Process for the preparation of conjugates useful in the treatment of prostate cancer

A process for the preparation of a compound of formula I:

• or a pharmaceutically acceptable salt thereof
• wherein
• oligopeptide is an oligopeptide which is selectively recognized by the free prostate specific antigen (PSA) and is capable of being proteolytically cleaved by the enzymatic activity of the free prostate specific antigen,
• Ra is —CH3, —CH2OH, —CH2OCO(CH2)3CH3, or —CH2OCOCH(OC2H5)2;
• Rb is —OCH3, —OH or —H;
• Rd is —OH, —OTHP or —H;
• and
• Re is —OH or —H, provided that Re is not —OH when Rd is —OH or —OTHP;
• R is selected from:
• a) acetyl;
• e) hydrogen;
• R1 and R2 are independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R3O—, R3C(O)NR3—, (R3)2NC(O)—, R32N—C(NR3)—, R4S(O)mNH, CN, NO2, R3C(O)—, N3, —N(R3)2, or R4OC(O)NR3—,
• c) unsubstituted C1-C6 alkyl,
• d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R3O—, R4S(O)mNH, R3C(O)NR3—, (R3)2NC(O)—, R32N—C(NR3)—, CN, R3C(O)—, N3, —N(R3)2, and R4OC(O)—NR3—;
• or
• R1 and R2 are combined to form —(CH2)s— wherein one of the carbon atoms is optionally replaced by a moiety selected from:
• O, S(O)m, —NC(O)—, NH and —N(COR4)—;
• R3 is selected from:
• hydrogen, aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl and C3-C10 cycloalkyl;
• R4 is selected from:
• aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl and C3-C10 cycloalkyl;
• m is 0, 1 or 2;
• n is 1, 2, 3 or 4;
• p is zero or an integer between 1 and 100;
• q is 0 or 1, provided that if p is zero, q is 1;
• r is an integer between 1 and 10;
• and
• s is 3, 4 or 5;
• that comprises the step of preparing the compound of the formula Ia:
• or a salt thereof;
• wherein
• oligopeptide, R, Ra, Rb, Rd and Re are described as above
• R′ is selected from:
• a) R as described above,
• b) a protected precursor to R, and
• c) an N-terminus protecting group;
• by mixing an oligopeptide of the formula A:
• wherein oligopeptide and R′ are described as above;
• or a salt thereof;
• with an anthracycline antibiotic of the formula B:
• wherein Ra, Rb, Rd and Re are as described hereinabove,
• or a salt thereof;
• in the presence of a carboxyl activating agent, an additive comprising the combination of HOPO and HOAt and, optionally, in the presence of a base.