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Refining method of osimertinib

A refining method and crude product technology, applied in the direction of organic chemistry, can solve problems such as low production efficiency, high cost, and inconspicuous effect, and achieve the effect of improving purity and reducing residue

Inactive Publication Date: 2021-03-12
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the study found that the residual amount of compound a reached about 0.7%, and the process impurities such as process by-products reached about 1%. After repeated purification, the effect was not obvious, and it could not meet the quality requirements of advanced intermediates - a single impurity remained below 0.1%, and After multiple purifications, the yield of ostinib is very low, resulting in low production efficiency and high cost

Method used

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  • Refining method of osimertinib
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  • Refining method of osimertinib

Examples

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preparation example Construction

[0050] In one of the embodiments, the preparation method of the crude ostinib comprises the following steps:

[0051] Compound a, solvent A and base are mixed and reacted;

[0052]

[0053] The alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methylate and potassium tert-butoxide;

[0054] The solvent is selected from one or more of acetone, dimethyl sulfoxide and tetrahydrofuran;

[0055] The reaction temperature of the reaction is 60°C to 100°C.

[0056] In one of the embodiments, after the step of cooling down to precipitate crystals, an operation of filtering is also included. Preferably, suction filtration is used for solid-liquid separation, and the filter cake and filtrate are collected separately. In order to further improve the purity of ostinib, for the same batch of crude product, after refining once, the refining method of the present invention can be repeated 2 to 3 times for the obtained product. In order to increase the...

Embodiment 1

[0060] This embodiment provides a kind of ostinib and its refining method, the steps are as follows:

[0061] Step 1) Synthetic Ostinib crude product:

[0062] Add 200 g of compound a, 23 g of sodium hydroxide and 600 mL of acetonitrile into a three-necked flask, and react at 80° C. for 10 h to obtain a crude ostinib, which has a purity of 98.1% as detected by HPLC.

[0063]

[0064] Step 2) refinement of crude product:

[0065] Take 200 g of the crude ostinib prepared in step 1), add it to 200 mL of tetrahydrofuran, heat to 60°C to dissolve the crude ostinib, then cool to 5°C at a rate of 3°C / min, crystallize for 1 hour, and filter with suction , dried under reduced pressure at 50° C. to obtain 190 g of the refined product of white crystals, which is the refined product of ostinib, and the yield is 95%.

Embodiment 2

[0067] This example provides an ostinib and its refining method, the steps of which are basically the same as in Example 1, the main difference being that the organic solvent used in the refining process is 2-butanone.

[0068] Step 1) Synthetic Ostinib crude product:

[0069] Add 200 g of compound a, 23 g of sodium hydroxide and 600 mL of acetonitrile into a three-necked flask, and react at 80° C. for 10 h to obtain a crude ostinib, which has a purity of 98.1% as detected by HPLC.

[0070]

[0071] Step 2) refinement of crude product:

[0072] Take 200g of crude ostinib prepared in step 1), add it to 200mL of 2-butanone, heat to 60°C to dissolve the crude ostinib, then cool to 5°C at a rate of 3°C / min, and crystallize for 1h , suction filtration, and dried under reduced pressure at 50° C. to obtain 185 g of refined products of white crystals, which is the refined product of ostinib, and the yield is 92.5%. The purity of the refined product of ostinib detected by HPLC is 9...

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Abstract

The invention relates to a refining method of osimertinib. The refining method of osimertinib comprises the following steps of mixing an organic solvent with an osimertinib crude product to dissolve the osimertinib crude product, then cooling to separate out crystals, and collecting the crystals, wherein the organic solvent is selected from one or more of 2-butanone, ethyl acetate, methylbenzene and tetrahydrofuran. Different from a conventional purification method, the method disclosed by the invention has the advantages that the osimertinib crude product is recrystallized by virtue of the specific organic solvent, so that the purity of osimertinib is effectively improved, residues of reactants can be remarkably reduced, and process byproducts are remarkably reduced. The purity of osimertinib detected by HPLC can reach 98.5% or above, and the impurity limit is less than 0.1%.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for refining ostinib. Background technique [0002] Osimertinib, also known as Osimertinib, original product name: Tagrisso, Chinese product name: Tagrisso, AZD9291 is its research and development code. The chemical name is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidine-2 -base] amino} phenyl) prop-2-enamide, molecular weight is 499.61, molecular formula is C28H33N7O2, chemical structural formula is as shown in formula (1): [0003] [0004] It is a lung cancer treatment drug, mainly used in non-small cell lung cancer (NSCLC), the most difficult type of lung cancer to be effectively treated, and is an oral, irreversible, third-generation EGFR inhibitor (EGFR-TKI). Preclinical model studies have shown significant effects, and the drug has a better therapeutic effect on NSCLC patients with existing EGFR-TKI resistance and T790M mut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 徐亮李彦雄蒙发明郭俊罗凤玲
Owner ENANTIOTECH CORP
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