Sibutramine (1) is an antidepressant used also for the treatment of obesity and Parkinson disease. Known methods for preparation of crucial intermediate in the synthesis of 1 - 1-(4-chlorophenyl)-1-cyanocyclobutane (2) - consist of cycloalkylation of 4-chlorophenylacetonitrile with 1,3-dibromopropane in the presence of such base/solvent systems as: NaH/DMSO/ether, solid KOH/DMSO/ether, solid KOH/toluene/quaternary ammonium salt as a catalyst (solid - liquid phase transfer catalysis, PTC). All of them are inconvenient for large scale applications. On the other hand, it is now commonly accepted, that liquid-liquid PTC (conc. aq. solution of NaOH as a base) is the best practical procedure for alkylation of carbanions of arylacetonitriles and their derivatives. However, with 1,3-dibromopropane under typical PTC conditions (50% NaOH aq. as a base) yields of 1-aryl-1-cyanocyclobutanes are low, b-elimination of HBr from the alkylating agent is often observed, leading to mono- and diallylated arylacetonitriles as by product, which are difficult to separate.

We found, that a simple change of 50% NaOH for 60% KOH overcomes all the difficulties mentioned above. Cycloalkylation of 4-chlorophenylacetonitrile with 1,3-dibromopropane carried out in the presence of 60% KOH and tetrabutylammonium bromide (TBAB) as a catalyst in toluene as a solvent proceeds in high yield, b-elimination of HBr from the alkylating agent practically does not proceed and isolation of 2 is very easy. This process was performed on a 10 mole scale, with the yields exceeding 70%.

After separation of the phases and addition of an appropriate amount of KOH to aqueous phase it is possible to use it again in the next synthesis.

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