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Regorafenib synthesis method by one kettle way

A technology of regorafenib and condensation reaction, which is applied in the field of one-pot synthesis of regorafenib, can solve the problems of unsuitability for industrial production and high production cost, achieve good production and practical value, low production cost, and simple operation Effect

Inactive Publication Date: 2015-09-16
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the method described in US2005038080, this method does not have much innovation, and column chromatography separation is required in the fourth post-treatment, which has high production cost and is not suitable for industrial production. The total yield of this method is only 38%.

Method used

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  • Regorafenib synthesis method by one kettle way
  • Regorafenib synthesis method by one kettle way
  • Regorafenib synthesis method by one kettle way

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 3-fluoro-4-aminophenol (50g, 225.67mmol), 4-chloro-3-trifluoromethylphenyl isocyanate (31.55g, 248.24mmol) and N,N-dimethyl Formamide. The reaction was stirred at 20°C for 10 minutes. After the reaction, sodium hydroxide (36.1g, 902.67mmol) was added to the reaction solution, stirred for 30min, 4-chloro-N-methyl-2-pyridinecarboxamide (42.35g, 248.24mmol) was added, and the temperature was raised to 130°C for reaction 4h, after the reaction is over, stop heating, cool to room temperature, pour the reaction solution into 1000ml of water, stir in an ice bath for 30min, a large amount of solids are formed, filter with suction, collect the filter cake, recrystallize with ethyl acetate:petroleum ether after drying Off-white solid regorafenib 54.3g, yield 49.83%. The H NMR spectrum of the target product is as figure 1 Shown: 1 H NMR (400MHz, DMSO) δ: 9.52(s, 1H, NHCO), 8.79(d, J=4.8Hz, 1H, CH), 8.74(d, J=1.4Hz, 1H, NHCO), 8.53(d, J=5.6Hz, 1H, CH), 8.16(t, J=9.1Hz, 1H,...

Embodiment 2

[0027] 3-Fluoro-4-aminophenol (50 g, 225.67 mmol), 4-chloro-3-trifluoromethylphenylisocyanate (34.42 g, 270.8 mmol) and dimethyl sulfoxide were added to the reactor. Stir the reaction at 0°C for 20 min. After the reaction, sodium hydroxide (36.1g, 902.67mmol) was added to the reaction solution, stirred for 30min, 4-chloro-N-methyl-2-pyridinecarboxamide (46.20g, 270.80mmol) was added, and the temperature was raised to 80°C for reaction 6h, after the reaction is over, stop heating, cool to room temperature, pour the reaction solution into 1000ml of water, stir in an ice bath for 30min, a large amount of solids are formed, filter with suction, collect the filter cake, recrystallize with ethyl acetate:petroleum ether after drying Off-white solid regorafenib 50.2g, yield 46.07%.

[0028] Melting point: 208.9~210.6℃

Embodiment 3

[0030] Add 3-fluoro-4-aminophenol (50g, 225.67mmol), 4-chloro-3-trifluoromethylphenyl isocyanate (37.29g, 293.37mmol) and N,N-dimethyl Formamide. Stir the reaction at -20°C for 30 minutes. After the reaction, sodium hydroxide (45.13g, 1.13mol) was added to the reaction solution, the reaction was stirred for 30min, 4-chloro-N-methyl-2-pyridinecarboxamide hydrochloride (56.07g, 270.8mmol) was added, and the temperature was raised React at 100°C for 5 hours. After the reaction, stop heating and cool to room temperature. Pour the reaction solution into 1000ml of water and stir for 30 minutes. A large amount of solids are formed. Filter with suction to collect the filter cake. After drying, use ethyl acetate:petroleum Ether recrystallized off-white solid regorafenib 51.0g, yield 46.81%.

[0031] Melting point: 207.9~209.1℃

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Abstract

The invention discloses a regorafenib synthesis method by one kettle way, which is characterized in that 4-chlorine-trifluoro- tolyl isocyanate and 3-fluorine-4-aminophenol are added in a solvent, the temperature is controlled, a condensation reaction is carried out to generate a regorafenib intermediate 1-(4-chlorine-3-(trifluoromethyl)phenyl)-3-(2-fluorine-4-hydroxyphenyl)carbamide, then alkali is added in a same reactor for stirring, 4-chlorine-N-methyl-2-pyridine methanamide hydrochloride or 4-chlorine-N-methyl-2-pyridine methanamide are subjected to a replacement reaction, and finally purifying processing is carried out to obtain regorafenib. The method has the advantages of short process flow, simple operation, high utilization rate of raw material, and low generation cost, and has better production and utility value.

Description

technical field [0001] The invention relates to a method for synthesizing regorafenib; in particular, it relates to a method for synthesizing regorafenib in one pot. Background technique [0002] Regorafenib is a new multikinase inhibitor anticancer drug developed by Bayer Healthcare in Germany. It can inhibit KIT, FGFR1 and other enzymes that promote cancer cell growth, thereby inhibiting tumor angiogenesis and tumor cell proliferation. , is the first oral small molecule multikinase inhibitor for the treatment of metastatic colorectal cancer, mainly for the treatment of metastatic advanced rectal cancer. Its structure is similar to that of sorafenib, another kinase targeting inhibitor already on the market, but its inhibitory activity and inhibitory range are stronger than the latter. [0003] Regorafenib, chemical name 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl Pyridine-2-carboxamide, its structure is as follows: [0004] ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 王德才苏鹏袁晨欢高瑞赵伟刘栓栓
Owner NANJING UNIV OF TECH
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