Preparation method of Axitinib

A preparation step and reaction technology, applied in the preparation field of axitinib, can solve the problems of increasing the potential risk of heavy metal residues, low yield and the like, and achieve the effects of promoting development, easy availability of raw materials and simple process

Active Publication Date: 2013-11-13
临泉县联正电子商务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no matter what route or preparation method, it involves the Heck reaction and uses expensive palladium catalysts

Method used

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  • Preparation method of Axitinib
  • Preparation method of Axitinib
  • Preparation method of Axitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 6-iodo-1H-indole (II) (2.42 g, 10 mmol), sodium nitrite (2.76 g, 40 mmol) and 50 mL of deionized water into a three-neck reaction flask, and stir at room temperature for 30 minutes. Within 30 minutes, 8 mL of 6N hydrochloric acid was slowly added dropwise to make the pH about 1-2, and the stirring reaction was continued for 5 hours. 100 mL of ethyl acetate was added, and the organic layer was separated after stirring for 15 minutes, and the aqueous layer was extracted twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure to obtain 2.45 g of brown solid (crude product) 6-iodo-3-formyl-1H-indazole (III), with a yield of 90.4%.

Embodiment 2

[0028] Under a dry and nitrogen atmosphere, add 6-iodo-3-formyl-1H-indazole (III) (1.36g, 5mmol) into a three-necked reaction flask, dissolve it with 25mL of N,N-dimethylformamide, Add [1,1'-bis(biphenyl-phosphino)ferrocene]palladium dichloride dichloromethane complex 0.18g and cesium carbonate 2.26g, after stirring at room temperature for 15 minutes, add 2-mercapto-N - Toluamide (1.0 g, 6 mmol), heated to 80° C., stirred for 12 hours, cooled to room temperature, added 50 mL of ethyl acetate, stirred and crystallized. After filtration, the obtained solid was dissolved in dichloromethane, passed through a silica gel column, the obtained liquid was concentrated and crystallized, filtered, and the filter cake was washed with water and ethyl acetate in sequence to obtain a brown solid N-methyl-2-[(3-formyl-1H -Indazol-6-yl)thio]benzamide (IV) 0.95 g, yield 61.1%.

Embodiment 3

[0030] Add triphenyl (2-methylenepyridine) phosphonium bromide (4.33g, 10mmol, 4eq) and 50mL tetrahydrofuran into a three-necked reaction flask, cool to -78°C under stirring, and add n-butyl dropwise under a dry nitrogen atmosphere. Lithium base (4.7mL, 1.6M, 3eq), after dropping, stirred for 30 minutes, heated up to 20°C, and transferred to the dropping funnel for use. Add N-methyl-2-[(3-formyl-1H-indazol-6-yl)sulfur]benzamide (IV) (0.78g, 2.5mmol) and 25mL tetrahydrofuran into a three-necked reaction flask, cool to 0°C, add the above-prepared ylide solution dropwise under stirring, and react with stirring for 30 minutes after dropping. Pour into saturated sodium bicarbonate solution to quench the reaction, extract twice with ethyl acetate, after the organic phase is concentrated, obtain off-white solid Axitinib (I) 0.82 through silica gel column chromatography (ethyl acetate / n-hexane). g, the yield is 85.0%.

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Abstract

The invention discloses a preparation method of Axitinib(I). The preparation method comprises the following steps of: with 6-halo-1H-indole (II) as a raw material, carrying out an oxidation rearrangement reaction to obtain 6-halo-3-formyl-1H-indole (III), carrying out a Migita reaction on the 6-halo-3-formyl-1H-indole (III) serving as an intermediate and N-methyl-2-mercaptobenzamide to obtain N-methyl-2-[(3-formyl-1H-6-yl)sulfur]benzamide (IV), and carrying out a Witting reaction on a ylide reagent (V) and the N-methyl-2-[(3-formyl-1H-6-yl)sulfur]benzamide(IV) serving as an intermediate to prepare Axitinib (I). The preparation method has the advantages that the raw materials are easily available and the process is concise, economicAL and environment-friendly; therefore, the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of axitinib. Background technique [0002] Axitinib is a multi-target tyrosine kinase inhibitor that can inhibit vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell growth factor receptor (c -KIT). The drug was developed by Pfizer Pharmaceuticals of the United States, and it was first listed in the United States on January 27, 2012. It was approved for the treatment of advanced renal cell carcinoma (renal cell carcinoma) that was ineffective for other drugs, and the trade name was Inlyta. [0003] The chemical name of Axitinib is: N-methyl-2-[(3-(1E-2-(pyridin-2-yl)ethene)-1H-indazol-6-yl)sulfur]benzamide, Its structural formula is: [0004] [0005] The research on the preparation method of axitinib has be...

Claims

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Application Information

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IPC IPC(8): C07D401/06
Inventor 许学农
Owner 临泉县联正电子商务有限公司
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