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Preparation method of 4-chloro-3-nitroanisole

A technology of nitroanisole and nitrophenol is applied in the field of preparation of 4-chloro-3-nitroanisole, and can solve the problems of difficulty in treating cuprous chloride wastewater, large environmental pollution, potential safety hazards and the like , to achieve the effect of simple and easy operation, improved yield and high economical practicability

Pending Publication Date: 2022-07-05
常州佳德医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method uses 4-amino-3-nitroanisole (also known as bay red base GP) as the starting material to prepare 4-chloro-3-nitroanisole, bay red base GP through diazotization hydrolysis reaction. It is highly toxic, and the diazotization reaction is a high-risk reaction. There are major safety hazards in this reaction process. Once improperly operated, it will cause irreversible production safety accidents; Difficulty, environmental pollution and other problems

Method used

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  • Preparation method of 4-chloro-3-nitroanisole
  • Preparation method of 4-chloro-3-nitroanisole
  • Preparation method of 4-chloro-3-nitroanisole

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Embodiment 1

[0021] 4-Chloro-3-nitroanisole is prepared by the method of the present invention, and the reaction process is shown in the appendix figure 1 , the specific operation steps are as follows:

[0022] Step S1: put (10g, 0.0781mol) p-chlorophenol, (12.3g, 0.0781mol) 2-bromopyridine, (24.8g, 0.1171mol) potassium phosphate), 50ml dimethyl sulfoxide into a three-necked flask, stir and mix And heat up to 100 ℃, keep the reaction for 16h, after the reaction, cool down to room temperature, filter and separate out the insoluble solid, the filtrate is black and clear; the filtrate is added dropwise to 200ml of water, and no solid precipitation is observed after the dropwise addition; then, the reaction mixture is Extract with dichloromethane and concentrate the organic phase to dryness under reduced pressure to give 14.71 g of product. HPLC results showed that the percentage content of 2-(4-chlorophenoxy)pyridine in the product was 98.76%, and the molar yield was 91.9% (calculated as p-c...

Embodiment 2

[0027]Step S1: put (10g, 0.0781mol) p-chlorophenol, (12.3g, 0.0781mol) 2-bromopyridine, (16.5g, 0.0781mol) potassium phosphate), 50ml dimethyl sulfoxide into a three-necked flask, stir and mix The temperature was raised to 80°C, and the reaction was kept for 24 hours. After the reaction was completed, the temperature was lowered to normal temperature. The insoluble solid was removed by filtration and separation. Extract with dichloromethane and concentrate the organic phase to dryness under reduced pressure to give 12.34 g of product. HPLC results showed that the percentage content of 2-(4-chlorophenoxy)pyridine in the product was 98.21%, and the molar yield was 77% (calculated as p-chlorophenol).

[0028] Step S2: put (22.68g, 0.234mol) 65wt% nitric acid into the three-necked flask, freeze and cool down to 0°C, slowly add (11.47g, 0.117mol) concentrated sulfuric acid dropwise to the reaction solution, there is obvious exothermic phenomenon, add dropwise Finished adding (12g,...

Embodiment 3

[0032] Step S1: put (10g, 0.0781mol) p-chlorophenol, (24.6g, 0.1562mol) 2-bromopyridine, (49.5g, 0.2343mol) potassium phosphate), 100ml dimethyl sulfoxide into a three-necked flask, stir and mix The temperature was raised to 120°C, and the reaction was kept for 16 hours. After the reaction was completed, the temperature was lowered to room temperature. The insoluble solid was removed by filtration and separation. Extract with dichloromethane, and concentrate the organic phase to dryness under reduced pressure to obtain 15.23 g of product. HPLC results showed that the percentage content of 2-(4-chlorophenoxy)pyridine in the product was 98.21%, and the molar yield was 95% (calculated as p-chlorophenol).

[0033] Step S2: put (34.02g, 0.351mol) 65wt% nitric acid in a three-necked flask, freeze and cool down to 0°C, slowly add (22.94g, 0.234mol) concentrated sulfuric acid dropwise to the reaction solution, there is obvious exothermic phenomenon, add dropwise Finished adding (12g,...

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Abstract

The invention discloses a preparation method of 4-chloro-3-nitroanisole, raw materials involved in each step do not belong to highly toxic products, the reaction safety involved in each step is high, the whole operation is simple and easy to implement, a scientific research foundation is laid for batch production of 4-chloro-3-nitroanisole, and the economic practicability is high; according to the preparation method of the 2-(4-chloro-3-nitrophenoxy) pyridine involved in the step S2, parachlorophenol is taken as a starting raw material, due to the positioning effect of a phenolic hydroxyl group, the nitration reaction is very easy to carry out on a site 2 in the nitration reaction process, and a site 3 is very difficult to introduce, so that the structure of a para-hydroxyl group needs to be changed, phenoxy pyridine is introduced as a positioning group to increase the steric hindrance of the para-hydroxyl group, and the preparation method of the 2-(4-chloro-3-nitrophenoxy) pyridine is easy to implement. And most of nitryl can react on the No.3 site, and the number 2 nitryl product is reduced, so that the yield of the target product is greatly improved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of 4-chloro-3-nitroanisole. Background technique [0002] Islamod (trade name: edoxin), as a class of innovative drugs independently developed in my country, is mainly used for the treatment of active rheumatoid arthritis. Compared with drugs such as methotrexate and leflunomide, islamod As a new type of disease-improving anti-rheumatic drug, Tak is not only the latest one among all anti-rheumatic drugs, but also has a new mechanism of action and clinical characteristics. It is not only suitable for rheumatoid arthritis, but also for the treatment of other autoimmune diseases, such as primary Sjögren's syndrome, systemic lupus erythematosus, ankylosing spondylitis, etc. market and development needs. Ellamod was launched in China and Japan in 2011 and 2012, and was successively written into the "Japanese Society of Rheumatology Guidelines for Diagnosis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/12C07C205/26C07C205/37C07D213/643
CPCC07C201/12C07D213/643C07C205/26C07C205/37
Inventor 邵翀吕列超张超
Owner 常州佳德医药科技有限公司
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