Processes for the preparation of uracil derivatives
The present invention relates to processes and intermediates for preparing Gonadotropin-Releasing Hormone (GnRH) receptor antagonists of structure (VI); and stereoisomers and pharmaceutically acceptable salts thereof.
1. A process for preparing a compound of structure (VI):
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
R 1a , R 1b and R 1c are the same or different and independently hydrogen, halogen, C 1-4 alkyl, hydroxy or alkoxy;
R 2a and R 2b are the same or different and independently hydrogen, halogen, trifluoromethyl, cyano or —SO 2 CH 3 ;
R 3 is hydrogen or methyl; and
R 4 is H, —C 1-6 alkanediyl-COOH, or —C(═O)O-(t-butyl);
comprising as an intermediate synthesis step:
reacting a compound of structure (VII):
wherein R 2 a, R 2b and R 3 are as defined above;
with a compound of structure (VIII):
wherein R is H or C 1-4 -alkyl, R′ is H or C 1-4 -alkyl or R and R′ taken together form C 1-6 alkanediyl; and
R 1a , R 1b , and R 1c are as defined above; and
reacting methanesulfonic acid-(S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester with the compound formed by reacting compound (VII) with compound (VIII), which compound has the structure:
in the presence of a base.
2. The process of claim 1 wherein said reaction of said compound of structure (VII) with said compound of structure (VIII) occurs in the presence of a palladium catalyst.
3. The process of claim 1 wherein R 1a is halogen, R 1b is methoxy and R 1c is H.
4. The process of claim 3 wherein R 2a is halogen and R 2b is halogen or trifluoromethyl.
5. The process of claim 1 , further comprising isolation of a compound of formula (VI) as an amorphous solid.