May 4, 2009
Here’s an improved route to a potentially valuable drug. J. Moormann, H.-R. Hoffmann, and R. Matusch describe a process for producing deoxypeganine (1), a compound that occurs in plants of the Zygophyllaceae (caltrop) family. Deoxypeganine is a reversibly active cholinesterase inhibitor and therefore of interest for treating drug and nicotine addiction and Alzheimer’s disease. The inventors summarize several methods for preparing 1 that produce large amounts of byproducts and use environmentally unacceptable reagents and solvents such as CHCl3 and PCl3. Also, expensive recovery methods, such as high-vacuum distillation, are needed to obtain pure product.
The new process is aimed at overcoming such problems by the route shown in the figure. The first step is to produce heterocycle 3 by treating amide anhydride 2 with an excess of 2-pyrrolidone at temperatures up to 180 °C. Surprisingly, using an excess of pyrrolidone reduces byproduct formation and allows easy crystallization of 3. The crystallization requires as much as 100 h at ambient temperature, but that time can be reduced to 48–72 h by increasing the temperature at least 25 °C. The yield of 3 from 2 is >90%, and the crystals of 3 contain as much as 30% pyrrolidone.
The wet crystals are used in the next stage, a Clemmensen reduction of 3 in which the zinc dust is added in small portions over an unspecified time period. The product is salt 4, recovered in 90% yield. Treating 4 with hot NaOH solution gives free base 1 that is crystallized from hot water and isolated in 90% yield at 99.9% purity by NMR analysis.
The inventors also describe reducing 3 in the presence of H2SO4 to produce the hydrogen sulfate salt. This can also be converted to 1. The effect of using excess pyrrolidone is shown in a comparative example with equimolar amounts of 2 and pyrrolidone; in this case, the yield of 3 was only 21%. Additional examples describe kilogram-scale experiments, thereby suggesting a process at an advanced stage of development. (HF Arzneimittelforschung GmbH [Werne, Germany]. US Patent 7,495,096, Feb. 24 2009; Keith Turner)
View patent information from CAS.
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