April 15, 2013
Here’s a better way to make a food animal weight-gain drug. Zilpaterol (1) is used to increase the rate of weight gain in livestock, poultry, and fish. The drug, available under the trade name Zilmax, is marketed as “beef-improvement technology”.
There are several methods for preparing 1. Inventors O. Krebs and S. Dubuis focus on a method reported in a 1986 patent (US 4,585,770) and compare it with the process they describe in the current patent. Their process, outlined in the figure, was scaled up to commercial scale, starting with 525 kg of acid 2.
Unfortunately, the yields of the reaction products are not reported for any of the steps. The process starts with the (COCl)2 chlorination of 2 to give acyl chloride 3; COCl2 and triphosgene are also suitable. The product is isolated as a solution in CH2Cl2.
In the next stage, an intramolecular Friedel–Crafts alkylation of 3 in the presence of AlCl3, followed by acid hydrolysis, forms tricyclic molecule 4. It is isolated as a wet solid and then converted to oxime 5 in DMF by treating it with NaNO2 and adding HCl.
Compound 5 is isolated as a dry solid and converted to its potassium salt (6) by treating it with 45% aq KOH. The salt is isolated as a solution, treated with active carbon, and hydrogenated over a Pd/C catalyst to form amino alcohol salt 7. The reaction appears to be stereoselective, but the inventors do not mention this.
Salt 7 is recovered as an aqueous solution for use in the next step. It is treated with Me2CO in the presence of HOAc at pH 7–8. Isopropylideneamino compound 8 is not isolated but is hydrogenated over a Pt/C catalyst to give the HOAc salt of 1. Free base 1 is obtained by treating the salt with NaOH in EtOH. A hydrochloride salt can be prepared from the free base.
The inventors discuss some aspects of the process, such as the quantities of washing solvents used, in detail. The process provides an effective route to the desired compound and is suitable for large-scale manufacture. (Intervet International [Boxmeer, The Netherlands]. US Patent 8,362,006, Jan. 29, 2013; Keith Turner)