Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
Disclosed herein are methods and processes of preparing vadadustat and pharmaceutically acceptable salts thereof, and intermediates of formula (I) and their salts useful for the synthesis of vadadustat.
1. A process for preparing a compound of Formula (8)
or a salt thereof, comprising:
contacting a compound of Formula (I) or a salt thereof,
wherein:
R 1 is C 1-4 alkyl, CH 2 Cl, phenyl, or benzyl, in which each of phenyl and benzyl may be independently substituted with one, two or three substituents selected from methyl, methoxy, nitro and halogen; and
R 2 is C 1-4 alkyl,
with a hydrolyzing agent,
wherein the compound of Formula (I) or a salt thereof is prepared by a process comprising:
a) contacting a compound of Formula (5) or a salt thereof,
with a compound of Formula (II) or a salt thereof in the presence of a base,
wherein R 1 is C 1-4 alkyl, CH 2 Cl, phenyl, or benzyl, in which each of phenyl and benzyl may be independently substituted with one, two or three substituents selected from methyl, methoxy, nitro and halogen; and
b) contacting a product formed in step a) with a compound of Formula (III) or a salt thereof in the presence of a base,
wherein R 2 is C 1-4 alkyl; and
c) washing the compound of Formula (I) from step b) with a solvent comprising water and a base,
to provide the compound of Formula (I) or a salt thereof,
2. The process of claim 1 , wherein R 1 is t-butyl and/or R 2 is methyl.
3. The process of claim 1 , wherein the hydrolyzing agent comprises an acid or a base.
4. The process of claim 3 , wherein the base is an alkali metal hydroxide, alkali metal carbonate, Polymer-SK, or tetrabutylammonium fluoride (TBAF).
5. The process of claim 3 , wherein the base
is an alkali metal hydroxide selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), and any combination thereof; or
is an alkali metal carbonate selected from lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), cesium carbonate (Cs 2 CO 3 ), and any combination thereof.
6. The process of claim 5 , wherein the alkali metal hydroxide is potassium hydroxide (KOH).
7. The process of claim 1 , which occurs in presence of a solvent comprising N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof.
8. The process of claim 7 , wherein the solvent comprises 2-methyltetrahydrofuran (ME-THF).
9. The process of claim 1 , wherein the purity of the compound of Formula (8) is at least 99%.
10. The process of claim 1 , wherein the compound of Formula (I) comprises less than about 0.5% of the compound of Formula (5).
11. The process of claim 1 , wherein each said base is independently an organic base.
12. The process of claim 11 , wherein each organic base is independently triethylamine (TEA), triisopropylamine, diisopropylamine (DIPEA), pyridine, 2,6-Di-tert-butylpyridine, 1,8-Diazabicycloundec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), or any combination thereof.
13. The process of claim 11 , wherein each organic base is independently diisopropylamine (DIPEA).
14. The process of claim 1 , which occurs in the presence of a solvent comprising ethanol, N,N-dimethylformide (DMF), diethylformamide (DEF), dimethylacetamide (DMA), diethylacetamide (DEA), dimethyl sulfoxide(DMSO), dioxane, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), or any combination thereof.
15. The process of claim 14 , wherein the solvent is tetrahydrofuran (THF).
16. The process of claim 1 , wherein R 1 is t-butyl and R 2 is methyl.
17. The process of claim 1 , wherein R 1 is C 1-4 alkyl.