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Sorafenib compound

A sorafenib and compound technology, applied in the field of drug preparation, can solve problems such as low yield and purity, long reaction time, and inconvenient operation, and achieve the effects of lower reaction temperature, shorter reaction time, and easy operation

Active Publication Date: 2016-06-08
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Purpose of the present invention is exactly in order to overcome the deficiency of existing preparation method, a kind of preparation and refining method of Sorafenib intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide are provided , to solve the problems of inconvenient operation, long reaction time, low yield and purity, and high cost in the preparation of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide in the prior art

Method used

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Examples

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preparation example Construction

[0041] Solid base carrier Al 2 o 3 Preparation of / KOH:

[0042] At room temperature, make 20 grams of KOH into a saturated aqueous solution, and add 60 grams of neutral Al 2 o 3 (100-200 mesh) stirred and reacted at 70°C for 1.5 hours, then evaporated to dryness, and dried the solid base at 120°C to constant weight to obtain the solid base carrier Al 2 o 3 / KOH.

[0043] Solid base carrier Al 2 o 3 Preparation of / KF:

[0044] Dissolve 58 grams of KF in 100ml of water, add 100 grams of neutral Al 2 o 3 (100-200 mesh) stirred and reacted at 65°C for 1 hour, evaporated to dryness, and dried the solid base at 120°C for 4 hours to obtain the solid base carrier Al 2 o 3 / KF.

[0045] Composite solid base Al 2 o 3 / KOH / K 2 CO 3 Preparation of:

[0046] At room temperature, 28 grams of KOH, 69 grams of K 2 CO 3 Prepare saturated aqueous solutions respectively, after mixing the above two protective aqueous solutions, add 101 grams of neutral Al 2 o 3 (100-200 mes...

Embodiment 1

[0060] 1) Preparation of crude product of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide

[0061] 4-Chloro-N-methylpyridine-2-carboxamide (170.6g, 1mol) and p-aminophenol (120g, 1.1mol) were stirred and dissolved in 853ml of acetonitrile, and 24.4g of phase transfer catalyst 18-crown- 6 and composite solid base carrier Al 2 o 3 / KOH / K 2 CO 3 1365g, heat to reflux for 1.5h after the reaction is complete, add 4.9g of filter aid diatomaceous earth for hot filtration, and then concentrate to obtain a light yellow powder.

[0062] 2) Recrystallization

[0063] Add the light yellow powder obtained in step 1) into 853ml of ethyl acetate, heat to reflux with stirring, continue to reflux for 30-40 minutes after dissolving, cool down to 25-35°C, keep stirring and wash the crystal for 3-8 hours, centrifuge The obtained wet product is dried at 45-50° C. for 10-15 hours to obtain the pure product of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide. Yield 92.5%, purity 99.8%, see ...

Embodiment 2

[0065] 1) Preparation of crude product of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide

[0066] 4-Chloro-N-methylpyridine-2-carboxamide (85.3g, 0.5mol) and p-aminophenol (54.6g, 0.5mol) were stirred and dissolved in DMF512ml, and a phase transfer catalyst tetrabutylammonium bisulfate was added (TBAB, 6.8g) and composite solid base support Al 2 o 3 / NaOH / K 2 CO 3 597g, react at room temperature for 1.8h After the reaction is complete, add 3.4g of filter aid perlite for hot filtration, and then concentrate to obtain a light yellow powder.

[0067] 2) Recrystallization

[0068] Add the light yellow powder obtained in step 1) into 512ml of isopropanol, heat to reflux under stirring conditions, continue to reflux for 30-40 minutes after dissolving, cool down to 25-35°C, keep stirring and wash the crystal for 3-8 hours, centrifuge The obtained wet product is dried at 45-50° C. for 10-15 hours to obtain the pure product of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide. ...

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Abstract

The invention relates to a sorafenib compound and a preparation method of an intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide of the sorafenib compound, and belongs to the technical field of medicine preparation. The preparation method comprises the steps that 4-chloro-N-methyl pyridine-2-formamide and p-aminophhenol are dissolved into polar organic solvent, a phase transfer catalyst and a solid inorganic base carrier are added, after a heating reflux reaction is complete, hot filtration is performed by adding a filter aid, and a crude product is recrystallized through ethyl acetate and methylbenzene or isopropanol to obtain a pure product. The problems that in the prior art, when 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide is prepared, operation is inconvenient, the general reaction time is too long, the yield and the purity are low, and the cost is high are solved. Accordingly, operation is easy, convenient and safe, the reaction time is short, the pure product with the higher purity and yield can be prepared under the normal temperature condition, the difficulty of final product purification is reduced, and the quality stability and medication safety of the sorafenib are further guaranteed.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a sorafenib compound and a method for preparing and refining an intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide. Background technique [0002] Sorafenib Tosylate Tablets (Sorafenib Tosylate Tablets), trade name: Nexavar (NEXAVAR), Sorafenib is a small molecular entity compound, is the first raf kinase inhibitor and VEGFR approved by the US FDA and China CFDA Inhibitor, also the first tyrosine kinase inhibitor approved for renal cells, and the first approved first-line treatment for advanced or metastatic hepatocellular carcinoma. [0003] Sorafenib was developed and marketed by Bayer and Onyx, and its chemical name is 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureide]-phenoxy}-N-methyl Basepyridine-2-carboxylic acid methylamine p-toluenesulfonate, its structural formula is formula (I). [0004] [0005] 4-(4-aminophenoxy)-N-methyl-2-pyridinecarbo...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 章杜前谢厅边红玲黄晔魏文登
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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