CRYSTALLINE PHARMACEUTICAL AND METHODS OF PREPARATION AND USE THEREOF
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:
comprising the steps:
a) 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.
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) base hydrolysis of Formula A:
with a base in an aprotic solvent; and
b) isolating a compound of Formula I.
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:
comprising the steps:
a) 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.
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) acid hydrolysis of Formula A:
with an acid in an aprotic solvent; and
b) isolating a compound of Formula I.
13 . The method of claim 12 , wherein the aprotic solvent is dioxane.
14 . The method of claim 12 , wherein the acid is hydrogen chloride.
15 . An isolated compound of Formula I:
wherein said compound is synthesized according to the method of claim 1 , and further wherein said compound has a lower level of residual palladium compared to a compound of Formula I prepared by palladium-catalyzed transfer hydrogenolysis.