Patent Watch

June 22, 2009 [Repeated from 1/19/09]

Here’s a practical route to a safer analgesic. The analgesic paracetamol (1) is used very widely, but it can cause liver damage and is fatal if high doses are taken. R. Rivolta and R. Aureli describe a process for preparing compound 2, a paracetamol derivative that is also a nitric oxide–donating analgesic but exhibits lower liver toxicity.

Alternative methods for preparing 2 use AgNO₃ as a nitrating agent in greater than stoichiometric amounts, making the process expensive and not commercially attractive. In the inventors’ process, the sodium salt of 1 is treated with nitrate–carbonyl chloride 3. This reaction is perhaps surprising because 3 is a strong oxidant and 1 is a reductant, so it may have been expected that redox reactions would occur. This was not the case nor were there any products from the nucleophilic substitution of the nitrate group.

The inventors also describe the preparation of 3 from 4 via 5 and 6. The final yield of 2 after purification by column chromatography is 40% based on the conversion from 1. The claims also cover the reaction of 1 with 6 in an aprotic dipolar solvent and a dehydrating agent, but there are no experimental details for this procedure. The key to the patent is that the commercial availability of 1 and 4 make this is an inexpensive route to prepare safer analgesics than 1. (Nicox S.A. [Sophia Antipolis, France]. US Patent 7,442,826, Oct. 28, 2008; Keith Turner)

View patent information from CAS.

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