Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino] acetic acid
Inventors
Gorin, Boris I. • Lanthier, Christopher M. • Luong, Anne Buu Chau • Copp, James Densmore • Gonzalez, Javier • Jautze, Sascha • Kraus, Erich • O'Connor, Alan
Assignees
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Publication Number
US-12269802-B2
Publication Date
2025-04-08
Expiration Date
Abstract
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.
Core Innovation
The invention relates to vadadustat, defined as 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid, and to pharmaceutically acceptable salts thereof. It is prepared through processes and intermediates involving compounds of Formula (I), Formula (IV), Formula (8), and Formula (5), including a hydrolysis conversion in which a compound of Formula (I), or a salt, is contacted with a hydrolyzing agent to give Formula (8).
The invention also relates to solid compositions comprising a compound of Formula (I) or a salt thereof and a compound of Formula (IV) or a salt thereof, where the composition comprises 80% or more of the compound of Formula (I) or its salt and 20% or less of the compound of Formula (IV) or its salt. The combined amount of the compound of Formula (I), or a salt thereof, and the compound of Formula (IV), or a salt thereof, is between about 99% and about 100% of the composition.
The compositions further define impurity control by including less than about 0.5% of the compound of Formula (5), with impurity thresholds described as <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.05%, and <0.01%. The described work includes embodiments culminating in compounds including Formula (5) or compound 7 and subsequent conversion to compound 8, and purity levels are supported by HPLC.
Claims Coverage
The consolidated content includes two independent claim themes covering vadadustat-related structures and solid compositions, with dependent claims refining substituent selections, impurity thresholds, and purity determination. Four inventive features are present across the items.
Formula (I) compound with constrained Formula (5) impurity
A compound of Formula (I), or a salt thereof, where R1 is C1-4 alkyl, CH2Cl, phenyl, or benzyl, and R2 is C1-4 alkyl, wherein the compound comprises less than about 0.5% of the compound of Formula (5).
Composition defined by Formula (I) and Formula (IV) proportions
A composition comprising 80% or more of a compound of Formula (I) or a salt thereof and 20% or less of a compound of Formula (IV) or a salt thereof, where the combined amount of Formula (I) and Formula (IV) is between about 99% and about 100% of the composition.
Impurity-limited composition with Formula (5) below a threshold
The composition comprises less than about 0.5% of the compound of Formula (5), with dependent claims reciting lower thresholds.
Substituent definitions for R1 and R2 in the Formula (I) framework
R1 is C1-4 alkyl, CH2Cl, phenyl, or benzyl, with phenyl and benzyl independently substituted with one, two or three substituents selected from methyl, methoxy, nitro and halogen, and R2 is C1-4 alkyl.
Coverage centers on a Formula (I) compound, or salt, and on solid compositions where Formula (I) or its salt predominates over Formula (IV) or its salt, while Formula (5) impurity is controlled below about 0.5%. The claim scope also confines the substituent range through R1 and R2 and supports purity determination by HPLC.
Stated Advantages
Controls the content of the compound of Formula (5) impurity, with dependent claims tightening to lower thresholds.
Provides defined composition ranges in which the combined amount of Formula (I) and Formula (IV) is between about 99% and about 100% of the composition.
Specifies minimum purity levels for the compound of Formula (I).
Specifies that purity is determined by HPLC.
Documented Applications
Manufacture of vadadustat and pharmaceutically acceptable salts using processes and intermediates involving compounds of Formula (I), Formula (IV), Formula (8), and Formula (5).
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