Preparation method of crizotinib intermediate

A technology for crizotinib and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of long process flow, high production cost, troublesome post-processing, etc., and achieves simple and safe process operation, good application prospect, and easy purchase. Effect

Active Publication Date: 2017-12-01
ZHANG JIA GANG VINSCE BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The existing method of iron powder reduction leads to a long process flow, many wastes, and great environmental pollution, resulting in high production costs, troublesome post-processing, and low production efficiency
N-bromosuccinimide (NBS) also has problems such as high production cost and troublesome post-processing

Method used

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  • Preparation method of crizotinib intermediate
  • Preparation method of crizotinib intermediate
  • Preparation method of crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine, sodium dithionate, sodium hydroxide and water in molar ratio 1:1:3:5, put it in the stainless steel reactor of the ball mill, react for 1h, take out the reaction mixture, add 2 times of water to stir, filter to get (R)-3-[1-(2,6-dichloro -3-fluorophenyl)ethoxy]-2-aminopyridine (1), 90% yield by HPLC analysis.

[0028] Compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine was dissolved in industrial alcohol, 1%Pd / C catalyst was added, and Temperature 20°C, H 2 React under the condition of pressure 0.1MPa. After the reaction is complete, filter, add water, extract with dichloromethane, and concentrate to obtain (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-aminopyridine (1) , HPLC analysis yield 95%.

[0029] Potassium persulfate and sodium bromide molar ratio of 1:1 was prepared as an aqueous solution, placed in a dry three-necked flask, T=15°C, compound (1) was dissolved in ...

Embodiment 2

[0031] Compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine, sodium dithionate, sodium hydroxide and water in molar ratio 1:2:4:8, placed in a stainless steel reactor of a ball mill, reacted for 2 hours, took out the reaction mixture, added 2 times of water for stirring, and filtered to obtain (R)-3-[1-(2,6-dichloro -3-fluorophenyl)ethoxy]-2-aminopyridine (1), the yield by HPLC analysis was 89%.

[0032] Dissolve compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine in methanol, add 2% Pt / C catalyst, at temperature 30°C, H 2 React under the condition of pressure 0.2MPa. After the reaction is complete, filter, add water, extract with dichloromethane, and concentrate to obtain (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-aminopyridine (1) , HPLC analysis yield 85%.

[0033] The molar ratio of potassium persulfate to sodium bromide was 1:1.5 to prepare an aqueous solution, which was placed in a dry three-necked flask at T=20°C. Compound ...

Embodiment 3

[0035] Compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine, sodium dithionate, sodium hydroxide and water in molar ratio 1:3:5:5, put it in the stainless steel reactor of the ball mill, react for 1h, take out the reaction mixture, add 2 times of water to stir, filter to get (R)-3-[1-(2,6-dichloro -3-fluorophenyl)ethoxy]-2-aminopyridine (1), the yield by HPLC analysis was 86%.

[0036] The compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine was dissolved in methanol and 2% Pd / Al was added 2 o 3 catalyst, at a temperature of 30 °C, H 2 React under the condition of pressure 0.2MPa. After the reaction is complete, filter, add water, extract with dichloromethane, and concentrate to obtain (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-aminopyridine (1) , HPLC analysis yield 89%.

[0037]Potassium persulfate and sodium bromide molar ratio of 1:1.5 was prepared as an aqueous solution, placed in a dry three-necked flask, T=15°C, compound (1...

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Abstract

The invention discloses a synthetic method of anti-tumor molecular targeted drug crizotinib, belongs to the field of pharmaceuticals, and relates to a synthetic method of a crizotinib intermediate. The method comprises two reduction processes: a bromination reaction process comprises the following reaction steps: a reduction process I: carrying out reduction reaction on a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound and sodium dithionate under a mechanical chemical condition to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; a reduction process II: dissolving the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound into an organic solvent, carrying out catalytic hydrogenation and reduction treatment to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; the bromination reaction process comprises a step of carrying out reaction between the compound and potassium hydrogen persulfate as well as bromate to obtain the crizotinib intermediate. The process is low in cost, the raw materials are easy to purchase, the operation is simple, convenient and safe, and the yield is high; moreover, the process is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of crizotinib intermediates. Background technique [0002] Crizotinib chemical name: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl) )-1H-pyrazol-4-yl]-2-aminopyridine, molecular formula C 21 h 22 C l2 FN 5 O, molecular weight 449, white powder, structure such as figure 1 shown. It is a small-molecule kinase inhibitor developed by Pfizer for the treatment of anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), and is currently the only drug for this type of disease , was approved by the FDA in August 2011 to be listed in the United States, and then listed in South Korea, Japan, and the European Union. In January 2013, it was approved by the SFDA to be listed in China. The product name is (The Chinese product name is Serek). This product targets ALK, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73C07D401/14
CPCC07D213/73C07D401/14
Inventor 彭学东张梅赵金召冯亦奇
Owner ZHANG JIA GANG VINSCE BIO PHARM
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