Method for synthesizing KPV tripeptide diamide derivatives

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) R1, R′1 and R″1 represent, independently from each other, a hydrogen atom or
• a linear or branched C1-C22 alkyl moiety, optionally interrupted by a heteroatom,
• C4-C10 cycloalkyl moiety,
• a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
• an aryl moiety optionally substituted by one or more halogen atoms or more linear or branched C1-C4 alkyl moieties,
• an aralkyl moiety,
• or R1 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 C1-C4 alkyl moieties and/or optionally containing a heteroatom,
• with the proviso that the R1(R′1) (R″1)CO group does not represent an amino acid residue or a peptide;
• b) R2 and R3 represent, independently from each other, a hydrogen atom or represent
• a linear or branched C1-C24 alkyl moiety, optionally interrupted by a heteroatom,
• a C4-C10 cycloalkyl moiety,
• a linear or branched C1-C22 polyfluoroalkyl or perfluoroalkyl moiety,
• an aryl moiety optionally substituted by one or more halogen atoms or one or more linear or branched C1-C4 alkyl moieties,
• an aralkyl moiety,
• or R2 and R3 could form with the nitrogen atom a saturated ring with from 5 or 6 atoms optionally substituted by one or more linear or branched C1-C4 alkyl moieties, said saturated ring optionally containing a heteroatom
• with the proviso that the N(R2) (R3) 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 P1 and P2, 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 P3 represents a protective group differing from any of the P1 and P2 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 P1, P2 and P3 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 NH2(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 P3 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 P2 protective group from the compound of formula (XII) to obtain the compound of the formula (I) or the mineral or organic salt thereof.