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Preparation method of Afatinib

A technology of afatinib and tetrahydrofuran, which is applied in the field of preparation of raw materials and can solve the problem of high cost of afatinib

Inactive Publication Date: 2015-04-01
KANGBOLAI TIANJIN DRUG RES & DEVCO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the cost of afatinib prepared by the current method is high

Method used

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  • Preparation method of Afatinib
  • Preparation method of Afatinib

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Embodiment 1

[0024] (1) Preparation of 3-nitro-4-fluorobenzonitrile (Ⅲ): Dissolve 4-fluorobenzonitrile (25g, 206mmol) in concentrated sulfuric acid (125mL), and add to the system in batches under temperature control at 0°C Potassium nitrate (20.8g, 206mmol) was added, reacted at 0°C for 30 minutes, and extracted twice with dichloromethane, each with 100mL. The organic phases were combined, washed with water (60 mL), dried, and concentrated to obtain 20 g of white solid product (III), yield: 58%. NMR, CDCl 3 ,400MHz, δ8.42(1H,d),7.88(1H,dd),7.41(1H,d).

[0025] (2) Preparation of 3-nitro-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (IV): Potassium tert-butoxide (16.8g, 150mmol), (S)-tetrahydrofuran -3-alcohol (8.8g, 100mmol) and 3-nitro-4-fluorobenzonitrile (Ⅲ) (16.6g, 100mmol) were mixed in DMF (100mL), heated to 60°C for 5 hours; cooled to room temperature, Add 100 mL of water to quench the reaction; extract twice with dichloromethane, each with 100 mL; combine the organic phases, was...

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Abstract

The invention discloses a preparation method of Afatinib. According to the method, 4-fluorobenzonitrile is taken as the raw material, and an intermediate 3-[4-(N,N-dimethylamino)-1-oxo-2- butene-1-yl] amino-4-[(S)-(tetrahydrofuran-3-yl) oxy]-6-aminobenzonitrile (IX) is obtained after nitrification, reduction, acylation, nitrification and reduction; the intermediate (IX) and formamidine acetate are subjected to ring closure to generate 4-amino-6-[[4-(N,N-dimethylamino)-1-oxo-2- butene-1-yl] amino]-7-[(S)-tetrahydrofuran-3-yl) oxy]quinazoline (X); the intermediate (X) and 3-chloro-4-phenylboronic acid have a Chan-Lam reaction to generateAfatinib (I). Cheap 4-fluorobenzonitrilewhich is easy to obtain is taken as the starting raw material, a preparation method of the intermediate (X) is not reported, and the preparation method of Afatinib (I) is not reported in literature.

Description

technical field [0001] The invention belongs to the technical field of preparation of crude drugs, in particular to a preparation method of afatinib. Background technique [0002] Afatinib is a multi-target small molecule drug developed by Boehringer Ingelheim of Germany, which belongs to the irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase , is also the first lung cancer treatment drug for the failure of epidermal growth factor receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced non-small cell lung cancer, advanced breast cancer and intestinal cancer. In July 2013, it was approved under the trade name of Gilotrif in the United States, and in September 2013, it was approved for marketing in the European Union. [0003] The original world patent No. WO0250043A1 and No. WO03094921A2 of Boehringer Ingelheim reported the preparation method of afatinib: the mother nucleus 4-[(3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 张秀菊
Owner KANGBOLAI TIANJIN DRUG RES & DEVCO
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