Process for the synthesis of peptides containing a 4-hydroxy-proline substructure

A process for preparing a compound of formula I

• wherein R1 is a reactive substituent or an attachment to a solid phase;
• R2 is a reactive substituent;
• and
• R3, R4 and R5 are each independently hydrogen or one or more substituents attached to each benzene ring and selected from hydroxy, amino, C1-10-alkyl, C1-10-alkoxy, C1-10-alkylamino, di-C1-10-alkylamino, carbamoyl, C1-10-alkylcarbamoyl, di-C1-10-alkylcarbamoyl, halo-C1-10-alkyl, halogeno and nitro;
• in free or salt form;
• comprising
• (a) reacting a compound of formula VI with an electrophile:
• wherein R3, R4 and R5 are as defined above;
• R9 is —OH, —OM or —OMX, where M is metal and X is a nucleophilic substituent;
• R10 is -M or -MX, where M is metal and X is a nucleophilic substituent;
• in free or salt form;
• and hydrolyzing the resulting compound to form a compound of formula I wherein R2 is hydroxy;
• (b) optionally converting a compound of formula I wherein R2 is hydroxy to a compound of formula I wherein R2 is other than hydroxy;
• (c) optionally converting R1 in a compound of formula I to an alternative R1 group;
• (d) optionally deprotecting a compound of formula I in protected form;
• and
• (e) where required, converting a compound of formula I obtained in free form into the desired salt form, or vice versa.