Crystalline pharmaceutical and methods of preparation and use thereof
View Patent ↗Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention.
1. A method of synthesizing a compound of Formula I:
or a salt thereof comprising the steps:
a) performing base hydrolysis of Formula AA with a base in an aprotic solvent:
wherein R is a carbon containing moiety; and
b) isolating a compound of Formula I, or a salt thereof, with an enantiomeric excess of greater than about 90%.
2. The method of claim 1 , wherein the aprotic solvent is dioxane.
3. The method of claim 1 , wherein the base is sodium hydroxide.
4. The method of claim 1 , wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups.
5. The method of claim 1 , comprising the steps:
a) performing base hydrolysis of Formula A:
with a base in an aprotic solvent; and
b) isolating a compound of Formula I or a salt thereof.
6. The method of claim 5 , wherein the aprotic solvent is dioxane.
7. The method of claim 5 , wherein the base is sodium hydroxide.
8. A method of synthesizing a compound of Formula I:
or a salt thereof comprising the steps:
a) performing acid hydrolysis of Formula AA with an acid in an aprotic solvent:
wherein R is a carbon containing moiety; and
b) isolating a compound of Formula I, or a salt thereof, with an enantiomeric excess of greater than about 90%.
9. The method of claim 8 , wherein the aprotic solvent is dioxane.
10. The method of claim 8 , wherein the acid is hydrogen chloride.
11. The method of claim 8 , wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups.
12. The method of claim 8 , comprising the steps:
a) performing acid hydrolysis of Formula A:
with an acid in an aprotic solvent; and
b) isolating a compound of Formula I or a salt thereof.
13. The method of claim 12 , wherein the aprotic solvent is dioxane.
14. The method of claim 12 , wherein the acid is hydrogen chloride.