Preparation method of erlotinib

Abstract

The invention discloses a preparation method of erlotinib and belongs to the technical field of medicament preparation. In the preparation method, 4,5-di(2-methoxylethoxy)-2-nitrobenzonitrile is used as a raw material and is subjected to reduction and hydrolysis to obtain an intermediate namely 2-amino-4,5-di(2-methoxylethoxy) benzamide which is subjected to cyclization with triethyl orthoformate directly to obtain an erlotinib key intermediate namely 6,7-di(2-methoxylethoxy)-3H-quinazoline-4-one, and a chlorinated product of quinazoline reacts with aminophenylacetylene to obtain erlotinib. By adopting the preparation method disclosed by the invention, the defects that an expensive catalyst is used by nitryl reduction in the conventional synthetic method and the temperature during cyclization is relatively high are overcome, a process with a formamidine intermediate is also avoided, the reaction step is shortened, the reaction cost is reduced, and the yield is improved. Moreover, all reaction conditions in the preparation method are very mild, so that the preparation method is particularly suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of erlotinib. Background technique [0002] Erlotinib, trade name Tarceva, is an epidermal growth factor EGFR tyrosine kinase small molecule inhibitor anti-cancer drug developed by OSI Pharmaceuticals of the United States. It was first launched in the United States in 2004 and is mainly used for the treatment of non-small cell lung cancer. The chemical name of Erlotinib is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, and its mechanism of action is to interact with the substrate in the cell Competitive binding inhibits EGFR phosphorylation, blocks the transduction of tumor cell signals, thereby inhibiting the growth of tumor cells and inducing their death. The structure of Erlotinib is shown in Formula V. [0003] [0004] The main steps in the synthetic method of erlotinib involve the synthesis of the key inte...

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Problems solved by technology

In the prior art, existing literature has reported the synthetic method of this intermediate, and the main problem in these methods is that nitration yield and purity are lower, nitro reduction uses expensive catalyst, and temperature is higher during cyclization etc.

[0007] Although the synthesis of 6,7-bis-(2-methoxyethoxy)-3H-quinazolin-4-ketone by this method can be carried out in industrialized production, the cyclization needs to pass through the formamidine intermediate, and the reaction steps are long and increase Reduced the reaction cost, but also affected the yield of erlotinib

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