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Synthesis method of osimertinib intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of expensive raw materials, difficult to obtain in the market, complicated process, etc., and achieve the effects of short reaction time, good impurity removal effect, and simple process

Pending Publication Date: 2021-02-09
烟台舜康生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] In order to solve the deficiencies in the prior art, the purpose of the present invention is to provide a synthetic method of an osimertinib intermediate, which solves the problem that the raw material is expensive and the market is not easy to obtain in the synthetic method of an osimertinib intermediate in the prior art. Problems of complex process and low yield

Method used

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  • Synthesis method of osimertinib intermediate
  • Synthesis method of osimertinib intermediate
  • Synthesis method of osimertinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Preparation of 3-fluoro-4,6-dinitroanisole (intermediate 1)

[0047] In a 1L reaction flask, add 792g of 98% concentrated sulfuric acid, add 160g of 3-fluoroanisole in batches under stirring, after stirring evenly, cool down to -10℃~-5℃, control the temperature -10~0℃ and add concentrated Nitric acid (98%) 183g, after dropwise addition, stir for 10 minutes, heat up to normal temperature 20-25°C, and stir for 3 hours. Spot the plate (developing agent: ethyl acetate: petroleum ether = 2:1), after the reaction is completed, slowly drop the system into 1500mL ice water, control the temperature below 20°C, after the dropwise addition, control the temperature at 30-35°C and stir for 3 hours . Filter, rinse the filter cake with a small amount of water, and dry to obtain 246.9 g of a khaki product. The purity is 98.5%, and the yield is 90%.

[0048] 2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline

[0049] In a 1L reaction flask, add 300mL of water, add 60g of 3-fluor...

Embodiment 2

[0051] 1) Preparation of 3-fluoro-4,6-dinitroanisole (intermediate 1)

[0052]In a 1L reaction flask, add 792g of 98% concentrated sulfuric acid, add 160g of 3-fluoroanisole in batches under stirring, after stirring evenly, cool down to -10℃~-5℃, control the temperature -10~0℃ and add concentrated Nitric acid (95%) 210g, after the dropwise addition, stir for 10 minutes, heat up to normal temperature 20-25°C, and stir for 3 hours. Spot the plate (developing agent: ethyl acetate: petroleum ether = 2:1), after the reaction is completed, slowly drop the system into 1500mL ice water, control the temperature below 20°C, after the dropwise addition, control the temperature at 30-35°C and stir for 3 hours . After filtering, the filter cake was rinsed with a small amount of water, and dried to obtain 230 g of a khaki product. The purity is 97.8%, and the yield is 83.8%.

[0053] 2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline

[0054] In a 1L reaction flask, add 300mL of water,...

Embodiment 3

[0056] 1) Preparation of 3-fluoro-4,6-dinitroanisole (intermediate 1)

[0057] In a 1L reaction flask, add 900g of 95% concentrated sulfuric acid, add 160g of 3-fluoroanisole in batches under stirring, after stirring evenly, cool down to -10℃~-5℃, control the temperature -10~0℃ and add concentrated Nitric acid (65%) 280g, after the dropwise addition, stir for 10 minutes, heat up to normal temperature 20-25°C, and stir for 3 hours. Spot the plate (developing agent: ethyl acetate: petroleum ether = 2:1), after the reaction is completed, slowly drop the system into 1500mL ice water, control the temperature below 20°C, after the dropwise addition, control the temperature at 30-35°C and stir for 3 hours . After filtration, 216 g of a khaki solid was obtained, with a purity of 97.5% and a yield of 78.7%.

[0058] 2) Preparation of 4-fluoro-2-methoxy-5-nitroaniline

[0059] In a 1L reaction flask, add 360mL of water, add 60g of 3-fluoro-4,6-dinitroanisole prepared above under stir...

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Abstract

The invention relates to a synthesis method of an osimertinib intermediate. The synthesis method comprises the following steps: 1, with 3-fluoroanisole as an initial raw material, adding 3-fluoroanisole into concentrated sulfuric acid, dropwise adding the concentrated nitric acid in a low-temperature environment, carrying out primary heating and stirring after completion of the addition, injectingthe formed system into ice water for quenching, carrying out secondary heating and stirring, and carrying out filtering to obtain a product, namely 3-fluoro-4, 6-dinitroanisole; and 2, adding the compound 3-fluoro-4,6-dinitroanisole obtained in the step 1 into water, adding alkali, conducting heating, adding a weak reducing agent in batches, performing stirring while keeping the temperature untila reaction endpoint is reached, carrying out filtering to obtain a crude product, and successively conducting washing, recrystallizing with methanol, crystallizing and filtering at a low temperatureand drying to finally obtain 4-fluoro-2-methoxy-5-nitroaniline. The method of the invention solves the problems that raw materials are expensive and hardly-available in the market, process is complexand yield is low in conventional synthesis methods of the osimertinib intermediate.

Description

technical field [0001] The invention relates to a method for synthesizing an osimertinib intermediate, belonging to the technical field of synthesizing pharmaceutical intermediates. Background technique [0002] Lung cancer is the number one killer among the top 10 cancers in the world. In 2017, the number of lung cancer in my country reached 800,000, and the death toll was 700,000, accounting for a quarter of all cancer deaths. It is estimated that by 2025, the number of deaths due to lung cancer in my country will reach 1 million each year. Among them, non-small cell lung cancer accounts for 80% of lung cancer. [0003] EGFR-positive mutations are more common in non-small cell lung cancer, so EGFR inhibitors have been developed accordingly. for targeted therapy drugs. [0004] First-generation EGFR-TKI inhibitor drugs: reversibly combined with EGFR, mainly including gefitinib, erlotinib and icotinib; second-generation EGFR-TKI drugs: mostly multi-target small molecule d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C213/10C07C217/84C07C201/08C07C205/37
CPCC07C213/02C07C213/10C07C201/08C07C205/37C07C217/84Y02P20/55
Inventor 陈化群位晓梅史汝金申川生
Owner 烟台舜康生物科技有限公司
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