PROCESS FOR PREPARATION OF CIS-(+-)-(1R,2S)-REL-2-(AMINOMETHYL)-N,N-DIETHYL-1-PHENYLCYCLOPROPANECARBOXAMIDE HYDROCHOLORIDE (18-Jan-2010)

PROCESS FOR PREPARATION OF CIS-(+-)-(1R,2S)-REL-2-(AMINOMETHYL)-N,N- DIETHYL-1-PHENYLCYCLOPROPANECARBOXAMIDE HYDROCHOLORIDE

    Z-(1R*,2S*)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide ("MLC") of the following formula:

is an intermediate in the synthesis of Cis-(+-)-(1R,2S)-rel-2-(Aminomethyl)-N,N-diethyl-1- phenylcyclopropanecarboxamide hydrocholoride ("MLC HCl") of the following formula

MLC HCl is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI).

    A process for recovering MLC from a reaction mixture where it is formed is described herein below. Also described process for preparation of MLC HCl salt.

    The recovery process includes extracting MLC from a reaction mixture where MLC is formed with n-butyl acetate; and evaporating the solvent to obtain MLC concentrate. This concentrate can be used to prepare MLC HCl.

    The extractions can be done either directly form the said reaction mixture or after addition of a base to the said reaction mixture. The base can be, for instance sodium hydroxide, and can be provided in aqueous solution, for example in concentration of about 20% to about 40%.

When not adding a base, the extractions can be repeated, for example 3 times.

The evaporation can be done under vacuum, typically to about 2/3 volume.

The obtained concentrate of MLC in n-butyl acetate can be used to prepare MLC HCl.

1

    The process can be done by using n-butyl acetate as the solvent, for example, as described in examples 1-4 herein. MLC HCl is formed in a suspenstion, from which it can be recovered, for example,,by washing and drying.

EXAMPLES

Example 1: Three extractions of MLC-base

    50.0 g (0.133 mol) of 1-phenyl-1-diethylaminocarbonyl-2-phtalimidomethyl cyclopropane, 245 ml 40% methylamine (aq.) and 33 ml of water were charged to a 500 ml three necked flask. The suspension was heated to 40^oC and retained for three hours at this temperature. Than reaction solution was cooled to room temperature (20-25^oC), added 250 ml of water and MLC base was extracted in n-butyl acetate. After three times extractions (1 x 600 ml and 2 x 400 ml of n-butyl acetate), n- butyl acetate fractions were collected, washed with 300 ml of water and vacuum evaporated on 2/3 of volume. Concentrate of MLC base in n-butyl acetate (volume about 950 ml) was cooled to room temperature (20 - 25^oC) and 55 ml of previous prepared solution of HCl in n-butyl acetate (about 2 mol solution of HCl in n-butyl acetate) was added dropwise to pH about 1.8 (less than 5). Crystallization of MLC hydrochloride started at pH about 9, during addition of HCl/n-butyl acetate solution. The suspension was mixed for one hour at room temperature (20 - 25^oC). MLC hydrochloride 33.86 g (yield 90.16 %) was obtained after filtration, washing with 210 ml of n-butyl acetate and d...