Scalable synthesis of reduced toxicity derivative of amphotericin B

Patent metadata

Field	Value
Publication number	US-10683318-B2
Application number	US-201816148255-A
Country	US
Kind code	B2
Filing date	Oct 1, 2018
Priority date	Oct 17, 2014
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Disclosed is a simplified, readily scalable series of individual methods that collectively constitute a method for the synthesis of C2′epiAmB, an efficacious and reduced-toxicity derivative of amphotericin B (AmB), beginning from AmB. Also provided are various compounds corresponding to intermediates in accordance with the series of methods.

First claim

We claim:

1. A compound, represented by

wherein, independently for each occurrence,
R 1 is C(O)OR a ;
R 2 is selected from the group consisting of 2-alken-1-yl, benzyl, and (R b ) 3 Si—;
R 3 is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R a is selected from the group consisting of tert-butyl, and benzyl; and
R b is substituted or unsubstituted aryl, or C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein R 2 is 2-alken-1-yl; and R 3 is substituted or unsubstituted aryl.

3. A compound, represented by

wherein, independently for each occurrence,
R 1 is C(O)OR a ;
R 2 is selected from the group consisting of 2-alken-1-yl, benzyl, and (R b ) 3 Si—;
R 3 is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R 4 is —C(O)R c ;
R a is selected from the group consisting of 2-alken-1-yl, tert-butyl, and benzyl;
R b is substituted or unsubstituted aryl, or C 1 -C 6 alkyl; and
R c is substituted or unsubstituted aryl.

4. The compound of claim 3 , wherein R a is 2-alken-1-yl; R 2 is 2-alken-1-yl; R 3 is substituted or unsubstituted aryl; and R c is substituted or unsubstituted phenyl.

5. The compound of claim 3 , represented by

6. A compound, represented by

wherein, independently for each occurrence,
R 1 is C(O)OR a ;
R 2 is selected from the group consisting of 2-alken-1-yl, benzyl, and (R b ) 3 Si—;
R 3 is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R 4 is —C(O)R c ;
R 5 is (R b ) 3 Si—;
R a is selected from the group consisting of 2-alken-1-yl, tert-butyl, and benzyl;
R b is substituted or unsubstituted aryl, or C 1 -C 6 alkyl; and
R c is substituted or unsubstituted aryl.

7. The compound of claim 6 , wherein R a is 2-alken-1-yl; R 2 is 2-alken-1-yl; R 3 is substituted or unsubstituted aryl; R c is substituted or unsubstituted phenyl; and R b is C 1 -C 6 alkyl.

8. The compound of claim 6 , represented by

9. A compound, represented by

wherein, independently for each occurrence,
R 1 is C(O)OR a ;
R 2 is selected from the group consisting of 2-alken-1-yl, benzyl, and (R b ) 3 Si—;
R 3 is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R 5 is (R b ) 3 Si—;
R a is selected from the group consisting of 2-alken-1-yl, tert-butyl, and benzyl; and
R b is substituted or unsubstituted aryl, or C 1 -C 6 alkyl.

10. The compound of claim 9 , wherein R a is 2-alken-1-yl; R 2 is 2-alken-1-yl; R 3 is substituted or unsubstituted aryl; and R b is C 1 -C 6 alkyl.

11. The compound of claim 9 , represented by

12. A method of making 2′epiAmB,

comprising the step of:

wherein, independently for each occurrence,
R 1 is C(O)OR a ;
R 2 is selected from the group consisting of 2-alken-1-yl, benzyl, and (R b ) 3 Si—;
R 3 is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R 4 is —C(O)R c ;
R 5 is (R b ) 3 Si—;
R a is selected from the group consisting of 2-alken-1-yl, tert-butyl, and benzyl;
R b is substituted or unsubstituted aryl, or C 1 -C 6 alkyl;
R c is substituted or unsubstituted aryl;
M is an alkali metal cation or alkaline earth metal cation; and
solvent 6 is a polar aprotic solvent, a polar protic solvent, or a mixture thereof.

13. The method of claim 12 , wherein M is an alkali metal cation.

14. The method of claim 12 , wherein solvent 6 is a mixture of a polar aprotic solvent and a polar protic solvent.

15. The method of claim 12 , wherein R 4 is p-(tert-butyl)benzoyl.

16. The method of claim 12 , wherein M is K.

17. The method of claim 12 , wherein solvent 6 is a mixture of tetrahydrofuran (THF) and MeOH.

18. The method of claim 12 , wherein R 4 is p-(tert-butyl)benzoyl; M is K; and solvent 6 is a mixture of tetrahydrofuran (THF) and MeOH.

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Uno Brice E
• Rakshit Souvik

Classifications

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H17/08 Primary

  Hetero rings containing eight or more ring members, e.g. erythromycins · CPC title