Process for preparing platinum-carbene complexes

A process for preparing platinum-carbene complexes of the following formula II:

• in which:
• R1 and R4 represent, independently of one another:
• (i) a linear or branched C1-C12 alkyl group, optionally substituted with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
• (ii) a linear or branched C2-C12alkenyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
• (iii) a linear or branched C2-C12alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
• (iv) an aryl group having 1, 2 or 3 aromatic rings or aralkyl with a C1-C12carbon chain, the aryl or aralkyl group being optionally substituted with a C1-C12 alkyl group, or with a C1-C12alkoxy group, with a CF3 group, or with a trimethylsilyl group,
• (v) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to carbon atoms, with a CF3 group, or with a trimethylsilyl group, or
• (vi) a polymer represented by the formula —(CH2CH2O)n—R′ or a polymer represented by the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 alkyl group,
• R2 and R3 represent, independently of one another:
• a hydrogen,
• an aryl or aralkyl group, or
• a linear or branched C2-C12 alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
• X represents iodine, bromine or chlorine,
• L2 represent:
• (i) an amine of formula
• in which R5, R6 and R7 represent, independently of one another:
• (a) a hydrogen,
• (b) a linear or branched C1-C18 alkyl, optionally substituted with an estradiol,
• (c) an aryl group having 1, 2 or 3 aromatic rings, or aralkyl with a C1-C12 carbon chain, the aryl or aralkyl group being optionally substituted with a C1-C12 alkoxy group, or an alkyl group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
• (d) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl,
• (e) a polymer represented by the formula —(CH2CH2O)n—R′ or the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 alkyl group, optionally substituted with an estradiol,
• (ii) a diamine of general formula NH2—(CH2)n—NH2, n=1 to 12 carbon atoms,
• (iii) a triamine of general formula NH2—(CH2)n—NH—(CH2)m—NH2, n=1 to 12 carbon atoms, m=1 to 12 carbon atoms,
• (iv) a linear or branched amino alcohol with 2 to 20 carbon atoms, (v) a linear or branched amino ester with 2 to 20 carbon atoms,
• (vi) a linear or branched amino amide with 2 to 20 carbon atoms,
• (vii) an amino acid or esters or amides thereof,
• (viii) a beta or gamma amino acid or its esters or amides,
• (ix) a peptide, optionally cyclic, comprising 2 to 30 amino acids,
• (x) a morpholine,
• (xi) a piperazine optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl,
• (xii) a piperazine N-substituted with a dansyl or dabsyl group
• (xiii) a hydrazine monosubstituted with an aryl having 1, 2 or 3 aromatic rings, or a linear or branched alkyl with 1 to 12 carbon atoms,
• (xiv) a glucamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms, (xv) a glucosamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms,
• (xvi) a pseudopeptide of general formula H—(NH—CH(R)—CH2—X—CO)n—NHR″, with R being a side chain of one of the 20 proteinogenic amino acids;
• X being independently, throughout the sequence, CH2, O or NH;
• n=1-15;
• R″═H, or a short alkyl or aralkyl chain,
• (xvii) a pseudopeptide of general formula Ra—CO—CH(Rb)—NH—CO—NH—CH(Rc)—CO—Rd in which Ra and Rd represent, independently of one another, H, a linear or branched C1-C6 alkyl group, a C3-C7 monocyclic cycloalkyl group, or a carboxylic acid protective group;
• Rb represents the side chain of lysine, the amine of said side chain being optionally substituted with a group —CO—(CH2)5—NH2;
• Rc represents a side chain of one of the 20 proteinogenic amino acids, optionally protected by an protective group,
• (xviii) a polymer represented by the general formula NH2—(CH2(CH2)iNH)(n-1)—H, in which i=1, 2 or 3, n=1 to 1000, said polymer forming m coordination bonds with m platinum atoms, one of said coordination bonds being formed between Pt and L2 of formula (II) and m-1 coordination bonds being formed with m-1 groups of formula 1:
• where R1, R2, R3, R4 and X are as defined above,
• the number m being between 1 and n, the ratio m/n representing the number of platinum atoms to the number of amines of type —NH— or —NH2, said process comprising reaction of the compound of formula I:
• in which:
• R1, R2, R3, R4 and X have the meanings given above,
• L1 representing a pyridine, or a pyridine substituted with iodine, bromine or chlorine, or disubstituted with iodine, bromine or chlorine,
• with a ligand L2, or a salt of a ligand L2, said reaction being carried out optionally in the presence of a solvent.