Process for the preparation of...

C - Chemistry – Metallurgy – 07 – K

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C07K 5/068 (2006.01) C07K 5/02 (2006.01)

Patent

CA 2311407

A process for preparing N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline (2) easily, efficiently and industrially advantageously, which comprises: the first step of conducting the alkaline hydrolysis of an N2-(1(S)-alkoxycarbonyl- 3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl-L-proline (1) by the use of n molar equivalents (wherein n 3) of an inorganic base per mol of the compound (1) either in a mixture of water with a hydrophilic organic solvent or in water; the second step of neutralizing the resulting reaction mixture with (n-1) to n molar equivalents (wherein n 3) of an inorganic acid, replacing the solvent system by a suitable one to thereby precipitate an inorganic salt formed by the above neutralization, and separating and removing the salt; and the third step of crystallizing the compound (2) present in the liquid mixture left after the above removal of the salt at its isoelectric point and recovering the compound (2) as a crystal, while salts mainly comprising organic acid salts resulting from trifluoroacetic acid remain dissolved in the mother liquor.

Cette invention concerne un procédé permettant de préparer du N?2¿-(1(S)-carboxy-3-phénylpropyl)-L-lysyl-L-proline (2) de manière simple, efficace et avantageuse sur le plan industriel, lequel procédé comprend les trois étapes suivantes: effectuer une hydrolyse alcaline d'un N?2¿-(1(S)-alcoxycarbonyl-3-phénylpropyl)-N?6¿-trifluoroacétyl-L-lysyl-L-proline (1) en utilisant n équivalents molaires (où n ? 3) d'une base inorganique par mole du composé (1) soit dans un mélange d'eau et d'un solvant organique hydrophile, soit dans de l'eau; neutraliser le mélange de réaction obtenu à l'aide de (n-1) à n équivalents molaires (où n ? 3) d'un acide inorganique, remplacer le système solvant par un système adéquat afin de précipiter un sel inorganique formé par la neutralisation susmentionnée, puis séparer et retirer le sel; et enfin, cristalliser le composé (2) se trouvant dans le mélange liquide restant après le retrait du sel à son point isoélectrique, et récupérer le composé (2) sous forme de cristal, tandis que les sels comprenant essentiellement des sels d'acide organique résultants de l'acide trifluoroacétique restent dissous dans la liqueur mère.

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