Method for preparing lapatinib key intermediates

Abstract

The invention discloses a method for preparing lapatinib key intermediates. The method includes steps of (1), carrying out chlorination on formamidine or salt of the formamidine and N-chlorosuccinimide to prepare compounds 2 or salt of the compounds 2; (2), carrying out reaction on the compounds 2 or the salt of the compounds 2 and compounds 3 to obtain compounds 5; (3), carrying out reaction on the compounds 5 and thionyl chloride to obtain compounds 6 which are the lapatinib key intermediates. The method has the advantages of inexpensive and easily available starting materials, simplified steps, high atom utilization rate, mild reaction conditions, high yield, suitability for industrial production and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of a lapatinib key intermediate. Background technique [0002] As an antitumor drug, the chemical name of lapatinib (lapatinib) is N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(( (2-(methylsulfonyl)ethyl)amino)methyl)-2-furyl)-4-quinazolinamine di-p-toluenesulfonate, which was approved for marketing by the US FDA in March 2007, is a 4-anilinoquinazoline receptor tyrosine kinase inhibitors for the treatment of advanced or metastatic breast cancer. [0003] 4-Chloro-6-nitroquinazoline is the key intermediate of lapatinib, the preparation method of lapatinib and related intermediates reported in patents WO05046678 and WO020255. In the known synthetic route, directly adopt 6-halo-quinazolin-4-one as raw material, prepare with chlorinating agents such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride,...

AI Technical Summary

Problems solved by technology

In the known synthetic route, directly adopt 6-halo-quinazolin-4-one as raw material, prepare with chlorinating agents such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride The obtained intermediate 6-halogenated-chloroquinazoline, the method directly adopts the expensive 6-halogenated-quinazolin-4-one as a raw material, which causes the high problem of industrial production cost and is not suitable for large-scale industrialization Production, the production process pollutes the environment and safety risks are difficult to control

[0004] Regarding the current preparation methods of lapatinib, although there are many methods for side chain linkage and quinazoline ring formation, there are still complicated processes, high requirements for reaction conditions and operations, expensive starting materials and low atom utilization, heavy metal pollution and Problems such as low yield

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