Process for the Preparation of 5-Fluorotryptophol

摘要

The present invention relates to a process for the preparation of 5-fluorotryptophol as well as a process for the preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4b]-indol]-4-amine using the 5-fluorotryptophol obtained by said first process. The process according to the invention provides 5-fluorotryptophol in improved yield and purity without the need for chromatographic purification of the product.

主权项

1. A process for preparing 5-fluorotryptophol comprising the steps of
a.) providing a mixture comprising 4-fluorophenyl-hydrazine, an activation reagent, water and at least one aprotic organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and isopropyl acetate; b) adding to the mixture a solution of at the most about 1.1 equivalents of 2,3-dihydrofuran in at least one aprotic organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran and isopropyl acetate to react with the 4-fluorophenylhydrazine to give 5-fluorotryptophol, wherein the aprotic solvent and water provided in steps a) and b) are provided in a ratio relative to each other such that a heterogeneous reaction mixture comprising a liquid organic and a liquid aqueous phase is formed either before or during addition step b); c) separating the organic from the aqueous phase; d) contacting the organic phase with an aqueous solution of at least one inorganic salt to form a heterogeneous mixture comprising a liquid organic phase and a liquid aqueous phase; e) separating the organic phase from the aqueous phase of the heterogeneous mixture; and f) isolating 5-fluorotryptophol from the organic phase via a precipitation step.