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Patent Watch

May 2, 2011

Here’s a better way to make an antipsychotic.
Paliperidone (9-hydroxyrisperidone, 1) is a metabolite of the schizophrenia drug risperidone and is itself a psychotropic agent. Current methods for preparing 1 are time-consuming and give low yields. S. Ini and co-inventors describe a process for preparing 1 by the reaction of chloroethyl heterocycle 2 with fluoro heterocycle 3 in the presence of an inorganic base and with an optional halide salt or phase-transfer catalyst (PTC). The preferred base is Na2CO3, although K2CO3 is also suitable. The halides used are KI or KBr, and the PTC is n-Bu4I or n-Bu4Br.

The reaction is carried out by heating the components as a suspension in MeCN or i-PrOH. After completion, the mixture is filtered, water is added, and the product is isolated by filtration. In one example that uses Na2CO3 but no halide, the yield of 1 is 82.5%; but the inventors do not report its purity. A process that uses Na2CO3, KI, and DMF solvent produces 1 in 58% yield and >90 % purity. This is the only example in which the product purity is given.

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The patent does not give the details of the preferred method of isolating and purifying 1, although crystallization from MeCN is mentioned as being suitable. Reactant 2 can be prepared by a method reported in US Patent 5,158,952 (1992), and 3 is commercially available.

The inventors claim to have found an efficient method of making the desired product, but they do not provide much evidence to back up that claim. (Teva Pharmaceutical Industries [Petach Tikva, Israel]. US Patent 7,915,412, March 29, 2011; Keith Turner)