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CN-121293102-B - Synthetic method of high-purity 2-bromo-6-nitrobenzaldehyde

CN121293102BCN 121293102 BCN121293102 BCN 121293102BCN-121293102-B

Abstract

The invention discloses a method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde, which belongs to the technical field of organic synthesis, and comprises the steps of mixing 1, 2-dichloroethane and 2-bromo-6-nitrotoluene at 20-30 ℃, stirring until the mixture is dissolved, adding N-bromophthalimide and an initiator, mixing, heating to 70-100 ℃, carrying out reflux reaction, cooling to 20-30 ℃, carrying out post treatment to obtain a compound A, mixing the compound A with acetonitrile, controlling the temperature to 0-10 ℃, adding urotropine in batches, stirring at 20-40 ℃, adding acetic acid, stirring at 70-100 ℃, and carrying out post treatment to obtain 2-bromo-6-nitrobenzaldehyde.

Inventors

  • ZHU JINBO
  • WEI HAI
  • ZHANG FUJIAN
  • WANG LIANJIN
  • YUAN JINTING
  • Wei Zhaojiang
  • ZHU XIANGZUO
  • WANG GANG
  • LIU XIAOPING

Assignees

  • 寿光富康制药有限公司
  • 山东瑞康精化有限公司
  • 山东寿光博康制药有限公司
  • 山东省富康药物研发有限公司
  • 寿光永康化学工业有限公司

Dates

Publication Date
20260508
Application Date
20251210

Claims (8)

  1. 1. A method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde is characterized by mixing 1, 2-dichloroethane and 2-bromo-6-nitrotoluene at 20-30 ℃, stirring until the mixture is dissolved, adding N-bromophthalimide and an initiator, mixing, heating to 70-100 ℃, carrying out reflux reaction for 15-20h, cooling to 20-30 ℃, carrying out first post treatment to obtain a compound A, mixing the compound A with acetonitrile, controlling the temperature to 0-10 ℃, adding urotropine in batches, stirring for 10-16h at 20-40 ℃, adding acetic acid, stirring for 6-10h at 70-100 ℃, and carrying out second post treatment to obtain 2-bromo-6-nitrobenzaldehyde; The structural formula of the compound A is as follows: 。
  2. 2. the method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 1, wherein the initiator is azobisisobutyronitrile or di-t-butyl peroxide.
  3. 3. The method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 1, wherein the mass ratio of 1, 2-dichloroethane to 2-bromo-6-nitrotoluene is 170-180:30; the mass ratio of the 2-bromo-6-nitrotoluene to the N-bromophthalimide is 30:38-40; the mass ratio of the 2-bromo-6-nitrotoluene to the initiator is 30:1.8-4.3; When the temperature is raised to 70-100 ℃, the temperature raising time is 1.8-2.2h.
  4. 4. The method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 1, wherein the first post-treatment method comprises the steps of filtering, eluting a filter cake by using 1, 2-dichloroethane, collecting filtrate and leacheate, adding a saturated aqueous sodium sulfite solution, stirring, standing, separating liquid, taking an organic phase, adding water, stirring, standing, separating liquid, taking the organic phase, distilling off 1, 2-dichloromethane in vacuum, cooling to 5-10 ℃, filtering, and taking filter residues.
  5. 5. The method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 4, wherein the mass ratio of 2-bromo-6-nitrotoluene to 1, 2-dichloroethane, saturated aqueous sodium sulfite solution and water in the first post-treatment is 30:9-11:145-155:95-105; In the first post-treatment, when the 1, 2-methylene dichloride is distilled out in vacuum, the temperature of the vacuum distillation is 50-52 ℃; the mass ratio of the compound A to the acetonitrile is 40:190-200; the mass ratio of the compound A to urotropine is 40:25.5-30; the mass ratio of the compound A to the acetic acid is 40:40.5-45.
  6. 6. The method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 1, wherein when urotropine is added in batches, the urotropine is divided into 3 parts in an average, and the urotropine is added in 3 batches, and the time interval between each batch is 15-20min; When acetic acid is added, a dripping method is adopted, and the dripping time is 25-35min; in the heating process before stirring for 6-10h at 70-100 ℃, the heating speed is 18-22 ℃ per h.
  7. 7. The method for synthesizing the high-purity 2-bromo-6-nitrobenzaldehyde according to claim 1, wherein the second post-treatment method comprises the steps of distilling acetonitrile under vacuum, adding a first part of ethyl acetate and a first part of water, stirring, standing, separating liquid to obtain a primary organic phase and a primary aqueous phase, adding a second part of water into the primary organic phase, stirring, standing to obtain a secondary organic phase and a secondary aqueous phase, combining the primary aqueous phase and the secondary aqueous phase, extracting with the second part of ethyl acetate to obtain an extract, combining the extract and the secondary organic phase, adding active carbon, stirring at 23-27 ℃, filtering, taking filtrate, distilling ethyl acetate under vacuum, cooling to 38-42 ℃, dropwise adding petroleum ether, cooling to 3-7 ℃, stirring for crystallization, filtering, taking filter residues, leaching with petroleum ether, and vacuum drying.
  8. 8. The method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde according to claim 7, wherein the mass ratio of the compound A to the first part of ethyl acetate, the first part of water, the second part of ethyl acetate, the activated carbon and the petroleum ether in the second post-treatment is 40:88-92:125-135:88-92:125-135:3.8-4.2:260-280; when petroleum ether is added dropwise, the adding time is 2-2.5h; stirring at 23-27 ℃ for 1-1.5h; when acetonitrile is distilled off in vacuum, the temperature of the vacuum distillation is 55-57 ℃; when ethyl acetate is distilled off in vacuum, the temperature of the vacuum distillation is 50-52 ℃; stirring and crystallizing for 2-2.5h; The drying is vacuum drying, the temperature of the vacuum drying is 50-55 ℃ and the time is 6-6.5h.

Description

Synthetic method of high-purity 2-bromo-6-nitrobenzaldehyde Technical Field The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing high-purity 2-bromo-6-nitrobenzaldehyde. Background 2-Bromo-6-nitrobenzaldehyde (2-Bromo-6-nitrobenzaldehyde) is an aromatic compound with important functional groups (aldehyde group, bromine and nitro group), so that the compound becomes a multifunctional high-reactivity synthetic block, and is an important organic synthetic intermediate. The core application of the compound is as a key intermediate for constructing molecules with more complex structures, and particularly plays an extremely important role in the fields of medicinal chemistry and material science. In the field of medicine, the compound can be used as a key intermediate for synthesizing sedative fluorobromoazepam and positional isomers thereof, can also be used as a starting material for synthesizing non-natural C-nucleoside analogues (such as 2-aminoquinazoline C-nucleoside), and the nitro and aldehyde groups in the structure are very suitable for constructing nitrogen-containing heterocycles such as quinoline, quinazoline, acridine and the like through cyclization reaction, and the heterocycles are core structures of a plurality of drug molecules, so that the compound plays a vital role in a plurality of treatment fields such as anti-infection, anti-cancer, cardiovascular diseases, nervous system diseases and the like, and in the aspect of organic functional materials, the molecular structure can be used as an aromatic skeleton unit for constructing organic semiconductors, fluorescent molecules or liquid crystal materials, so that the performance of the materials can be obviously improved, such as stability, conductivity and the like of the materials. With the research and development of novel medicines and the development of multifunctional materials, the market prospect of using 2-bromo-6-nitrobenzaldehyde as a key intermediate is better. At present, the synthesis method of 2-bromo-6-nitrobenzaldehyde is reported to be mainly used as a main intermediate synthesis next product .Design of Triple Helix Forming C-Glycoside Molecules;Jian-Sen Li,Yun-HuaFan,Yi Zhang,Luis A.Marky,Barry Gold;Journal of the American Chemical Society;2003,125(8):2084-2093, 2-bromo-6-nitrobenzaldehyde is synthesized by a three-step method, 2-bromo-6-nitrotoluene is used as a starting material, a bromine simple substance is used as a reagent, heating is carried out for 2 hours at the oil bath temperature of 145-150 ℃, simultaneously 800W sun lamps are used for irradiation, then the irradiation is continued for 2 hours to generate a brominated product, N-dimethyl-p-nitrosoaniline and NaOH are added into ethanol from the brominated product, nitrone is generated by reaction, and then the brominated product is heated and hydrolyzed with concentrated sulfuric acid in a boiling water bath to synthesize a final product. In the reaction, bromine is a second type of easy-to-poison chemical which is unfavorable for the health of personnel, the bromine needs to react with liquid bromine at a temperature of more than 145 ℃, has extremely strong corrosion to equipment, is extremely toxic to bromine steam and dangerous to operate, uses a 800W solar lamp for illumination reaction, has the problems of uniform irradiation and temperature control during industrial amplification, and finally hydrolyzes in concentrated sulfuric acid, and the final step needs a large amount of water for washing after treatment, so that bromine-containing byproducts, nitrogen-containing organic matters and acid wastewater are generated in the reaction, the treatment difficulty is high, the environmental protection cost is high, and therefore, the method is not suitable for direct industrial production. Chinese patent CN108484623B discloses camptothecin derivatives, a preparation method and application thereof, and in the patent, it is mentioned that o-nitrobenzaldehyde and N-bromosuccinimide are subjected to free radical substitution reaction in concentrated sulfuric acid under the condition of illumination (40-45 ℃) to generate brominated o-nitrobenzaldehyde. The reaction is a free radical reaction under illumination, the reaction efficiency is possibly sensitive to the wavelength and the intensity of a light source, the challenges of reproducibility and uniformity can exist during industrialized amplification, the purity of the product is more than or equal to 98%, and the quality requirement of the production of the downstream high-end bulk drug is not met. Diels-Alder approach to polysubstituted biaryls:rapid entry to tri- and tetra-ortho-substituted phosphorus-containingbiaryls;Bradley O.Ashburn,Rich G.Carter Prof;Angewandte Chemie;2007 And Synthesis of Tetra-ortho-substituted,Phosphorus-Containing and Carbonyl-Containing Biaryls Utilizing a Diels−AlderApproach;Bradley O.Ashburn,Rich G.Carter,Lev N.Zakharov;Journal o