Patent ID: 7683026

Claim:
A method for the synthesis of a KPV tripeptide diamide derivative represented by the following formula (I) or for a salt thereof, independent of stereochemistry wherein: a) R 1 , R′ 1 and R″ 1 represent, independently from each other, a hydrogen atom or a linear or branched C 1 -C 22 alkyl moiety, optionally interrupted by a heteroatom, C 4 -C 10 cycloalkyl moiety, a linear or branched C 1 -C 22 polyfluoroalkyl or perfluoroalkyl moiety, an aryl moiety optionally substituted by one or more halogen atoms or more linear or branched C 1 -C 4 alkyl moieties, an aralkyl moiety, or R 1 and R′ 1 could form with C(R″ 1 ) a saturated ring with from 3 to 7 atoms, optionally substituted by one or more linear or branched C 1 -C 4 alkyl moieties and/or optionally containing a heteroatom, with the proviso that the R 1 (R′ 1 ) (R″ 1 )CO group does not represent an amino acid residue or a peptide; b) R 2 and R 3 represent, independently from each other, a hydrogen atom or represent a linear or branched C 1 -C 24 alkyl moiety, optionally interrupted by a heteroatom, a C 4 -C 10 cycloalkyl moiety, a linear or branched C 1 -C 22 polyfluoroalkyl or perfluoroalkyl moiety, an aryl moiety optionally substituted by one or more halogen atoms or one or more linear or branched C 1 -C 4 alkyl moieties, an aralkyl moiety, or R 2 and R 3 could form with the nitrogen atom a saturated ring with from 5 or 6 atoms optionally substituted by one or more linear or branched C 1 -C 4 alkyl moieties, said saturated ring optionally containing a heteroatom with the proviso that the N(R 2 ) (R 3 ) group does not represent an amino acid or a peptide; said method comprising: a) reacting a lysine diprotected residue having the following formula (II): optionally salified by a mineral or organic base, wherein P 1 and P 2 , are different and each represent independently from one another a protective group, with a proline residue having the following formula (III): optionally salified by a mineral or organic acid, wherein P 3 represents a protective group differing from any of the P 1 and P 2 protective groups, in the presence of an activation reagent or a coupling reagent and in a solvent, so as to obtain the following compound having the formula (IV): wherein P 1 , P 2 and P 3 have the abovementioned meanings, b) 1) removing the P1 protective group of the compound of formula (IV) to obtain the compound of formula (IX): 2) amidating a NH 2 (α) group of the lysine residue of the compound of the formula (IX) with a compound having formula (VI-A) or a compound having formula (VI-B) to obtain the compound of formula (X): 3) removing the P 3 protective group from the compound of formula (X) to obtain the compound of formula (XI): 4) coupling the compound of formula (XI) with the valine compound of formula (V), or the mineral or organic salt thereof, to form the compound of formula (XII): c) removing the P 2 protective group from the compound of formula (XII) to obtain the compound of the formula (I) or the mineral or organic salt thereof.