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:
or a pharmaceutically acceptable salt thereof,
comprising:
reacting 3-chlorophenyl boronic acid:
with [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]acetic acid methyl ester:
in the presence of a catalyst to form the following compound:
2. The process of claim 1 , wherein the [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]acetic acid methyl ester:
is prepared by a process comprising:
(a) reacting 3,5-dichloro-2-cyanopyridine:
with benzyl alcohol to form 3,5-bis-benzyloxy-pyridine-2-carbonitrile:
(b) reacting 3,5-bis-benzyloxy-pyridine-2-carbonitrile obtained from step (a) with sodium hydroxide to form 3,5-bis-benzyloxy-pyridine-2-carboxylic acid:
(c) reacting 3,5-bis-benzyloxy-pyridine-2-carboxylic acid obtained from step (b) with glycine methyl ester:
in the presence of coupling reagents to form [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester:
(d) reacting [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester obtained from step (c) under an atmosphere of H 2 in the presence of a catalyst to form [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester:
and
(e) reacting [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester obtained from step (d) with N-phenyl trifluoromethansulfonimide ((CF 3 SO2) 2 NC 6 H 5 ) to form [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]acetic acid methyl ester:
3. The process of claim 1 , further comprising reacting {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester:
with sodium hydroxide to form {(5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid:
4. The process of claim 1 , wherein the catalyst is [1,1′-bis (diphenylphosphino)ferrocine]dichloro palladium(II).
5. The process of claim 1 , wherein the reaction is conducted in the presence of a base that is K 3 PO 4 .
6. The process of claim 2 , wherein the coupling reagents in step (c) are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (MCI) and 1-hydroxybenzotriazole (HOBt).
7. The process of claim 2 , wherein the catalyst in step (d) is Pd/C.