Patent Watch
September 7, 2009
Use a molybdenum complex in the synthesis of a key drug intermediate. 3-(5-Nitrocyclohex-1-eneyl) acrylic acid (3) is an intermediate in the synthesis of compounds that act as thrombin receptor antagonists (TRAs) and are used to treat thrombotic, inflammatory, and atherosclerotic disorders. T. K. Thiruvengadam and co-inventors discuss methods of making nitro compounds by oxidizing oximes and conclude that the known processes are not suitable for use with compounds that contain other functional groups. In particular, no double bonds should be oxidized or isomerized during the reaction. Hence, the objective is to convert an unsaturated oxime to an unsaturated nitro compound.
The inventors achieve this goal with a process that uses a Mo(VI–VII) peroxo complex catalyst. The figure illustrates the method used to prepare 3 by oxidizing oxime 2 produced from ketal 1. The first step is removing the protecting group in 1 to give a ketone that is converted to 2 in 77% yield; TsOH is p-toluenesulfonic acid. Oxime 2 is oxidized to 3 by treating it with an equimolar amount of Na2MO4 in alkaline solution. The crude product 3 is isolated in 69% yield and then purified by stirring it in MeCN–H2O under acidic or basic conditions. The 97–98% pure product is recovered in >88% yield.
The patent claims that the reaction uses catalytic amounts of the molybdenum peroxo compound, but this is not the case. The oxidation uses an equimolar amount of the complex and oxime 2 and a 50% excess of H2O2. Hence, the cost of the catalyst is significant, and the disposal of the heavy metal residue poses an additional problem and additional expense. The main advantage is that the oxidation reaction is selective. (Schering Corp. [Kenilworth, NJ]. US Patent 7,553,987, June 30, 2009; Keith Turner)
View patent information from CAS.
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