CN116969824A - Preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde - Google Patents
Preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde Download PDFInfo
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- CN116969824A CN116969824A CN202311026797.8A CN202311026797A CN116969824A CN 116969824 A CN116969824 A CN 116969824A CN 202311026797 A CN202311026797 A CN 202311026797A CN 116969824 A CN116969824 A CN 116969824A
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- methoxybenzaldehyde
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- DTMJGFBJQBQOIA-UHFFFAOYSA-N 2-chloro-3-hydroxy-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(Cl)=C1O DTMJGFBJQBQOIA-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims abstract description 68
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 32
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000005406 washing Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 15
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 159
- 239000000203 mixture Substances 0.000 claims description 88
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 52
- 239000007787 solid Substances 0.000 claims description 47
- 239000011259 mixed solution Substances 0.000 claims description 35
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 28
- 238000000967 suction filtration Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000001276 controlling effect Effects 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 abstract description 45
- 239000002994 raw material Substances 0.000 abstract description 26
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 28
- 229910052801 chlorine Inorganic materials 0.000 description 28
- 239000007788 liquid Substances 0.000 description 24
- 239000012295 chemical reaction liquid Substances 0.000 description 23
- 238000012544 monitoring process Methods 0.000 description 22
- 230000000052 comparative effect Effects 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012847 fine chemical Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 method for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, which takes 3-hydroxy-4-methoxybenzaldehyde and sodium hypochlorite aqueous solution as raw materials, uses an organic solvent to adjust the pH of the reaction, reacts at low temperature, and obtains the 2-chloro-3-hydroxy-4-methoxybenzaldehyde through hydrolysis and washing. The synthesis process of the invention has simple operation, high product yield and purity, and the purity of the liquid phase is 98.6%, and the yield is 96.6%.
Description
Technical Field
The invention discloses a preparation method for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and belongs to the field of chemical synthesis.
Background
2-chloro-3-hydroxy-4-methoxybenzaldehyde, CAS number: 37687-57-3, molecular weight: 186.59, density: 1.377g/cm 3 Boiling point: 291.3 ℃, molecular formula: c (C) 8 H 7 ClO 3 Melting point: 204-208 ℃ and is an 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 preparing the antibiotic cefdinir.
Stephen T et al in document J.Heterochemistry chem.,23,1805 (1986) uses methylene dichloride as a solvent, isovanillin and chlorine as raw materials, and performs chlorination reaction by bubbling chlorine into the system, the reaction route is short, but toxic gas chlorine is required to be used, the risk coefficient is high, pollution is easily caused, and the yield is low.
Baleeva et al, in Georg Thieme Verlag Stuttgart New York-SynOpen 2018,2,240-245, describe the synthesis of 2-chloro-3-hydroxy-4-methoxybenzaldehyde from isovanillin and sulfonyl chloride in anhydrous chloroform at room temperature. The process has mild reaction conditions and higher product yield, but the reaction time is too long, is unfavorable for industrial production, is easy to cause environmental pollution and does not meet the production requirements of the green process.
In documents New Journal of Chemistry and 2020, the 2-chloro-3-hydroxy-4-methoxybenzaldehyde is synthesized by taking glacial acetic acid as a solvent and taking isovanillin and NCS as raw materials, and the process has simple reaction conditions, but low product yield and low economic benefit, and is not beneficial to industrial production.
In view of the above, the prior art methods for synthesizing 2-chloro-3-hydroxy-4-methoxybenzaldehyde have disadvantages, and it is necessary to develop more economical, more efficient and safer synthetic techniques.
Disclosure of Invention
Aiming at the defects in the prior art, the invention solves the problem that the 2-chloro-3-hydroxy-4-methoxybenzaldehyde is obtained by the low-temperature reaction of 3-hydroxy-4-methoxybenzaldehyde and sodium hypochlorite aqueous solution. The technical scheme of the invention for solving the problems is as follows:
the invention provides a preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, which comprises the following specific preparation equation:
adding 3-hydroxy-4-methoxybenzaldehyde into an organic solvent, regulating the pH of a reaction solution, stirring, controlling the temperature, slowly dropwise adding sodium hypochlorite aqueous solution, stirring, regulating the temperature of a system after the reaction is finished, transferring the reaction solution to a hydrolysis mixed solution to precipitate solid, and washing with a mixed solution of methanol and water after suction filtration to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde.
In the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, concentrated sulfuric acid is used for adjusting the pH of a mixed solution of the 3-hydroxy-4-methoxybenzaldehyde and an organic solvent, and the pH is adjusted to be 2-4, preferably 3.
In the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the dripping speed of the aqueous solution of the sodium hypochlorite for the reaction is 2.5-4.0 mL/min, preferably 3.0mL/min; the reaction temperature of the reaction is-10 to-5 ℃, preferably-7 ℃.
In the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the hydrolysis mixed solution is ethanol and concentrated hydrochloric acid mixed solution, isopropanol and concentrated hydrochloric acid mixed solution, ethanol and concentrated sulfuric acid mixed solution, isopropanol and concentrated sulfuric acid mixed solution, and preferably the hydrolysis mixed solution is isopropanol and concentrated hydrochloric acid mixed solution; the molar ratio of alcohol to acid in the hydrolysis mixture is 2.5-3.5: 1, preferably in a molar ratio of 3.0:1.
in the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the molar ratio of the 3-hydroxy-4-methoxybenzaldehyde to sodium hypochlorite is 1:1.0 to 1.5, preferably in a molar ratio of 1:1.2; the volume ratio of methanol to water in the used washing liquid is 0.5-2.0: 1, preferably a volume ratio of 1:1.
in the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the organic solvent used in the reaction is methanol, isopropanol, acetic acid and the like, and the organic solvent is preferably isopropanol.
In the preparation method of the 2-chloro-3-hydroxy-4-methoxybenzaldehyde, the temperature is raised to 38-45 ℃ and preferably 42 ℃ before the reaction liquid is transferred to a mixed liquid of methanol and concentrated sulfuric acid with a certain molar ratio.
The invention has the beneficial effects that:
(1) The solvent used in the traditional synthesis reaction method using chlorine is not easy to operate, and the leakage of the chlorine is extremely easy to cause injury and pollution, and does not accord with green synthesis. The invention uses sodium hypochlorite as raw material, which meets the production requirement of green technology.
(2) The invention adjusts the pH of the mixed solution of 3-hydroxy-4-methoxybenzaldehyde and organic solvent, and the obtained product has high yield and high purity.
(3) The reaction is safe and reliable, the cost is low, the operation is simple, and the method has good industrial amplifying prospect.
Detailed Description
For a further understanding of the present invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are merely intended to illustrate further features and advantages of the invention, and are not limiting of the claims of the invention.
3-hydroxy-4-methoxybenzaldehyde (analytically pure), shanghai Haique chemical Co., ltd; sodium hypochlorite (available chlorine 8%), part of the scientific sciences, cybernation; sulfuric acid (98%), tabacco, far east fine chemical company, inc; hydrochloric acid (37%), a company of fine chemical industry, fujia far east; isopropyl alcohol (analytically pure), rich and fine limited in Tianjin; ethanol (analytically pure), rich and fine limited in Tianjin; methanol (analytically pure), shandong Yuwang and new materials, inc. under the sky; acetic acid (analytically pure), rich and refined company of Tianjin.
Example 1
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 98.6% and the yield was 96.6%.
Example 2
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 2 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.1% and the yield was 93.2%.
Example 3
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 4 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.5% and the yield was 94.3%.
Example 4
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (effective chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise (2.5 mL/min), and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.7% and the yield was 93.3%.
Example 5
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (effective chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise (4.0 mL/min), and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.4% and the yield was 94.7%.
Example 6
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-5℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-5℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.0% and the yield was 94.0%.
Example 7
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-10℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-10℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of ethanol (92.14 g) and concentrated hydrochloric acid (mass fraction is 37 percent, 66.02 g), the transfer speed is 20mL/min, stirring is carried out for 1h, suction filtration is carried out, off-white solid is obtained, and 400mL of methanol and water are used for volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.5% and the yield was 95.2%.
Example 8
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of ethanol (92.14 g) and concentrated hydrochloric acid (mass fraction is 37 percent, 66.02 g), the transfer speed is 20mL/min, stirring is carried out for 1h, suction filtration is carried out, off-white solid is obtained, and 400mL of methanol and water are used for volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.5% and the yield was 95.2%.
Example 9
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of ethanol (92.14 g) and concentrated sulfuric acid (with the mass fraction of 98 percent and 64.68 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.1% and the yield was 94.4%.
Example 10
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated sulfuric acid (with the mass fraction of 98 percent and 64.68 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 96.2% and the yield was 93.3%.
Example 11
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (mass fraction is 37%,55.02 g), the transfer speed is 20mL/min, stirring is carried out for 1h, suction filtration is carried out, off-white solid is obtained, and 400mL of methanol and water are used for volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 96.4% and the yield was 95.2%.
Example 12
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 77.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 95.9% and the yield was 94.1%.
Example 13
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (available chlorine 8%) (274 mL,1.0 eq) was slowly added dropwise (3.0 mL/min), and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 98.0% and the yield was 93.9%.
Example 14
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (available chlorine 8%) (417 mL,1.5 eq) was slowly added dropwise (3.0 mL/min), and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was measured to be 96.7% and the yield was 94.2%.
Example 15
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-10℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 0.5:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 96.8% and the yield was 93.2%.
Example 16
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 2:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 96.5% and the yield was 94.4%.
Example 17
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 38 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.8% and the yield was 96.0%.
Example 18
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 45 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 97.7% and the yield was 94.8%.
Comparative example 1
A1000 mL three-necked flask was taken, and then (50.00 g,1 eq) of 3-hydroxy-4-methoxybenzaldehyde was weighed and added thereto, and then 200mL of methanol was weighed and added thereto, and stirring was carried out for 20 minutes, and the raw materials were not completely dissolved, and then placed in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 87.1% and the yield was 72.2%.
Comparative example 2
A1000 mL three-necked flask was taken, and then (50.00 g,1 eq) of 3-hydroxy-4-methoxybenzaldehyde was weighed and added thereto, and then 200mL of methanol was weighed and added thereto, and stirring was carried out for 20 minutes, and the raw materials were not completely dissolved, and then placed in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (effective chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise (3.0 mL/min), and after the completion of the dropwise addition, the reaction mixture was adjusted to pH 3 with concentrated sulfuric acid, and then stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 83.2% and the yield was 74.3%.
Comparative example 3
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 5 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 42 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 81.1% and the yield was 69.6%.
Comparative example 4
A1000 mL three-necked flask was taken, 3-hydroxy-4-methoxybenzaldehyde (50.00 g,1 eq) was weighed and added thereto, 200mL of methanol was further weighed and added thereto, the pH of the mixture was adjusted to 3 with concentrated sulfuric acid, stirring was carried out for 20 minutes, the raw materials were not completely dissolved, and then the mixture was left in a low temperature environment to precipitate solids. The temperature of the system was lowered to-7℃and an aqueous sodium hypochlorite solution (3.0 mL/min) (available chlorine 8%) (334 mL,1.2 eq) was slowly added dropwise, and after the completion of the dropwise addition, the mixture was stirred at-7℃for 2 hours. After the liquid phase monitoring reaction is finished, the system is heated to 33 ℃, the reaction liquid is transferred to a mixed liquid of isopropanol (120.19 g) and concentrated hydrochloric acid (with the mass fraction of 37 percent and 66.02 g), the transfer speed is 20mL/min, the mixture is stirred for 1h and is filtered by suction, and an off-white solid is obtained by using 400mL of methanol and water with the volume ratio of 1:1, washing the mixed solution, and carrying out suction filtration to obtain the product. The purity of the liquid phase was 82.4% and the yield was 71.7%.
The foregoing description of the embodiments of the present invention has been presented in conjunction with examples, but is not intended to limit the scope of the invention. Various modifications or variations that may be made by those skilled in the art without the need for inventive faculty are within the scope of the present invention, as will be apparent to those skilled in the art based upon the teachings herein.
Claims (7)
1. A preparation method of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, which is characterized in that the preparation equation is as follows:
the preparation method comprises the following steps: adding 3-hydroxy-4-methoxybenzaldehyde into an organic solvent, regulating the pH of a reaction solution by using a pH regulator, stirring, controlling the temperature, slowly dropwise adding a sodium hypochlorite aqueous solution, stirring, regulating the temperature of a system after the reaction is finished, transferring the reaction solution to a hydrolysis mixed solution to precipitate a solid, and washing with a mixed solution of methanol and water after suction filtration to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde.
2. The method for producing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the reaction solution of the method has a pH of 2 to 4, and the pH adjustor is concentrated sulfuric acid.
3. The method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the dropwise adding rate of sodium hypochlorite aqueous solution in the preparation method is 2.5-4.0 mL/min, and the reaction temperature is-10 to-5 ℃.
4. The method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the hydrolysis mixture of the preparation method is ethanol and concentrated hydrochloric acid mixture, isopropanol and concentrated hydrochloric acid mixture, ethanol and concentrated sulfuric acid mixture, isopropanol and concentrated sulfuric acid mixture; the molar ratio of alcohol to acid in the hydrolysis mixture is 2.5-3.5: 1.
5. the method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the molar ratio of 3-hydroxy-4-methoxybenzaldehyde to sodium hypochlorite is 1:1.0 to 1.5, and the volume ratio of the methanol to the water in the post-treatment is 0.5 to 2.0:1.
6. the method for preparing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the organic solvent is methanol, isopropanol or acetic acid.
7. The process for producing 2-chloro-3-hydroxy-4-methoxybenzaldehyde according to claim 1, wherein the reaction solution is heated to 38 to 45 ℃ before being transferred to a mixture of methanol and concentrated sulfuric acid.
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