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Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-picoline-2-carboxamide and its monohydrate method

A monohydrate and compound technology, applied in the direction of organic chemistry, can solve the problems of inorganic salt residues and affecting the purity of drugs, etc.

Active Publication Date: 2016-06-29
LIANGJIANG MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the defect of this conventional technical means is that it is easy to cause inorganic salt residue, which affects the purity of the drug.

Method used

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  • Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-picoline-2-carboxamide and its monohydrate method
  • Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-picoline-2-carboxamide and its monohydrate method
  • Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-picoline-2-carboxamide and its monohydrate method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2 -Formamide hydrochloride

[0046] Add 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine (50g, 0.191mol) and 450mL tetrahydrofuran into a 1L four-necked flask, and stir to dissolve. At room temperature, a solution of 4-chloro-3-trifluoromethylphenylisocyanate (46.6 g, 0.210 mol) dissolved in 100 mL of tetrahydrofuran was added dropwise, and the addition was completed within 1.5-2 hours. The reaction was then stirred at room temperature for 2-3 hours to complete the reaction. Concentrated hydrochloric acid (20.7 mL, 0.248 mol) was added dropwise, and the addition was completed within 15-20 minutes. Stir and crystallize at room temperature for 2 hours. Filter, wash the filter cake with tetrahydrofuran and acetone in turn, and dry to obtain 89.5 g.

Embodiment 2

[0047] Example 2: Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2 -Formamide hydrochloride

[0048] Add 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine (10g, 38.3mmol) and 90mL dichloromethane into a 250mL four-necked flask, and stir to dissolve. A solution of 4-chloro-3-trifluoromethylphenylisocyanate (8.9 g, 40.2 mmol) dissolved in 20 mL of dichloromethane was added rapidly at room temperature. The reaction was then stirred at room temperature for 5-6 hours to complete the reaction. Hydrochloric acid (3.5 mL, 42.0 mmol) was added dropwise, and the addition was completed within 15-20 minutes. Stir and crystallize at room temperature for 2 hours. Filter, wash the filter cake with acetone, and dry to obtain 18.0 g.

Embodiment 3

[0049] Example 3: Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2 -Formamide Sulfate

[0050] Add 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine (2g, 7.65mmol) and 18mL dichloromethane into a 50mL four-necked flask, and stir to dissolve. A solution of 4-chloro-3-trifluoromethylphenylisocyanate (1.9 g, 8.42 mmol) dissolved in 4 mL of dichloromethane was added rapidly at room temperature. The reaction was then stirred at room temperature for 4-5 hours to complete the reaction. Concentrated sulfuric acid (0.47mL, 8.4mmol) was added dropwise, and the addition was completed within 15-20 minutes. Stir and crystallize at room temperature for 2 hours. Filter, wash the filter cake with acetone, and dry to obtain 3.5 g.

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Abstract

The invention discloses a preparation method of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide and a hydrate thereof. The method comprises the following steps: performing addition reaction between 4-(4-amino-3-fluorophenoxy) pyridine-2-methylamine carboxylate and 4-chloro-3-trifluoromethyl phenyl isocyanate in an appropriate solvent; then reacting with acid to obtain a salt; washing the salt with pure water; and crystallizing with an organic solvent to obtain the target compounds. The method disclosed by the invention is low in production cost, simple and convenient to operate, low in environmental protection pressure and low in metal residue and burning residue content in the target products, so that the method is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. Involving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide and The preparation method of its monohydrate. Background technique [0002] Stivarga (trade name), commonly known as Regorafenib or Regorafenib, is a new oral multikinase inhibitor anticancer drug. Developed by Bayer Pharmaceuticals of Germany, it was reviewed by the U.S. Food and Drug Administration (FDA) for priority review and was approved for marketing on September 27, 2012. It is used for the treatment of metastatic colorectal cancer whose condition worsens after conventional treatment (mCRC). [0003] Regorafenib chemical name: 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl Pyridine-2-carboxamide monohydrate, 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N- The structural formula of picoline-2-carb...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 朱绪成邹毅邵攀霖贺耘
Owner LIANGJIANG MEDICINE CO LTD
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