Preparation of cyclosporin derivatives

A process for the preparation of a compound of Formula 1a or a pharmaceutically acceptable salt thereof,

• wherein
• Ra is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl;
• R1 and R2 are independently selected from H, C1 to C6 alkyl, or wherein R1 and R2 are joined together to form a C3 to C6 cycloalkyl or heterocycloalkyl ring;
• R3 and R4 are independently selected from H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, benzyl, carbonyl, carboxyl, sulfonyl;
• or wherein R3 and R4 are joined together to form a C3 to C6 cycloalkyl or heterocycloalkyl ring;
• R5 and R6 are independently selected from H, C1 to C6 alkyl, substituted C1 to C6 alkyl, or wherein R5 and R6 are joined together to form a C3 to C6 cycloalkyl or heterocycloalkyl ring;
• wherein the process comprises a step of reacting a compound of Formula 2a with an amino alcohol in the presence of a copper salt and a trialkylsilyl halide;
• wherein the compound of Formula 2a is:
• wherein Ra is selected from ethyl, 1-hydroxyethyl, isopropyl, and n-propyl;
• and
• wherein Rb is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• and
• wherein the amino alcohol is of Formula 3:
• wherein R1, R2, R3, R4, R5 and R6 are as defined for Formula 1a.