Preparation method of tucatinib

Abstract

The invention relates to a preparation method of tucatinib. The method comprises the following steps: by taking 4-hydroxy-6-chloroquinazoline as a raw material, firstly carrying out copper-catalyzed C-N cross-coupling reaction on the 4-hydroxy-6-chloroquinazoline and 2-amino-4, 4-dimethyl-4, 5-dihydrooxazole, then activating the 4-hydroxy of quinazolinone by adopting a BOP, and enabling product and 4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-yloxy)-3-methylaniline to be subjected to a nucleophilic substitution reaction to obtain tucatinib. With the method, using of high-corrosivity and high-toxicity reagents is avoided, and the method has low requirements on equipment, the operation difficulty and environmental protection requirements are reduced, and the method has the advantages of high product yield and high product purity; the process is simple and environment-friendly and suitable for large-scale production.

Description

technical field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of tucatinib. Background technique

[0002] Tucatinib (Tucatinib; Tucatinib; Irbinitinib, ARRY-380, ONT-380) is a small-molecule oral tyrosine kinase (TKI) inhibitor that has Highly specific target selectivity. On April 17, 2020, the U.S. FDA approved tucatinib in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adults with previously treated advanced HER2-positive breast cancer that cannot be surgically removed or metastasized patient. Tucatinib was originally developed by Array Biopharma, and after being transferred to Oncothyreon (ONTY) (later renamed Cascadian Therapeutics), it was acquired by Seattle Genetics Inc. and launched on the market. Tucatinib has good blood-brain barrier permeability, which is of great significance to the treatment of HER2-positive breast cancer brain metastases. A...

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