Preparation method of intermediate of medicine for treating chronic dry eye

Abstract

The invention relates to a preparation method of an intermediate of a medicine for treating chronic dry eye. The method comprises the following steps: (a) adding methyl alcohol, m-hydroxybenzoic acid,NaOH and NaI to a reaction vessel; and dropwise adding NaClO water solution with stirring in order to react under the temperature of -10 to -5 DEG C; (b) adding tetrahydrofuran, a compound II, a catalyst and trimethylamine to another reaction vessel; dropwise adding trimethylsilylacetylene under inert gas; and stirring to react; and (c) adding methyl alcohol, a compound III, cuprous iodide and trimethylamine to a third reaction vessel; reacting under the temperature of 50-80 DEG C; filtering; collecting filtrate; dropwise adding NaOH solution; stirring to react; removing methyl alcohol and trimethylamine in a pressure reduction manner; regulating pH through an acid solution; filtering; and drying to obtain the product. According to the method, the finished product can be prepared by threesteps; the yield and the purity are high; the cost is low; and industrial production can be carried out.

Description

Technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and relates to a dry eye syndrome drug intermediate, in particular to a preparation method of a dry eye syndrome drug Ritamilast intermediate. Background technique [0002] Lipalast (ie Lifitegrast) can bind to integrin lymphocyte function associated antigen-1 (LFA-1), a cell surface protein found on the surface of white blood cells and blocking its associated ligand intracellular adhesion molecule-1 ( ICAM-1), and then ICAM-1 expression in cornea and conjunctival tissues in dry eye disease. [0003] Benzofuran-6-carboxylic acid (CAS: 77095-51-3) is a key intermediate for the formation of tadilast. The existing benzofuran-6-carboxylic acid intermediates usually have the following two routes: 1. Using 3-bromophenol as a raw material, the ring is closed to obtain 6-bromobenzofuran, which is then combined with CO under Pd catalysis. 2 Coupling to obtain the target compound, this route is short,...

AI Technical Summary

Problems solved by technology

The existing benzofuran-6-carboxylic acid intermediate usually has the following two routes: 1. With 3-bromophenol as raw material, 6-bromobenzofuran is obtained by ring closure, and then reacted with CO under Pd catalysis 2 Coupling to obtain the target compound, the route is short, but ring formation will inevitably produce isomers, which cannot be amplified; Reaction to get [2-(1,3-dioxolan-2-yl) ethyl] diethyl phosphonate, then react with furan-2-carbaldehyde to get (E)-2-[( 1,3-dioxolan-2-yl)methyl]-3-(furan-2-yl)ethyl acrylate, and then cyclized to obtain ethyl benzofuran-6-carboxylate, which was subjected to alkali hydrolysis and acidification That’s right; the cost of this route is relatively high, and more phosphorus by-products will be produced, which will seriously pollute the environment

Images