Prolyl hydroxylase inhibitors and methods of use
The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
1. A process for preparing a compound having the formula:
comprising:
(a) reacting a 4-chlorophenyl boronic acid:
with methyl 4-bromo-2-methoxybenzoate:
in the presence of a catalyst to form 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester:
(b) reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester obtained from step (a) with lithium hydroxide to form 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid:
and
(c) reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid obtained from step (b) with glycine ethyl ester, in the presence of coupling agents to form [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester:
2. The process of claim 1 , further comprising reacting [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester:
with BBr 3 to form [(4′-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid:
3. The process of claim 1 , wherein the catalyst in step (a) is [1,1′-bis (diphenylphosphino)ferrocine]dichloro palladium(II).
4. The process of claim 1 , wherein the reaction in step (a) is conducted in the presence of a base that is K 3 PO 4 .
5. The process of claim 1 , wherein the coupling reagents in step (c) are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl) and 1-hydroxybenzotriazole (HOBt).