Background and overview[1][2]
4-Bromochlorobenzene, also known as p-bromochlorobenzene in Chinese, can be used as a pharmaceutical and chemical synthesis intermediate. If parachlorobromobenzene is inhaled, please move the patient to fresh air; if the skin comes into contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical treatment if you feel uncomfortable; if the eyes come into contact, separate Rinse the eyelids with running water or saline and seek medical attention immediately. If ingested, rinse mouth immediately. Do not induce vomiting and seek medical attention immediately.
Apply[1-4]
P-Bromochlorobenzene can be used as an intermediate for pharmaceutical and chemical synthesis. Examples of its application are as follows:
1. Synthesis of p-chlorophenylhydrazine hydrochloride.
P-Chlorophenylhydrazine, with the molecular formula C6H7ClN2, is an important synthetic intermediate for pyraclostrobin. It is obtained by diazotization, sodium bisulfite reduction and hydrolysis of p-chloroaniline, and this method has been used for a long time. The synthesis method includes the following steps: using p-bromochlorobenzene and hydrazine hydrate as reaction raw materials, adding a phase transfer catalyst, a solvent, and a catalyst to carry out the reaction; after the reaction is completed, the solid is separated by filtration, and the filtrate is distilled to remove the solvent; and the residue obtained by distillation is added to Add hydrochloric acid, stir and filter; wash the filter residue with water and dry it to obtain p-chlorophenylhydrazine hydrochloride.
In order to solve the large amount of wastewater problem caused by the currently commonly used diazotization and reductive acidification method of prochloroaniline, p-bromochlorobenzene and hydrazine hydrate are used as reaction raw materials, and phase transfer catalysts, solvents, and catalysts are added to carry out the reaction. , the reaction steps are simple, greatly reducing the amount of wastewater generated during the synthesis of p-chlorophenylhydrazine, and avoiding the reduction of sodium sulfite to produce sulfur dioxide. Excess hydrazine hydrate and solvent can be recycled and reused after the reaction of this method, which is green and environmentally friendly.
2. Synthesis of pyraclostrobin intermediate 1-(4-chlorophenyl)-3-pyrazolin.
Pyrazole compounds are a class of nitrogen-containing heterocyclic compounds with broad-spectrum biological activity and good insecticidal activity. Among them, 1-(4-chlorophenyl)-3-pyrazoles are the pesticide pyrazoles. An important intermediate of pyraclostrobin, it is mentioned in “Pesticide Science and Management” that 1-(4-chlorophenyl)-3-pyrazolin is synthesized from p-chlorophenylhydrazine through cyclization and chlorination. , under optimal conditions, the total yield of 1-(4-chlorophenyl)-3-pyrazolinol synthesis can be achieved is 68.35%, and the content is 98.5%.
The specific synthesis method is to use p-bromochlorobenzene and hydrazine hydrate as reaction raw materials, add a phase transfer catalyst, solvent, and catalyst to react to prepare p-chlorophenylhydrazine hydrochloride; use the above-mentioned p-chlorophenylhydrazine hydrochloride and alkali , sodium alkoxide and acrylate reaction, in the presence of toluene, a toluene solution of the intermediate pyrazolone is obtained; after removing toluene from the above toluene solution, adding alkali and hydrogen peroxide for oxidation, 1-(4-chlorobenzene is obtained base)-3-pyrazolinol.
The above synthesis method uses p-bromochlorobenzene and hydrazine hydrate to prepare p-chlorophenylhydrazine hydrochloride, which can greatly reduce the amount of wastewater generated during the synthesis process, avoid the use of sulfite reducing agent and a large amount of acid, and avoid the entire process It can eliminate the generation of harmful substances and realize green production. It can achieve 1-(4-chlorophenyl)-3-pyrazole alcohol HPLC content ≥98% and yield ≥90%.
3. Synthetic hormone drug intermediate 9(11)-pregnene-16β-methyl-17α, 21-diol-3,20-dione-21-acetate.
9(11)-Pregnantrol-16β-methyl-17α, 21-diol-3,20-dione-21-acetate is used as a hormone drug intermediate, mainly used in the synthesis of betamethasone drugs . Betamethasone is a hormonal drug. Mainly used for anti-inflammation and anti-allergy. Suitable for rheumatoid arthritis and various skin diseases. Betamethasone has the same effect as dexamethasone. Its anti-inflammatory effect is stronger than dexamethasone, triamcinolone, and hydrocortisone, and it has fewer side effects.
Most of the existing synthesis methods use sodium dichromate solution and sulfuric acid solution as reactants. Since sodium dichromate solution pollutes the environment greatly, it is not suitable for large-scale industrial production. Using sulfuric acid solution as a reactant will cause the reaction process to The degree of danger increases, and the entire synthesis process is relatively complex, so it is necessary to propose a new synthesis method.
There is research to develop a new synthesis method, which includes the following steps: adding 2-chloro-4-hydroxy-9(11)-pregnantene-16β-methyl-3β, 17α, 21- Triol-20-keto-21-acetate, potassium chloride solution, 2-methylpyridine solution, lower the solution temperature, control the stirring speed, and continue the reaction; add diisobutylamine solution, increase the solution temperature, react, and add Antimonide hydrogen powder, raise the temperature, react, let stand, filter, obtain crystals, wash with sodium nitrate solution, benzonitrile solution, p-bromochlorobenzene solution, recrystallize in diethylene glycol dibutyl ester solution, dehydrate The agent is dehydrated to obtain the finished product 9(11)-pregnantene-16β-methyl-17α, 21-diol-3,20-dione-21-acetate.
4. Preparation of 1-(4-chlorophenyl)-3-pyrazolinol.
Most of the previous synthesis methods of 1-(4-chlorophenyl)-3-pyrazolinol first synthesized p-chlorophenylhydrazine hydrochloride through p-chloroaniline, and then synthesized 1-(4 -Chlorophenyl)pyrazolidin-3-one, and finally reacts with potassium hydroxide solution to form the final product. However, p-chlorophenylhydrazine hydrochloride is usually obtained by diazotization of p-chloroaniline, reduction with sodium bisulfite, and hydrolysis. During its production process, a large amount of acid and sulfite will be used, and a huge amount of wastewater will be generated; There are potential safety hazards in the diazotization and reduction processes. The concentration of diazonium salts cannot be high, otherwise it will increase the dangerous performance of production. The sulfite used in the reduction process will have by-productsSulfur oxide gas is generated. With the increasing awareness of environmental protection and green production in recent years, and the increasing safety requirements, the problems of safety and three wastes have become the problem of using this method to prepare 1-(4-chlorophenyl)-3-pyridine. The maximum limiting conditions for azole alcohol.
Use hydrazine hydrate and acrylate as raw materials to synthesize pyrazole-3-one, and then oxidize it to pyrazole alcohol. Finally, react pyrazole alcohol with p-bromochlorobenzene to generate 1-(4-chlorophenyl)-3-pyrazole Azole alcohol. Compared with the traditional diazotization method, the above-mentioned preparation method avoids the use of a large amount of acid and sulfite. No harmful gases are generated during the entire preparation process, significantly reducing waste gas emissions; and there is no diazotization reaction in this reaction process. The reaction is mild and safer; before synthesizing 1-(4-chlorophenyl)-3-pyrazolone, the reaction solution is refluxed and water-divided to control the moisture content of the reaction solution, which can reduce the generation of waste water; chlorination Iron serves as a catalyst and can be returned to the reaction system for reuse after simple treatment after the reaction. The above synthesis method reduces the emission of three wastes, improves the safety of the reaction, and has good industrial application value.
Preparation [1]
Originated from bromination of chlorobenzene. Heat chlorobenzene and iron powder to 80°C, add bromine dropwise, and react at 90-100°C for 2.5 hours. After cooling slightly, put it into water, filter and wash, and the crude product is recrystallized with ethanol to obtain the finished product.
Main reference materials
[1] CN201610396824.4 A synthesis method of p-chlorophenylhydrazine hydrochloride
[2] CN201610396823.X A method for synthesizing pyraclostrobin intermediate 1-(4-chlorophenyl)-3-pyrazolin
[3] CN201710527036.9 Synthesis method of hormone drug intermediate 9(11)-pregnantene-16β-methyl-17α, 21-diol-3,20-dione-21-acetate
[4] CN201810578006.5 A preparation method of 1-(4-chlorophenyl)-3-pyrazole alcohol
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