Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamdes
View Patent ↗A fungicidal 4-methoxy-3-acetyloxypicolinamide may be conveniently prepared in processes that include the coupling together of 4-methoxy-3-acetyloxypicolinic acid or 4-methoxy-3-hydroxypicolinic acid with a key 2-aminopropanoate ester derived from a 1,1-bis(4-fluorophenyl)propane-1,2-diol.
1. A process for the preparation of the compound of Formula A
wherein Y is CH 3 CO;
from the compound of Formula B
which comprises the following steps:
a) creating a first mixture containing the compound of Formula B, an acylating agent or a chlorinating agent, and a base;
b) adding at least one of the compounds of Formula C and Formula J
wherein X is Cl, Br, HSO 4 , H 2 PO 4 or CH 3 SO 3 and
to the first mixture to form a second mixture; and
c) isolating the compound of Formula A from the second mixture.
2. The process of claim 1 wherein the acylating agent is an alkyl chloroformate of the Formula ClCO 2 R, wherein R is a C 1 -C 4 alkyl or benzyl, or an acid chloride of the Formula RCOCl, wherein R is a C 1 -C 4 alkyl.
3. The process of claim 1 wherein the chlorinating agent is oxalyl chloride or thionyl chloride.
4. The process of claim 1 wherein the base may be selected from the group including triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, potassium carbonate, and mixtures thereof.
5. The process of claim 1 wherein the first mixture further comprises a solvent selected from the group including dichloromethane (DCM), 1,2-dichloroethane (DCE), isopropyl acetate, tetrahydrofuran (THF), 2-MeTHF, acetonitrile (ACN), and mixtures thereof.
6. A process for the preparation of the compound of Formula A
wherein Y is CH 3 CO or CH 3 COOCH 2 ,
which comprises the following steps:
a) creating a first mixture containing the compound of Formula D,
an acylating agent, and a first base;
b) adding at least one of the compounds of Formula C and Formula J
wherein X is Cl, Br, HSO 4 , H 2 PO 4 or CH 3 SO 3 and
to the first mixture to form a second mixture; and
c) isolating the compound of Formula E from the second mixture;
wherein R 1 is a C 1 -C 4 alkyl or a benzyl;
d) creating a third mixture containing the compound of Formula E, an alkali metal base and water;
e) isolating the compound of Formula F from the third mixture;
f) creating a fourth mixture containing the compound of Formula F, an acetylating agent or an alkylating agent, and a second base; and
g) isolating the compound of Formula A from the fourth mixture.
7. The process of claim 6 wherein the acylating agent is an alkyl chloroformate of the Formula ClCO 2 R, wherein R is a C 1 -C 4 alkyl or a benzyl.
8. The process of claim 6 wherein the first mixture further comprises a solvent selected from the group including dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (ACN), isopropyl acetate, THF, 2-MeTHF, and mixtures thereof.
9. The process of claim 6 wherein the first base may be selected from the group including triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine and potassium carbonate.
10. The process of claim 6 wherein about 3 equivalents of the first base and about 2 equivalents of the acylating agent are used.
11. The process of claim 6 wherein the alkali metal base may be selected from the group including LiOH, NaOH, KOH, and mixtures thereof.
12. The process of claim 6 wherein the third mixture further comprises a co-solvent selected from the group including THF, 2-MeTHF, DME, dioxane, ACN and a C 1 -C 4 alcohol.
13. The process of claim 6 wherein the acetylating agent may be selected from acetic anhydride and acetyl chloride.
14. The process of claim 6 wherein the alkylating agent is CH 3 COOCH 2 Br.
15. The process of claim 6 wherein the second base may be selected from the group including pyridine, TEA, DIPEA, and mixtures thereof.