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Preparation method for Stivarga midbody of medicine for treating cancer

A technology of regorafenib and intermediates, applied in the field of medicinal chemical preparation, can solve problems such as low yield, complicated reaction process, and difficult reaction treatment, and achieve the effects of simple operation, reduced side reactions, and easy industrialization

Inactive Publication Date: 2017-05-10
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In view of the complex reaction process of the existing regorafenib intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide, the difficulty of reaction processing and the low yield, A preparation method of regorafenib intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide is proposed

Method used

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  • Preparation method for Stivarga midbody of medicine for treating cancer
  • Preparation method for Stivarga midbody of medicine for treating cancer
  • Preparation method for Stivarga midbody of medicine for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of regorafenib intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide

[0022] In a three-necked flask, add 12.7g of 3-fluoro-4-aminophenol, 0.95g of cuprous iodide, and 63.7g of potassium phosphate, start stirring and heat to 85°C, and then add 4-chloro-2-pyridinecarboxamide in three batches Add 18.6g of hydrochloride into the reaction system, keep the temperature and continue the reaction for 6 hours, contact reaction in N,N-dimethylformamide to obtain regorafenib intermediate 4-(4-amino-3-trifluoromethyl) -21.4 g of N-methylpyridine-2-carboxamide, yield 91.1%. MS(ESI):m / z[M+H] + 262.10.

[0023] 1 HNMR (400MHz, d 6 -DMSO)δ: 8.81(q,1H), 8.50(d,1H), 7.41(d,1H), 7.13(dd,1H), 7.07(dd,1H), 6.97(t,1H), 6.87(dd ,1H), 5.50(brs,2H), 2.80(d,3H). .

Embodiment 2

[0025] Preparation of regorafenib intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide

[0026] In a three-necked flask, add 12.7g of 3-fluoro-4-aminophenol, 1.9g of cuprous iodide, and 106.1g of potassium phosphate, start stirring and heat to 90°C, and then add 4-chloro-2-pyridinecarboxamide in three batches Add 18.6g of hydrochloride into the reaction system, keep the temperature and continue the reaction for 5 hours, contact reaction in N,N-dimethylformamide to obtain regorafenib intermediate 4-(4-amino-3-trifluoromethyl) -21.2 g of N-methylpyridine-2-carboxamide, yield 90.3%.

Embodiment 3

[0028] Preparation of regorafenib intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide

[0029] In a three-necked flask, add 12.7g of 3-fluoro-4-aminophenol, 0.95g of cuprous iodide, and 55.2g of potassium carbonate, start stirring and heat to 100°C, and then add 4-chloro-2-pyridinecarboxamide in three batches Add 20.7g of hydrochloride into the reaction system, keep the temperature and continue the reaction for 7 hours, contact reaction in N,N-dimethylformamide to obtain regorafenib intermediate 4-(4-amino-3-trifluoromethyl) -23.5 g of N-methylpyridine-2-carboxamide, yield 89.9%.

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Abstract

The invention discloses a preparation method for a Stivarga midbody of a medicine for treating cancer. The Stivarga midbody is 4-(4-amino-3-trifluoromethyl)-N-picoline-2-formamide. The structure is shown as formula I. The preparation method comprises the step of performing contact reaction on 3-fluorine-4-aminophenol and 4-chlorine-2-pyridine carboxamide hydrochloride in an organic solvent under the existence of copper salt and acid-binding agent, thereby acquiring the Stivarga midbody. According to the preparation technology for the Stivarga midbody provided by the invention, the potassium phosphate and the copper salt are used, so that the target product acquired through reaction is high in yield; besides, even if under higher temperature, the substrate still can stably exist and the happening of side reaction can be reduced; the preparation technology is simple in operation and is easy to be industrialized.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry preparation, and in particular relates to a preparation method of an intermediate of regorafenib, a medicine for treating cancer. Background technique [0002] Regorafenib is a new type of multikinase inhibitor anticancer drug developed by Bayer Healthcare in Germany. It is used for the treatment of metastatic colorectal cancer. Its chemical name is 4-[4-({[4-chloro- 3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, the specific structure is as follows: [0003] [0004] At present, in the synthesis of regorafenib, the intermediate 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-carboxamide is widely used, although there are many However, there are still common problems of complex reaction processing and low yield. [0005] CN1721397A discloses a preparation method of regorafenib, specifically, the method uses 3-fluoro-4-nitrophenol and 4-chloropyr...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 吕燕华
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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