Process for the manufacture of cyclic undecapeptides

A process for preparing a compound of formula 4 or a salt thereof,

• wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl, the method comprising the steps of:
• i) acylation of cyclosporin A to form acetyl-Cyclosporin A;
• ii) ring opening of the acetyl-Cyclosporin A;
• and;
• iii) crystallizing the ring opened acetyl-Cyclosporin A to obtain a compound of formula 3
• or salt thereof;
• iv) Edman degradation of the compound of formula 3;
• and then
• v) crystallizing the compound to obtain a compound of formula 4 or a salt thereof.

A process for preparing a compound of formula 3 or a salt thereof from from Cyclosporin A, Cyclosporin B, or from Cyclosporin D, or from Cyclosporin G,

• wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R2 is methyl, ethyl, or propyl, the method comprising the steps of acylation of cyclosporin A, B, D, or G, to form acetyl-Cyclosporin A, B, D, or G;
• ring opening of the acetyl-Cyclosporin A, B, D, or G;
• and
• crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3.

A process for preparing a compound of formula 4 or a salt thereof,

• wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R2 is methyl, ethyl, or propyl, the method comprising the steps of:
• vi) acylation of cyclosporin A, B, D, or G, to form acetyl-Cyclosporin A, B, D, or G;
• vii) ring opening of the acetyl-Cyclosporin A, B, D, or G;
• and
• viii) crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3 or salt thereof
• ix) Edman degradation of compound of formula 3;
• and then
• x) crystallizing the compound to obtain a compound of formula 4 or a salt thereof.