Patent Watch

May 9, 2011

Make a blood pressure drug more efficiently. Losartan (1) and its potassium salt are used to treat hypertension. A. Veera Reddy and co-inventors summarize several processes for preparing 1: Some require six or more steps and give low overall yields; and one has only two steps but requires a reaction time of 13 days and gives only a 21% yield. Other patents on the synthesis of 1 have been reviewed previously (Turner, K. Org. Process Res. Dev. 2006, 10, 866–875).

The inventors describe a short, simple process that starts from commercially available reagents and is an improvement over the alternatives. In the first step, cyanobiphenyl 2 is brominated with N,N-dibromodimethylhydantoin (3) in the presence of benzoyl peroxide. This gives bromomethyl derivative 4, which is isolated as the crude product and used directly in the next step. In this reaction, 4 is treated with 2-n-butyl-4-chloro-5-formylimidazole (5) in aq NaOH and toluene in the presence of a base and a phase-transfer catalyst to form cyano aldehyde 6, isolated in 83% yield and 98% HPLC purity.

Compound 6 is treated with Bu3SnCl and NaN3 at room temperature for up to 32 h. The reaction is followed by TLC to ensure its completion. Aldehyde 7 is not isolated but is reduced in situ with NaBH4 to give 1. The product is isolated in 75% yield and >97% purity (HPLC). The potassium salt can be prepared by treating 1 with KOH–MeOH; it is isolated after crystallization from acetone in 87.15% yield with 99.79% purity (HPLC).

The patent contains IR, 1H NMR, and 13C NMR data for compounds 6, 7, and 1. The process has fewer steps and is more efficient than the published alternatives. (Suven Life Sciences [Hyderabad, India]. US Patent 7,915,425, March 29, 2011; Keith Turner)