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A new method for preparing n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine

A technology of quinazoline amine and fluorophenyl, which is applied in the field of organic chemical manufacturing technology, and can solve problems such as difficult availability of raw materials

Active Publication Date: 2021-08-27
JIANGSU FOOD & PHARMA SCI COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Methods (2) and (3) have fewer synthetic steps, but the raw materials are not easy to obtain, and the same heavily polluted nitric acid-sulfuric acid and SOCl are used 2 or POCl 3

Method used

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  • A new method for preparing n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine
  • A new method for preparing n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Preparation of 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzamidine

[0025]In a special microwave reaction flask equipped with a drying tube and a condenser, add 2-bromo-4-fluoro-5-nitrobenzonitrile (2.44 g, 10 mmol), 3-chloro-4-fluoroaniline (1.60 g , 11 mmol), cuprous chloride (0.30 g, 3 mmol), absolute ethanol (20 mL), and reflux for 30 min under microwave irradiation. Cool the reaction solution to room temperature, filter with suction, distill off ethanol under reduced pressure, filter with suction, wash the solid with water, and dry to obtain 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro as a pale yellow solid - 5-nitrobenzamidine (2.96 g, 76%).

Embodiment 2

[0026] Example 2: Preparation of 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzamidine

[0027] In a special microwave reaction flask equipped with a drying tube and a condenser, add 2-bromo-4-fluoro-5-nitrobenzonitrile (2.44 g, 10 mmol), 3-chloro-4-fluoroaniline (1.45 g , 10 mmol), cuprous bromide (0.14 g, 1 mmol), glacial acetic acid (30 mL), and reflux for 25 min under microwave irradiation. The reaction solution was cooled to room temperature, suction filtered, acetic acid was distilled off under reduced pressure, suction filtered, the solid was washed with water, and dried to obtain a pale yellow solid 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro - 5-nitrobenzamidine (3.17 g, 81%).

Embodiment 3

[0028] Example 3: Preparation of 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro-5-nitrobenzamidine

[0029] In a special microwave reaction flask equipped with a drying tube and a condenser, add 2-bromo-4-fluoro-5-nitrobenzonitrile (2.44 g, 10 mmol), 3-chloro-4-fluoroaniline (1.45 g , 10 mmol), cuprous iodide (0.38 g, 2 mmol), absolute ethanol (10 mL), and reflux under microwave irradiation for 20 min. Cool the reaction solution to room temperature, filter with suction, distill off ethanol under reduced pressure, filter with suction, wash the solid with water, and dry to obtain 2-bromo-N-(3-chloro-4-fluorophenyl)-4-fluoro as a pale yellow solid - 5-nitrobenzamidine (3.66 g, 94%).

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Abstract

The invention discloses a new method for preparing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, which uses 2-bromo-4-fluoro-5 ‑Nitrobenzonitrile is used as the starting material, and under the promotion of catalyst and microwave, it is added with 3‑chloro‑4‑fluoroaniline, and then reacted with formamide in series for amination and condensation cyclization to synthesize anticancer drug N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, the key intermediate of Afatinib and Dacomitinib, total The rate is 90%. The method has short synthesis route, mild reaction conditions, short reaction time, high product yield, avoids the use of seriously polluted thionyl chloride and phosphorus oxychloride, is more friendly to the environment, and provides a good source for the synthesis of 4 quinazoline amines An efficient and simple method has been developed, which has potential industrial application prospects.

Description

technical field [0001] The invention relates to a new method for manufacturing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, which belongs to the field of organic chemical manufacturing technology. Background technique [0002] Afatinib and Dacomitinib are potent and irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors developed by Boehringer Ingelheim of Germany and Pfizer of the United States respectively. It is used for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutation and advanced lung squamous cell carcinoma with exacerbated chemotherapy. It is also a potential therapeutic drug for liver cancer, ovarian cancer, breast cancer, head and neck cancer, brain tumor, skin squamous cell carcinoma, etc. . [0003] Afatinib, chemical name N-[4-[(3-chloro-4-fluorophenyl)amino)-7-[[(3S)-tetrahydrofuran-3-yl]oxy]quinazoline-6- Base]-4-(dimethylamino)-2-butenamide, the structural formula is as follows: [0004] . ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 刘长春
Owner JIANGSU FOOD & PHARMA SCI COLLEGE
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