An o-nitrobenzaldehyde and a method for synthesizing the same

Abstract

The application discloses o-nitrobenzaldehyde and a synthesis method thereof, and belongs to the technical field of medical intermediates. The synthesis method comprises the following steps: dissolving o-nitrotoluene, dibromohydantoin and azobisisobutyronitrile in mixed organic solvents to perform a bromination reaction, then performing filtration, impurity removal, extraction and organic phase drying in sequence, and separating o-nitrodibromobenzene; adding the o-nitrodibromobenzene into a DMSO solution, adding calcium carbonate to perform an oxidation reaction, then performing filtration, extraction, organic phase drying and purification and decoloration in sequence, and obtaining o-nitrobenzaldehyde. The o-nitrobenzaldehyde is obtained through a bromination oxidation two-step reaction, the synthesis method has the advantages of simple process, low cost, small pollution and high product yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates technology, specifically relating to o-nitrobenzaldehyde and its synthesis method. Background Technology

[0002] o-Nitrobenzaldehyde (chemical formula C7H5NO3, o-nitrobenzaIdehyde, ONBD) is an important fine chemical intermediate with wide applications in pharmaceuticals, pesticides, and dyes. It is a pale yellow crystalline powder with a melting point of 43–44℃ and a boiling point of 153℃ (3.1 kPa). It has a benzaldehyde odor, is readily soluble in common organic solvents, and volatilizes with water vapor. In the pharmaceutical field, o-nitrobenzaldehyde can be used to synthesize drugs for treating cardiovascular diseases, such as nifedipine, nisodipine, and encaine. Furthermore, the demand for its use in the synthesis of the antianginal drug nifedipine (commonly known as Adalat) is increasing year by year. In the pesticide field, o-nitrobenzaldehyde can be used to synthesize the plant growth regulator indole-3-ethyl, which exhibits significant inhibitory activity against various plant fungal diseases. In the dye industry, it is also an important raw material for preparing high-grade disperse yellow E-3G and other products. These dyes are highly favored in the textile industry due to their excellent color fastness and vibrant colors. o-Nitrobenzaldehyde has a wide range of industrial applications and a large demand. Therefore, finding a low-cost, efficient, convenient, and environmentally friendly preparation method is of great practical significance for promoting the development of downstream industries.

[0003] The main synthesis methods for o-nitrobenzaldehyde are currently chemical synthesis methods: (1) using inexpensive o-nitrotoluene as raw material, the routes are diverse, including bromination, oxidation, nitration, oxidation, condensation, etc. The industrial method used is bromination hydrolysis oxidation, but this method has problems such as complicated steps, high pollution, and low yield; (2) using o-nitrobenzyl alcohol as raw material, the route is short, and it is synthesized in one step by catalyst oxidation, but it faces problems such as high raw material cost, harsh reaction conditions, and difficulty in recycling catalysts; (3) using benzaldehyde as raw material is an early industrial method, which obtains the product through acid anhydride esterification, followed by nitration oxidation, which is complicated, polluting, and has a low yield, and is not suitable for green production. In summary, there is an urgent need to provide a simple and environmentally friendly preparation method to improve industrial production efficiency and reduce pollution. Summary of the Invention

[0004] In order to overcome the shortcomings of the prior art, the present invention aims to provide o-nitrobenzaldehyde and its synthesis method. o-nitrobenzaldehyde is obtained through a two-step reaction of bromination and oxidation. The synthesis method is simple, low-cost, low-pollution, and has a high product yield.

[0005] To achieve the above objectives, the present invention employs the following technical solution: This invention provides a method for synthesizing o-nitrobenzaldehyde, comprising the following steps: o-nitrotoluene, dibromohydantoin and azobisisobutyronitrile were dissolved in a mixed organic solvent to carry out a bromination reaction, and then filtered, removed impurities, extracted and dried in organic phase to separate o-nitrodibromobenzyl. o-Nitrobenzyl dibromo was added to a DMSO solution, followed by the addition of calcium carbonate for oxidation. The mixture was then filtered, extracted, dried in the organic phase, and purified and decolorized to obtain o-nitrobenzaldehyde.

[0006] In one embodiment, the mixed organic solvent is composed of carbon tetrachloride and 1,2-dichloroethane in a volume ratio of 3:2.

[0007] In one embodiment, the molar ratio of o-nitrotoluene, azobisisobutyronitrile and dibromohydantoin is 1:(0.15-1):(1.2-2).

[0008] In one embodiment, the ratio of the total mass of o-nitrotoluene, azobisisobutyronitrile and dibromohydantoin to the amount of mixed organic solvent is 0.1461 g: 1 mL.

[0009] In one embodiment, the bromination reaction is carried out at a temperature of 80-90°C for 18-24 hours.

[0010] In one embodiment, the molar ratio of o-nitrodibromobenzyl, calcium carbonate and DMSO solution is 1:2.5:125.

[0011] In one embodiment, the oxidation reaction is carried out at a temperature of 100-120°C for 12-24 hours.

[0012] In one embodiment, the concentration of the DMSO solution is 99.7%.

[0013] In one embodiment, the purification and decolorization method is column chromatography separation, and the eluent used for purification and decolorization is composed of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 20:1.

[0014] The present invention also provides a method for synthesizing o-nitrobenzaldehyde to obtain o-nitrobenzaldehyde.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a method for synthesizing o-nitrobenzaldehyde using a two-step bromination-oxidation method. The synthesis method is simple, shortens the experimental steps compared to traditional routes, and simplifies the process. It uses a green brominating agent, reducing pollution from industrial wastewater and making it environmentally friendly. Furthermore, the reaction conditions are mild, making the process safer. This method uses o-nitrotoluene as a raw material, which is lower in cost than o-nitrobenzyl alcohol and other raw materials. The shorter two-step process reduces production costs and also decreases wastewater treatment costs. The use of green brominating and initiating agents makes the reaction more efficient and environmentally friendly, increasing yield and product purity. Attached Figure Description

[0016] Figure 1 This is a synthetic route diagram of a method for synthesizing o-nitrobenzaldehyde according to the present invention; Figure 2 The liquid chromatography-mass spectrum of o-nitrobenzaldehyde in Example 1; Figure 3 The hydrogen spectrum of the synthesis of o-nitrodibromobenzyl in Example 1; Figure 4 The image shows the 1H NMR spectrum of o-nitrobenzaldehyde from Example 1. Detailed Implementation

[0017] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0018] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0019] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0020] In this article, unless otherwise specified, “contains,” “includes,” “containing,” “has,” or similar terms cover the meanings of “composed of” and “mainly composed of,” for example, “A contains a” covers the meanings of “A contains a and others” and “A contains only a.”

[0021] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0022] This invention provides o-nitrobenzaldehyde and its synthesis method. The synthesis method uses the green brominating agent dibromohydantoin to brominate o-nitrobenzaldehyde, and then oxidizes it with DMSO to obtain the product. After final purification and decolorization, the purity is 99.8%.

[0023] The technical approach is as follows:

[0024] The above-mentioned method for synthesizing o-nitrobenzaldehyde includes the following specific steps: (1) Dissolve o-nitrotoluene, dibromohydantoin and azobisisobutyronitrile together in a mixed organic solvent and stir and heat to carry out bromination reaction; (2) After the reaction is complete, the above solution is filtered, impurities in the reaction are removed with sodium bicarbonate solution, the aqueous phase is extracted with dichloromethane, the organic phase is dried with anhydrous sodium sulfate, and o-nitrodibromobenzyl is obtained by separation. (3) The above-separated o-nitrodibromobenzyl is added to DMSO solution, and then calcium carbonate is added and stirred and heated to carry out an oxidation reaction to generate o-nitrobenzaldehyde; (4) After the reaction is complete, the above solution is filtered, extracted with dichloromethane and water, the organic phase is collected, dried with anhydrous sodium sulfate, and purified to obtain crude o-nitrobenzaldehyde. (5) Purify and decolorize the crude o-nitrobenzaldehyde to obtain the pure product.

[0025] In step (1), the mixed organic solvent is a mixture of carbon tetrachloride and 1,2-dichloroethane in a volume ratio of 3:2. In step (1), the molar ratio of o-nitrotoluene, azobisisobutyronitrile, and dibromohydantoin is 1:0.15-1:1.2-2. The bromination reaction temperature is 80-90℃; the bromination reaction time is 18-24 h, preferably 80℃ for 24 h. The ratio of the total mass of o-nitrotoluene, azobisisobutyronitrile, and dibromohydantoin to the amount of the mixed organic solvent is 0.1461 g:1 mL.

[0026] In step (2), the sodium bicarbonate solution is a saturated solution, the separation method is column chromatography, and the eluent is petroleum ether.

[0027] In step (3), the molar ratio of o-nitrodibromobenzyl, calcium carbonate, and DMSO is 1:2.5:125; the oxidation reaction temperature is 100-120℃; and the oxidation reaction time is 12-24 h. The concentration of the DMSO solution is 99.7%.

[0028] In step (5), the purification and decolorization method used is column chromatography separation, and the eluent is petroleum ether: ethyl acetate = 20: 1. The organic solvent is removed to obtain the pure product.

[0029] The present invention also provides an o-nitrobenzaldehyde prepared by the above-described synthesis method, wherein the o-nitrobenzaldehyde is obtained by bromination of o-nitrobenzaldehyde with the green brominating agent dibromohydantoin, followed by bromination oxidation.

[0030] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0031] The following examples use instruments and equipment conventional in the art. Experimental methods in the following examples, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. All raw materials used in the following examples are conventional commercially available products with specifications conventional in the art. In this specification and the following examples, unless otherwise specified, "%" refers to weight percentage, "parts" refers to parts by weight, and "ratio" refers to weight proportion.

[0032] Example 1 This embodiment provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: 1.0 g of o-nitrotoluene, 2.54 g of dibromohydantoin, and 0.15 g of AIBN were dissolved in a mixed organic solvent of 15 mL carbon tetrachloride and 10 mL dichloroethane. The solution was added to a 100 mL reaction tube and heated to 80 °C. The temperature was maintained for 24 h. The reaction mixture was then extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected and purified by column chromatography to obtain 1.3575 g of o-nitrodibromobenzyl (63.05% yield) and 0.4061 g of o-nitromonobromobenzyl (25.75% yield). 1.3574 g of o-nitrodibromobenzyl, 35 mL of DMSO solution, and 1.15 g of calcium carbonate were added to a 100 mL flask and heated to 100 °C. After 24 h, the mixture was extracted with water and dichloromethane solution. The organic phase was collected, concentrated by rotary evaporation to obtain 0.6602 g of crude o-nitrobenzaldehyde. After column chromatography and decolorization, 0.652 g of crude o-nitrobenzaldehyde was obtained. g o-nitrobenzaldehyde, yield 93.79%, with a total yield of 59.1% based on raw materials.

[0033] Example 2 This embodiment provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: 5.0 g of o-nitrotoluene, 12.5124 g of dibromohydantoin, and 0.75 g of AIBN were dissolved in a mixture of 75 mL of carbon tetrachloride and 50 mL of dichloroethane. The solution was added to a 500 mL flask and heated to 80 °C. After reacting for 24 h, the reaction mixture was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected and purified by column chromatography to obtain 7.0031 g of o-nitrodibromobenzyl (65.09% yield) and 2.701 g of o-nitromonobromobenzyl (34.29% yield). 7.0031 g of o-nitrodibromobenzyl, 150 mL of DMSO solution, and 5.9362 g of calcium carbonate were added to a 250 mL flask and heated to 100 °C. After reacting for 24 h, the mixture was extracted with water and dichloromethane solution. The organic phase was collected, concentrated by rotary evaporation, and purified by column chromatography to obtain 2.9541 g of crude o-nitrobenzaldehyde. g o-nitrobenzaldehyde, yield 81.28%, based on a total yield of 53.62% of raw materials.

[0034] Example 3 This embodiment provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: 5.0 g of o-nitrotoluene, 12.506 g of dibromohydantoin, and 0.75 g of AIBN were dissolved in a mixed organic solvent of 75 mL carbon tetrachloride and 50 mL dichloroethane. The solution was added to a 250 mL flask and heated to 80 °C. After reacting for 24 h, the reaction mixture was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was collected and purified by column chromatography to obtain 7.5309 g of o-nitrodibromobenzyl (70.04% yield) and 2.4746 g of o-nitromonobromobenzyl (31.42% yield). 7.5309 g of o-nitrodibromobenzyl, 200 mL of DMSO solution, and 6.3916 g of calcium carbonate were added to a 500 mL flask and heated to 100 °C. After reacting for 24 h, the mixture was extracted with water and dichloromethane solution. The organic phase was collected, concentrated by rotary evaporation, and yielded crude o-nitrobenzaldehyde. After column chromatography and decolorization, 3.0203 g of crude o-nitrobenzaldehyde was obtained. g o-nitrobenzaldehyde, yield 78.17%, based on a total yield of 54.83% from raw materials.

[0035] like Figure 2 The figure shows the liquid chromatography-mass spectrum of o-nitrobenzaldehyde, the final purified product of Example 1. The figure shows a retention time of 7.73 minutes, a peak area of ​​827.53, and a peak height of 3421.058. The area normalization method was used for quantitative calculation, and the results showed that the purity of o-nitrobenzaldehyde was 99.8%.

[0036] like Figure 3 The image shown is the 1H NMR spectrum of the product o-nitrodibromobenzyl after purification by the bromination reaction in Example 1. 1 In HNMR (400 MHz, DMSO), the carbon atom of the benzene ring attached to the dibromomethyl group was determined to be position 1, and the carbon atom attached to the nitro group was determined to be position 2. A doublet (d, ) at δ = 8.21 ppm is observed. J = 8.0 Hz, 1H)) is attributed to the hydrogen on the 3rd carbon of the benzene ring, and the doublet at δ = 7.97 ppm (d, J = 8.1 Hz, 1H) is attributed to hydrogen on the 6th carbon, and the triplet at δ = 7.89 ppm (t, J The multiplet (m, 1H) at δ = 7.7 Hz is attributed to hydrogen on the 5th carbon, the multiplet (m, 1H) at δ = 7.70–7.65 ppm is attributed to hydrogen on the 4th carbon, and the singlet (s, 1H) at δ = 7.50 ppm is attributed to the methine hydrogen on dibromomethyl (–CHBr2). This hydrogen is a singlet because the adjacent carbon does not contain a proton, and it is clearly separated from the benzene ring signal. 1 H NMR (400 MHz, DMSO) δ 8.21 (d, J = 8.0 Hz, 1H), 7.97 (d, J= 8.1 Hz, 1H), 7.89 (t, J =7.7 Hz, 1H), 7.70 – 7.65 (m, 1H), 7.50 (s, 1H). like Figure 4 The image shown is the 1H NMR spectrum of o-nitrobenzaldehyde, the product purified by the oxidation reaction in Example 1. 1 In HNMR (400 MHz, DMSO), the carbon atom on the benzene ring attached to the aldehyde group is at position 1, and the carbon atom attached to the nitro group is at position 2. The singlet (s, 1H) at δ=10.27 ppm is assigned to the hydrogen atom on the aldehyde group, and the doublet (dt, 1H) at δ=8.18 ppm is assigned to the hydrogen atom on the aldehyde group. J = 6.7, 1.4 Hz, 1H) is attributed to the hydrogen atom on the 3rd carbon atom of the benzene ring. The multiplet (m, 3H) at δ=7.99~7.92 ppm contains three hydrogen atoms, which are attributed to the hydrogen atom on the 6th carbon atom of the benzene ring (shifted to a lower field due to the influence of the electron-withdrawing group) and the hydrogen atoms on the 4th and 5th carbon atoms, respectively. 1 H NMR (400 MHz, DMSO) δ 10.27 (s, 1H),8.18 (dt, J = 6.7, 1.4 Hz, 1H), 7.99 – 7.92 (m, 3H). Comparative Example 1 This comparative example provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: o-Nitrotoluene (58.15 g, 0.424 mol) was mixed with benzoyl peroxide (3.0 g) and water (50.0 g), and bromine (30.5 g) and hydrogen peroxide / azobisisobutyronitrile were added dropwise at 45-50 °C to bromate the mixture, yielding an organic layer containing approximately 69.75% o-nitrobenzyl bromide. This organic layer (50.0 g) was then hydrolyzed with 15% sodium carbonate solution (200 mL) and tetrabutylammonium bromide (0.5 g) at 80 °C for 5-10 h to obtain a wet filter cake of o-nitrobenzyl alcohol (24.76 g, 7.8% water content). The entire wet filter cake was then oxidized at 40 °C for 18 hours with dioxane (45 mL), 48% hydrobromic acid (3.9 mL), and 27.5% hydrogen peroxide (30.0 mL). h, after purification with sodium metabisulfite and alkaline crystallization, 15.26 g of light yellow o-nitrobenzaldehyde was obtained with an HPLC purity of 99.6% and a single-pass total yield of 41.81% based on o-nitrotoluene.

[0037] Compared with the synthesis method in Example 1, the above method has a 18% lower yield, uses bromine as a brominating agent, pollutes the environment, has complicated experimental steps, and has a higher synthesis cost.

[0038] Comparative Example 2 This comparative example provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: 3.06 g (20 mmol) of o-nitrobenzyl alcohol, 0.12 g of catalyst (Ru mass fraction 6%), and 8 mL of ionic liquid 1-butyl-3-methylimidazolium bromide were added to a three-necked flask. Oxygen was bubbled through the flask under normal pressure, and the mixture was heated to 80 °C with stirring for 3 h. The oxygen bubbling was stopped, and the mixture was cooled to room temperature. The reaction solution was extracted with ethyl acetate, washed with water, dried over anhydrous calcium chloride, and the ethyl acetate was removed by vacuum distillation. The residue was recrystallized from ethanol / water and dried under vacuum at room temperature to give 2.82 g of o-nitrobenzaldehyde, with a yield of 93.4%.

[0039] Although the above method has a higher yield than the synthesis method in Example 2, the raw materials and catalysts used are more expensive, resulting in lower economic benefits. The catalyst synthesis is also more difficult, and the requirements for reaction equipment are higher, which is not conducive to large-scale production.

[0040] Comparative Example 3 This comparative example provides a method for synthesizing o-nitrobenzaldehyde, including the following specific steps: Benzyl diacetate was generated from acetic anhydride and benzaldehyde. Fuming nitric acid was added at 0°C and stirred to obtain a yellow blocky solid. Then, an aqueous sodium carbonate solution was added and heated for hydrolysis. The products were separated to obtain o-nitrobenzaldehyde and p-nitrobenzaldehyde, with an o-nitrobenzaldehyde yield of 30%.

[0041] Compared with the synthesis method in Example 3, the above method has a 24.83% lower yield. It uses reagents such as acid anhydride and nitric acid, which have problems such as difficult waste liquid treatment, equipment corrosion, and serious pollution, and the yield is low.

[0042] This invention provides a method for synthesizing o-nitrobenzaldehyde. The method uses o-nitrotoluene as a raw material and synthesizes o-nitrobenzaldehyde through a two-step reaction involving bromination and oxidation. Using the green brominating agent dibromohydantoin and AIBN as an initiator, the reaction is carried out in an organic solvent to first synthesize o-nitrodibromobenzyl, which is then oxidized by DMSO to obtain o-nitrobenzaldehyde. This invention uses inexpensive raw materials, has a short procedure time, and produces minimal pollution, while yielding a product with high yield and purity.

[0043] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of this invention.

Claims

1. A method for synthesizing o-nitrobenzaldehyde, characterized in that, Includes the following steps: o-nitrotoluene, dibromohydantoin and azobisisobutyronitrile were dissolved in a mixed organic solvent to carry out a bromination reaction, and then filtered, removed impurities, extracted and dried in organic phase to separate o-nitrodibromobenzyl. o-Nitrobenzyl dibromo was added to a DMSO solution, followed by the addition of calcium carbonate for oxidation. The mixture was then filtered, extracted, dried in the organic phase, and purified and decolorized to obtain o-nitrobenzaldehyde.

2. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The mixed organic solvent is composed of carbon tetrachloride and 1,2-dichloroethane in a volume ratio of 3:

2.

3. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The molar ratio of o-nitrotoluene, azobisisobutyronitrile and dibromohydantoin is 1:(0.15-1):(1.2-2).

4. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The ratio of the total mass of o-nitrotoluene, azobisisobutyronitrile, and dibromohydantoin to the amount of mixed organic solvent is 0.1461 g: 1 mL.

5. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The bromination reaction is carried out at a temperature of 80-90℃ for 18-24 hours.

6. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The molar ratio of o-nitrodibromobenzyl, calcium carbonate and DMSO solution is 1:2.5:

125.

7. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The oxidation reaction is carried out at a temperature of 100-120℃ for 12-24 hours.

8. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The concentration of the DMSO solution is 99.7%.

9. The method for synthesizing o-nitrobenzaldehyde according to claim 1, characterized in that, The purification and decolorization method is column chromatography separation, and the eluent used for purification and decolorization is composed of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of 20:

1.

10. o-Nitrobenzaldehyde prepared by the method for synthesizing o-nitrobenzaldehyde according to any one of claims 1 to 9.

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