Process for preparing [(3-hydroxypyridine-2-carbonyl)aminojalkanoic acids, esters and amides
Disclosed are processes for preparing [(3-hydroxypyridine-2-carbonyl)amino]-alkanoic acids, derivatives, inter alia, 5-aryl substituted and 5-heteroaryl substituted [(3-hydroxypyridine-2-carbonyl]amino}acetic acids. Further disclosed are methods for making prodrugs of [(3-hydroxypyridine-2-carbonyl)-amino]acetic acids, for example, [(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2-carbonyl]amino}acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase inhibitors or for treating conditions wherein prolyl hydroxylase inhibition is desired.
1 . A process for preparing a compound having the following structure:
comprising:
A. reacting (3-chlorophenyl) boronic acid:
with 3,5-dichloro-2-cyanopyridine:
in the presence of a catalyst and a base to form 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine:
B. reacting 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine with sodium methoxide to form 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine:
C. reacting 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine with hydrobromic acid or hydrochloric acid to form 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid:
2 . The process of claim 1 , wherein the catalyst of step (A) is [1,1′-bis (diphenyphosphino) ferrocene] dichloro palladium (II).
3 . The process of claim 1 , wherein the base of step (A) is LiOH, NaOH, KOH, Ca(OH) 2 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , or CaCO 3 .
4 . The process of claim 3 , wherein the base is K 2 CO 3 .
5 . The process of claim 1 , wherein the acid of step (C) is hydrochloric acid.
6 . A process for preparing compound (5):
wherein said process comprises steps (A)-(C) of claim 1 .
7 . A process for preparing compound (5)
comprising reacting 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid
with a glycine methyl ester
8 . The process of claim 7 , further comprising reacting 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine
with hydrobromic acid or hydrochloric acid to form 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid
9 . The process of claim 8 , further comprising reacting 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine
with sodium methoxide to form 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine
10 . The process of claim 9 , further comprising reacting (3-chlorophenyl) boronic acid
with 3,5-dichloro-2-cyanopyridine
in the presence of a catalyst to form 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine
11 . The process according to claim 10 , wherein said catalyst is [1,1′-bis (diphenyphosphino) ferrocene] dichloro palladium (II).
12 . The process of claim 10 , wherein the reaction of step is conducted in the presence of a base.
13 . The process of claim 12 , wherein the base is LiOH, NaOH, KOH, Ca(OH) 2 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , or CaCO 3 .
14 . The process of claim 13 , wherein the base is K 2 CO 3 .