A process for the preparation of o-carboxybenzaldehyde

Abstract

The application belongs to the field of organic synthesis and particularly relates to a preparation method of ortho-carboxybenzaldehyde. The method comprises the following steps: (a) ring-opening hydrolysis of a compound of formula (3) with a strong alkali solution to prepare a compound of formula (2) or a salt thereof; and (b) oxidation of the compound of formula (2) or the salt thereof with an oxidant in a solvent under the catalysis of a nitrogen-oxygen free radical to prepare a compound of formula (1) or a salt thereof. The ortho-carboxybenzaldehyde prepared by the method is an important intermediate for synthesis of antipyretic analgesics. The method solves the problems of environmental pollution and personnel injury and high energy consumption and cost in the prior art which generally uses bromine, chlorine and a large amount of toxic solvents and high-temperature reflux reaction, and initiatively provides a method for directly ring-opening hydrolysis under the action of a strong alkali and then oxidation in a homogeneous system to prepare ortho-carboxybenzaldehyde, which is simple and convenient to operate, safe and controllable, and suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and relates to a preparation method of o-carboxybenzaldehyde, in particular to a preparation method of o-carboxybenzaldehyde by phthalide oxidation. BACKGROUND

[0002] O-carboxybenzaldehyde (2-Carboxybenzaldehyde, CAS: 119-67-5), the chemical structure is shown as formula (1):

[0003]

[0004] O-carboxybenzaldehyde is an important intermediate for the synthesis of antipyretic analgesic. In the prior art, o-carboxybenzaldehyde is mostly prepared by halogenation and then hydrolysis of phenol or phthalide.

[0005] CN101735041A discloses that phthalide is used as raw material, chlorobenzene or toluene is used as solvent, 3-bromophthalide is prepared by first reacting with bromine, then o-carboxybenzaldehyde wet product is obtained by hydrolysis of 3-bromophthalide, and finally o-carboxybenzaldehyde is obtained by recrystallization of the o-carboxybenzaldehyde wet product. The invention uses bromine as a reactant, which is easy to volatilize and can freeze into a solid at low temperature, has extremely strong toxicity and corrosivity, and the controllability of the experiment is not ideal.

[0006] CN104447303A discloses that phthalide is used as raw material, bromine water is used as a reaction reagent, heated to reflux in chloroform organic solvent, nitrogen is introduced during the reaction process, the solvent is removed under reduced pressure after the reaction is completed, cooled, crystallized, and filtered to obtain 3-bromophthalide; then the 3-bromophthalide is added to a hydrolysis kettle, heated by water bath, cooled, crystallized, and filtered to obtain o-carboxybenzaldehyde wet product; finally, o-carboxybenzaldehyde is prepared by recrystallization of the o-carboxybenzaldehyde wet product. The invention uses bromine water as a reaction reagent, which has great pollution hazards, and will be gradually eliminated in the trend of pursuing green environmental protection.

[0007] CN104447304A discloses that phthalide is used as raw material, chlorine gas is used as a reaction reagent, refluxed under pressure in carbon tetrachloride organic solvent, carbon dioxide is introduced into the reaction kettle and evaporated under reduced pressure, cooled and dried to obtain 3-chlorophthalide; then the 3-chlorophthalide is added to a hydrolysis kettle, heated by water bath, cooled, crystallized, and filtered to obtain o-carboxybenzaldehyde wet product; finally, o-carboxybenzaldehyde is prepared by recrystallization of the o-carboxybenzaldehyde wet product. The invention uses chlorine gas as a reactant, which is extremely easy to diffuse and has great harm to people, and is not conducive to green production.

[0008] The above-mentioned prior art has low yield, and due to the use of bromine, chlorine and a large amount of toxic solvents, as well as high-temperature reflux reaction, there are problems of environmental pollution and personnel injury, high energy consumption and high cost. SUMMARY

[0009] The present application is to overcome the deficiencies in the prior art, developed a method for the preparation of o-carboxybenzaldehyde in homogeneous system by adding solvent after direct ring-opening hydrolysis of phthalide under alkaline conditions, and oxidation. The method is green and environmentally friendly, simple and controllable process, low energy consumption, low cost, simple work-up, high purity, and high yield.

[0010] The present application provides a preparation method of a compound of formula (2) or a salt thereof,

[0011]

[0012] comprising the following steps:

[0013] ring-opening hydrolysis reaction of a compound of formula (3)

[0014]

[0015] with a strong base solution to obtain a compound of formula (2) or a salt thereof.

[0016] As a further improvement of the present application, the strong base solution is selected from an aqueous alkali metal hydroxide solution, preferably 5% to 40% sodium hydroxide aqueous solution, 5% to 40% potassium hydroxide aqueous solution.

[0017] As a further improvement of the present application, the molar ratio of the strong base solution to the compound of formula (3) is (1-3):1, preferably (1-1.5):1.

[0018] As a further improvement of the present application, the temperature of the ring-opening hydrolysis reaction is 35-100℃, preferably 40-70℃, more preferably 50-60℃.

[0019] As a further improvement of the present application, the compound of formula (2) or a salt thereof obtained by ring-opening hydrolysis can be directly used in subsequent reactions without treatment, or the compound of formula (2) or a salt thereof obtained by ring-opening hydrolysis is treated with acid before being used in subsequent reactions.

[0020] The present application also provides a preparation method of a compound of formula (1) or a salt thereof,

[0021]

[0022] comprising the following steps:

[0023] ring-opening hydrolysis reaction of a compound of formula (2) or a salt thereof

[0024]

[0025] oxidation with an oxidizing agent in a solvent under the catalysis of a nitrogen-oxygen radical to prepare a compound of formula (1) or a salt thereof.

[0026] As a further improvement of the present application, the oxidizing agent is selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium chlorite, hydrogen peroxide, trichloroisocyanuric acid, peroxyacetic acid, peroxyformic acid; preferably sodium hypochlorite, potassium hypochlorite, calcium hypochlorite; more preferably sodium hypochlorite.

[0027] As a further improvement of the present application, the oxidizing agent is preferably an aqueous solution with a concentration of 5% to 20%, more preferably an aqueous solution with a concentration of 8% to 15%, in some embodiments, the oxidizing agent is an aqueous solution of 5% sodium hypochlorite or an aqueous solution of 10% sodium hypochlorite.

[0028] As a further improvement of the present application, the molar ratio of the oxidizing agent to the compound of formula (2) or its salt is (0.5-1.5):1, preferably (0.8-1.2):1.

[0029] As a further improvement of the present application, the solvent is miscible with water and does not have the property of being oxidized, selected from one or more of aromatic hydrocarbons, aliphatic hydrocarbons, ketones, esters or water, preferably one or more of toluene, benzene, xylene, hexane, pentane, heptane, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate or water, more preferably water.

[0030] As a further improvement of the present application, the volume of the solvent (mL) is 2 to 10 times, preferably 2 to 5 times, the mass of the compound of formula (2) or its salt (g).

[0031] As a further improvement of the present application, the nitroxyl radical catalyst is preferably one or more of TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-Oxo-TEMPO, ABNO, AZADO, 1-Me-AZADO, oxa-AZADO, TsN-AZADO, DiAZADO, norpin-N-oxyl, 7-azabicyclo[2.2.1]heptane-N-oxyl or 3-BocNH-ABNO.

[0032] As a further improvement of the present application, the molar ratio of the nitroxyl radical catalyst to the compound of formula (2) or its salt is (0.001-0.2):1, preferably (0.002-0.02):1.

[0033] As a further improvement of the present application, the oxidation reaction is carried out in the presence of an additive, the additive is selected from bromides, preferably one or more of sodium bromide, potassium bromide or calcium bromide, more preferably sodium bromide or potassium bromide.

[0034] As a further improvement of the present application, the molar ratio of the additive to the compound of formula (2) or its salt is (0.01-0.5):1, preferably (0.02-0.2):1.

[0035] As a further improvement of the present application, the oxidation reaction is carried out in the presence of a buffer selected from one or more of alkali metal carbonates, alkali metal bicarbonates or phosphates, preferably one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate or disodium hydrogen phosphate.

[0036] As a further improvement of the present application, the molar ratio of the buffer to the compound of formula (2) or its salt is (0.1-0.5):1.

[0037] As a further improvement of the present application, the temperature of the oxidation reaction is ≤35℃, preferably -5-20℃.

[0038] As a further improvement of the present application, the compound of formula (2) or its salt is obtained by ring-opening hydrolysis of the compound of formula (3) with a strong base solution.

[0039] As a further improvement of the present application, the strong base solution is selected from aqueous alkali metal hydroxide solution, preferably 5%-40% sodium hydroxide solution or 5%-40% potassium hydroxide solution.

[0040] As a further improvement of the present application, the molar ratio of the strong base solution to the compound of formula (3) is (1-3):1, preferably (1-1.5):1.

[0041] As a further improvement of the present application, the temperature of the ring-opening hydrolysis reaction is 35-100℃, preferably 40-70℃, more preferably 50-60℃.

[0042] As a further improvement of the present application, the compound of formula (2) or its salt obtained by the ring-opening hydrolysis reaction can be directly used in the oxidation reaction to prepare the compound of formula (1) or its salt without further treatment, or the compound of formula (2) or its salt obtained by the ring-opening hydrolysis reaction is treated with an acid and then used in the oxidation reaction to prepare the compound of formula (1) or its salt.

[0043] As a further improvement of the present application, the oxidation reaction comprises a salting-out purification step: adjusting the pH to make the solution acidic, adding an organic solvent, cooling to induce crystallization, filtering, and drying.

[0044] As a further improvement of the present application, the pH is ≤5; the organic solvent is a conventional solvent such as toluene, ethyl acetate, dichloromethane, etc.; and the volume of the organic solvent (mL) is 1-4 times the mass of the compound of formula (2) or its salt (g).

[0045] The chemical reagents used in the present application are shown in the following Table 1:

[0046] Table 1

[0047]

[0048]

[0049] Compared with the prior art, the present application has the following advantages:

[0050] (1) The present application provides a preparation method of o-carboxybenzaldehyde, which uses a specific solvent in a homogeneous reaction system, and uses a low-pollution reagent or solvent, etc., which has a great environmental protection advantage and cost advantage compared with other bromination reagents such as liquid bromine, bromine water, etc., in combination with an organic solvent.

[0051] (2) After the phthalide is directly ring-opened and hydrolyzed in a strong base, an oxidation reaction is carried out, the temperature is relatively low, and the whole reaction process is in a safe and controllable state. In large-scale industrial production, this production method can avoid the instantaneous explosive reaction caused by high temperature, and can avoid the dangerous working conditions such as material spraying. DETAILED DESCRIPTION

[0052] In order to facilitate the understanding of the content of the present application by those skilled in the art, the technical solutions of the present application are further described below in combination with specific examples. It should be understood that the following examples are not intended to limit the scope and spirit of the claims of the present application. The raw materials, reagents or solvents used in the present application are commercially available or prepared according to the conventional methods in the art, and the experimental methods of specific conditions not specifically described are carried out according to the conventional operations in the art.

[0053] Example 1:

[0054] Phthalide (100 g, 0.75 mol) and 30% sodium hydroxide (120 g, 0.9 mol) were added to a reaction bottle, the reaction temperature was controlled at 50°C, and the reaction was carried out for 3 h. After the reaction was completed, the loss of the intermediate product was ignored in liquid phase detection. Then TEMPO (0.23 g, 0.0015 mol), potassium bromide (1.78 g, 0.015 mol), water (500 mL), sodium phosphate (36.9 g, 0.225 mol), 10% sodium hypochlorite (558.3 g, 0.75 mol) were added dropwise at -5~20°C, and stirred for 30 min after the dropwise addition was completed. Hydrochloric acid was added to adjust pH=3, toluene (100 mL) was added, and the temperature was lowered to below 10°C. After filtration, the filter cake was washed with water and dried to obtain o-carboxybenzaldehyde. The product HPLC purity was 98.7%, and the yield was 71%.

[0055] Example 2:

[0056] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), potassium bromide (1.78 g, 0.015 mol), water (500 mL), sodium phosphate dibasic (21.29 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 98.4%, the yield is 73%.

[0057] Example 3:

[0058] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), potassium bromide (1.78 g, 0.015 mol), water (500 mL), sodium phosphate dibasic (21.29 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 98.4%, the yield is 73%.

[0059] Example 4:

[0060] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), potassium bromide (1.78 g, 0.015 mol), water (500 mL), sodium phosphate dibasic (21.29 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 98.4%, the yield is 73%.

[0061] Example 5:

[0062] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, react for 3 h, after the reaction, the loss of intermediate product is negligible according to liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 97.4%, the yield is 77.2%.

[0063] Example 6:

[0064] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, react for 3 h, after the reaction, the loss of intermediate product is negligible according to liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 97.4%, the yield is 77.2%.

[0065] Example 7:

[0066] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, react for 3 h, after the reaction, the loss of intermediate product is negligible according to liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add toluene (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 97.4%, the yield is 77.2%.

[0067] Example 8:

[0068] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, and react for 3 h. After the reaction, the loss of the intermediate product is negligible according to liquid phase detection. Then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), and drop 10% sodium hypochlorite (667 g, 0.9 mol) at -5-20°C. After the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH = 3, add ethyl acetate (100 mL), cool to below 10°C, filter, rinse the filter cake with water, and dry to obtain ortho-carboxyl benzaldehyde. The product has a HPLC purity of 99.3% and a yield of 69.7%.

[0069] Example 9:

[0070] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, and react for 3 h. After the reaction, the loss of the intermediate product is negligible according to liquid phase detection. Then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), and drop 10% sodium hypochlorite (667 g, 0.9 mol) at -5-20°C. After the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH = 3, add ethyl acetate (100 mL), cool to below 10°C, filter, rinse the filter cake with water, and dry to obtain ortho-carboxyl benzaldehyde. The product has a HPLC purity of 99.3% and a yield of 69.7%.

[0071] Example 10:

[0072] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature at 50°C, and react for 3 h. After the reaction, the loss of the intermediate product is negligible according to liquid phase detection. Then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), and drop 10% sodium hypochlorite (667 g, 0.9 mol) at -5-20°C. After the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH = 3, add ethyl acetate (100 mL), cool to below 10°C, filter, rinse the filter cake with water, and dry to obtain ortho-carboxyl benzaldehyde. The product has a HPLC purity of 99.3% and a yield of 69.7%.

[0073] Example 11:

[0074] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (558.3 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=1, add dichloromethane (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 95.2%, the yield is 79.6%.

[0075] Example 12:

[0076] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), acetone (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (1116.6 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add dichloromethane (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 95.8%, the yield is 68.4%.

[0077] Example 13:

[0078] To the reaction bottle, add phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), control the reaction temperature to be 50°C, react for 3 h, after the reaction, the loss of the intermediate product is negligible according to the liquid phase detection; then add TEMPO (0.23 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol), drop 10% sodium hypochlorite (1116.6 g, 0.75 mol) at -5~20°C, after the drop is completed, stir for 30 min, add hydrochloric acid to adjust pH=3, add dichloromethane (100 mL), cool to below 10°C, filter, wash the filter cake with water and dry, to obtain ortho-carboxyl benzaldehyde, the product HPLC purity is 95.8%, the yield is 68.4%.

[0079] Example 14:

[0080] To the reaction bottle, phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol) were added, the reaction temperature was controlled at 50°C, and the reaction was carried out for 3 h. After the reaction was completed, the loss of the intermediate product was ignored according to the liquid phase detection. Then, AZADO (0.228 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol) were added, and 5% sodium hypochlorite (1116.6 g, 0.75 mol) was added dropwise at -5-20°C. After the dropwise addition was completed, the mixture was stirred for 30 min. Hydrochloric acid was added to adjust the pH to 3. Toluene (100 mL) was added, and the mixture was cooled to below 10°C. Filtration was performed, and the filter cake was washed with water and then dried to obtain ortho-carboxyl benzaldehyde. The product had a purity of 96.2% by HPLC, and the yield was 64.9%.

[0081] Comparative Example 1:

[0082] To the reaction bottle, phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol) were added, the reaction temperature was controlled at 50°C, and the reaction was carried out for 3 h. After the reaction was completed, the loss of the intermediate product was ignored according to the liquid phase detection. Then, AZADO (0.228 g, 0.0015 mol), sodium bromide (1.54 g, 0.015 mol), water (500 mL), sodium bicarbonate (12.6 g, 0.225 mol) were added, and 5% sodium hypochlorite (1116.6 g, 0.75 mol) was added dropwise at -5-20°C. After the dropwise addition was completed, the mixture was stirred for 30 min. Hydrochloric acid was added to adjust the pH to 3. Toluene (100 mL) was added, and the mixture was cooled to below 10°C. Filtration was performed, and the filter cake was washed with water and then dried to obtain ortho-carboxyl benzaldehyde. The product had a purity of 96.2% by HPLC, and the yield was 64.9%.

[0083] Comparative Example 2:

[0084] Into a reaction flask was added phthalide (100 g, 0.75 mol), 30% sodium hydroxide (120 g, 0.9 mol), the reaction temperature was controlled at 50°C, and the reaction was carried out for 3 hours. After the reaction, liquid phase detection showed that the loss of the intermediate product was negligible. Then TEMPO (0.23 g, 0.0015 mol), potassium bromide (8.9 g, 0.075 mol), water (500 mL), dichloromethane (750 mL), sodium bicarbonate for adjusting pH = 8.6, 10% sodium hypochlorite (558.3 g, 0.75 mol) were added dropwise at -5~20°C. After the dropwise addition was completed, the mixture was stirred for 30 min. Hydrochloric acid was added to adjust the pH to 3. Toluene (100 mL) was added, and the temperature was lowered to below 10°C. Filtration was carried out, the filter cake was washed with water, and then dried to obtain ortho-carboxyl benzaldehyde. The product had a HPLC purity of 94.2% and a yield of 46%.

Claims

1. A method for preparing a compound of formula (1) or a salt thereof, comprising the following steps: (1) reacting a compound of formula (2) or a salt thereof with a strong base solution to obtain a compound of formula (2) or a salt thereof (2) and (b) oxidizing the compound of formula (2) or a salt thereof obtained in step (a) with an oxidant, an additive and a buffer in water in the presence of a nitrogen-oxygen radical catalyst to obtain a compound of formula (1) or a salt thereof, wherein the nitrogen-oxygen radical catalyst is selected from TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-Oxo-TEMPO, ABNO, AZADO, 1-Me-AZADO, oxa-AZADO, TsN-AZADO, DiAZADO, norpin-N-oxyl, 7-azabicyclo[2.2.1]heptane-N-oxyl or 3-BocNH-ABNO; the oxidant is selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium chlorite, hydrogen peroxide, trichloroisocyanuric acid, peroxyacetic acid, peroxyformic acid; the additive is selected from sodium bromide, potassium bromide or calcium bromide; the buffer is selected from one or more of alkali metal carbonate, alkali metal bicarbonate or phosphate. (1) The molar ratio of the oxidant to the compound of formula (2) or a salt thereof is (0.5-1.5):

1. The oxidant is in the form of an aqueous solution with a concentration of 5-20%. (2) The molar ratio of the buffer to the compound of formula (2) or a salt thereof is (0.1-0.5):

1.

2. A method for preparing a compound of formula (1) or a salt thereof, comprising the following steps: (a) reacting a compound of formula (3) with a strong base solution to obtain a compound of formula (2) or a salt thereof (b) oxidizing the compound of formula (2) or a salt thereof obtained in step (a) with an oxidant, an additive and a buffer in water in the presence of a nitrogen-oxygen radical catalyst to obtain a compound of formula (1) or a salt thereof, wherein the nitrogen-oxygen radical catalyst is selected from TEMPO, 4-OH-TEMPO, 4-MeO-TEMPO, 4-Oxo-TEMPO, ABNO, AZADO, 1-Me-AZADO, oxa-AZADO, TsN-AZADO, DiAZADO, norpin-N-oxyl, 7-azabicyclo[2.2.1]heptane-N-oxyl or 3-BocNH-ABNO; the oxidant is selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium chlorite, hydrogen peroxide, trichloroisocyanuric acid, peroxyacetic acid, peroxyformic acid; the additive is selected from sodium bromide, potassium bromide or calcium bromide; the buffer is selected from one or more of alkali metal carbonate, alkali metal bicarbonate or phosphate. The molar ratio of the oxidant to the compound of formula (2) or a salt thereof is (0.5-1.5):

1. The oxidant is in the form of an aqueous solution with a concentration of 5-20%. The molar ratio of the buffer to the compound of formula (2) or a salt thereof is (0.1-0.5):

1. (1) The oxidant is selected from sodium hypochlorite, potassium hypochlorite, calcium hypochlorite. The molar ratio of the oxidant to the compound of formula (2) or a salt thereof is (0.8-1.2):

1. (3) And / or, the oxidant is in the form of an aqueous solution with a concentration of 8-15%. (2)； ​ ​ ​ ​ 3. The production method according to claim 1 or 2, characterized by, ​ 4. The production method according to claim 1 or 2, characterized by, ​ ​ 5. The production method according to claim 1 or 2, characterized by, The volume amount mL of water is 2 to 10 times the mass amount g of the compound of formula (2) or salt thereof.

6. The production method according to claim 5, wherein The volume amount mL of water is 2 to 5 times the mass amount g of the compound of formula (2) or salt thereof.

7. The production method according to claim 1 or 2, characterized by, The molar ratio of the nitroxyl radical catalyst to the compound of formula (2) or salt thereof is (0.001 to 0.2):

1.

8. The preparation method according to claim 7, characterized in that, The molar ratio of the nitroxyl radical catalyst to the compound of formula (2) or salt thereof is (0.002 to 0.02):

1.

9. The production method according to claim 1 or 2, characterized by, The molar ratio of the additive to the compound of formula (2) or salt thereof is (0.01 to 0.5):

1.

10. The method of claim 9, wherein, The molar ratio of the additive to the compound of formula (2) or salt thereof is (0.02 to 0.2):

1.

11. The production method according to claim 1 or 2, characterized by, The additive is selected from sodium bromide or potassium bromide.

12. The production method according to claim 1 or 2, characterized by, The buffer is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate or disodium hydrogen phosphate.

13. The production method according to claim 1 or 2, characterized by, The temperature of the oxidation reaction is ≤ 35℃.

14. The method of claim 13, wherein, The temperature of the oxidation reaction is -5 to 20℃.

15. The preparation method according to claim 2, characterized in that, The strong base solution in the step (a) ring-opening hydrolysis reaction is an aqueous alkali metal hydroxide solution; The molar ratio of the strong base solution in the step (a) ring-opening hydrolysis reaction to the compound of formula (3) is (1 to 3): 1; The temperature of the step (a) ring-opening hydrolysis reaction is 35 to 100℃.

16. The method of claim 15, wherein, The strong base solution in the step (a) ring-opening hydrolysis reaction is selected from 5% to 40% aqueous sodium hydroxide solution, 5% to 40% aqueous potassium hydroxide solution; The molar ratio of the strong base solution in the step (a) ring-opening hydrolysis reaction to the compound of formula (3) is (1 to 1.5): 1; The temperature of the step (a) ring-opening hydrolysis reaction is 40 to 70℃.

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