CN113087628B - Preparation method of o-nitrobenzaldehyde - Google Patents
Preparation method of o-nitrobenzaldehyde Download PDFInfo
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Abstract
The invention discloses a preparation method of o-nitrobenzaldehyde, which comprises the following steps: (1) adding the o-nitrobenzyl alcohol, the catalyst, the bromide salt and the solvent into a reaction kettle, and stirring uniformly at room temperature; (2) controlling the reaction temperature, slowly dropwise adding a sodium hypochlorite solution into the reaction kettle, and simultaneously adding a weak alkaline substance or an acidic substance to control the pH value of the reaction; (3) standing for layering, adding an organic solvent to extract a product, and concentrating to obtain a crude product; (4) crystallizing by using an organic solvent, centrifuging, and drying in vacuum to obtain the o-nitrobenzaldehyde. The invention uses cheap and easily obtained 2- (2, 2, 6, 6-tetramethyl piperidine nitroxide free radical-4-subunit) acetic acid as a catalyst, uses a sodium hypochlorite solution as an oxidant, uses a mixed solvent of water and chlorinated hydrocarbon as a reaction solvent, and prepares the o-nitrobenzaldehyde by oxidation under a mild temperature condition.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of o-nitrobenzaldehyde.
Background
The o-nitrobenzaldehyde is an important medical and organic synthesis intermediate, has wide application in the preparation of medicines, dyes, pesticides and the like, is an important intermediate for synthesizing nifedipine, nisoldipine, emcamide and the like which are cardiovascular disease medicines, and is a key intermediate for synthesizing the expectorant ambroxol hydrochloride parent 3, 5-dibromo-o-aminobenzaldehyde.
At present, the synthesis of o-nitrobenzaldehyde has more starting materials, mainly including o-nitrotoluene, o-nitrobenzyl alcohol, benzaldehyde, o-nitrobenzyl diacetate, o-nitrobenzoic acid and the like. The synthesis method using the o-nitrobenzol as the raw material has the shortest synthesis route and the highest efficiency.
In patent document CN 108164421 a; the method uses about 60 percent nitric acid as an oxidant, and oxidizes the o-nitrobenzyl alcohol to prepare the o-nitrobenzaldehyde at the temperature of 65-70 ℃, nitrous oxide is generated in the process, the corrosion to production equipment is great, and a great part of o-nitrobenzoic acid is generated due to the strong oxidizing property of the nitric acid, so that the yield of the product is only about 70 percent, and meanwhile, the waste liquid containing nitrate radicals is generated, and the requirement on environmental protection facilities is high.
In patent document CN 105585540a, the swern oxidation method is used to prepare o-nitrobenzaldehyde, the swern reagent used needs to be synthesized in multiple steps, the reaction needs to be carried out at-15 ℃, and the reaction yield is 76.6%.
In patent document CN 105439867a, o-nitrobenzyl alcohol is oxidized by hydrogen peroxide under reflux condition to obtain o-nitrobenzaldehyde, the reflux time is 20-30 hours, the reaction time is long, and o-nitrobenzaldehyde by-product is also generated.
Therefore, in the existing method for preparing o-nitrobenzaldehyde by oxidizing o-nitrobenzyl alcohol, the oxidation condition is too strong, the generation of o-nitrobenzoic acid by-products cannot be avoided, or the used oxidizing reagent needs to be synthesized in multiple steps, the treatment cost of the generated waste liquid is higher, and the large-scale and safe production of o-nitrobenzaldehyde is limited.
Disclosure of Invention
The invention aims to make up the defects of the prior art and provides a preparation method of o-nitrobenzaldehyde.
In order to achieve the above object, the present invention provides the following technical solutions:
a method for preparing o-nitrobenzaldehyde comprises the following steps:
(1) adding the o-nitrobenzyl alcohol, the catalyst, the bromide salt and the solvent into a reaction kettle, and stirring uniformly at room temperature;
(2) controlling the reaction temperature, slowly dropwise adding a sodium hypochlorite solution into the reaction kettle, and simultaneously adding a weak alkaline substance or an acidic substance to control the pH value of the reaction;
(3) standing for layering, adding an organic solvent to extract a product, and concentrating to obtain a crude product;
(4) crystallizing by using an organic solvent, centrifuging, and drying in vacuum to obtain the o-nitrobenzaldehyde.
Further, the catalyst in the step (1) is 2- (2, 2, 6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid, and the dosage of the catalyst is 0.001-0.1 of the equivalent of the o-nitrobenzyl alcohol.
Further, the bromide salt in the step (1) is sodium bromide or potassium bromide, and the dosage of the bromide salt is 0.001-0.2 of the equivalent of the o-nitrobenzyl alcohol.
Further, the solvent in the step (1) is a mixed solvent of chlorinated hydrocarbon and water.
Further, the chlorinated hydrocarbon is one or two of dichloromethane and 1, 2-dichloroethane.
Furthermore, the volume weight ratio of the o-nitrobenzol to the water is 1-10ml/g, and the volume weight ratio of the o-nitrobenzol to the chlorinated hydrocarbon is 2-10 ml/g.
Further, the weakly alkaline substance in the step (2) is sodium bicarbonate, and the acidic substance is one of hydrochloric acid, sulfuric acid, acetic acid and sodium bisulfate.
Further, the reaction temperature in the step (2) is 0-30 ℃, and the reaction pH value is 7.0-9.0.
Further, the organic solvent in the step (3) is one or two of dichloromethane and 1, 2-dichloroethane.
Further, the organic solvent in the step (4) is one or more of petroleum ether, ethyl acetate, methyl tert-butyl ether and 1, 2-dichloroethane.
The invention has the advantages that:
the method provided by the invention uses cheap and easily-obtained 2- (2, 2, 6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid as a catalyst, uses a sodium hypochlorite solution as an oxidant, uses a mixed solvent of water and chlorinated hydrocarbon as a reaction solvent, and quickly oxidizes the o-nitrobenzyl alcohol to prepare the o-nitrobenzaldehyde under a mild temperature condition, wherein the sodium hypochlorite solution used as the oxidant in the preparation method is cheap and easily-obtained, the preparation process time is short, the oxidizing property is mild and moderate, the reaction selectivity is high, the separation yield of a final product is more than 90%, and the prepared waste liquid is waste water only containing salts, so that the method is convenient for environment-friendly treatment, and solves the problems that the oxidizing agent used for oxidizing the o-nitrobenzyl alcohol is too strong in oxidizing property and byproducts cannot be generated in the preparation process; or the used oxidizing reagent is expensive and is not easy to obtain; and waste liquid which is difficult to treat is generated in the preparation process, so that the problems of environmental protection and safety are caused.
Drawings
FIG. 1 shows the chemical reaction formula of o-nitrobenzaldehyde according to the present invention.
Detailed Description
The following examples are merely illustrative of the present invention in detail, but it should be understood that the scope of the present invention is not limited to these examples.
Example 1
153g of o-nitrobenzyl alcohol, 1.5g of 2- (2, 2, 6, 6-tetramethylpiperidinyloxy radical-4-ylidene) acetic acid, 300g of dichloromethane and 1.5g of potassium bromide are added to a 2000ml reaction flask, dissolved in 300g of water, cooled to 5 ℃ by an ice bath, and 84g of NaHCO is added to the reaction system3Dissolving in 1000g 10% sodium hypochlorite solution, adjusting pH to about 8.5, slowly adding into a reaction flask, controlling dropping speed to make reaction temperature not higher than 10 deg.C, detecting by TLC, reacting for 2 hr, and reacting completelyThe solution was left to separate the phases, the aqueous phase was extracted with 500gx2 dichloromethane, the organic phases were combined, washed once with 500g of water and the organic phase was washed with anhydrous Na2SO4Drying, filtering, concentrating to obtain light yellow oily substance, adding methyl tert-butyl ether 300g, stirring, standing at 0 deg.C for crystallization, filtering, and vacuum drying at 30 deg.C to obtain light yellow solid product o-nitrobenzaldehyde 136.5g with yield of 90.3%.
Example 2
To a 100ml reaction flask were added 7.65g of o-nitrobenzyl alcohol, 7.5mg of 2- (2, 2, 6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid, 15g of methylene chloride, and 7.5mg of sodium bromide dissolved in 15g of water, followed by addition to the reaction system, cooling to 5 ℃ with an ice bath, and 4.2g of NaHCO3Dissolving in 65g of 10% sodium hypochlorite solution, adjusting pH to about 8.5, slowly adding into a reaction bottle, controlling dropping speed to make reaction temperature not higher than 20 deg.C, detecting by TLC after dropping, reacting completely for 0.5 hr, standing the reaction solution for liquid separation, extracting water phase with 25gx2 dichloromethane, combining organic phases, washing once with 25g of water, and adding anhydrous Na into the organic phase2SO4Drying, filtering, concentrating to obtain light yellow oily substance, adding petroleum ether 15g, stirring, standing at 0 deg.C for crystallization, filtering, and vacuum drying at 30 deg.C to obtain light yellow solid product o-nitrobenzaldehyde 6.8g with yield of 90.1%.
Example 3
To a 100ml reaction flask were added 7.65g of o-nitrobenzyl alcohol, 0.8mg of 2- (2, 2, 6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid, 15g of methylene chloride, and 7.5mg of potassium bromide dissolved in 15g of water, followed by addition to the reaction system, cooling to 5 ℃ with an ice bath, and 4.2g of NaHCO3Dissolving in 65g of 10% sodium hypochlorite solution, adjusting pH to about 8.5, slowly adding into a reaction bottle, controlling dropping speed to make reaction temperature not higher than 20 deg.C, detecting by TLC after dropping, reacting completely for 0.5 hr, standing the reaction solution for liquid separation, extracting water phase with 25gx2 dichloromethane, combining organic phases, washing once with 25g of water, and adding anhydrous Na into the organic phase2SO4Drying, filtering, concentrating to obtain yellowish oily substance, adding petroleum ether 15g, stirring, standing at 0 deg.C for crystallization, and filteringFiltering, and vacuum drying at 30 ℃ to obtain 6.89g of light yellow solid product o-nitrobenzaldehyde with the yield of 91.2%.
Example 4
Into a 100ml reaction flask were charged 7.65g of o-nitrobenzyl alcohol, 7.5mg of 2- (2, 2, 6, 6-tetramethylpiperidinyloxy-4-ylidene) acetic acid, 15g of 1, 2-dichloroethane, and 7.5mg of potassium bromide dissolved in 15g of water, followed by addition to the reaction system, cooling to 5 ℃ with an ice bath, and 4.2g of NaHCO3Dissolving in 65g of 10% sodium hypochlorite solution, adjusting pH to about 8.5, slowly adding into a reaction bottle, controlling dropping speed to make reaction temperature not higher than 20 deg.C, detecting by TLC after dropping, reacting completely for 0.5 hr, standing the reaction solution for liquid separation, extracting water phase with 25gx2 dichloromethane, combining organic phases, washing once with 25g of water, and adding anhydrous Na into the organic phase2SO4Drying, filtering, concentrating to obtain light yellow oily substance, adding petroleum ether 15g, stirring, standing at 0 deg.C for crystallization, filtering, and vacuum drying at 30 deg.C to obtain light yellow solid product o-nitrobenzaldehyde 7.1g with yield of 94%.
Example 5
Adding 7.65g of o-nitrobenzyl alcohol, 7.5mg of 2- (2, 2, 6, 6-tetramethylpiperidine nitroxyl radical-4-subunit) acetic acid, 15g of 1, 2-dichloroethane and 7.5mg of potassium bromide into a 100ml reaction bottle, dissolving in 15g of water, adding into a reaction system, cooling to 0 ℃ by using an ice bath, dropwise adding 65g of 10% sodium hypochlorite solution into the reaction bottle, dropwise adding 1N hydrochloric acid into the reaction bottle, controlling the pH of the reaction to be 7.5-9.0, controlling the dropping speed to ensure that the reaction temperature is not higher than 20 ℃, detecting by TLC after dropwise adding, completing the reaction for 1 hour, standing and separating the reaction solution, extracting an aqueous phase by 25g of dichloromethane of 2, combining organic phases, washing once by 25g of water, and using anhydrous Na for the organic phase2SO4Drying, filtering, concentrating to obtain light yellow oily substance, adding petroleum ether 15g, stirring, standing at 0 deg.C for crystallization, filtering, and vacuum drying at 30 deg.C to obtain light yellow solid product o-nitrobenzaldehyde 6.92g with yield 91.7%.
Example 6
7.65kg of o-nitrobenzyl alcohol and 7.5g of 2- (2, 2, 6 are added into a 100L reaction kettle,6-tetramethyl piperidine nitroxyl free radical-4-subunit) acetic acid, 15kg of dichloromethane, 15kg of water, 7.5g of sodium bromide and 4.2kg of sodium bicarbonate are uniformly stirred, the temperature is reduced to 5 ℃, 50kg of 10% sodium hypochlorite solution is slowly added into a reaction kettle, the reaction pH is controlled to be 7.5-8.5, the dropping speed is controlled to ensure that the reaction temperature is not higher than 20 ℃, TLC detection is carried out after dropping is finished, the reaction solution is completely reacted for 2 hours, liquid separation is carried out after standing, the water phase is extracted by 25kgx2 dichloromethane, organic phases are combined and washed once by 25kg of water, and the organic phases are washed by anhydrous Na2SO4Drying, filtering, concentrating to obtain light yellow oily substance, adding petroleum ether 15kg, cooling to 0 deg.C, stirring for crystallization, filtering, and vacuum drying at 30 deg.C to obtain light yellow solid product o-nitrobenzaldehyde 7.1kg with yield of 94%.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method of o-nitrobenzaldehyde is characterized by comprising the following steps:
(1) adding the o-nitrobenzyl alcohol, the catalyst, the bromide salt and the solvent into a reaction kettle, and stirring uniformly at room temperature;
(2) controlling the reaction temperature, slowly dropwise adding a sodium hypochlorite solution into the reaction kettle, and simultaneously adding a weak alkaline substance or an acidic substance to control the pH value of the reaction;
(3) standing for layering, adding an organic solvent to extract a product, and concentrating to obtain a crude product;
(4) crystallizing by using an organic solvent, centrifuging, and drying in vacuum to obtain o-nitrobenzaldehyde;
wherein the catalyst in the step (1) is 2- (2, 2, 6, 6-tetramethyl piperidine nitroxide radical-4-subunit) acetic acid, and the dosage of the catalyst is 0.001-0.1 of the equivalent of the o-nitrobenzyl alcohol.
2. The process for producing o-nitrobenzaldehyde according to claim 1, wherein the bromide salt used in step (1) is sodium bromide or potassium bromide in an amount of 0.001 to 0.2 equivalent to the o-nitrobenzyl alcohol.
3. The process for producing o-nitrobenzaldehyde according to claim 1, wherein the solvent used in step (1) is a mixed solvent of a chlorinated hydrocarbon and water.
4. The method for preparing o-nitrobenzaldehyde according to claim 3, wherein the chlorinated hydrocarbon is one or both of dichloromethane and 1, 2-dichloroethane.
5. The method for preparing o-nitrobenzaldehyde according to claim 3, wherein the o-nitrobenzol and water have a volume to weight ratio of 1 to 10ml/g, and the o-nitrobenzol and chlorinated hydrocarbon have a volume to weight ratio of 2 to 10 ml/g.
6. The method for preparing o-nitrobenzaldehyde according to claim 1, wherein said weakly basic substance in step (2) is sodium bicarbonate, and said acidic substance is one of hydrochloric acid, sulfuric acid, acetic acid and sodium bisulfate.
7. The process for producing o-nitrobenzaldehyde according to claim 1, wherein said reaction temperature in step (2) is 0 to 30 ℃ and said reaction pH is 7.0 to 9.0.
8. The method for preparing o-nitrobenzaldehyde according to claim 1, wherein the organic solvent used in step (3) is one or both of dichloromethane and 1, 2-dichloroethane.
9. The method for preparing o-nitrobenzaldehyde according to claim 1, wherein the organic solvent in step (4) is one or more of petroleum ether, ethyl acetate, methyl tert-butyl ether, and 1, 2-dichloroethane.
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Effective date of registration: 20230713 Address after: 722299 Fufeng Technology Industrial Park, Jiangzhang Town, Fufeng County, Baoji City, Shaanxi Province Patentee after: Shaanxi Xiyue Pharmaceutical (Fufeng) Co.,Ltd. Patentee after: Shaanxi Normal University Address before: 721000 jiangzhang Industrial Park, jiangzhang Town, Fufeng County, Baoji City, Shaanxi Province Patentee before: Shaanxi Haichen Fengyang Pharmaceutical Technology Co.,Ltd. Patentee before: Shaanxi Normal University Patentee before: Shaanxi Xiyue Pharmaceutical (Fufeng) Co.,Ltd. |
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