Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
View Patent ↗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 formula:
wherein R 1 is chosen from:
L is a linking unit having the formula:
—(CR 7a R 7b ) n —
R 7a and R 7b are each independently:
i) hydrogen; or
ii) C 1 -C 6 linear, C 3 -C 6 branched or C 3 -C 6 cyclic alkyl;
R 8 is chosen from hydrogen, methyl, or ethyl; and
the index n is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof,
comprising:
A) reacting a boronic acid with a 3,5-dihalo-2-cyanopyridine having the formula:
each Z is independently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine having the formula:
B) reacting the 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine formed in step (A) with an alkoxide anion having the formula:
⊖ OR 2
wherein R 2 is C 1 -C 12 linear alkyl or C 3 -C 12 branched alkyl, to form a 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine having the formula:
C) reacting the 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine having the formula:
and
D) reacting the 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine formed in step (C) with an amino acid having the formula:
wherein the boronic acid is chosen from 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenyl-boronic acid, 4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyano-phenylboronic acid, 4-cyanophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, 4-nitrophenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluoromethylphenylboronic acid, 2-carbamoylphenylboronic acid, 3-carbamoylphenylboronic acid, 4-carbamoylphenyl-boronic acid, 2-(pyrrolidine-1-carbonyl)phenylboronic acid, 3-(pyrrolidine-1-carbonyl)phenylboronic acid, 4-(pyrrolidine-1-carbonyl)phenylboronic acid, 2-(cyclopropanecarbonylamino)phenylboronic acid, 3-(cyclopropanecarbonyl-amino)phenylboronic acid, 4-(cyclopropanecarbonylamino)phenylboronic acid, 3-chloro-6-methylphenylboronic acid, and 2-chloro-5-methylphenylboronic acid.
2. The process according to claim 1 , wherein the catalyst in step (A) is [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II).
3. The process according to claim 1 , wherein the alkoxide in step (B) is methoxide.
4. The process according to claim 1 , wherein the amino acid of step (D) is chosen from glycine, alanine, isoleucine, leucine, valine, 2-amino-2-methylpropanoic acid, 3-aminobutanoic acid, 3-amino-3-methylbutanoic acid, 3-amino-2-methylbutanoic acid, and 4-aminobutanoic acid.
5. A process for preparing a compound having the formula:
wherein A is a phenyl;
R 10 is hydrogen halogen, alkyl, methoxy, cyano, nitro, trifluoromethyl, carbamoyl, pyrrolidine-1-carbonyl, cyclopropanecarbonylamino, 3-chloro-6-methyl, and 2-chloro-5-methyl;
X is chosen from:
i) —OH;
ii) —OR 3 ;
iii) —NR 4 R 5 ; and
iv) —OM 1 ;
R 3 is C 1 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkyl; C 2 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkenyl; or C 2 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkynyl, or benzyl;
R 4 and R 5 are each independently hydrogen, C 1 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkyl; C 2 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkenyl; or C 2 -C 12 linear, C 3 -C 12 branched or C 3 -C 12 cyclic alkynyl; benzyl; or R 4 and R 5 can be taken together with the nitrogen atom to form a 3 to 10 member ring, wherein the ring can optionally contain one or more heteroatoms chosen from oxygen (O), nitrogen (N), or sulfur (S);
M 1 is a pharmaceutically acceptable cation;
R 7a and R 7b are each independently:
i) hydrogen; or
ii) C 1 -C 6 linear, C 3 -C 6 branched or C 3 -C 6 cyclic alkyl;
R 8 is chosen from hydrogen, methyl, or ethyl; and
the index n is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof,
comprising:
A) reacting a boronic acid with a 3,5-dihalo-2-cyanopyridine having the formula:
each Z is independently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine having the formula:
B) reacting the 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine formed in step (A) with an alkoxide anion having the formula:
⊖ OR 2
wherein R 2 is C 1 -C 12 linear alkyl or C 3 -C 12 branched alkyl, to form a 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine having the formula:
C) reacting the 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine having the formula:
and
D) reacting the 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine formed in step (C) with a compound having the formula:
wherein the boronic acid is chosen from phenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenyl-boronic acid, 4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyano-phenylboronic acid, 4-cyanophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, 4-nitrophenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluoromethylphenylboronic acid, 2-carbamoylphenylboronic acid, 3-carbamoylphenylboronic acid, 4-carbamoylphenyl-boronic acid, 2-(pyrrolidine-1-carbonyl)phenylboronic acid, 3-(pyrrolidine-1-carbonyl)phenylboronic acid, 4-(pyrrolidine-1-carbonyl)phenylboronic acid, 2-(cyclopropanecarbonylamino)phenylboronic acid, 3-(cyclopropanecarbonyl-amino)phenylboronic acid, 4-(cyclopropanecarbonylamino)phenylboronic acid, 3-chloro-6-methylphenylboronic acid, and 2-chloro-5-methylphenylboronic acid.
6. The process according to claim 5 , wherein the catalyst in step (A) is [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II).
7. The process according to claim 5 , wherein the compound of step (D) is chosen from glycine, alanine, isoleucine, leucine, valine, 2-amino-2-methylpropanoic acid, 3-aminobutanoic acid, 3-amino-3-methylbutanoic acid, 3-amino-2-methylbutanoic acid, and 4-aminobutanoic acid.
8. The process according to claim 5 , wherein X is —OR 3 or —NR 4 R 5 further comprising the step of hydrolyzing the compound formed in step (D) to form a compound wherein X is —OH.
9. The process according to claim 8 , wherein the hydrolysis is conducted in the presence of an acid catalyst.
10. The process according to claim 8 , wherein the hydrolysis is conducted in the presence of a base catalyst.