Method for acylating a cyclic peptide
View Patent ↗The present invention relates to a process for acylating cyclic peptides bearing an amino group and to the application of said process in the preparation of anidulafungin and micafungin.
1. A method for selectively acylating a cyclic peptide bearing an amino group at the amino group without protecting the hydroxyl groups of the cyclic peptide prior to the acylation step, the method comprising the steps of:
(a) reacting an acid R 1 CO 2 H with a compound of general formula (1)
to give a compound of general formula (2)
(b) mixing said compound of general formula (2) with said unprotected cyclic peptide bearing an amino group to selectively acylate the cyclic peptide at the amino group to form a cyclic lipopeptide;
wherein R 1 is alkyl comprising from 10-25 carbon atoms, substituted alkyl comprising from 10-25 carbon atoms, aryl comprising from 10-25 carbon atoms or substituted aryl comprising from 10-25 carbon atoms, R 2 is alkyl, R 3 is alkyl, substituted alkyl, halogen, hydrogen or NO 2 and R 4 is alkyl, substituted alkyl, halogen, hydrogen or NO 2 .
2. The method according to claim 1 wherein said cyclic lipopeptide obtained in step (b) is isolated.
3. The method according to claim 1 wherein R 3 is hydrogen, methyl or NO 2 and R 4 is hydrogen, methyl or NO 2 .
4. The method according to claim 1 wherein R 1 is (CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 or
5. The method according to claim 1 wherein said unprotected cyclic peptide bearing an amino group is the echinocandin B nucleus or FR 179642 or salts thereof.
6. The method according to claim 1 wherein said compound of general formula (2) is isolated prior to step (b).
7. A method for the preparation of anidulafungin or a pharmaceutically acceptable salt thereof comprising the steps of:
(a) contacting an unprotected echinocandin B nucleus that is unprotected at the hydroxyl groups with a compound of general formula (2)
wherein R 1 is
and R 2 is ethyl or methyl in the presence of a base to selectively acylate the amino group of the unprotected echinocandin B nucleus;
(b) isolating the anidulafungin salt obtained in step (a);
(c) converting the anidulafungin salt obtained in step (b) into a pharmaceutically acceptable salt of anidulafungin;
(d) isolating said pharmaceutically acceptable salt of anidulafungin obtained in step (c).
8. The method according to claim 7 wherein said base is diisopropylethylamine and said anidulafungin salt is the diisopropylethylamine salt of anidulafungin.
9. The method according to claim 5 wherein said unprotected cyclic peptide bearing an amino group is FR 179642 or a salt thereof.
10. The method according to claim 5 wherein said unprotected cyclic peptide bearing an amino group is the echinocandin B nucleus or a salt thereof.