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Method for continuously preparing letrozole intermediate 4-((1H-1,2,4-tri-1-zole)methyl) benzonitrile

A technology of letrozole and methyl is applied in the field of preparation of letrozole, and can solve the problems of difficulty in product separation, low conversion rate of cyanobenzyl chloride, etc.

Inactive Publication Date: 2016-06-01
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical purpose of the present invention is to provide a method to continuously produce and separate 4-((1H-1,2,4-tri-1-azole)methyl)benzene by using p-cyanobenzyl chloride and 1,2,4-triazole The method of nitrile mainly solves the problem that the conversion rate of reactants to cyanobenzyl chloride is not high and the product separation is difficult in the process of producing 4-((1H-1,2,4-tri-1-azole)methyl)benzonitrile in the prior art The problem

Method used

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  • Method for continuously preparing letrozole intermediate 4-((1H-1,2,4-tri-1-zole)methyl) benzonitrile
  • Method for continuously preparing letrozole intermediate 4-((1H-1,2,4-tri-1-zole)methyl) benzonitrile
  • Method for continuously preparing letrozole intermediate 4-((1H-1,2,4-tri-1-zole)methyl) benzonitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The qualitative and quantitative detection method of the reaction substrate and product is: using KromasilC 18 Column (12.5cm×4.6mm×5μm), mobile phase: acetonitrile:water (30:70); UV detection wavelength 230nm; flow rate: 1.0mL / min; column temperature 40°C.

[0019] Pump p-cyanobenzyl chloride, 1,2,4-triazole, potassium carbonate (molar ratio 1:1:1) and solvent acetone into the reaction kettle, heat to the reaction temperature of 75°C, and stir vigorously for 3 hours. The reaction solution is pumped into the suction filter tank from the bottom of the reaction kettle, and the filtrate flows out from the bottom of the tank into the crystallization kettle, and 15% concentrated hydrochloric acid is added to carry out salt formation and crystallization for 2 hours, and then pumped into the suction filter tank, the obtained reaction product 4-((1H The yield of -1,2,4-tris-1-azole)methyl)benzonitrile is greater than 82.61%, and the chemical purity is greater than 98.75%.

Embodiment 2

[0021] Reaction substrate and product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar ratio and each operating parameter are as follows:

[0022] Pump p-cyanobenzyl chloride, 1,2,4-triazole, potassium carbonate (molar ratio 1:3:1) and solvent acetone into the reaction kettle, heat to the reaction temperature of 70°C, and vigorously stir for 3.5 hours. Pump the reaction liquid from the bottom of the reaction kettle into the suction filter tank, the filtrate flows out from the bottom of the tank into the crystallization kettle, add 17% concentrated hydrochloric acid to carry out salt formation, salt crystallization and crystallization for 3 hours, and then pump into the suction filter tank, the obtained reaction product 4- The yield of ((1H-1,2,4-tri-1-azole)methyl)benzonitrile was greater than 83.61%, and the chemical purity was greater than 98.88%.

Embodiment 3

[0024] Reaction substrate and product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar ratio and each operating parameter are as follows:

[0025] Pump p-cyanobenzyl chloride, 1,2,4-triazole, potassium carbonate (molar ratio 1:5:1) and solvent acetone into the reaction kettle, heat to the reaction temperature of 60°C, and stir vigorously for 5 hours. The reaction solution is pumped into the suction filter tank from the bottom of the reaction kettle, and the filtrate flows out from the bottom of the tank into the crystallization kettle, and 18% concentrated hydrochloric acid is added to carry out salt formation, salt crystallization and crystallization for 1h, and then pumped into the suction filter tank, and the obtained reaction product 4-( The yield of (1H-1,2,4-tri-1-azole)methyl)benzonitrile was greater than 84.51%, and the chemical purity was greater than 98.98%.

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Abstract

The invention relates to a method for continuously preparing letrozole intermediate 4-((1H-1,2,4-tri-1-zole)methyl) benzonitrile (I).The problems that in the process of producing a compound (I) in the prior art, the reactant p-cyanobenzyl chloride is low in conversion rate, and a product is difficult to separate are mainly solved.The continuous coupling process of separating and purifying the compound (I) is achieved by adopting reacting, salifying and filtering.The reaction product is continuously separated from a system in time, the compound (I) can be produced continuously, easily and fast with low energy consumption, the yield of the obtained reaction product compound (I) is larger than 80%, and the chemical purity is larger than 98%.

Description

technical field [0001] The invention relates to a continuous production and separation of letrozole intermediate 4-((1H-1,2,4-tri-1 The method of -azole) methyl) benzonitrile relates to the preparation technology of letrozole in the field of chemical industry. Background technique [0002] Letrozole is a new generation of aromatase inhibitors. It is a synthetic derivative of benzyltriazole. Letrozole reduces the level of estrogen by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on tumor growth. [0003] Studies have shown that compared with the first-generation aromatase inhibitor aminoglutethimide, letrozole is far more active than aminoglutethimide in vivo and in vitro, and has high selectivity, no potential toxicity, and good tolerance Good, strong pharmacological effect, no significant effect on the production of adrenal gland substances, etc., so its anti-tumor effect is stronger, it is the first choice drug for the treatment of advanced ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08
CPCC07D249/08
Inventor 卢定强王新仙严国荣凌岫泉吉文喆刘桐岐
Owner NANJING UNIV OF TECH
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