Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic 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 compound having the formula:
comprising:
reacting a meta substituted aryl boronic acid:
with 3,5-dichloro-2-cyanopyridine:
in the presence of a catalyst,
wherein R 10 is Cl or Br.
2. The process of claim 1 , wherein the catalyst is [1,1′-bis (diphenylphosphino)ferrocine]dichloro palladium(II).
3. The process of claim 1 , wherein the reaction is conducted in the presence of a base.
4. The process of claim 3 , 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 .
5. The process of claim 4 , wherein the base is K 2 CO 3 .
6. A process comprising reacting (3-chlorophenyl)boronic acid:
with 3,5-dichloro-2-cyanopyridine:
in the presence of a catalyst to form 3-chloro-5-(3-chlorophenyl)picolinonitrile:
7. The process according to claim 6 , wherein the catalyst in step (A) is [1,1′-bis (diphenyphosphino)ferrocene]dichloro palladium(II).
8. The process of claim 6 , wherein the reaction of step is conducted in the presence of a base.
9. The process of claim 8 , 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 .
10. The process of claim 9 , wherein the base is K 2 CO 3 .
11. The process of claim 6 , further comprising reacting 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine with sodium methoxide to form 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine:
reacting 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine with hydrobromic acid to form 5-(3-chlorophenyl)-3-hydroxy-2-cyanopyridine-2-carboxylic acid:
12. The process of claim 6 , further comprising reacting 5 5-(3-chlorophenyl)-3-hydroxy-2-cyanopyridine-2-carboxylic acid with glycine methyl ester:
in the presence of a coupling reagent to form methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate:
13. The process of claim 12 , wherein the coupling reagent in is carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N′,N′-dimethylamino)propylcarbodiimide (EDC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(benzotriazol-1-yl)-N,N,N′N′-tertaetyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′N′-tertamethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HCTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (TDBTU), or 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT).
14. The process of claim 13 , wherein the coupling reagent is carbonyldiimidazole (CDI).
15. The process of claim 6 , further comprising reacting methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate with sodium hydroxide to form compound (5):