7-phenyl-substituted tetracycline compounds
View Patent ↗7-phenyl-substituted tetracycline compounds which are substantially free of positional isomers, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7-phenyl-substituted tetracycline compounds are described. 7-substituted tetracycline compounds which are substantially free of positional isomers, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7-substituted tetracycline compounds are described.
1. A method for preparing a 7-substituted tetracycline compound at least 75% free of positional isomers, comprising:
(a) reacting an unsubstituted tetracycline compound with at least one equivalent of N-iodosuccinimide in trifluoroacetic acid to result in a 7-iodo tetracycline compound at least 75% free of positional isomers;
(b) reacting the 7-iodo tetracycline compound with a boronic acid, a palladium catalyst and aqueous sodium carbonate in a solvent; and
(c) purifying the resultant solution from step (b).
2. The method of claim 1 , wherein the unsubstituted tetracycline compound is sancycline.
3. The method of claim 1 , wherein the boronic acid is a phenylboronic acid.
4. The method of claim 1 , wherein the palladium catalyst is Pd(OAc) 2 .
5. The method of claim 1 , wherein the 7-iodo tetracycline compound is at least 80% free of positional isomers.
6. The method of claim 1 , wherein the 7-iodo tetracycline compound is at least 90% free of positional isomers.
7. The method of claim 1 , wherein the 7-iodo tetracycline compound is at least 95% free of positional isomers.
8. The method of claim 1 , wherein the boronic acid is selected from the group consisting of: 3-nitrophenyl boronic acid, 4-aminophenyl boronic acid, 4-N,N-dimethylaminophenyl boronic acid, phenylboronic acid, 4-Cl-phenylboronic acid and 4-F-phenylboronic acid.
9. A method for preparing a 7-substituted tetracycline compound at least 75% free of positional isomers, comprising:
(a) reacting an unsubstituted tetracycline compound with at least one equivalent of N-iodosuccinimide in trifluoroacetic acid to result in a 7-iodo tetracycline compound at least 75% free of positional isomers;
(b) reacting the 7-iodo tetracycline compound with a tin reagent, a palladium catalyst and, optionally, copper iodide; and
(c) purifying the resultant solution from step (b).
10. The method of claim 9 , wherein the unsubstituted tetracycline compound is sancycline.
11. The method of claim 9 , wherein the tin reagent is a SnBu 3 reagent.
12. The method of claim 9 , wherein the palladium catalyst is selected from the group consisting of: Pd(PPh 3 ) 2 Cl 2 and Pd(AsPh 3 ) 2 Cl 2 .
13. The method of claim 9 , wherein the 7-iodo tetracycline compound is at least 80% free of positional isomers.
14. The method of claim 9 , wherein the 7-iodo tetracycline compound is at least 90% free of positional isomers.
15. The method of claim 9 , wherein the 7-iodo tetracycline compound is at least 95% free of positional isomers.