Synthesis of echinocandin antifungal agent
The present invention relates to echinocandin cyclopeptides and to methods for preparing echinocandin cyclopeptides.
1. A method of synthesizing compound 1:
said method comprising:
(a) providing a first composition comprising a boronate ester of anidulafungin;
(b) providing a second composition comprising a salt of choline;
(c) combining the first composition, the second composition, and trifluoroacetic acid in a solvent system that comprises acetonitrile and trifluoroacetic anhydride to form a precipitate of a reaction product having formula (I):
wherein
X − is an anion; and
R is C 1 -C 6 alkyl or C 6 -C 10 aryl;
and;
(d) hydrolyzing the compound of formula (I) to form compound 1, or a salt or neutral form thereof.
2. The method of claim 1 , wherein the concentration of the mixture is at least 0.01 moles per L relative to the compound of formula (I).
3. The method of claim 1 , wherein step (c) comprises forming a mixture in a solvent system comprising a mixture of tetrahydrofuran and acetonitrile.
4. The method of claim 1 , wherein step (c) comprises forming a mixture comprising at least 10 molar equivalents of the salt of choline and at least 1 molar equivalents of the boronate ester of anidulafungin.
5. The method of claim 1 , wherein step (c) is performed at a temperature of less than 40° C.
6. The method of claim 1 , wherein step (c) comprises forming a mixture in which at least 50% of the compound of formula (I) is precipitated.
7. The method of claim 1 , wherein R is C 6 -C 10 aryl.
8. The method of claim 1 , wherein R is C 1 -C 6 alkyl.
9. A method of synthesizing compound 1:
said method comprising:
(a) providing a first composition comprising an aryl boronate ester of anidulafungin;
(b) providing a second composition comprising a salt of choline;
(c) combining the first composition, the second composition, and an acid to form a mixture comprising a compound of formula (II):
wherein
X − is an anion; and
Ar is substituted C 6 aryl; and
(d) hydrolyzing the compound of formula (II) to form compound 1, or salt or neutral form thereof.
10. The method of claim 9 , wherein Ar is selected from 3,4-dimethoxyphenyl, 2,6-dimethylphenyl, and 4-trifluoromethylphenyl.
11. The method of claim 9 , wherein step (c) comprises combining at least 10 molar equivalents of the salt of choline with at least 1 molar equivalents of the boronate ester of anidulafungin.
12. The method of claim 9 , wherein the first composition comprises a solution of the boronate ester of anidulafungin dissolved in an organic solvent selected from acetonitrile, butyronitrile, tetrahydrofuran, or 2-methyltetrahydrofuran, or a mixture thereof.
13. The method of claim 9 , wherein the second composition comprises a solution of the salt of choline dissolved in a mixture of acetonitrile and trifluoroacetic acid.
14. The method of claim 9 , wherein the second composition comprises a solution of the salt of choline dissolved in a mixture of acetonitrile, trifluoroacetic acid, and trifluoroacetic anhydride.
15. The method of claim 9 , wherein step (c) further comprises adding acetonitrile to the mixture to reduce the level of beta-diastereomer.
16. The method of claim 9 , wherein step (d) further comprises diluting with at least 5 volumes relative to anidulafungin of water:acetonitrile mixture of about 80:20 to 50:50 and adjusting the pH with base to a pH of from 2 to 5.
17. The method of claim 9 , wherein step (d) comprises forming a reaction product comprising greater than 70% compound 1 and less than 4% compound 1 beta-diastereomer.
18. The method of claim 9 , wherein the hydrolyzing is performed at a temperature of less than 15° C.
19. The method of claim 9 , wherein the method further comprises producing a pharmaceutical composition by combining the compound 1 with a pharmaceutically acceptable excipient.
20. The method of claim 9 , wherein the acid of step (c) is trifluoroacetic acid.
21. The method of claim 9 , wherein the solvent system of step (c) comprises acetonitrile and trifluoroacetic anhydride.
22. The method of claim 9 , wherein the method further comprises the step (e) purifying compound 1, or a salt or neutral form thereof, by reverse phase preparative high performance liquid chromatography or reverse phase preparative medium pressure liquid chromatography.
23. The method of claim 1 , wherein the method further comprises step (e) purifying compound 1, or a salt or neutral form thereof, by reverse phase preparative high performance liquid chromatography or reverse phase preparative medium pressure liquid chromatography.