合成路线1

Flesinoxan hydrochloride is obtained in a multiple-step synthesis, including the resolution of one of the racemic intermediates (VIII), starting with the monobenzyl ether of catechol (I). Treatment of (I) with sulfuryl chloride in methylene chloride gives (II). This chloro compound is nitrated with nitric acid resulting in the mononitro derivative (III). In a one-pot procedure compound (III) is converted to the racemic benzodioxan structure (V) by condensation with epichlorohydrin, followed by treatment of the intermediate (IV) with hydrochloric acid and with potassium hydroxide, respectively. After conversion of the hydroxymethyl derivative to the benzoic ester (VI), compound (VII) can be obtained by catalytic hydrogenation of (VI). Treatment of (VII) with bischloroethylamine results in the racemic piperazine analogue (VIII). In this phase the resolution of the piperazine is carried out with (+)-camphorsulfonic acid. After several recrystallizations, the optically pure (+)-enantiomer is obtained. Reaction of this (+)-N-[2-(hydroxymethyl)-1,4-benzodioxan-5-yl]piperazine (VIII) with N-(4-fluorobenzoyl)aziridine, saponification of the benzoate ester and treatment with hydrochloric acid gives flesinoxan monohydrochloride.