4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and preparation method and application thereof

Abstract

The invention discloses a 4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and a preparation method and the application thereof. The method comprises the following steps: dissolving 2-amino-3-phenyl cyano benzofuran and ortho-formate in a solvent A; reacting in acid catalysis and heating conditions; concentrating to obtain an intermediate after reaction; performing backflow reaction on the intermediate and an amine compound in a solvent B to obtain a reaction product, and performing separation and purification on the reaction product to obtain a product. The compound provided by the invention can be used for preparing antikinase and anti-tumour and anti-vascular medicines. The compound has remarkable EGFR tyrosine kinase inhibitory activity, significant study value and good application prospect; the preparation method is wild in reaction condition, easy to operate, short in reaction time, high in yield, and low in cost and facilitates large-scale preparation.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a 4-substituted amino-6-methoxycarbonylbenzofuro[2,3-d]pyrimidine compound and its preparation and application. Background technique [0002] Benzofuropyrimidine derivatives are a class of fused heterocyclic compounds with good biological activity, for example: N-(3-bromophenyl)-benzofuro[3,2-d]pyrimidine (structural formula A) has Inhibitory activity of epidermal growth factor receptor tyrosine kinase (J.Med.Chem.1999, 42, 5464-5474); 4-Alkylamino-8-methylsulfonylbenzofuro[3,2-d]pyrimidine -2-amine (structural formula B) is a histamine H 4 Receptor modulator with antihistamine H 4 Mediated various immune and inflammatory reactions and other activities (EP2020412A1, [P] 2009-02-04); derivatives of benzofuro[3,2-d]pyrimidin-2-one (structural formula C) can inhibit HIV The expression of -1 reverse transcriptase has better anti-HIV-1 virus activity (Bioorg. Med. Chem...

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Problems solved by technology

[0004] At present, the reported synthesis methods of benzofuropyrimidines mainly include the following: (1) Electrochemical oxidation of 3,4-dihydroxybenzoic acid and coupling of 1,3-dimethylbarbituric acid Decarboxylation reaction (J.Org.Chem., 2002, 67, 5036-5039), but this type of method requires special electrode materials, long reaction time, and narrow substrate applicability; (2) o-methoxyarylboronic acid compounds Suzuki coupling reaction with aminopyrimidines (WO2007 / 090852A1, [P] 2007-08-16), but this method requires expensive Pd metal complexes to catalyze, the reaction conditions are harsh, and the production cost is high; (3) base Catalyzes the coupling ring closure series reaction of o-cyanophenol and α-bromocarbonyl compound (Bioorg.Med.Chem.Lett., 2013,23,2775-2780), but the reaction reagents of this method are highly toxic and cause serious environmental pollution , and the synthetic route is longer

At present, compared with benzofuro[3,2-d]pyrimidines, there is no literature report on the synthesis method of benzofuro[2,3-d]pyrimidines, and there is no use of renewable resources for Starting materials, related reports on the preparation of 4-substituted amino-6-methoxycarbonylbenzofuro[2,3-d]pyrimidines by metal-free catalysis

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