High-purity afatinib preparation method

A kind of afatinib, high-purity technology, applied in the field of drug synthesis, can solve the problems of unfriendly environment, unsuitable for industrial production, poor product purity, etc., and achieve the effect of simple and convenient post-processing

Active Publication Date: 2017-11-07
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Chinese patent CN105061410A discloses that carbon tetrabromide and organophosphorus compounds are used as condensation reagents, and methylene chloride is used as solvent to obtain afatinib through one-step condensation, but the product obtained by this method has more impurities, and the purity after recrystallization with isopropanol It only reaches 95%-98%, and carbon tetrabromide and organophosphorus compounds are highly toxic, unfriendly to the environment, and are not suitable for industrial production
[0010] Chinese patent CN106045983A discloses a similar method, and the used acid chlorination solvent is methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-...

Method used

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  • High-purity afatinib preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0058] (1) Add 50g of trans-4-dimethylaminocroton hydrochloride, 125g of N-methylpyrrolidone, and 375g of ethyl acetate into a 1L three-necked flask, cool down to 0°C, and dropwise add chlorinated chlorinated 36.1 g of sulfone, after the dropwise addition, stirred at 0° C., monitored by HPLC until the reaction was complete (0.8% of SM1 remained).

[0059] (2) N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6,-diamine (SM2) 55g with N- 260 g of methylpyrrolidone was dissolved, and the solution was added dropwise to the reaction system of step (1). After the dropwise addition was completed, the reaction was carried out at 0° C., and the reaction was monitored by TLC until the SM2 reaction was complete.

[0060] (3) Control the temperature below 20°C, add 1.4kg of purified water dropwise to the system of step (2), adjust pH=9 with 20% by weight sodium hydroxide solution, extract with ethyl acetate 685g*2, and control the extraction temperature to Combin...

Embodiment 2

[0063] (1) Add 50g of trans-4-dimethylaminocroton hydrochloride, 125g of N-methylpyrrolidone, and 375g of ethyl acetate into a 1L three-necked flask, cool down to -5°C, and dropwise add chloride 36.1 g of sulfoxide, after the dropwise addition, stirred at -5°C, monitored by HPLC until the reaction was complete (SM1 residue 1.2%).

[0064] (2) N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6,-diamine (SM2) 45g with N- 225 g of methylpyrrolidone was dissolved, and the solution was added dropwise to the reaction system of step (1). After the dropwise addition was completed, the reaction was carried out at 0° C., and the reaction was monitored by TLC until the SM2 reaction was complete.

[0065] (3) Control the temperature below 20°C, add 1.35kg of purified water dropwise to the system in step (2), adjust the pH to 9 with 20% by weight sodium hydroxide solution, extract with ethyl acetate 675g*2, and control the extraction temperature to 45 °C, combine ...

Embodiment 3

[0068] (1) Add 50g of trans-4-dimethylaminocroton hydrochloride, 100g of N-methylpyrrolidone, and 400g of ethyl acetate into a 1L three-necked flask, cool down to 5°C, and dropwise add chlorinated chlorinated 36.1 g of sulfone, after the dropwise addition, stirred at 5°C, monitored by HPLC until the reaction was complete (1.8% of SM1 remained).

[0069] (2) N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6,-diamine (SM2) 45g with N- 225 g of methylpyrrolidone was dissolved, and the solution was added dropwise to the reaction system of step (1). After the dropwise addition was completed, the reaction was carried out at 0° C., and the reaction was monitored by TLC until the SM2 reaction was complete.

[0070] (3) Control the temperature below 20°C, add 1.35kg of purified water dropwise to the system in step (2), adjust the pH to 9 with 20% by weight sodium hydroxide solution, extract with ethyl acetate 675g*2, and control the extraction temperature to 4...

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Abstract

The invention discloses a high-purity afatinib preparation method, which comprises: (1) adding a trans-4-dimethylaminocrotonic acid hydrochloride to the mixed solvent of N-methylpyrrolidone and ethyl acetate, cooling, adding thionyl chloride to the system in a dropwise manner, and stirring until the reaction is completely performed; (2) dissolving N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine by using N-methylpyrrolidone, adding the obtained solution to the reaction system obtained in the step (1), and stirring until the reaction is completely performed; and (3) adding purified water to the reaction system obtained in the step (2), quenching the reaction, adjusting the pH value with a sodium hydroxide solution, extracting with ethyl acetate, carrying out pressure reducing concentration, carrying out cooling crystallization, carrying out suction filtration, and drying to obtain the high-purity afatinib product. According to the present invention, the post-treatment of the preparation method is simple and convenient, the high purity product can be obtained without the additional refining, and the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing a high-purity afatinib. Background technique [0002] Afatinib is a multi-target small molecule oral drug developed by Boehringer Ingelheim, Germany, which can irreversibly bind to EGFR-HER2 tyrosine kinase, inhibit its tyrosine kinase activity, and block EGFR - HER2-mediated tumor cell signal transduction, inhibits the proliferation and metastasis of tumor cells, and promotes the apoptosis of tumor cells. The drug was approved by the US FDA in July 2013, then approved by the EMA for marketing in September 2013, and approved by the PMDA for marketing in January 2014, under the trade name Gilotrif. In February 2017, CFDA approved it for the first-line treatment of patients with advanced non-small cell lung cancer and the treatment of patients with HER2-positive advanced breast cancer. [0003] Afatinib (Afatinib), the chemical name is (E)-4-dimethylamino-but-...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 梁慧兴尹利献黄猛胡涛董志奎石莹王士康刘旭徐镜人
Owner YANGTZE RIVER PHARM GRP CO LTD
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