Ceritinib synthesis intermediate and preparation method thereof

Abstract

The invention provides a synthesis intermediate 8 of an anti-tumor drug ceritinib, a preparation method thereof, and an application of the intermediate 8 in synthesizing ceritinib. The preparation method of the intermediate 8 comprises the following steps: step (1), a compound 1 and an acid HX are subjected to salt formation, such that a compound 7 is obtained; step (2), the compound 7 is reduced through sodium borohydride, such that the compound 8 is obtained. The reaction formula is as the following. With prior arts, expensive platinum oxide is needed as a hydrogenation catalyst for preparing an intermediate 2 in a next step. With the intermediate 8, the above problem is avoided. Therefore, the intermediate 8 is suitable to be used in industrialized production of ceritinib.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthetic intermediate of an antitumor drug-ceritinib and a preparation method thereof. Background technique [0002] Ceritinib, the chemical name is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-( Propane-2-sulfonyl)-phenyl)-pyrimidine-2,4-diamine, the chemical structure is as follows: [0003] [0004] Ceritinib is an oral anaplastic lymphoma kinase (ALK) receptor inhibitor developed by Novartis. On April 29, 2014, the drug was approved by the FDA for marketing in the United States for the treatment of ALK-positive advanced non-small cell lung tumors. [0005] Regarding the synthesis of ceritinib, the synthetic route proposed in the patent CN200780051064.2 is shown in route 1: [0006] [0007] In this preparation route, the step of preparing intermediate 2 from compound 1 involves the complete reduction of the pyridine ring to the piper...

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Problems solved by technology

[0007] In this preparation route, the step of preparing intermediate 2 from compound 1 involves the complete reduction of the pyridine ring to the piperidine ring and the reduction of the benzene ring nitro group to the amino group. The reaction conditions of this step are harsh, it is difficult to complete the reaction, and a very expensive Platinum oxide is not suitable for industrial production as a hydrogenation catalyst

And in the follow-up synthetic route of the synthesis of Ceritinib from the above-mentioned intermediate 2, in order to avoid the substitution side reaction between the piperidine secondary amino group of the intermediate 2 and the synthon 4, BOC (tert-butoxycarbonyl) was introduced as a protecting group in advance, As a result, there are two additional steps in the overall route of introducing the protecting group and removing the protecting group, so the overall synthetic route is not economical enough and is not suitable for the requirements of large-scale production

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