PROCESS OF MAKING PROSTACYCLIN COMPOUNDS WITH LINKER THIOL AND PEGYLATED FORMS

摘要

A process provides for producing chiral prostacyclin derivatives of Formula (I);in high yield from meso anhydrides.

主权项

1. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof: the process comprising:
coupling a meso anhydride of Formula III with an ester compound of Formula IV in the presence of a chiral ligand, to provide a compound of Formula V: coupling the compound of Formula V with a compound of Formula VI to form a thiol, hydrolyzing the thiol with a hydrolyzing agent to form a compound of Formula VIII; deprotecting the compound of Formula VIII to form the compound of Formula II:and
coupling the compound of Formula II with a PEG-maleimide compound to form the compound of Formula I;wherein
X is O or CH2; Z is O or CH2; L is p=0 or 1; r=1-8; t=1, 2 or 3; w=1, 2, or 3; PEG is a polyethylene glycol moiety; R1 represents an acid protective group; and R4 represents a thiol protecting group.