Solution phase processes for the manufacture of macrocyclic depsipeptides and new intermediates

A method or process for the preparation of a cyclic depsipeptide compound of the formula I solely by solution phase synthesis,

• wherein
• A1 is a bivalent moiety of an amino acid with a terminal carboxy or carbamoyl group, and is bound in formula I via a carbonyl to the rest of the molecule;
• or is C1-8-alkanoyl or phosphorylated hydroxy-C1-8-alkanoyl;
• X is bound via an N of A1 and is acyl, or is absent if A1 is C1-8-alkanoyl or phosphorylated hydroxy-C1-8-alkanoyl;
• R2 is C1-8-alkyl;
• R3 is the side chain of an amino acid;
• R5 is the side chain of an amino acid;
• R6 is the side chain of a hydroxy amino acid;
• R7 is the side chain of an amino acid;
• and
• Y is hydrogen or C1-8-alkyl;
• or a salt thereof,
• said method comprising
• in a first variant (A)
• reacting the free hydroxyl group of a compound of the formula (II),
• wherein Y is as defined for a compound of the formula I and X*, A1*, R2*, R3*, R5*, R6*, and R7* correspond to X, A1, R2, R3, R5, R6, and R7 in formula I, respectively, but with the proviso that reactive functional groups on these moieties are present in protected form at least if they could participate in undesired side reactions,
• under oxidizing conditions to form a compound of the formula III,
• and removing remaining protecting groups to yield a compound of the formula I, or a salt thereof,
• and, if desired, converting a free compound of the formula I into a salt, a salt of a compound of the formula I into a different salt of a compound of the formula I or into the free compound of the formula I and/or and/or converting a dehydrate analogue and/or five ring analogue of a compound of the formula I formed as by-product into the corresponding compound of the formula I;
• where the compound of the formula III is prepared by macrolactamization of a compound of the formula IV,
• wherein Y, R2*, R3*, R7*, R6* and R5*, X* and A1* are as defined for a compound of the formula II;
• where, in a further embodiment, the method or process described above, is further comprising manufacturing the compound of the formula IV in solution phase by simultaneously or sequentially removing the protecting group ProtA, the protecting group(s) of protected amino group Z and the protecting group Prot from a compound of the formula V,
• wherein ProtA is carboxy protecting group, Prot is a hydroxyl protecting group, Z is a protected amino group either of the formula NHProt** wherein Prot** is an amino protecting group;
• or Z is a protected amino group of the formula N(Prot*)2 wherein each Prot* is an amino protecting group;
• and Y, R2*, R3*, R7*, R6* and R5*, X* and A1* are as defined for a compound of the formula II;
• the method or process mentioned above further comprising manufacturing the compound of the formula V in solution phase by coupling a compound of the formula VI,
• wherein ProtA is as defined above for a compound of the formula V and Y, R2*, R3*, R7*, R6* and R5*, X* and A1* are as defined above for a compound of the formula II, with an amino acid of the formula VII,
• wherein ProtA and Z are as defined above for a compound of the formula V, or an activated derivative thereof (end of variant A);
• and/or in parallel or alternatively, in a variant (B),
• deprotecting a compound of the formula II*
• wherein the aldehyde protecting group(s) Rk and Rl are independently of each other unsubstituted or substituted alkyl or together with the two binding O atoms and the carbon atom to which the two O atoms are bound form a ring that is unsubstituted or substituted, Y is as defined for a compound of the formula I and X*, A1*, R2*, R3*, R5*, R6*, and R7* correspond to X, A1, R2, R3, R5, R6, and R7 in formula I, respectively, but with the proviso that reactive functional groups on these moieties are present in protected form at least if they could participate in undesired side reactions, to result in a compound of the formula I;
• and, if desired, converting a free compound of the formula I, into a salt, a salt of a compound of the formula I into a different salt of a compound of the formula I, or into the free compound of the formula I, and/or converting a dehydrate analogue and/or five ring analogue of a compound of the formula I formed as by-product into the corresponding compound of the formula I.