Preparation method of n-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[(5-formyl)furan-2-yl]-4-quinazolinamine

Abstract

The invention provides a synthetic method of N-[3-chloro-4-[(3-fluorophenyl)methoxyl]phenyl]-6-[(5-formyl)furan-2-yl]-4-quinazolineamine (IV). A reaction is carried out between a Grignard reagent (III) which is prepared from 2-(5-bromofuran-2-yl)-1,3-dioxolane (II) and N-[4-3-chloro-4-[(3-fluorophenyl)methoxyl]phenyl]-6-iodo-4-quinazolineamine (I) under catalysis of ferric acetylacetonate, and the reaction equation is shown in the specification.

Description

Technical field: [0001] The invention relates to the preparation of a quinazoline derivative. Background technique: [0002] N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[(5-formyl)furan-2-yl]-4-quinazolinamine (IV) (CAS:) It is a key intermediate for the synthesis of lapatinib [0003] WO9935146A1 reported the synthesis process of the key intermediate of lapatinib, the method is outlined in the following reaction scheme: [0004] [0005] This method uses a highly toxic organotin reagent, which is likely to cause environmental pollution and has a safety risk for pharmaceutical production. [0006] Ji Xing et al. (Chinese Journal of Pharmaceutical Industry, 2009, 40 (11), 801) reported a synthetic method for lapatinib, which involved intermediate (2) N-[4-3-chloro-4 -[(3-Fluorophenyl)methoxy]phenyl]-6-iodo-4-quinazolinamine. The method is outlined as follows: [0007] [0008] During the synthesis of the intermediate N-[4-3-chloro-4-[(3-fluorophenyl)methoxy]...

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Problems solved by technology

[0012] The above-mentioned synthetic method uses 6-iodo-4-ketoquinazoline (7) as a raw material, and carries out chlorination reaction with 1.2 times the amount of phosphorus oxychloride, and the purity of the product prepared by the reaction is not high, and column chromatography is required for purification, while the product The yield is lower, only 40%

[0013] Chinese patent CN102911164A discloses a synthetic method of compound IV, using N-[4-3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-iodo-4-quinazoline Amine and 5-formylfuran-2-boronic acid undergo suzuki coupling reaction to obtain compound IV. This method uses boron-containing raw materials. On the one hand, the price is expensive, and on the other hand, the boron-containing waste after the reaction is completed is also difficult to handle.

[0018] The reaction carried out with THF / NMP solvent has a lower yield

However, there are many by-products, and the reaction yield is low when ether is used as a solvent, indicating that although iron acetylacetonate can catalyze the coupling reaction of Grignard reagent and alkane halide, it is greatly affected by reactants and reaction conditions.

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