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Method for preparing intermediate of axitinib and application of intermediate in preparation of axitinib

A technology of axitinib and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve problems such as incomplete reaction and generation of new impurities, and achieve the effects of reducing reaction steps, high product yield, and cost reduction

Active Publication Date: 2014-02-12
湖南欧亚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This method has a long synthetic route, harsh reaction conditions, complicated process and low overall yield, so it is not suitable for large-scale industrial production

Method used

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  • Method for preparing intermediate of axitinib and application of intermediate in preparation of axitinib

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] A kind of preparation method of Axitinib intermediate, comprises the following steps:

[0054] (1) Synthesis of 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0055] Add acetonitrile (2L) to a 5L reaction flask, then add 6-nitroindazole (163.1g, 1.0mol), 3,4-dihydro-2H-pyran (168.2g, 2.0mol), 2,3- Dichloro-5,6-dicyano-p-benzoquinone (22.7g, 0.1mol), heated to 82°C and refluxed for 2 hours until the reaction was complete, cooled to room temperature, rotary evaporated to dryness, added 2L of dichloromethane and 2L of water, Stir for 1 hour, separate layers, wash the organic phase with brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate to dryness, then dissolve in 2 L of acetonitrile, freeze in an ice-salt bath to -5°C and stir for 2 hours, suction filter, filter cake Wash with a small amount of cold acetonitrile, recrystallize from ethanol, and dry under vacuum at 60°C for 12 hours to obtain an off-white solid, 6-nitro-1-(tetrahydro-2H-pyran-2-yl)...

Embodiment 2

[0085] A kind of preparation method of Axitinib intermediate, comprises the following steps:

[0086] (1) Synthesis of 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0087] Add ethyl acetate (2L) to a 5L reaction flask, then add 6-nitroindazole (163.14g, 1.0mol), 3,4-dihydro-2H-pyran (210.3g, 2.5mol), p-toluene Sulfonic acid (20.7g, 0.12mol), heat up to 78°C and reflux for 3 hours until the reaction is complete, cool to room temperature, rotary evaporate to dryness, add 2L of dichloromethane and 2L of water, stir for 1 hour, separate layers, and use brine for the organic phase washed, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, then dissolved in 2L of acetonitrile, frozen in an ice-salt bath to -5°C and stirred for 2 hours, filtered with suction, washed with a small amount of cold acetonitrile, recrystallized from ethanol, 60 After vacuum drying at ℃ for 12 hours, 223.3 g of off-white solid was obtained, 6-nitro-1-(tetrahydro-2H-pyran-...

Embodiment 3

[0117] A kind of preparation method of Axitinib intermediate, comprises the following steps:

[0118] (1) Synthesis of 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0119] Add toluene (2L) to a 5L reaction flask, then add 6-nitroindazole (163.1g, 1.0mol), 3,4-dihydro-2H-pyran (193.5g, 2.3mol), methanesulfonic acid ( 14.4g, 0.15mol), heated to 85°C and refluxed for 3.5 hours until the reaction was complete, cooled to room temperature, rotary evaporated to dryness, added 2L of dichloromethane and 2L of water, stirred for 1 hour, separated, washed the organic phase with brine, Dry over anhydrous sodium sulfate, filter, rotary evaporate to dryness, then dissolve in 2L of acetonitrile, freeze in an ice-salt bath to -5°C and stir for 2 hours, filter with suction, wash the filter cake with a small amount of cold acetonitrile, recrystallize with ethanol, vacuum at 60°C After drying for 12 hours, an off-white solid was obtained, 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole, 2...

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Abstract

The invention relates to a method for preparing an intermediate of axitinib and application of the intermediate in preparation of axitinib. The preparation method for the intermediate of axitinib 3-iodine-6-nitro-1-(teralin-2H-pyran-2-base)-1H-indazole comprises the following steps that 6-nitroindazole and 3,4-dihydro-2H-pyran react under the action of catalyst so as to protect perssad tetralin-2H-pyran-2-base at N-H site, and the key intermediate with high yield is obtained through iodination at site 3. The application of the intermediate in preparation of axitinib is as follows: Heck coupled reaction is carried out on the intermediate and 2-vinyl pyridine, then nitro reduction and diazo-reaction for iodination are sequentially carried out, finally, the axitinib is obtained after docking of 2-sulfydryl-N-methyl benzamide and deprotection. The related main initial raw materials are easy to purchase in markets, and the method has high yield and high molecule economic efficiency, is efficient and environment-friendly, and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of an axitinib intermediate and an application in the preparation of axitinib. Background technique [0002] Axitinib (Axitinib, AG-013736, CAS: 319460-85-0) is a new small-molecule anticancer drug developed by Pfizer, mainly targeting VEGFR tyrosine kinase and inhibiting angiogenesis. Named Inlyta, it is used for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC) that is ineffective by other systemic treatments. It has been approved for clinical use in China in 2008. Tini is also a multi-target potent selective tyrosine kinase inhibitor, which can inhibit vascular endothelial growth factor receptor (VEGFR), including VEGF1 receptor, VECF2 receptor and VECF3 receptor, can Inhibits platelet-derived growth factor receptor (PDGFR) and c-KIT. Axitinib is known as the second generation of sunitinib, which is superior to sunitin...

Claims

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Application Information

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IPC IPC(8): C07D405/04C07D401/06
CPCC07D401/06C07D405/04
Inventor 林开朝莫国宁薛海鹏闵雄
Owner 湖南欧亚药业有限公司
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