Preparation method of osimertinib

An intermediate, nitroanisole technology, applied in the field of organic synthesis technology medicinal chemistry, can solve problems such as being unsuitable for scale-up production, high equipment requirements, very low temperature, etc., and achieves mild reaction conditions, safe operation, and easy post-processing. Effect

Active Publication Date: 2017-06-23
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The fifth step reaction of this method requires very low temperature, and the requirements for equipment are relatively high when it is scaled up. At the same time, iron powder is also used for the reduction reaction, so it is not suitable for scaled-up production.

Method used

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  • Preparation method of osimertinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of Intermediate 1

[0022] Weigh 50g of 5-fluoro-2-nitroanisole into a three-necked flask equipped with a thermometer, add 300ml of DMF, raise the temperature to 85°C, stir for 10min, add dropwise N,N,N'-trimethylethylenediamine 31.4 g. Stir for 4h. After the reaction was complete, 600ml of water was added dropwise. After stirring for 3 h, intermediate 1 was obtained as a yellow solid by filtration, with a yield of 90%.

[0023] Preparation of intermediate 2

[0024] Weigh 50g of intermediate 1, weigh 1.0g of Pd / C, add 250ml of methanol into a three-necked flask, and inject H 2 Keep 0.02MPa and react at 35°C for 5h. After the reaction was completed, Pd / C was filtered out, and the feed solution was concentrated to obtain a white solid with a yield of 85%.

[0025] Preparation of intermediate 3

[0026] Weigh 50g of intermediate 2, put it in a three-neck flask with 250ml of methanol, stir evenly, cool down to -10°C, add HNO dropwise 3 The amount was 14...

Embodiment 2

[0036]Preparation of Intermediate 1

[0037] Weigh 50g of 5-fluoro-2-nitroanisole into a three-necked flask equipped with a thermometer, add 300ml of DMF, raise the temperature to 85°C, stir for 20min, add dropwise N,N,N'-trimethylethylenediamine 32.8 g. Stir for 5h. After the reaction was complete, 600ml of water was added dropwise. After stirring for 3 h, the intermediate 1 was obtained as a yellow solid by filtration, with a yield of 95%.

[0038] Preparation of Intermediate 2

[0039] Weigh 50g of intermediate 1, weigh 0.5g~1.0g of RancyNi, add 250ml of methanol into a three-necked flask, and pour in H 2 Keep 0.02MPa and react at 35°C for 5h. After the reaction was completed, RancyNi was filtered out, and the feed liquid was concentrated to obtain a white solid with a yield of 70%.

[0040] Preparation of Intermediate 3

[0041] Weigh intermediate 2 as 50g, place 250mlH 2 SO 4 In a three-neck flask, stir evenly, cool down to -10°C, add HNO dropwise 3 The amount w...

Embodiment 3

[0051] Preparation of Intermediate 1

[0052] Weigh 50g of 5-fluoro-2-nitroanisole into a three-necked flask equipped with a thermometer, add 250ml of DMF, raise the temperature to 85°C, stir for 20min, add dropwise N,N,N'-trimethylethylenediamine 32.8 g. Stir for 5h. After the reaction was complete, 600ml of water was added dropwise. After stirring for 3 h, the intermediate 1 was obtained as a yellow solid by filtration, with a yield of 95%.

[0053] Preparation of Intermediate 2

[0054] Weigh 50g of intermediate 1, add 250ml of methanol and 100ml of water into a three-neck flask, stir, and add 25g of NH 4 Cl was reacted at 80°C for 6h. Fe powder was filtered out after the reaction was completed, and the feed solution was concentrated to obtain a white solid with a yield of 70%.

[0055] Preparation of Intermediate 3

[0056] Weigh intermediate 2 as 50g, place 250mlH 2 SO 4 In a three-neck flask, stir evenly, cool down to -10°C, weigh KNO 3 The amount is 26.0g, dis...

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Abstract

The invention relates to a preparation method of osimertinib. The method comprises the steps: taking 5-fluorine-2-nitroanisole as a starting material, performing aminolysis, reduction, nitration and Lewis acid reaction, carrying out chlorination with N-methyl indol, performing nitryl reduction and amidation to form a product, and finally performing salification. The yield of each step of the technology is higher and reaches above 80%; the method is simple to operate and suitable for amplified production; and the purity is high.

Description

technical field [0001] The invention belongs to the field of organic synthesis technology medicinal chemistry, and specifically relates to a preparation method of osimertinib. Background technique [0002] Osimertinib is a third-generation targeted drug for the treatment of advanced lung cancer, and it is now on the market in the United States. Its appearance has brought hope to patients with advanced non-small cell lung cancer, so the research on its synthesis method is of great significance. [0003] At present, there are many methods for preparing osimertinib at home and abroad, and most of them have relatively large shortcomings, which need to be solved. In the patent CN105601620A, the preparation method of meritinib mesylate (osimertinib) was reported. This patent report uses N-benzyloxycarbonyl-2-methoxy-4-fluoro-5-nitroaniline as the starting material. Aminolysis with N,N',N',-trimethylethane-1,2-diamine gives N-benzyloxycarbonyl-2-methoxy-4-[2-dimethylaminoethyl met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 赵金召张梅彭学东黄显明
Owner ZHANG JIA GANG VINSCE BIO PHARM
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