PREPARATION METHOD OF (-)PYRIDOBENZOXAZINE CARBOXYLIC ACID DERIVATIVES

摘要

PURPOSE: A method for the preparation of (-)pyridobenzoxazine carboxylic acid derivatives and pharmaceutically acceptable salt thereof is provided which is cost effective and mass-produces them by using a starting material prepared from 4-chloro-5-fluoro-2-halo-3-nitrobenzoic acid derivatives of the lower cost. CONSTITUTION: A preparation method of optically active (-)pyridobenzoxazine carboxylic acid represented by formula (1) and pharmaceutically acceptable salt thereof, comprises the steps of: substituting the compound of formula (V) with reaction material having R group defined as below to give a compound of formula (IV) in the presence of base; carrying out cyclization of the compound of formula (IV) to give a compound of formula (III) in the presence of an organic polar solvent and base; selectively substituting the compound of formula (III) with the substituted piperazine derivative in the presence of an organic polar solvent and base to give a compound of formula (II); and carrying out hydrolysis and cyclization of the compound of formula (II) using metalhydroxide and the organic solvent. In the formulas, X is halogen atom; R is hydrogen or -(CO)R2 (wherein, R2 is C1-C5 lower alkyl, substituted or unsubstituted phenyl, C1-C5 (cyclo)alkoxy, substituted or unsubstituted phenoxy, substituted or unsubstituted amine or C1-C5 alkylthio); and R1 is hydrogen atom or lower alkyl.