Patent Watch

April 28, 2014

Here’s a better way to make a rivastigmine intermediate. Inventors C. Mathes, M. Foulkes, and M. Kesselgruber prepared compound 6, an intermediate in the synthesis of rivastigmine, a drug for treating Alzheimer's disease. They say that the current methods for producing rivastigmine “are thermodynamically inefficient or economically inconvenient.”

The inventors’ process is shown in the figure. It begins with an asymmetric transfer hydrogenation of m-hydroxyacetophenone (1) with AcOH that uses ruthenium catalyst 2. The reaction is carried out in the presence of Et3N and produces chiral diol 3. After two solvent exchanges, the product is isolated in 90% yield with 99.3% ee.

Synthesis of rivastigmine intermediate 6

In the next step, 3 is treated with (MeSO2)2O in the presence of 4-dimethylaminopyridine (DMAP) and i-PrNEt to give the dimesylate 4. This intermediate is obtained as a suspension in EtOAc; it is treated with Me2NH in a reaction that the inventors describe as moderately exothermic on the laboratory scale. Product 5 is recovered as a solution EtOAc, which is used in the final step. The solution of 5 is treated with 30% aq NaOH to give acid 6. The product is isolated as colorless crystals in 79% yield and 99.9% ee after an extensive crystallization procedure that is fully described in the patent.

The inventors provide 1H NMR and IR data for the intermediates and final product. The claims cover the use of 6 for preparing rivastigmine, but the experimental procedure is not described. The process is an efficient route to this key compound that does not require isolation of the intermediates. (Novartis AG [Basel, Switzerland]. US Patent 8,637,713, Jan. 28, 2014; Keith Turner)