Supernucleophilic 4-substituted-pyridine catalysts, and processes useful for preparing same
View Patent ↗Processes for preparing a 4-(secondary or tertiary)aminopyridine are provided. The processes comprise reacting a 4-substituted pyridine base having a leaving group as the 4-substituent, with an activating agent so as to form a corresponding 1,4-substituted pyridine; reacting the 1,4-substituted pyridine with a primary or secondary amine to substitute an amino group at the 4-position, and thereby form a corresponding 1-substituted-4-(secondary or tertiary) aminopyridine, wherein the reacting is conducted in a substitution reaction medium essentially free from strong base; and treating the 1-substituted-4-aminopyridine compound to remove the 1-substituent and thereby form a product medium including the 4-(secondary or tertiary) amino-pyridine.
1. A process for preparing a 4-(secondary or tertiary)aminopyridine, comprising:
reacting a 4-substituted pyridine base having a leaving group as the 4-substituent, with an activating agent of the formula:
wherein R 3 and R 4 , which may be the same as or may differ from one another, are each —H or a C 1 -C 4 alkyl group, and Z is —OR 7 or NR 5 R 6 , wherein R 5 and R 6 , which may be the same as or may differ from one another, and may taken together form a ring, are each —H or C 1 -C 8 alkyl; and R 7 is —H or C 1 -C 8 alkyl; so as to form a corresponding 1,4-substituted pyridine;
reacting said 1,4-substituted pyridine with a primary or secondary amine to substitute an amino group for the leaving group at the 4-position, and thereby form a corresponding 1-substituted-4-(secondary or tertiary) aminopyridine, wherein said amine is included in a molar ratio of at least about 2:1 relative to the 1,4-substituted pyridine and said reacting is conducted in a substitution reaction medium essentially free from strong base; and
treating the 1-substituted-4-aminopyridine compound to remove the 1-substituent and thereby form a product medium including the 4-(secondary or tertiary) amino-pyridine.
2. The process of claim 1 wherein the amine is a dialkylamine.
3. The process of claim 2 wherein the dialkylamine is dimethylamine.
4. The process of claim 1 , wherein said substitution reaction medium at the completion of said reacting has a pH of about 8 to about 10.
5. The process of claim 1 , wherein said substitution reaction medium has a basic pH essentially as provided by said 1,4-substituted pyridine and said amine.
6. The process of claim 5 , wherein the amine is dimethylamine.
7. The process of claim 1 , wherein said activating agent is acrylic acid or methacrylic acid.
8. The process of claim 7 , wherein said activating agent is acrylic acid.
9. The process of claim 8 , wherein said activating agent is acrylamide or methacrylamide.
10. The process of claim 1 , also comprising:
extracting the 4-aminopyridine compound from product medium into an organic solvent to form an extracted medium; and
distilling the extracted medium to separate the organic solvent from the 4-(secondary or tertiary) aminopyridine.
11. The process of claim 10 , also comprising:
after said distilling and without recrystallization of the 4-(secondary or tertiary) aminopyridine, melt-processing the 4-(secondary or tertiary) aminopyridine to a particulate form.
12. The process of claim 11 , wherein the 4-(secondary or tertiary) aminopyridine is a 4-N,N-dialkylaminopyridine.
13. The process of claim 12 , wherein the 4-dialkylaminopyridine is 4-N,N-dimethylaminopyridine.
14. The process of claim 13 , wherein the melt-processing comprises flaking.
15. The process of claim 13 , wherein the melt-processing comprises extrusion granulating.
16. A process of claim 1 , which is conducted in a continuous fashion.
17. The process of claim 16 , wherein the process is conducted in one or more tube reactors.
18. A process for preparing a 4-(secondary or tertiary)aminopyridine, comprising:
reacting a 4-substituted pyridine base having a leaving group as the 4-substituent, with an activating agent of the formula:
wherein R 3 and R 4 , which may be the same as or may differ from one another, are each —H or a C 1 -C 4 alkyl group, and Z is —OR 7 or NR 5 R 6 , wherein R 5 and R 6 , which may be the same as or may differ from one another, and may taken together form a ring, are each —H or C 1 -C 8 alkyl; and R 7 is —H or C 1 -C 8 alkyl; so as to form a corresponding 1,4-substituted pyridine, and
wherein the leaving group is selected from the group consisting of cyano; halo; arylsulfonyl having from six to ten carbon atoms, optionally substituted with one or more alkyl groups having from one to four carbon atoms; arylsulfonyloxy having from six to ten carbon atoms; alkylsulfonyloxy having from one to eight carbon atoms; aryloxy having from six to ten carbon atoms; arylthio having from six to ten carbon atoms; and nitro;
reacting said 1,4-substituted pyridine with a primary or secondary amine to substitute an amino group for the leaving group at the 4-position, and thereby form a corresponding 1-substituted-4-(secondary or tertiary)aminopyridine, wherein said amine is included in a molar ratio of at least about 2:1 relative to the 1,4-substituted pyridine and said reacting is conducted in a substitution reaction medium essentially free from strong base; and
treating the 1-substituted-4-aminopyridine compound to remove the 1-substituent and thereby form a product medium including the 4-(secondary or tertiary) amino-pyridine.