Preparation method of 3, 4-dihydroxy-5-nitrobenzaldehyde

Abstract

The invention discloses a preparation method of 3, 4-dihydroxy-5-nitrobenzaldehyde, and belongs to the technical field of fine chemical engineering. The method specifically comprises the following steps: 1, mixing vanillin, a catalyst and a solvent to obtain a material A; dissolving concentrated nitric acid with or without mixing with water to obtain a material B; respectively pumping the material A and the material B into a continuous flow reactor for chemical reaction, and performing post-treatment to obtain the 5-nitrovanillin, and 2, adding 5-nitrovanillin and aluminum chloride into a solvent, stirring, adding a catalyst, heating to reflux while stirring, reacting, evaporating out the solvent, adding diluted hydrochloric acid, cooling, filtering, drying to obtain a crude product, and finally purifying. The method has the characteristics of high yield, high safety, better economical efficiency, few impurities and the like.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, specifically, it relates to a method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde. Background Technology

[0002] 3,4-Dihydroxy-5-nitrobenzaldehyde is an intermediate that can be used in pharmaceuticals and pesticides.

[0003] Currently, the main synthetic route for 3,4-dihydroxy-5-nitrobenzaldehyde uses vanillin as a raw material, which is nitrated to obtain 5-nitrovanillin, and then demethylated to obtain the target product. However, the production of this substance in existing technologies mainly relies on traditional reactors. Traditional reactors not only release large amounts of NO2 gas, but also generate a lot of heat, leading to temperature surges, which pollutes the operating environment and poses low process safety risks. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde, which has the advantages of high yield, high safety, better economy, and fewer impurities.

[0005] The objective of this invention can be achieved through the following technical solutions: A method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde, the synthetic route is as follows: Specifically, it includes the following steps: Step 1: Preparation of 5-nitrovanillin using a continuous flow reactor (1) Vanillin and catalyst are mixed with solvent to obtain material A; (2) Dissolve commercially available 68% concentrated nitric acid in water or without water to obtain material B; (3) The obtained materials A and B are pumped into a continuous flow reactor for chemical reaction; (4) After the reaction is completed, the reaction mixture flows out through the outlet and is separated by a gas-liquid separator. A small amount of acid gas is absorbed by water. The reaction solution is cooled, filtered, and dried to obtain 5-nitrovanillin.

[0006] The amount of solvent used in step (1) is 3 to 8 times the volume of vanillin, preferably 4 to 6 times the volume.

[0007] The solvent used in step (1) is selected from water, dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, toluene, benzene, cyclohexane, and n-hexane, with dichloromethane and dichloroethane being preferred.

[0008] The catalyst in step (1) is one or a mixture of two of sodium dodecyl sulfate, sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, Triton X-10, tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium bromide, octadecyltrimethylammonium chloride, and benzyltrimethylammonium chloride, preferably one or a mixture of two of sodium dodecyl sulfate and tetrabutylammonium bromide.

[0009] The amount of catalyst used in step (1) is 1.2-10% of vanilla quality, preferably 2.0-5.0%.

[0010] In step (2), the amount of concentrated nitric acid used is 1 to 1.5 times the molar amount of vanillin, preferably 1.1 to 1.3 times; the amount of water used is 0 to 6 times the mass of concentrated nitric acid, preferably 1 to 4 times.

[0011] The reaction temperature in step (3) is 0~50℃, preferably 20~30℃; the reaction time is 20s~180s, preferably 60~120s.

[0012] In step (4), after separation by a gas-liquid separator, a small amount of acid gas is absorbed by conventional methods or by alkaline solution (sodium hydroxide solution).

[0013] The cooling mentioned in step (4) refers to cooling the mixture to 0~25℃.

[0014] Step 2: Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde ① Add 5-nitrovanillin and aluminum chloride to the solvent and stir; ② Add the catalyst to the above solution, heat to reflux with stirring, and carry out the reaction; ③ After the reaction is complete, the solvent is distilled off under normal or reduced pressure. 2.5N dilute hydrochloric acid is added to the resulting residue to precipitate a solid. After cooling, the solid is filtered and dried to obtain crude 3,4-dihydroxy-5-nitrobenzaldehyde. ④ The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained in step ③ is added to a solvent, then decolorized with activated carbon, then crystallized by adding water, filtered, and dried to obtain pure 3,4-dihydroxy-5-nitrobenzaldehyde.

[0015] The solvent mentioned in step ① is selected from dichloromethane, 1,2-dichloroethane, acetone, and ethyl acetate, with dichloromethane and 1,2-dichloroethane being preferred.

[0016] The amount of solvent used in step ① is 2 to 8 times the volume of 5-nitrovanillin, preferably 3 to 6 times the volume.

[0017] The amount of aluminum chloride used in step ① is 0.8 to 5 times the molar amount of 5-nitrovanillin, preferably 1 to 3 times.

[0018] The catalyst mentioned in step ② is one or a mixture of two of pyridine and N,N-dimethylformamide.

[0019] The amount of catalyst used in step ② is 0.5 to 3 times the molar amount of 5-nitrovanillin, preferably 1 to 2 times.

[0020] The reaction time in step ② is 2 to 18 hours, preferably 3 to 15 hours.

[0021] The amount of dilute hydrochloric acid used in step ③ is 5 to 10 times the mass of the amount of 5-nitrovanillin used in step ①, preferably 6 to 8 times the mass.

[0022] The solvent used for purifying the crude product in step ④ is selected from methanol, ethanol, acetone, and acetonitrile, with methanol and ethanol being preferred.

[0023] In step ④, the amount of solvent used for crude product purification is 0.5 to 4 times the mass of 3,4-dihydroxy-5-nitrobenzaldehyde, preferably 1 to 2.5 times the mass.

[0024] In step ④, the amount of water used for crude product purification is 3 to 9 times the mass of methanol, preferably 4 to 6 times the mass.

[0025] The beneficial effects of this invention are: (1) The method of preparing 5-nitrovanillin using a continuous flow reactor of the present invention can significantly reduce the amount of nitric acid used compared with the traditional batch reactor process of mechanical stirring, while avoiding secondary reactions, and the impurity content of the obtained product meets the impurity limit requirements of the product.

[0026] (2) The method of preparing 5-nitrovanillin using a continuous flow reactor of the present invention limits the release of NO2 because the system is closed during the reaction, allowing the NO2 generated during the nitration process to fully participate in the reaction. This reduces the amount of nitric acid used and avoids the pollution of the operating environment by a large amount of NO2 gas released during the reaction. At the same time, the traditional batch nitration reaction is prone to temperature surge due to the large amount of heat released, while the application of the continuous flow reactor avoids this, greatly improving the safety of the process.

[0027] (3) The preparation method of 3,4-dihydroxy-5-nitrobenzaldehyde of the present invention has simple reaction conditions, few side reactions, high yield, and the solvent can be recycled, resulting in less waste liquid and effectively reducing the waste liquid treatment cost.

[0028] (4) The preparation method of 3,4-dihydroxy-5-nitrobenzaldehyde of the present invention has a purity of ≥99.2% after purification of the crude product, which fully meets the impurity limit requirements of the final product. Detailed Implementation

[0029] The technical solutions 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.

[0030] Example 1 1. Preparation of 5-nitrovanillin The method for preparing 5-nitrovanillin, using a continuous flow reactor assembly, comprises a feed tank, a constant flow pump, a continuous flow reactor, and a gas-liquid separator. It includes the following steps: (1) Add 240g vanillin and 15g sodium dodecyl sulfate to 1200g 1,2-dichloroethane, mix well to obtain material A; (2) Add 176g of concentrated nitric acid to 800g of water, mix well, and obtain material B; (3) Material A was pumped into a continuous flow reactor at a rate of 34.3 mL / min and material B at a rate of 28.2 mL / min respectively for chemical reaction. The reaction temperature was 22℃ and the reaction time was 120s.

[0031] (4) After the reaction is completed, the reaction mixture flows into the gas-liquid separator through the back pressure valve. After gas-liquid separation, a small amount of acid gas is absorbed by water. After the reaction liquid is cooled to 15°C, the solid is filtered out and dried to obtain 235g of 5-nitrovanillin with a yield of 77.5%.

[0032] 2. Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde Add 200g of 5-nitrovanillin and 200g of aluminum chloride to 1,2-dichloroethane and stir.

[0033] Add 98g of pyridine to the above solution, and heat to reflux with stirring for 3 hours; After the reaction was completed, the solvent was distilled off under normal pressure. 1200g of 2.5N dilute hydrochloric acid was added to the resulting residue, and a solid precipitated. After cooling to room temperature, the solid was filtered and dried to obtain 162.8g of crude 3,4-dihydroxy-5-nitrobenzaldehyde, with a yield of 87.6%.

[0034] 3. Purification of 3,4-dihydroxy-5-nitrobenzaldehyde The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained above was added to 150g of methanol, and then 18g of activated carbon was added for decolorization for 1 hour. After filtration, 800g of water was added to the filtrate for crystallization. After filtration and drying, 125.3g of pure 3,4-dihydroxy-5-nitrobenzaldehyde was obtained, with a yield of 85.4%.

[0035] Example 2 1. Preparation of 5-nitrovanillin The method for preparing 5-nitrovanillin, using a continuous flow reactor assembly, comprises a feed tank, a constant flow pump, a continuous flow reactor, and a gas-liquid separator. It includes the following steps: (1) Add 240g vanillin and 20g tetrabutylammonium bromide to 1100g dichloromethane, mix well and obtain material A; (2) Add 220g of concentrated nitric acid to 1000g of water, mix well, and obtain material B; (3) Material A was pumped into the continuous flow reactor at a rate of 38.6 mL / min and material B at a rate of 44.7 mL / min respectively for chemical reaction. The reaction temperature was 32℃ and the reaction time was 90s.

[0036] (4) After the reaction is completed, the reaction mixture flows into the gas-liquid separator through the back pressure valve. After gas-liquid separation, a small amount of acid gas is absorbed by water. After the reaction liquid is cooled to 15°C, the solid is filtered out and dried to obtain 247.8g of 5-nitrovanillin, with a yield of 79.6%.

[0037] 2. Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde Add 200g of 5-nitrovanillin and 300g of aluminum chloride to dichloromethane and stir.

[0038] 155g of pyridine was added to the above solution, and the mixture was heated to reflux with stirring for 16 hours. After the reaction was completed, the solvent was distilled off under normal pressure. 1800g of 2.5N dilute hydrochloric acid was added to the resulting residue, and a solid precipitated. After cooling to room temperature, filtration and drying yielded 146.8g of crude 3,4-dihydroxy-5-nitrobenzaldehyde, with a yield of 79.0%.

[0039] 3. Purification of 3,4-dihydroxy-5-nitrobenzaldehyde The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained above was added to 280g of methanol, and then 22g of activated carbon was added for decolorization for 0.5h. After filtration, 1100g of water was added to the filtrate for crystal precipitation. After filtration and drying, 125.0g of pure 3,4-dihydroxy-5-nitrobenzaldehyde was obtained, with a yield of 76.8%.

[0040] Example 3 1. Preparation of 5-nitrovanillin The method for preparing 5-nitrovanillin, using a continuous flow reactor assembly, comprises a feed tank, a constant flow pump, a continuous flow reactor, and a gas-liquid separator. It includes the following steps: (1) Add 240g vanillin, 11.5g sodium dodecyl sulfate and 16g tetrabutylammonium bromide to 800g water and mix well to obtain material A; (2) Add 190g of concentrated nitric acid to 800g of water, mix well, and obtain material B; (3) Material A was pumped into the continuous flow reactor at a rate of 21.2 mL / min and material B at a rate of 20.4 mL / min respectively for chemical reaction. The reaction temperature was 20℃ and the reaction time was 180s.

[0041] (4) After the reaction is completed, the reaction mixture flows into the gas-liquid separator through the back pressure valve. After gas-liquid separation, a small amount of acid gas is absorbed by water. After the reaction liquid is cooled to 22°C, the solid is filtered off and dried to obtain 264.8g of 5-nitrovanillin, with a yield of 84.8%.

[0042] 2. Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde Add 200g of 5-nitrovanillin and 520g of aluminum chloride to dichloromethane and stir.

[0043] 205g of N,N-dimethylformamide was added to the above solution, and the mixture was heated to reflux with stirring for 9 hours. After the reaction was completed, the solvent was distilled off under normal pressure. 1800g of 2.5N dilute hydrochloric acid was added to the resulting residue, and a solid precipitated. After cooling to room temperature, filtration and drying yielded 139.7g of crude 3,4-dihydroxy-5-nitrobenzaldehyde, with a yield of 75.2%.

[0044] 3. Purification of 3,4-dihydroxy-5-nitrobenzaldehyde The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained above was added to 220g of methanol, and then 14g of activated carbon was added for decolorization for 0.5h. After filtration, 850g of water was added to the filtrate for crystal precipitation. After filtration and drying, 119.4g of pure 3,4-dihydroxy-5-nitrobenzaldehyde was obtained, with a yield of 85.5%.

[0045] Example 4 1. Preparation of 5-nitrovanillin The method for preparing 5-nitrovanillin, using a continuous flow reactor assembly, comprises a feed tank, a constant flow pump, a continuous flow reactor, and a gas-liquid separator. It includes the following steps: (1) Add 240 g vanillin, 4.7 g sodium dodecylbenzenesulfonate and 6.1 g tetrabutylammonium bromide to 1170 g cyclohexane and mix well to obtain material A; (2) Add 160.8g of concentrated nitric acid to 360g of water, mix well, and obtain material B; (3) Material A was pumped into a continuous flow reactor at a rate of 58.5 mL / min and material B at a rate of 16.5 mL / min respectively for chemical reaction. The reaction temperature was 35℃ and the reaction time was 100s.

[0046] (4) After the reaction is completed, the reaction mixture flows into the gas-liquid separator through the back pressure valve. After gas-liquid separation, a small amount of acid gas is absorbed by water. After the reaction liquid is cooled to 24°C, the solid is filtered off and dried to obtain 267.3g of 5-nitrovanillin, with a yield of 85.9%.

[0047] 2. Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde Add 200g of 5-nitrovanillin and 167g of aluminum chloride to 1050g of 1,2-dichloroethane and stir.

[0048] Add 150g of N,N-dimethylformamide to the above solution, and heat to reflux with stirring for 4.5h. After the reaction was completed, the solvent was distilled off under normal pressure. 1300g of 2.5N dilute hydrochloric acid was added to the resulting residue, and a solid precipitated. After cooling to room temperature, filtration and drying yielded 166.3g of crude 3,4-dihydroxy-5-nitrobenzaldehyde, with a yield of 89.5%.

[0049] 3. Purification of 3,4-dihydroxy-5-nitrobenzaldehyde The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained above was added to 389g of methanol, and then 24.9g of activated carbon was added for decolorization for 0.5h. After filtration, 1300g of water was added to the filtrate for crystal precipitation. After filtration and drying, 132.5g of pure 3,4-dihydroxy-5-nitrobenzaldehyde was obtained, with a yield of 79.6%.

[0050] Example 5 1. Preparation of 5-nitrovanillin The method for preparing 5-nitrovanillin, using a continuous flow reactor assembly, comprises a feed tank, a constant flow pump, a continuous flow reactor, and a gas-liquid separator. It includes the following steps: (1) Add 240g vanillin and 3.2g tetrabutylammonium bromide to 570g acetonitrile and mix well to obtain material A; (2) Add 175.5g of concentrated nitric acid to 120g of water, mix well, and obtain material B; (3) Material A was pumped into the continuous flow reactor at a rate of 94.9 mL / min and material B at a rate of 26.0 mL / min respectively for chemical reaction. The reaction temperature was 30℃ and the reaction time was 62s.

[0051] (4) After the reaction is completed, the reaction mixture flows into the gas-liquid separator through the back pressure valve. After gas-liquid separation, a small amount of acid gas is absorbed by water. After the reaction liquid is cooled to 2°C, the solid is filtered out and dried to obtain 220.6g of 5-nitrovanillin, with a yield of 70.8%.

[0052] 2. Preparation of 3,4-dihydroxy-5-nitrobenzaldehyde Add 200g of 5-nitrovanillin and 265g of aluminum chloride to 800g of ethyl acetate and stir.

[0053] Add 96g of pyridine and 89g of N,N-dimethylformamide to the above solution, and heat to reflux with stirring for 5 hours; After the reaction was completed, the solvent was distilled off under normal pressure. 1600g of 2.5N dilute hydrochloric acid was added to the resulting residue, and a solid precipitated. After cooling to room temperature, filtration and drying were performed to obtain 154.3g of crude 3,4-dihydroxy-5-nitrobenzaldehyde, with a yield of 83.1%.

[0054] 3. Purification of 3,4-dihydroxy-5-nitrobenzaldehyde The crude 3,4-dihydroxy-5-nitrobenzaldehyde obtained above was added to 265g of methanol, and then 21.5g of activated carbon was added for decolorization for 1 hour. After filtration, 1300g of water was added to the filtrate for crystal precipitation. After filtration and drying, 124.2g of pure 3,4-dihydroxy-5-nitrobenzaldehyde was obtained, with a yield of 80.5%.

[0055] The above description is merely an example and illustration of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described, or use similar methods to replace them, as long as they do not deviate from the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde, characterized in that, The method comprises the following steps: Step one, using a continuous flow reactor to prepare 5-nitrovanillin (1) mixing vanillin and a catalyst with a solvent to obtain material A; (2) dissolving 68% concentrated nitric acid with or without water to obtain material B; (3) pumping the obtained material A and material B into a continuous flow reactor for chemical reaction; (4) after the reaction is completed, post-treatment is performed to obtain 5-nitrovanillin; Step two, preparing 3,4-dihydroxy-5-nitrobenzaldehyde ① adding 5-nitrovanillin and aluminum chloride into a solvent and stirring; ② adding a catalyst into the solution of step ①, and stirring to heat to reflux to perform reaction; ③ after the reaction is completed, the solvent is evaporated, dilute hydrochloric acid is added, and after cooling, the crude product is obtained after filtration and drying; ④ the crude product is purified to obtain 3,4-dihydroxy-5-nitrobenzaldehyde.

2. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The solvent in step (1) is used in an amount of 3-8 times the volume of vanillin; and the solvent is selected from one of water, dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, toluene, benzene, cyclohexane, and n-hexane.

3. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The catalyst in step (1) is one or a mixture of two of sodium dodecyl sulfate, sodium dodecyl sulfonate, sodium dodecyl benzene sulfonate, Triton X-10, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, cetyl trimethyl ammonium bromide, octadecyl trimethyl ammonium chloride, and benzyl trimethyl ammonium chloride; and the catalyst is used in an amount of 1.2-10% of the mass of vanillin.

4. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The amount of concentrated nitric acid in step (2) is 1-1.5 times the molar amount of vanillin; and the amount of water is 0-6 times the mass of concentrated nitric acid.

5. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The reaction temperature in step (3) is 0-50°C; and the reaction time is 20s-180s.

6. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The solvent in step ① is selected from one of dichloromethane, 1,2-dichloroethane, acetone, and ethyl acetate; and the solvent is used in an amount of 2-8 times the volume of 5-nitrovanillin.

7. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The amount of aluminum chloride in step ① is 0.8-5 times the molar amount of 5-nitrovanillin.

8. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The catalyst in step ② is one or a mixture of two of pyridine and N,N-dimethylformamide; and the catalyst is used in an amount of 0.5-3 times the molar amount of 5-nitrovanillin.

9. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The reaction time in step ② is 2-18h.

10. The method for preparing 3,4-dihydroxy-5-nitrobenzaldehyde according to claim 1, characterized in that, The amount of dilute hydrochloric acid in step ③ is 5-10 times the mass of the amount of 5-nitrovanillin in step ①.

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