Preparation method and key intermediates of Nintedanib

Abstract

The present invention relates to a completely-new preparation method of Nintedanib, and key intermediates thereof (such as 4-(1-alkoxy-1,3-dioxo-3-phenylpropane-2-yl)-3-nitro methyl benzoate and 3-benzoyl-2-oxodihydroindol-6-methyl formate), and a preparation method of the key intermediates. According to the present invention, the method has advantages of easily available raw materials, simple process, economy and environmental protection, and is suitable for industrial production; and the preparation method comprises that 1, 4-(1-alkoxy-1,3-dioxo-3-phenylpropane-2-yl)-3-nitro methyl benzoateis prepared from 4-halo-3-nitro-methyl benzoate and 3-oxo-3-phenylpropionate, 2, the compound reacts to generate a compound 3-benzoyl-2-oxodihydroindol-6-methyl formate, and 3, the compound reacts with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide to generate Nintedanib (I).

Description

Technical field:

[0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw material drug intermediates, and particularly relates to a preparation method of nintedanib, a drug used for treating idiopathic pulmonary fibrosis, its key intermediates, and its key Methods of preparation of intermediates. Background technique:

[0002] Nintedanib is a new oral drug developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease that seriously harms humans. The median survival time of patients after diagnosis is only 2 to 3 years. Nintedanib simultaneously blocks vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor. Blockade of these receptors results in inhibition of angiogenesis. Nintedanib is the first and only tyrosine kinase inhibitor approved for the treatment of idiopathic pulmo...

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