the crude product, adding ethyl acetate (1V), n-hexane (5V) and 5% activated carbon, heating and reflux for 1.5h, hot filtering, cooling the filtrate by 0-5°C, filtering and drying.

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