Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids
View Patent ↗4,6-Dibromo-3-hydroxypicolinonitrile may be prepared from furfural in a series of chemical steps selected from cyano-amination, amine salt formation and bromination-rearrangement. 4-Alkoxy-3-hydroxypicolinic acids may be conveniently prepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series of chemical steps selected from bromo substitution, nitrile hydrolysis and halogen reduction.
1. A biphasic process for the preparation of the compound of Formula A
comprising the steps of:
a) creating a first mixture by combining together a 2-phase water-organic solvent system, an ammonia source, a cyanide source and a furan-2-aldehyde of Formula B
b) separating a second mixture from the first mixture which includes the compound of Formula C as a solution in the organic solvent;
c) adding an aqueous solution of a mineral acid to the second mixture to form a third mixture;
d) separating a fourth mixture from the third mixture which is an aqueous mixture that includes the compound of formula D;
wherein X is Br, HSO 4 , NO 3 or H 2 PO 4 ;
e) adding a brominating agent to the fourth mixture to form a fifth mixture; and
f) isolating the compound of Formula A from the fifth mixture.
2. The process of claim 1 wherein the organic solvent is at least one organic solvent selected from the group of organic solvents consisting of: diethyl ether, methyl t-butyl ether, methylene chloride, ethyl acetate, 2-methyltetrahydrofuran, toluene and xylene.
3. The process of claim 1 further comprising the steps of:
a) creating a sixth mixture which includes the alkali metal alkoxide of Formula E
MOR 1 E
wherein M is Na or K, and R 1 is a C 1 -C 3 alkyl; and
the compound of Formula A;
b) heating the mixture; and
c) isolating a compound of Formula F from the sixth mixture;
wherein R 1 is a C 1 -C 3 alkyl.
4. The process of claim 3 further comprising the steps of:
a) creating a seventh mixture which includes the compound of Formula F, water, and at least one of a mineral acid and a strong base;
b) heating the mixture; and
c) isolating the compound of Formula G
wherein R 1 is a C 1 -C 3 alkyl;
from the seventh mixture.
5. The process of claim 4 wherein the seventh mixture includes the compound of Formula F, water, and a mineral acid.
6. The process of claim 4 wherein the seventh mixture includes the compound of Formula F, water, and a strong base.
7. The process of claim 4 further comprising the following steps:
a) creating an eighth mixture which includes the compound of Formula G and a reducing agent; and
b) isolating the compound of Formula H from the eighth mixture;
wherein R 1 is a C 1 -C 3 alkyl.
8. The process of claim 3 further comprising the following steps:
a) creating a ninth mixture which includes the compound of Formula F and a reducing agent; and
b) isolating the compound of Formula I from the ninth mixture;
wherein R 1 is a C 1 -C 3 alkyl.
9. The process of claim 8 further comprising the steps of:
a) creating a tenth mixture which includes the compound of Formula I, water, and one of a mineral acid and a strong base; and
b) isolating a compound of Formula H from the tenth mixture;
wherein R 1 is a C 1 -C 3 alkyl.
10. The process of claim 9 further comprising the step of;
heating the tenth mixture.
11. The process of claim 9 wherein the tenth mixture includes the compound of Formula I, water, and a mineral acid.
12. The process of claim 9 wherein the tenth mixture includes the compound of Formula I, water, and a strong base.
13. A process for preparing the compound of Formula F
wherein R 1 is a C 1 -C 3 alkyl;
comprising the steps of:
a) creating a mixture which includes at least one alkali metal alkoxide of Formula E
MOR 1 E
wherein M is Na or K, and R 1 is a C 1 -C 3 alkyl; and
the compound of Formula A;
b) heating the mixture; and
c) isolating a compound of Formula F from the mixture.
14. The process of claim 13 wherein M is Na and R 1 is a C 1 -C 3 alkyl.
15. The process of claim 13 further comprising a solvent mixture comprised of a protic solvent and a polar aprotic solvent.
16. The process of claim 15 wherein the protic solvent is selected is at least one solvent selected from the group consisting of: methanol and ethanol.
17. The process of claim 15 wherein the aprotic solvent is at least one solvent selected from the group consisting of: DMSO, DMF, sulfolane and NMP.
18. The process of claim 15 wherein the volume percent ratio of the protic solvent to the polar aprotic solvent in the solvent mixture is from about 100:0 to about 0:100.