CN114507142A - Preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde - Google Patents
Preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde Download PDFInfo
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- CN114507142A CN114507142A CN202210109158.7A CN202210109158A CN114507142A CN 114507142 A CN114507142 A CN 114507142A CN 202210109158 A CN202210109158 A CN 202210109158A CN 114507142 A CN114507142 A CN 114507142A
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- HNOIAPRHNXBCAE-UHFFFAOYSA-N 2-chloro-4-fluoro-5-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=C(Cl)C=C1F HNOIAPRHNXBCAE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 238000006396 nitration reaction Methods 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims abstract description 15
- CSARJIQZOSVYHA-UHFFFAOYSA-N 2-chloro-4-fluoro-1-methylbenzene Chemical compound CC1=CC=C(F)C=C1Cl CSARJIQZOSVYHA-UHFFFAOYSA-N 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000010333 potassium nitrate Nutrition 0.000 claims abstract description 12
- 239000004323 potassium nitrate Substances 0.000 claims abstract description 12
- 239000004342 Benzoyl peroxide Substances 0.000 claims abstract description 8
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000019400 benzoyl peroxide Nutrition 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 11
- 239000005457 ice water Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- -1 2-chloro-4-fluoro-5-nitro bromotoluene Chemical compound 0.000 claims description 5
- 229910002651 NO3 Inorganic materials 0.000 claims description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- YXVJHZWHPLOEAP-UHFFFAOYSA-N 1-chloro-5-fluoro-2-methyl-4-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=C(F)C=C1Cl YXVJHZWHPLOEAP-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 229910001963 alkali metal nitrate Inorganic materials 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 22
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 239000012024 dehydrating agents Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 23
- 238000004809 thin layer chromatography Methods 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- 125000003172 aldehyde group Chemical group 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 3
- 230000000802 nitrating effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- KMQWNQKESAHDKD-UHFFFAOYSA-N 2-chloro-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Cl)=C1 KMQWNQKESAHDKD-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention discloses a preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde, which comprises the following steps: carrying out nitration reaction on 2-chloro-4-fluorotoluene serving as a starting raw material, 1, 2-dichloroethane serving as a solvent and concentrated sulfuric acid serving as a dehydrating agent and potassium nitrate to obtain a compound a; then NBS is used as a brominating agent, 1, 2-dichloroethane is used as a solvent, and the compound a undergoes a bromination reaction in the presence of benzoyl peroxide to generate a compound b; and finally, heating the mixture in the presence of hydrogen peroxide by using ethanol as a solvent to perform hydrolysis and oxidation reaction on the compound b to obtain the product 2-chloro-4-fluoro-5-nitrobenzaldehyde.
Description
Technical Field
The invention relates to the technical field of fine chemical synthesis, in particular to a preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde.
Background
2-chloro-4-fluoro-5-nitrobenzaldehyde is an important organic intermediate, is used for synthesizing medicines and pesticides, such as agricultural herbicide-tetrahydro-phthalimide compound containing isoroline, aryl tetrahydro-phthalimide and the like, and has good market prospect.
Currently, in the reports on the synthesis method of 2-chloro-4-fluoro-5-nitrobenzaldehyde, the most common process is to use 2-chloro-4-fluorotoluene as a starting material, firstly carry out halogenation reaction to generate 2-chloro-4-fluorohalotoluene, then hydrolyze to generate 2-chloro-4-fluorobenzaldehyde, and finally carry out nitration reaction to obtain the target product 2-chloro-4-fluoro-5-nitrobenzaldehyde. In the halogenation stage, the bromination can be carried out in the presence of benzoyl peroxide, using NBS as brominating agent (patent US 4846875); there is also a method (patent JPS60152465) in which bromine is directly used and azobisisobutyronitrile is used as a catalyst for reaction, but the price is relatively expensive; in fuqiang et al (patent CN111848406), a photocatalytic chlorination method is adopted, which not only needs to perform a reaction in a high-pressure ultraviolet box, but also easily generates a byproduct hydrogen chloride gas. After halogenation, the aldehyde group is hydrolyzed to generate aldehyde, and during the subsequent nitration reaction, the aldehyde group is inevitably partially oxidized to carboxylic acid due to the oxidizing property of nitric acid, so that the yield is reduced. In the nitration stage, a mixed acid solution of concentrated sulfuric acid and fuming nitric acid is basically prepared, acid mist generated when the concentrated nitric acid is used pollutes the experimental environment, certain potential safety hazards exist, and in order to dissolve reactants, the use amount of sulfuric acid needs to be increased, so that the cost is increased.
Disclosure of Invention
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.
One of ordinary skill in the art will understand "about" or "approximately" and will vary somewhat in the context in which the term is used. If the use of a term is not clear to one of ordinary skill in the art, in view of the context in which it is used, "about" or "approximately" will mean up to plus or minus 20% of the particular term.
The term "and/or" when used to connect two or more selectable items should be understood to mean any one of the selectable items or any two or more of the selectable items.
As used herein, the terms "comprises" or "comprising" are intended to cover the recited elements, integers or steps, but not to exclude any other elements, integers or steps. When the term "comprising" or "includes" is used herein, unless otherwise specified, it also encompasses the presence of stated elements, integers or steps. For example, when reference is made to "comprising" or "including" a particular ingredient, it is also intended to encompass mixtures consisting of that particular ingredient.
As used herein, "consisting essentially of … …" means that the major component of the mixture is made up. Unless otherwise specified, a content of more than 50% by weight is usually referred to as a main component. The principal components may be pure or may be composed of a mixture of a class of compounds having similar structural or chemical properties, which one skilled in the art would know can generally be classified as a class.
Any reference herein to temperature ranges, pH ranges, weight (mass) ranges, molecular weight ranges, percentage ranges, and the like, whether expressed using the phrases "range" or "respective ranges," includes the endpoints specified, as well as points between the endpoints.
In order to solve various defects in the method for synthesizing the 2-chloro-4-fluoro-5-nitrobenzaldehyde by taking the 2-chloro-4-fluorotoluene as the starting material through reaction, the invention discloses a novel preparation process of the 2-chloro-4-fluoro-5-nitrobenzaldehyde, which avoids aldehyde groups from being oxidized in the nitration process, reduces the use amount of concentrated sulfuric acid in the nitration stage and saves the preparation cost.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde comprises the following steps:
(1) nitration reaction
Dissolving 2-chloro-4-fluorotoluene in a first organic solvent, slowly adding concentrated sulfuric acid, and cooling to about 0 ℃. And adding nitrate into the reaction system, controlling the temperature to be about 0-10 ℃, stirring and reacting for about 4 hours, and preferably tracking the reaction through Thin Layer Chromatography (TLC). After the reaction is completed, the reaction solution is added to cold water (preferably an ice-water mixture), stirred, allowed to stand, and separated. The aqueous phase after separation is extracted once or several times with a second organic solvent (preferably dichloromethane, the same solvent as the first organic solvent may be used), and the extracted organic phases are combined. The combined organic phases extracted above are washed, preferably with a saturated aqueous sodium bicarbonate solution, more preferably further washed with water and then with a saturated aqueous sodium chloride solution. Finally, drying is carried out, preferably by using anhydrous sodium sulfate, and concentration is carried out to obtain the compound a (namely, the 2-chloro-4-fluoro-5-nitrotoluene).
In one or more embodiments, the first organic solvent is preferably a halogenated hydrocarbon or an aromatic solvent, more preferably dichloromethane or 1, 2-dichloroethane or nitrobenzene, etc., and most preferably 1, 2-dichloroethane.
In one or more embodiments thereof, the nitrate salt is preferably an alkali metal nitrate; further preferably potassium nitrate, sodium nitrate, or the like; more preferably potassium nitrate.
(2) Bromination reaction
Dissolving the compound a in a third organic solvent, adding N-bromosuccinimide (NBS) and benzoyl peroxide, heating to about 80-100 ℃ for reacting for about 20 hours, and preferably tracking the reaction by TLC. And cooling to room temperature after the reaction is finished, adding the reaction solution into the washing solution, stirring for about 30min, standing, and separating. The organic phase after separation is washed, preferably with water, and then with saturated sodium chloride. Finally, the mixture is dried by anhydrous sodium sulfate and concentrated to obtain a compound b (namely 2-chloro-4-fluoro-5-nitro bromotoluene).
In one or more embodiments, the third organic solvent is preferably a halogenated hydrocarbon solvent, more preferably 1, 2-dichloroethane or chloroform or carbon tetrachloride, etc., and most preferably 1, 2-dichloroethane.
In one or more embodiments thereof, the washing solution is preferably a saturated aqueous sodium sulfite solution or sodium bicarbonate or sodium thiosulfate solution, and more preferably a saturated aqueous sodium sulfite solution.
(3) Hydrolysis reaction
The compound b is dissolved in a fourth organic solvent (preferably an organic solvent which is easily soluble in water such as methanol or ethanol, and more preferably ethanol), hydrogen peroxide (preferably about 15% aqueous hydrogen peroxide) is added thereto, and the reaction is carried out at an elevated temperature under reflux for about 15 hours, preferably by follow-up reaction by TLC. After the reaction is completed, the temperature is lowered to room temperature, and the reaction solution is added to a washing solution (preferably a saturated aqueous solution of sodium sulfite or sodium thiosulfate, and more preferably a saturated aqueous solution of sodium sulfite), stirred for about 30min, allowed to stand, and subjected to liquid separation. The aqueous phase after separation was extracted with ethyl acetate, and the organic phases were combined (the organic phase after extraction and the organic phase after separation were combined). Washing the organic phase (preferably with water and then with saturated sodium chloride), drying (preferably with anhydrous sodium sulfate), and concentrating to obtain the target product 2-chloro-4-fluoro-5-nitrobenzaldehyde.
Further, the molar ratio of the 2-chloro-4-fluorotoluene to the concentrated sulfuric acid to the potassium nitrate in the step (1) is 1: 7-10: 1.25-1.5.
Further, the molar ratio of the compound a to NBS to benzoyl peroxide in the step (2) is 1: 1.3-1.5: 0.012-0.015.
Further, the molar ratio of the compound b to the hydrogen peroxide in the step (3) is 1: 1.5-2.
Further, the volume ratio of the TLC developing agent petroleum ether to ethyl acetate in the steps (1) (2) (3) is about 3: 1.
Compared with the prior three-step reaction synthesis method technology taking 2-chloro-4-fluorotoluene as the starting material, the invention has the following advantages and beneficial effects:
according to the preparation process of the 2-chloro-4-fluoro-5-nitrobenzaldehyde, in the reaction sequence, the nitration is carried out firstly, then the hydrolysis is carried out, and the aldehyde group is generated in the last step, so that the reduction of the yield caused by partial oxidation of the aldehyde group caused by the nitration is avoided; the nitration reaction adopts a mode of nitration in an organic solvent 1, 2-dichloroethane, and avoids using a large amount of sulfuric acid as a solvent. The method has the advantages that potassium nitrate is used as a nitrating agent instead of fuming nitric acid, the nitrating agent is safer and cleaner in use, the dosage proportion of the 2-chloro-4-fluorotoluene, the concentrated sulfuric acid and the potassium nitrate is optimized, and the problem that the amount of salifying sulfuric acid is increased due to excessive dosage, so that the nitration promoting capability of the nitrating agent is weakened is solved. The preparation process of the invention not only reduces the preparation cost, but also greatly improves the yield of nitration and hydrolysis reaction, has less by-products and simple operation, and is more suitable for industrial production.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1
Nitration reaction: 100ml of methylene chloride was charged into a three-necked flask, 28.91g (0.20mol) of 2-chloro-4-fluorotoluene was added thereto to dissolve the methylene chloride, and 40ml (0.74mol) of 98% concentrated sulfuric acid was slowly added thereto to cool the mixture to 0 ℃. Then 20.22g (0.20mol) of potassium nitrate is added into the reaction system, the temperature is controlled to be 0-10 ℃, the reaction is stirred for 4 hours, and the reaction is followed by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was poured into an ice-water mixture, stirred, allowed to stand, and separated. The aqueous phase was extracted 2 times with dichloromethane and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then washed with water and then with saturated aqueous sodium chloride solution. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 15.52g of a compound a in 53.7% yield.
Example 2
Nitration reaction: 100ml of 1, 2-dichloroethane was charged into a three-necked flask, 28.91g (0.20mol) of 2-chloro-4-fluorotoluene was added thereto and dissolved, and 76ml (1.40mol) of 98% concentrated sulfuric acid was slowly added thereto and the temperature was lowered to 0 ℃. Then 20.22g (0.20mol) of potassium nitrate is added into the reaction system, the temperature is controlled to be 0-10 ℃, the reaction is stirred for 4 hours, and the reaction is followed by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was poured into an ice-water mixture, stirred, allowed to stand, and separated. The aqueous phase was extracted 2 times with dichloromethane and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then washed with water and then with saturated aqueous sodium chloride solution. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 23.88g of a compound a in 82.6% yield.
Example 3
Nitration reaction: 100ml of 1, 2-dichloroethane was charged into a three-necked flask, 28.91g (0.20mol) of 2-chloro-4-fluorotoluene was added thereto and dissolved, and 108ml (2.00mol) of 98% concentrated sulfuric acid was slowly added thereto and the temperature was lowered to 0 ℃. Then 20.22g (0.20mol) of potassium nitrate is added into the reaction system, the temperature is controlled to be 0-10 ℃, the reaction is stirred for 4 hours, and the reaction is followed by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was poured into an ice-water mixture, stirred, allowed to stand, and separated. The aqueous phase was extracted 2 times with dichloromethane and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then washed with water and then with saturated aqueous sodium chloride solution. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 21.80g of a compound a in a yield of 75.4%.
Example 4
Nitration reaction: 100ml of 1, 2-dichloroethane was charged into a three-necked flask, 28.91g (0.20mol) of 2-chloro-4-fluorotoluene was added thereto and dissolved, and 76ml (1.40mol) of 98% concentrated sulfuric acid was slowly added thereto and the temperature was lowered to 0 ℃. Then 25.28g (0.25mol) of potassium nitrate is added into the reaction system, the temperature is controlled to be 0-10 ℃, the reaction is stirred for 4 hours, and the reaction is followed by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was poured into an ice-water mixture, stirred, allowed to stand, and separated. The aqueous phase was extracted 2 times with dichloromethane and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then washed with water and then with saturated aqueous sodium chloride solution. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 27.26g of a compound a in a yield of 94.3%.
Example 5
Nitration reaction: 100ml of 1, 2-dichloroethane was charged into a three-necked flask, 28.91g (0.20mol) of 2-chloro-4-fluorotoluene was added thereto and dissolved, and 76ml (1.40mol) of 98% concentrated sulfuric acid was slowly added thereto and the temperature was lowered to 0 ℃. 30.33g (0.30mol) of potassium nitrate is added into the reaction system, the temperature is controlled to be 0-10 ℃, the reaction is stirred for 4 hours, and the reaction is followed by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was poured into an ice-water mixture, stirred, allowed to stand, and separated. The aqueous phase was extracted 2 times with dichloromethane and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then washed with water and then with saturated aqueous sodium chloride solution. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 24.63g of a compound a in 85.2% yield.
Example 6
Bromination reaction: 37.91g (0.20mol) of the compound a is dissolved in 100ml of 1, 2-dichloroethane, 46.27g (0.26mol) of NBS and 0.58g (2.4mmol) of benzoyl peroxide are added, the temperature is raised to 80-100 ℃ for reaction for 20h, and the reaction is followed by TLC. Then, the reaction solution was cooled to room temperature, added to 100ml of a saturated aqueous sodium sulfite solution, stirred for 30min, allowed to stand, and separated. The organic phase was washed with water and then with saturated sodium chloride. Finally, the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 32.90g of a compound b in 86.8% yield.
Example 7
Bromination reaction: 37.91g (0.20mol) of the compound a is dissolved in 100ml of 1, 2-dichloroethane, 53.39g (0.30mol) of NBS and 0.73g (3.0mmol) of benzoyl peroxide are added, the temperature is raised to 80-100 ℃ for reaction for 20h, and the reaction is followed by TLC. Then, the reaction solution was cooled to room temperature, added to 100ml of a saturated aqueous sodium sulfite solution, stirred for 30min, allowed to stand, and separated. The organic phase was washed with water and then with saturated sodium chloride. Finally, the reaction mixture was dried over anhydrous sodium sulfate and concentrated to obtain 31.73g of a compound b in 83.7% yield.
Example 8
And (3) hydrolysis reaction: 26.85g (0.10mol) of Compound b was dissolved in 150ml of ethanol, 30ml (0.15mol) of 15% aqueous hydrogen peroxide was added thereto, and the reaction was followed by TLC after refluxing at elevated temperature for 15 hours. The temperature is reduced to room temperature, the reaction solution is added into 100ml of saturated sodium sulfite aqueous solution, and the mixture is stirred for 30 min. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The organic phase is washed by water, then washed by saturated sodium chloride, finally dried by anhydrous sodium sulfate and concentrated to obtain the target product 2-chloro-4-fluoro-5-nitrobenzaldehyde 24.54g with the yield of 91.4%.
Example 9
And (3) hydrolysis reaction: 26.85g (0.10mol) of Compound b was dissolved in 150ml of ethanol, 40ml (0.20mol) of 15% aqueous hydrogen peroxide was added thereto, and the reaction was followed by TLC after refluxing at elevated temperature for 15 hours. The temperature is reduced to room temperature, the reaction solution is added into 100ml of saturated sodium sulfite aqueous solution, and the mixture is stirred for 30 min. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The organic phase is washed by water, washed by saturated sodium chloride, dried by anhydrous sodium sulfate and concentrated to obtain 23.52g of the target product 2-chloro-4-fluoro-5-nitrobenzaldehyde with the yield of 87.6 percent.
The total yield of examples 4, 6 and 8 is 74.8%.
The above examples are only preferred embodiments of the present invention, and should not be construed as limiting the scope of the present invention. Any improvement or equivalent replacement made by the technical solution of the present invention without departing from the principle of the present invention shall be covered within the protection scope of the present invention.
Claims (10)
1. A preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde is characterized by comprising the following steps:
(1) nitration reaction
Dissolving 2-chloro-4-fluorotoluene in a first organic solvent, adding concentrated sulfuric acid, and cooling; adding nitrate, stirring and reacting, and controlling the reaction temperature to be below 10 ℃; adding the reaction solution into the ice-water mixture after the reaction is finished, stirring, standing, separating, washing, drying and concentrating to obtain 2-chloro-4-fluoro-5-nitrotoluene;
(2) bromination reaction
Dissolving 2-chloro-4-fluoro-5-nitrotoluene in a third organic solvent, adding N-bromosuccinimide and benzoyl peroxide, and heating to 80-100 ℃ for reaction; cooling to room temperature after the reaction is finished, adding the reaction solution into a washing solution, stirring, standing, separating, washing, drying and concentrating to obtain 2-chloro-4-fluoro-5-nitro bromotoluene;
(3) hydrolysis reaction
Dissolving 2-chloro-4-fluoro-5-nitro bromotoluene in a fourth organic solvent, adding hydrogen peroxide, heating to react under a reflux condition, cooling to room temperature after the reaction is finished, adding the reaction liquid into a washing liquid, stirring, standing, separating, washing, drying and concentrating to obtain the target product 2-chloro-4-fluoro-5-nitrobenzaldehyde.
2. The process for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1, wherein said first organic solvent is selected from one or more of halogenated hydrocarbon and aromatic solvent; the nitrate is alkali metal nitrate; the third organic solvent is a halogenated hydrocarbon solvent; the fourth organic solvent is an organic solvent which is easy to dissolve in water; the washing solution is a saline solution.
3. The preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1 or 2, wherein the molar ratio of 2-chloro-4-fluorotoluene to concentrated sulfuric acid to nitrate in step (1) is 1:7 to 10:1.25 to 1.5.
4. The preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1 or 2, wherein the molar ratio of 2-chloro-4-fluoro-5-nitrotoluene to N-bromosuccinimide to benzoyl peroxide in step (2) is 1:1.3 to 1.5:0.012 to 0.015.
5. The preparation process of 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1 or 2, wherein the molar ratio of 2-chloro-4-fluoro-5-nitro bromotoluene to hydrogen peroxide in step (3) is 1: 1.5-2.
6. The process for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 1 or 2, wherein the completion of the reaction in steps (1) (2) (3) is followed by TLC using a developing solvent selected from the group consisting of petroleum ether and ethyl acetate at a volume ratio of petroleum ether to ethyl acetate of 3: 1.
7. The process for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 2, wherein the first organic solvent is one or more selected from dichloromethane, 1, 2-dichloroethane and nitrobenzene.
8. The process for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to claim 2, wherein said nitrate is potassium nitrate.
9. The process according to claim 2, wherein the third organic solvent is one or more selected from the group consisting of 1, 2-dichloroethane, chloroform and carbon tetrachloride.
10. The process for preparing 2-chloro-4-fluoro-5-nitrobenzaldehyde according to any of claims 7 to 9, wherein the fourth organic solvent is selected from one or more of methanol and ethanol; the washing solution is saturated sodium sulfite or saturated sodium bicarbonate or saturated sodium thiosulfate aqueous solution.
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