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A kind of preparation method of Axitinib intermediate and its application in the preparation of Axitinib

A technology of axitinib and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve the problems of new impurities and incomplete reactions, and achieve the effects of reducing reaction steps, reducing costs, and high product yields

Active Publication Date: 2016-02-24
湖南欧亚药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] This method has advantages over the first and second methods, and can scale up production, but the reaction in the reaction step is not complete, and new impurities will be generated, which need to be purified by column

Method used

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  • A kind of preparation method of Axitinib intermediate and its application in the preparation of Axitinib
  • A kind of preparation method of Axitinib intermediate and its application in the preparation of Axitinib
  • A kind of preparation method of Axitinib intermediate and its application in the preparation of Axitinib

Examples

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

A preparation method of an axitinib intermediate and the application of the intermediate in the preparation of axitinib, an axitinib intermediate 3-iodo-6-nitro-1-(tetrahydro-2H-pyridine The preparation method of pyran-2-yl)-1H-indazole: 6-nitroindazole reacts with 3,4-dihydro-2H-pyran under the action of a catalyst, and the protecting group tetrahydro-2H on the N-H position -Pyran-2-yl, then react with iodine at the 3-position to obtain a high-yield key intermediate, the application of the intermediate in the preparation of Axitinib: the Heck coupling reaction between the intermediate and 2-vinylpyridine , followed by nitro reduction and diazotization reaction to add iodine, and finally docked with 2-mercapto-N-methylbenzamide and then deprotected to prepare Axitinib. The main starting materials involved are all readily available on the market. The purchased raw materials have high yield and high molecular economic efficiency, which is an efficient green and environmentally friendly process method, which is suitable for large-scale industrial 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, which mainly targets VEGFR tyrosine kinase and inhibits angiogenesis. Named Inlyta, it is used for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC) that is ineffective in other systemic treatments. It has been approved for clinical use in China in 2008. It is also a multi-target potent selective tyrosine kinase inhibitor, which can inhibit the vascular endothelial growth factor receptor (VEGFR), including VEGF1 receptor, VECF2 receptor and VECF3 receptor, can inhibit the platelet-derived growth factor receptor Body (Platelet-derived growth factor receptor, PDGFR) and c-KIT. Axitinib is known as the second ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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