LFA-1 inhibitor and methods of preparation and polymorph thereof
View Patent ↗Methods of preparation and purification of a compound of Formula I, intermediates thereof, a polymorph thereof, and related compounds are disclosed. Formulations and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed.
1. A method of synthesizing a compound of Formula I:
or a salt thereof, comprising the steps:
a) performing hydrolysis of Formula AA with a base under biphasic conditions:
wherein R is a carbon-containing moiety or a silyl-containing moiety; and
b) isolating said compound of Formula I or a salt thereof.
2. The method of claim 1 , wherein the biphasic conditions include aqueous acetone.
3. The method of claim 2 , wherein the aqueous acetone is about 30% aqueous acetone.
4. The method of claim 2 , wherein the aqueous acetone is present in an amount ranging from about 1:1 to about 5:1 by weight with respect to Formula AA.
5. The method of claim 1 , wherein the base is sodium hydroxide.
6. The method of claim 5 , wherein the sodium hydroxide is added in an amount ranging from about 1.0 to about 1.5 equivalents.
7. The method of claim 6 , wherein the sodium hydroxide is added in an amount of about 1.2 equivalents.
8. The method of claim 1 , further comprising a phase transfer catalyst.
9. The method of claim 8 , wherein said phase transfer catalyst is a quaternary ammonium salt.
10. The method of claim 9 , wherein said quaternary ammonium salt is tetrabutylammonium hydroxide.
11. The method of claim 8 , wherein said phase transfer catalyst is present in an amount ranging from about 0.01 equivalents to about 0.5 equivalents.
12. 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.
13. The method of claim 1 , wherein Formula AA is:
14. The method of claim 1 , further comprising purifying said compound of Formula I by recrystallization.
15. The method of claim 14 , wherein said recrystallization is performed with aqueous acetone.
16. A composition comprising a compound of Formula I:
wherein said compound is synthesized by a process comprising the following steps:
a) performing hydrolysis of Formula AA with a base under biphasic conditions:
wherein R is a carbon-containing moiety or a silyl-containing moiety; and
b) isolating said compound of Formula I or a salt thereof, and further wherein said compound has an optical purity of >98%.