On the Production Of N ɛ -Trifluoroacetyl-L-Lysine

Abstract

The method for large-scale production of Nɛ -trifluoroacetyl-L-lysine, a starting compound for the production of the antihypertensive agent, lisinopril (an angiotensin converting enzyme inhibitor) was investigated. It has been hitherto reported that Nɛ -trifluoroacetyl-L-lysine could be obtained by reactive crystallization of L-lysine and a trifluoroacetic ester. However, it was found that, in this method, the reaction mixture became a stiff slurry that has the appearance of whipped cream, causing problems with product yield, quality and operability. In order to solve these problems, the reactive crystallization process was divided into two separate processes, the reaction process and the crystallization process. Both of these processes were investigated. As a result, it was found that the operation conditions suitable for each process were considerably different from the conditions for the reactive crystallization process. For instance, in order to suppress formation of the stiff slurry and maximize the product yield, the reaction should be carried out at pH 11, and the crystallization should be carried out at a minimum of 40°C. In addition, it was confirmed that the reaction process and the crystallization process could be operated separately by conducting each process under suitable conditions. By doing so, the problems in the conventional method were overcome and high quality Nɛ-trifluoroacetyl-L-lysine was readily obtained.