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Synthesis method of astemizole drug intermediate p-fluorobenzylamine

A technology of p-fluorobenzylamine and astemizole, which is applied in the field of organic synthesis, can solve the problems that need to be improved and the reaction process is complicated, and achieve the effect of increased reaction yield, simple reaction steps, and improved reaction yield

Inactive Publication Date: 2016-10-12
CHENGDU QIESITE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Liu Guangsheng (Liu Guangsheng, Jia Tiecheng, Li Degang, Yin Lihua. Improved synthetic process of p-fluorobenzylamine[J]. Fine Chemical Industry, 2014, 02:270-272.) Using p-fluorobenzaldehyde, ammonia water and hydrogen as raw materials, ethanol as solvent, Raney nickel is used as a catalyst to synthesize p-fluorobenzylamine under the hydrogen pressure of 1.5-2.0 MPa. However, this synthesis method needs to feed nitrogen gas first, and then hydrogen gas. The reaction process is more complicated, and the reaction yield is about 85.7% % still needs to be improved, therefore, it is necessary to propose a new synthetic method

Method used

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  • Synthesis method of astemizole drug intermediate p-fluorobenzylamine
  • Synthesis method of astemizole drug intermediate p-fluorobenzylamine
  • Synthesis method of astemizole drug intermediate p-fluorobenzylamine

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Experimental program
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Effect test

Embodiment 1

[0025] A method for synthesizing p-fluorobenzylamine, an astemizole drug intermediate, includes the following steps:

[0026] A. In a reaction vessel equipped with a stirrer and a reflux condenser, add 0.33 mol of N-(4-fluorobenzyl) phthalimide, with a mass fraction of 180 ml of 25% dichloromethane solution, and the mass fraction It is 0.39 mol of 37% p-cresol phenylacetate solution, the stirring speed is controlled at 170 rpm, the temperature of the solution is raised to 46°C, and the reaction is refluxed for 5 hours;

[0027] B. Add 380ml of 28% potassium bisulfite solution, reduce the temperature of the solution to 15℃, add 280ml of 40% sodium nitrate solution, control the stirring speed at 290rpm, filter with suction, add the mass fraction to the filtrate 300ml of 52% 2,6-dichloro-4-nitrophenol solution, extract 8 times with 59% isopropanol solution, combine the extracts, wash with 35% potassium bromide solution, anhydrous The potassium carbonate dehydrating agent is dehydrate...

Embodiment 2

[0029] A method for synthesizing p-fluorobenzylamine, an astemizole drug intermediate, includes the following steps:

[0030] A. In a reaction vessel equipped with a stirrer and a reflux condenser, add 0.33 mol of N-(4-fluorobenzyl) phthalimide, with a mass fraction of 150 ml of 23% dichloromethane solution, and the mass fraction It is a 36% p-cresol phenylacetate solution of 0.39 mol, the stirring speed is controlled at 150 rpm, the temperature of the solution is raised to 43 °C, and the reaction is refluxed for 4 hours;

[0031] B. Add 350ml of 28% potassium bisulfite solution, lower the temperature of the solution to 13°C, add 250ml of 42% sodium nitrate solution, control the stirring speed at 250rpm, filter with suction, add 49% to the filtrate % 2,6-dichloro-4-nitrophenol solution 300ml, extract 6 times with 59% isopropanol solution, combine the extracts, wash with 35% potassium bromide solution, solid sodium hydroxide The dehydrating agent was dehydrated, filtered, and disti...

Embodiment 3

[0033] A method for synthesizing p-fluorobenzylamine, an astemizole drug intermediate, includes the following steps:

[0034] A. In a reaction vessel equipped with a stirrer and a reflux condenser, add 0.33 mol of N-(4-fluorobenzyl) phthalimide, 130 ml of a dichloromethane solution with a mass fraction of 20%, mass The fraction of 31% p-cresol phenylacetate solution is 0.39mol, the stirring speed is controlled at 130rpm, the temperature of the solution is raised to 40℃, and the reaction is refluxed for 3h;

[0035] B. Add 300ml of 25% potassium bisulfite solution, lower the temperature of the solution to 10℃, add 200ml of 36% sodium nitrate solution, control the stirring speed at 210rpm, filter with suction, and add the mass fraction to the filtrate 300ml of 46% 2,6-dichloro-4-nitrophenol solution, extract 5 times with 55% isopropanol solution, combine the extracts, and wash with 30% potassium bromide solution. Water potassium carbonate dehydrating agent was dehydrated, filtered, ...

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Abstract

The invention discloses a synthesis method of an astemizole drug intermediate p-fluorobenzylamine. The method consists of: adding N-(4-fluorobenzyl)phthalimide into a mixed solution of dichloromethane and p-tolyl phenylacetate to carry out heating reflux reaction, adding a potassium bisulfate solution, performing cooling, adding a sodium nitrate solution, conducting pumping filtration, adding a 2, 6-dichloro-4-nitrophenol solution into the filtrate, using an isopropanol solution conduct extraction 5-8 times, combining the extracted solutions, performing washing with a potassium bromide solution, using a dehydrant to conduct dehydration, and carrying out filtering, pressure reduction distillation, and recrystallization in an acetonitrile solution, thus obtaining the crystal p-fluorobenzylamine. The synthesis method of the astemizole drug intermediate p-fluorobenzylamine provided by the invention has no need of introducing gas, the reaction steps are much simpler, and the reaction yield is obviously improved. At the same time, the invention provides a new synthesis route, and lays good foundation for further improving the reaction yield.

Description

Technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, belonging to the field of organic synthesis, and in particular to a method for synthesizing p-fluorobenzylamine as an astemizole pharmaceutical intermediate. Background technique [0002] Astemizole is mainly used to treat perennial and seasonal allergic rhinitis, allergic conjunctivitis, chronic urticaria and other allergic reactions. This product is a strong and long-acting H1 receptor antagonist. Because it does not easily pass through the blood-brain barrier, it does not have central sedation and no anticholinergic effect. It competes with H1 receptors on effector cells with histamine released from tissues, thereby preventing allergic effects. After oral administration, the absorption is very fast, and the blood concentration reaches the peak 1 to 4 hours after administration, but the effect is slow, and the effect is obvious after 3 to 4 days. The protein binding rate is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/62C07C211/29
CPCC07C209/62C07C211/29
Inventor 彭飞
Owner CHENGDU QIESITE TECH CO LTD