Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-05-12
2004-06-01
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06743920
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to processes for preparing 1H-imidazo[4,5-c]pyridin-4-amines and to intermediates for use in preparing 1H-imidazo[4,5-c]pyridin-4-amines.
BACKGROUND OF THE INVENTION
Certain antiviral immunomodulator 1H-imidazo[4,5-c]pyridin-4-amines and methods for their preparation are known and disclosed. For example, U.S. Pat. No. 5,494,916 (Lindstrom et al.), incorporated herein by reference, discloses a method involving the steps of forming a 1H-imidazo[4,5-c]pyridine substituted at the 4 position with a hydrogenolyzable amine and hydrogenolyzing using known catalytic hydrogenation conditions to provide the 4-amino compound.
Methods of making certain 1H-imidazo[4,5-c]quinolin-4-amines are also known. For example U.S. Pat. Nos. 4,689,338 and 4,929,624 (Gerster) disclose a method involving the step of heating the corresponding 4-chloro compound in the presence of ammonium hydroxide or ammonia under pressure to provide the 4-amino compound. U.S. Pat. No. 4,988,815 (Andre et al.) discloses a process involving amination of the 4-position of a 3-nitro-2,4-dichloroquinoline. This process too involves as a final step the reaction of animonia with 4-chloro-1H-imidazo[4,5-c]quinoline. U.S. Pat. No. 5,175,296 (Gerster) discloses a process involving the reaction of a 1H-imidazo[4,5-c]quinoline 5N-oxide with an organic isocyanate and hydrolyzing the product to provide the 4-amino compound. U.S. Pat. No. 5,367,076 (Gerster) discloses a process involving the reaction of a 1H-imidazo[4,5-c]quinoline 5N-oxide with an acylating agent and reacting the product with an aminating agent to provide the 4-amino compound. U.S. Pat. No. 5,395,937 (Nikolaides) discloses a process involving amination of the 4-position of a 3-nitroquinolin-2,4-disulfonate with a substituted amine. The final step of the process involves hydrogenolysis to provide the 4-amino compound. U.S. Pat. No. 5,741,908 (Gerster et al.) discloses a process involving the reaction of a 6H-imidazo[4,5-c]tetrazolo[1,5-a] quinoline with triphenylphosphine to provide an N-triphenylphosphinyl-1H-imidazo[4,5-c]quinolin-4-amine and a subsequent hydrolysis to provide a 1H-imidazo[4,5-c]quinoline-4-amine.
Methods of making certain 1-(substituted aryl)alkyl-1H-imidazo[4,5-c]quinolin-4-amines, 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amines, 1,6,7,8-tetrahydrocyclopenta[b]imidazo[4,5-d]pyridin-4-amines, and 1,6,7,8,9,10-hexahydrocyclohepta[b]imidazo[4,5-d]pyridin-4-amines are also known. Japanese Unexamined Patent Publication No. 11-80156 discloses a process involving the reaction of the corresponding 4-chloro compound and phenol with an alkali to form the corresponding 4-phenoxy compound, which is reacted with ammonium acetate to provide the 4-amino compound.
Despite these developments in methods for making certain imidazoquinolin- and imidazopyridin-4-amines, there is a continuing need for useful, alternative processes and intermediates for preparing imidazo[4,5-c]pyridin4-amines.
SUMMARY OF THE INVENTION
This invention provides a process (I) for preparing a 1H-imidazo[4,5-c]pyridin-4-amine compound of Formula I
or a pharmaceutically acceptable salt thereof wherein
R
1
is selected from hydrogen; CHR
x
R
y
wherein R
x
is hydrogen and R
y
is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, straight chain or branched chain alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and —C═CR
z
R
z
wherein each R
z
is independently alkyl or cyclic alkyl of one to six carbon atoms;
R
2
is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; and phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms;
R
3
and R
4
are independently selected from hydrogen and alkyl of one to five carbon atoms; which process comprises the steps of:
(1) providing a compound of Formula II
wherein R
3
and R
4
are as described above;
(2) reacting the compound of the Formula II with a chlorinating agent to provide a compound of Formula III
(3) reacting the compound of the Formula III with a compound of formula R
1
NH
2
, wherein R
1
is as defined above, to provide a compound of Formula IV
(4) reacting the compound of the Formula IV with an alkali metal phenoxide to provide a compound of Formula V
(5) reducing the compound of the Formula V to provide a compound of Formula VI
(6) reacting the compound of the Formula VI with a carboxylic acid of the formula R
2
CO
2
H; an equivalent thereof selected from the corresponding acyl halide, R
2
C(O-alkyl)
3
, and R
2
C(O-alkyl)
2
(O(O═)C-alkyl); or a mixture thereof, wherein R
2
is as defined above and each alkyl contains 1 to 8 carbon atoms, to provide a compound of Formula VIII
(7) reacting the compound of the Formula VIII with an aminating agent to provide the compound of the Formula I.
In some embodiments, in step (6) the compound of the Formula VI is reacted with the carboxylic acid of the formula R
2
CO
2
H; an equivalent thereof selected from the corresponding acyl halide, R
2
C(O-alkyl)
3
, and R
2
C(O-alkyl)
2
(O(O═)C-alkyl); or a mixture thereof; in the presence of cyclization conditions to provide a compound of the Formula VIII.
In some embodiments, step (6) includes the steps of:
(6a) reacting the compound of the Formula VI with a carboxylic acid of the formula R
2
CO
2
H or the corresponding acyl halide to provide a compound of Formula VII
(6b) subjecting the compound of the Formula VII to cyclization conditions, during step (6a) or subsequent to the completion of step (6a), to provide a compound of the Formula VIII.
In some embodiments the above process (I) further comprises the step of isolating the compound of the Formula I or a pharmaceutically acceptable salt thereof.
In another embodiment this invention provides a process (II) for preparing a 1H-imidazo[4,5-c]pyridin-4-amine compound of the Formula I
or a pharmaceutically acceptable salt thereof wherein
R
1
is selected from hydrogen; CHR
x
R
y
wherein R
x
is hydrogen and R
y
is selected from alkyl or cyclic alkyl containing one to ten carbon atoms, straight chain or branched chain alkenyl containing two to ten carbon atoms, hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, and phenylethyl; and —C═CR
z
R
z
wherein each R
z
is independently alkyl or cyclic alkyl of one to six carbon atoms;
R
2
is selected from hydrogen; alkyl containing one to eight carbon atoms; hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl; phenylethyl; and phenyl; the benzyl, phenylethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms;
R
3
and R
4
are independently selected from hydrogen and alkyl of one to five carbon atoms; which process comprises the steps of:
(1) providing a compound of Formula II
wherein R
3
and R
4
are as described above;
(2) reacting the compound of the Formula II with a chlorinating agent to provide a compound of Formula III
(3) reacting the compound of the Form
Dressel Luke T.
Lindstrom Kyle J.
3M Innovative Properties Company
Ersfeld Dean A.
Seaman D. Margaret
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