Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor

Abstract

The invention relates to a novel quinazoline compound and a method for preparing a quinazoline crotyl compound for treating or preventing various adaptation diseases related to EGFR and HER2 kinase functions from the quinazoline compound. The method comprises the following steps: firstly, reacting a raw material with amino with diethylphosphonoacetic acid and N,N'-carbonyl dimidazole in a solvent at 25 DEG C to 50 DEG C, so as to transform the amino in the raw material into diethyl phosphorus acetamido to obtain an intermediate, and subsequently reacting the intermediate with N,N'-di-substituted acetaldehyde in a solvent in the presence of an alkali substance at minus 30 DEG C to minus 20 DEG C, thereby generating the target compound. By adopting the procedures, by virtue of simple aftertreatment, the target product of which the purity is greater than 98% is obtained, the total yield of the target product is as high as 74%, and in addition, by adopting the method, preparation of kilo-rate target products is successfully achieved, and batch production is easy to achieve.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to quinazoline compounds, their preparation method and their application in the preparation of tyrosine kinase inhibitors. Background technique [0002] CN102838550A discloses the quinazoline crotyl compound with general formula (I), [0003] [0004] where: R 1 for CH 2 F, CHF 2 , C 2 ~C 12 Fluorocarbonyl, C 2 ~C 12 Chlorinated hydrocarbon group; R 2 , R 3 independently hydrogen, C 1 ~C 12 Hydrocarbyl. [0005] The above-mentioned quinazoline crotyl compounds have been proved to be ideal high-efficiency dual irreversible tyrosine kinase inhibitors, which can inhibit the activity and phosphorylation of kinases by acting on the intracellular part of EGFR and competitively binding with ATP, and block EGFR tyrosine kinase. ATP-binding site of amino acid kinase to achieve the purpose of specific inhibition of EGFR. Such compounds can be used for the preparat...

AI Technical Summary

Problems solved by technology

Although the reduction reaction from compound 2 to compound 1 can obtain a yield of 97.8%, this is only a 10-gram scale process that can be completely reproduced and cannot be scaled up; the reaction from compound 1 to compound Ia is an anhydrous reaction. The conversion rate is lower than 50%, and the purity of the crude product is lower than 70%; and the compound 1 cannot be completely converted, and the product is complex and has many impurities, and the obtained crude product is an oily substance that is difficult to solidify, and must be purified by column chromatography, and the batch yield is low

On the whole, the method has low yield, difficult purification, high cost and low batch yield, and is not suitable for the industrialized production of such quinazoline crotyl compounds.

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