Method for preparing sorafenib

An amino and compound technology, applied in the field of preparing sorafenib, can solve the problems of cumbersome operation, low yield, increased cost and the like, and achieve the effects of simplified operation, simple operation and low cost

Inactive Publication Date: 2013-01-16
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the prior art can be used to prepare compound (I), there are many shortcomings: cumbersome operation, low yield, poor purity, etc.
According to the prior art, in the preparation of compound (V), method one uses the organic solution reaction of methylamine to obtain compound (V), and methylamine will attack the chlorine atom in compound (IV) at the same time, thereby generating obvious impurities, In addition, the use of a large amount of organic solvents not only increases the cost but also is not friendly to the environment; and method two, although a low-cost methylamine aqueous solution is used, the compound (III) is prone to hydrolysis in the aqueous solution, resulting in the occurrence of by-product acid; Method 3 Since compound (III) has good solubility in organic solvents, it is difficult to purify by recrystallization
According to the prior art, the conversion of compound (V) to compound (VI) is not high, and a large amount of raw materials remain, which affects the yield and purity of the preparation of intermediate (VI)
In addition, when compound (I) is prepared according to the temperature described in the prior art, there are too many impurities

Method used

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  • Method for preparing sorafenib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of embodiment one 4-chloropyridine-2-formyl chloride hydrochloride (III)

[0037] Add 2.7L of thionyl chloride and 90mL of N,N-dimethylformamide into the reaction flask, and stir thoroughly; then add 1.5Kg of pyridine-2-carboxylic acid, raise the temperature to 75°C, react for 24 hours, and distill under reduced pressure to fully remove Thionyl chloride was used to obtain the crude product of 4-chloropyridine-2-formyl chloride hydrochloride (III), which was directly carried out to the next reaction.

Embodiment 2

[0038] The synthesis of embodiment two 4-chloropyridine-2-formic acid methyl ester hydrochloride (IV)

[0039] Add 1L of toluene to the above crude compound (III), heat to 50°C, and add 1L of methanol under full stirring. After the dropwise addition, filter to obtain a solid with a purity of 70%; add 7L of water and 3L of ethyl acetate to the solid , liquid separation to obtain the aqueous solution of compound (IV), directly used in the next step reaction. The purity of compound (IV) in aqueous solution is 97%.

Embodiment 3

[0040] The synthesis of embodiment three 4-chloro-N-methylpyridine-2-carboxamides (V)

[0041] The above aqueous solution of compound (IV) and 2.3 Kg of 30% methylamine aqueous solution were thoroughly mixed and then stirred at room temperature for 2 hours. Subsequently, the reaction solution was extracted three times with 5 L of ethyl acetate each time, and the organic phase was obtained by liquid separation. The organic phase was extracted once again with 5L saturated brine, and after the organic phase was dried, the organic solvent was removed under reduced pressure to obtain 1.77Kg 4-chloro-N-methylpyridine-2-carboxamide (V), which was directly used in the next step reaction, The three-step reaction yield is 85%.

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Abstract

The invention discloses a method for preparing sorafenib. 2-picolinic acid is subjected to chlorination, esterification and methylamination to form a key intermediate, namely 4-chloropyridine-N-methyl-2-formamide, the intermediate and p-aminophenol are subjected to coupled reaction under alkaline condition, and a reaction product is reacted with 4-chloro-3-trifluoromethyl phenyl isocyanate to form a target compound.

Description

technical field [0001] The present invention relates to a method for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-methyl Method for amides (I). Background technique [0002] The earliest report of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (I) In the patent WO 2000042012, it was first developed by the German Bayer Pharmaceutical Company. Compound (I) is known as an inhibitor of the enzyme Raf kinase and can be used to treat diseases such as cancer. [0003] [0004] There are many documents and patents reporting the synthesis of compound (I). Such as CN 1721397A, US 2002165394, US2003105091, US 2003144278, US 2009068146, Organic Process Research and Development.2002, 777, etc., these literature methods can be represented by the following schemes: [0005] [0006] These preparation methods all use pyridine-2-carboxylic acid (II) as an initial raw ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81C07D213/803C07D213/79
Inventor 陈宇梁俊竺伟陈欢生
Owner SHANGHAI AOBO PHARMTECH INC LTD
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