A preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde

Abstract

The invention discloses a preparation method for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and belongs to the field of chemical synthesis. The invention provides a synthesis method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, using 3-hydroxy-4-methoxybenzaldehyde and sodium hypochlorite aqueous solution as raw materials, using an organic solvent, adjusting the reaction pH, reacting under low temperature conditions, and obtaining 2-chloro-3-hydroxy-4-methoxybenzaldehyde by hydrolysis and washing. The synthesis process of the present invention is simple to operate, and the product yield and purity are high, the liquid phase purity is measured to be 98.6%, and the yield is 96.6%.

Description

Technical Field

[0001] The invention discloses a preparation method for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and belongs to the field of chemical synthesis. Background Art

[0002] 2-Chloro-3-hydroxy-4-methoxybenzaldehyde, CAS No.: 37687-57-3, molecular weight: 186.59, density: 1.377 g / cm 3 , boiling point: 291.3℃, molecular formula: C8H7ClO3, melting point: 204~208℃, off-white solid. 2-Chloro-3-hydroxy-4-methoxybenzaldehyde is an important fine chemical and pharmaceutical and material intermediate, and is an important intermediate for the preparation of the antibiotic cefiderocol.

[0003] Stephen T et al. in the literature J. Heterocyclic Chem., 23, 1805 (1986) used dichloromethane as solvent, isovanillin and chlorine as raw materials, and carried out chlorination reaction by bubbling chlorine into the system. The process has a short reaction route, but requires the use of toxic gas chlorine, has a high risk factor, is easily contaminated, and has a low yield.

[0004]

[0005] NSBaleeva et al. described in the document Georg Thieme Verlag Stuttgart·New York-SynOpen2018,2,240-245. that 2-chloro-3-hydroxy-4-methoxybenzaldehyde was synthesized by reaction in anhydrous chloroform at room temperature using isovanillin and sulfonyl chloride as raw materials. The process reaction conditions are mild and the product yield is high, but the reaction time is too long, which is not conducive to industrial production, and it is easy to cause environmental pollution, which does not meet the requirements of green process production.

[0006]

[0007] F. Carmona Viglianco et al. used glacial acetic acid as solvent and isovanillin and NCS as raw materials to synthesize 2-chloro-3-hydroxy-4-methoxybenzaldehyde in the document New Journal of Chemistry, 2020. The process reaction conditions are simple, but the product yield is low, the economic benefit is low, and it is not conducive to industrial production.

[0008]

[0009] In summary, the existing methods for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde all have shortcomings, and it is necessary to develop a more economical, more effective and safer synthesis technology. Summary of the invention

[0010] The present invention aims to solve the problem of obtaining 2-chloro-3-hydroxy-4-methoxybenzaldehyde by reacting 3-hydroxy-4-methoxybenzaldehyde with an aqueous sodium hypochlorite solution at low temperature. The technical solution of the present invention is as follows:

[0011] The present invention provides a method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and the specific preparation formula is:

[0012]

[0013] 3-Hydroxy-4-methoxybenzaldehyde is added to an organic solvent, the pH of the reaction solution is adjusted, the reaction solution is stirred, the temperature is controlled, and a sodium hypochlorite aqueous solution is slowly added dropwise, the reaction solution is stirred, and the system temperature is adjusted after the reaction is completed. The reaction solution is transferred to a hydrolysis mixed solution to precipitate a solid, and the solid is filtered and washed with a methanol and water mixed solution to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde.

[0014] In the preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the reaction uses concentrated sulfuric acid to adjust the pH of a mixed solution of 3-hydroxy-4-methoxybenzaldehyde and an organic solvent to a pH of 2 to 4, preferably a pH of 3.

[0015] In the preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the dropping speed of the sodium hypochlorite aqueous solution is 2.5 to 4.0 mL / min, preferably 3.0 mL / min; the reaction temperature is -10 to -5°C, preferably -7°C.

[0016] In the preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the hydrolysis mixture used is a mixture of ethanol and concentrated hydrochloric acid, a mixture of isopropanol and concentrated hydrochloric acid, a mixture of ethanol and concentrated sulfuric acid, and a mixture of isopropanol and concentrated sulfuric acid. Preferably, the hydrolysis mixture is a mixture of isopropanol and concentrated hydrochloric acid. The molar ratio of alcohol to acid in the hydrolysis mixture is 2.5-3.5:1, and preferably the molar ratio is 3.0:1.

[0017] In the preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the molar ratio of 3-hydroxy-4-methoxybenzaldehyde to sodium hypochlorite is 1:1.0-1.5, preferably 1:1.2; the volume ratio of methanol to water in the washing liquid is 0.5-2.0:1, preferably 1:1.

[0018] In the preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the organic solvent used in the reaction is methanol, isopropanol, acetic acid, etc., and the preferred organic solvent is isopropanol.

[0019] In the method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the temperature of the reaction solution is raised to 38-45°C, preferably 42°C, before the reaction solution is transferred to a mixture of methanol and concentrated sulfuric acid in a certain molar ratio.

[0020] The beneficial effects of the present invention are:

[0021] (1) The solvent used in the traditional synthesis reaction method using chlorine is not easy to operate, and chlorine leakage is very likely to cause harm and pollution, which does not meet the requirements of green synthesis. The present invention uses sodium hypochlorite as a raw material, which is more in line with the requirements of green process production.

[0022] (2) The present invention adjusts the pH of the mixed solution of 3-hydroxy-4-methoxybenzaldehyde and an organic solvent to obtain a product with high yield and high purity.

[0023] (3) The reaction is safe and reliable, low cost, simple to operate, and has good prospects for industrial scale-up. DETAILED DESCRIPTION

[0024] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0025] 3-Hydroxy-4-methoxybenzaldehyde (analytical grade), Shanghai Haiqu Chemical Co., Ltd.; sodium hypochlorite (effective chlorine 8%), Xilong Science Co., Ltd.; sulfuric acid (98%), Yantai Yuandong Fine Chemical Co., Ltd.; hydrochloric acid (37%), Yantai Yuandong Fine Chemical Co., Ltd.; isopropanol (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.; ethanol (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.; methanol (analytical grade), Shandong Yuwang Hetianxia New Materials Co., Ltd.; acetic acid (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.

[0026] Example 1

[0027] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 98.6% and the yield was 96.6%.

[0028] Example 2

[0029] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 2 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.1% and the yield was 93.2%.

[0030] Example 3

[0031] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 4 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.5% and the yield was 94.3%.

[0032] Example 4

[0033] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (2.5mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.7% and the yield was 93.3%.

[0034] Example 5

[0035] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (4.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.4% and the yield was 94.7%.

[0036] Example 6

[0037] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -5℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -5℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.0% and the yield was 94.0%.

[0038] Example 7

[0039] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixed solution to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -10℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), keep -10℃ and stir for 2h after the addition. After the reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of ethanol (92.14g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.5% and the yield was 95.2%.

[0040] Example 8

[0041] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition. After the reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of ethanol (92.14g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.5% and the yield was 95.2%.

[0042] Example 9

[0043] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of ethanol (92.14g) and concentrated sulfuric acid (mass fraction 98%, 64.68g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.1% and the yield was 94.4%.

[0044] Example 10

[0045] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction liquid to a mixture of isopropanol (120.19g) and concentrated sulfuric acid (mass fraction 98%, 64.68g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 96.2% and the yield was 93.3%.

[0046] Embodiment 11

[0047] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 55.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 96.4% and the yield was 95.2%.

[0048] Example 12

[0049] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 77.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 95.9% and the yield was 94.1%.

[0050] Example 13

[0051] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (278mL, 1.0eq), and keep stirring at -7℃ for 2h after the addition. After the reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 98.0% and the yield was 93.9%.

[0052] Embodiment 14

[0053] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (417mL, 1.5eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 96.7% and the yield was 94.2%.

[0054] Embodiment 15

[0055] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), keep -10℃ and stir for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL methanol and water volume ratio 0.5:1 mixture, filter to obtain the product. The liquid phase purity was measured to be 96.8% and the yield was 93.2%.

[0056] Example 16

[0057] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 2:1, and filter to obtain the product. The liquid phase purity was measured to be 96.5% and the yield was 94.4%.

[0058] Embodiment 17

[0059] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 38℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.8% and the yield was 96.0%.

[0060] Embodiment 18

[0061] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 45℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 97.7% and the yield was 94.8%.

[0062] Comparative Example 1

[0063] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction liquid to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity is 87.1% and the yield is 72.2%.

[0064] Comparative Example 2

[0065] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. The system temperature is reduced to -7℃, and sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq) is slowly added dropwise (3.0mL / min), and after the addition is completed, the reaction solution is adjusted to pH 3 with concentrated sulfuric acid, and then kept at -7℃ and stirred for 2h. After the liquid phase monitoring reaction is completed, the system is heated to 42℃, and the reaction solution is transferred to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g) at a transfer speed of 20mL / min, stirred for 1h, and filtered to obtain an off-white solid, which is washed with a mixture of 400mL methanol and water with a volume ratio of 1:1, and filtered to obtain the product. The liquid phase purity was measured to be 83.2% and the yield was 74.3%.

[0066] Comparative Example 3

[0067] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 5 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 42℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 81.1% and the yield was 69.6%.

[0068] Comparative Example 4

[0069] Take a 1000mL three-necked flask, weigh (50.00g, 1eq) 3-hydroxy-4-methoxybenzaldehyde and add it, then weigh 200mL methanol and add it, adjust the mixture to pH 3 with concentrated sulfuric acid, stir for 20min, the raw material is not completely dissolved, and solids are precipitated when placed in a low temperature environment. Lower the system temperature to -7℃, slowly add (3.0mL / min) sodium hypochlorite aqueous solution (effective chlorine 8%) (334mL, 1.2eq), and keep stirring at -7℃ for 2h after the addition is completed. After the liquid phase monitoring reaction is completed, heat the system to 33℃, transfer the reaction solution to a mixture of isopropanol (120.19g) and concentrated hydrochloric acid (mass fraction 37%, 66.02g), transfer speed 20mL / min, stir for 1h, filter, and obtain an off-white solid, wash with 400mL of a mixture of methanol and water with a volume ratio of 1:1, and filter to obtain the product. The liquid phase purity was measured to be 82.4% and the yield was 71.7%.

[0070] Although the above describes the specific implementation of the present invention in combination with the embodiments, it is not intended to limit the implementation of the present invention. For those skilled in the art, various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without creative work are still within the protection scope of the present invention.

Claims

1. A method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, characterized in that: The preparation formula is: The preparation method comprises the following steps: adding 3-hydroxy-4-methoxybenzaldehyde to methanol, adjusting the pH of the reaction solution with a pH regulator, stirring, controlling the temperature, slowly dripping a sodium hypochlorite aqueous solution, stirring, adjusting the system temperature after the reaction is completed, transferring the reaction solution to a hydrolysis mixed solution to precipitate a solid, filtering and washing with a methanol and water mixed solution to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde, wherein the pH of the reaction solution is 2-4, the pH regulator is concentrated sulfuric acid, the hydrolysis mixed solution is a mixed solution of ethanol and concentrated hydrochloric acid, a mixed solution of isopropanol and concentrated hydrochloric acid, a mixed solution of ethanol and concentrated sulfuric acid, and a mixed solution of isopropanol and concentrated sulfuric acid; and the molar ratio of alcohol to acid in the used hydrolysis mixed solution is 2.5-3.5:

1.

2. The method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein: The sodium hypochlorite aqueous solution in the preparation method has a dropping speed of 2.5 to 4.0 mL / min and a reaction temperature of -10 to -5°C.

3. The method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein: In the preparation method, the molar ratio of 3-hydroxy-4-methoxybenzaldehyde to sodium hypochlorite is 1:1.0-1.5, and the volume ratio of methanol to water in the post-treatment is 0.5-2.0:

1.

4. The method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein: The temperature of the reaction solution in the preparation method is raised to 38-45° C. before being transferred to a mixture of methanol and concentrated sulfuric acid.

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