Synthesis method of indometacin and analogues thereof

Abstract

The invention belongs to the technical field of indometacin synthesis, and discloses a synthesis method of indometacin and analogues thereof. The synthesis method of indometacin and analogues thereofcomprises the following steps: directly introducing alkyl, aromatic ring or heteroaromatic ring to the C2 position of indole through palladium catalyzed reaction; introducing a carboxylic acid fragment to the C3 position of the indole; and introducing an aroyl group to the N1 position of the indole. The method solves the problems that most of existing indometacin synthesis methods carry out modification by constructing an indole ring, simple structure change of indometacin molecules based on the synthesis strategy often needs de novo synthesis and synthesis steps for later modification and structure-activity relationship research of the indometacin molecules are tedious.

Description

technical field [0001] The invention belongs to the technical field of indomethacin synthesis, in particular to a method for synthesizing indomethacin and analogues thereof. Background technique [0002] Indomethacin is a nonsteroidal antiinflammatory drug (NSAIDs), which regulates a series of cell Behavioral, clinically commonly used for anti-inflammatory, pain relief. In recent years, some indomethacin analogs have been found to have the ability to reverse tumor drug resistance (J. Med. Chem. 2012, 55, 8152-63). COX enzymes are found to be highly expressed in many tumor cells, so COX inhibitors are also used in clinical research for adjuvant therapy of tumors (Br.J.Cancer.2011,105,452-459), and COX inhibitors are used in tumor immune escape Also played an important role (Cancer. Immunol. Res. 2017, 5, 695-709; Cell. 2015, 162, 1257-1270). Although many non-steroidal anti-inflammatory drugs have been developed, there is still a lot of room for more efficient anti-inflamm...

AI Technical Summary

Problems solved by technology

[0014] In summary, the existing problems in the prior art are: most of the existing indomethacin synthesis methods are to construct the indole ring and then modify it. Based on this synthesis strategy, simple structural changes are carried out on the indomethacin molecule. De novo synthesis is often required, the steps are relatively lengthy, and there are certain functional groups and substrate limitations, which is not conducive to the structural modification of indomethacin molecules and further research on biological functions

However, how to selectively introduce corresponding substituents at the C2 and C3 positions of indole while avoiding the use of redundant protecting groups is obviously quite challenging.

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