Yasuyoshi Ueda

On the Production Of Nɛ -Trifluoroacetyl-L-Lysine

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.

Desalination and crystallization processes of lisinopril

An industrially advantageous method to separate Lisinopril and salts, formed by hydrolysis of Lisinopril ester with a base and subsequent neutralization with an acid, using a practical combination of base/acid, was investigated. This is an alternative to ion exchange treatment. In one method of crystallizing Lisinopril alone from the above neutralization mixture, while retaining a large amount of the salts dissolved therein, the presence of the inorganic salts had an adverse effect on crystallization of Lisinopril. In another method, by removing the salts in advance from the neutralization mixture by crystallization and filtration and then crystallizing Lisinopril, the inorganic salts were crystallized and removed, with little or no precipitation of Lisinopril, from a supersaturated solution of Lisinopril and then Lisinopril was crystallized. However, in production on an industrial scale which requires a long period of operation, this method involves a risk where the supersaturation is broken and the precipitation of Lisinopril occurs during the operation for removal of the salts. The above risk was overcome by introducing a protonation/deprotonation stage which controls the dissolution/precipitation of Lisinopril, and high quality Lisinopril dihydrate was effectively obtained.

Molecular recognition and crystallization behavior of Lisinopril ester

Abstract The influence of the solvent on the crystallization of N 2 -((S)-1-ethoxycarbonyl-3-phenylpropyl) -N 6 -trifluoroacetyl-L-lysyl-L-proline (Lisinopril ester) was investigated. It was found that Lisinopril ester could be crystallized from about 20 kinds of solvent, all of which had some similarities in molecular structure. The amount of the solvent inside the obtained crystals was approximately 1 to 100 mol% per Lisinopril ester and it was influenced by the molecular form or the bulkiness of the solvent molecule and the kind of substituents present therein. It was recognized that the presence of a suitable substituent in the solvent molecule is essential for crystallization and that there was a possibility that the substituent in the solvent molecule interacts with, at a minimum, the trifluoroacetylamino group in a Lisinopril ester molecule. It is suggested that the above crystallization of Lisinopril ester is a kind of adductive crystallization wherein the host is Lisinopril ester and the guest is the crystallizing solvent itself.