Method for producing nitrogen-containing heteroarylcarboxamide acetic acid derivative
Inventors
OOTSUKI, Kazufumi • Kishida, Muneki • Moroda, Atsushi • FUKUHARA, Kohki • YAGISHITA, Hirotoshi
Assignees
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Publication Number
US-12612367-B2
Publication Date
2026-04-28
Expiration Date
Abstract
The present invention provides a novel process for preparing the compound I containing the compound [I(A)] (vadadustat) and the compound [I(B)] (roxadustat) which are useful as a medicine in an industrially advantageous manner, and a process for preparing the compound I which comprises reacting the compound (a1) or the compound (b1), the compound (2) or salts of the compound (2), with carbon monoxide in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to prepare the compound I (wherein structure formulae of the compound (a1), the compound (b1) or the compound (2), and the definitions of groups in the formulae are defined in the description.
Core Innovation
The disclosure relates to the palladium-catalyzed carbonylation of halogenated heteroaryl precursors with glycine derivatives and carbon monoxide to prepare hydroxypyridine-glycine carboxamide-acetic-acid intermediates. These synthetic intermediates provide routes to compounds [I(A)] and [I(B)], identified as vadadustat and roxadustat, and encompass related protected, ester, and acid forms. Nitrile solvents serve to increase the desired-product-to-byproduct ratio during the carbonylation reaction.
The disclosed synthetic processes operate in fewer steps with lower-cost starting materials, rendering the procedures suitable for industrial-scale manufacturing in good yields. The subject matter further encompasses precursor compound (a1-a) alongside characterized crystal forms of intermediate (a3-1-A). Type II crystals of intermediate (a3-1-A) facilitate impurity removal, whereas type I crystals exhibit higher thermodynamic stability and robustness for industrial processing.
Claims Coverage
The independent claims encompass eight inventive features across preparation processes, an intermediate precursor compound, and crystalline forms.
Preparation of compound (a3)
A claim covers preparing compound (a3) from a halogen-substituted compound of formula (a1), a compound of formula (2) or its salt, and carbon monoxide via palladium-catalyzed carbonylation in the presence of a base and a solvent. [procedural detail omitted for safety]
Preparation of compound [I(A)] through intermediate (a3-1-a)
A claim covers preparing compound [I(A)] via intermediate (a1-1-a) formed from compounds of formulas (a4) and (a5), carbonylation with compound (2-1) or its salt and carbon monoxide to yield intermediate (a3-1-a), and subsequent conversion to compound [I(A)]. [procedural detail omitted for safety]
Preparation of compound [I(A)] through intermediate (a3-2-a)
A claim covers preparing compound [I(A)] via intermediate (a1-3-a) from compounds of formulas (a4-1) and (a5), conversion to intermediate (a1-4-a), carbonylation with compound (2-1) or its salt and carbon monoxide to form intermediate (a3-2-a), and conversion to compound [I(A)]. [procedural detail omitted for safety]
Preparation of compound (b3-1)
A claim covers preparing compound (b3-1) by carbonylating a compound of formula (b1) with compound (2) and carbon monoxide to yield intermediate (b3), followed by palladium-catalyzed coupling with compound (b4). [procedural detail omitted for safety]
Preparation of compound (bI-1)
A claim covers preparing compound (bI-1) through formula (b3-4) and formula (b3-5) intermediates comprising carbonylation, coupling, and subsequent conversion. [procedural detail omitted for safety]
Compound of formula (a1-a)
A claim covers a precursor compound of formula (a1-a), wherein Z1 is selected from chlorine, bromine, or iodine and Za2 is a hydroxy group or a substituent bearing a hydroxy-protecting group.
Type I crystal of compound (a3-1-A)
A claim covers a crystal of compound (a3-1-A) characterized by an X-ray powder diffraction pattern comprising peaks at 7.96, 11.82, 14.14, 15.94, 24.68, or 39.22° 2θ (±0.2° tolerance).
Type II crystal of compound (a3-1-A)
A claim covers a crystal of compound (a3-1-A) characterized by an X-ray powder diffraction pattern comprising peaks at 8.52, 10.78, 20.16, 22.64, 23.56, or 34.4° 2θ (±0.2° tolerance).
The claims define carbonylation- and coupling-mediated processes for producing intermediates and target compounds across the (a3), [I(A)], (b3-1), and (bI-1) families, precursor compound (a1-a), and two distinct crystalline polymorphs of intermediate (a3-1-A).
Stated Advantages
The route operates in fewer steps and uses lower-cost starting materials than prior processes, providing an industrially advantageous preparation in good yields.
Nitrile solvents increase the desired-product-to-byproduct ratio during carbonylation.
Type II crystals of intermediate (a3-1-A) provide more effective impurity removal.
Type I crystals of intermediate (a3-1-A) exhibit higher thermodynamic stability and robustness for industrial processing.
Documented Applications
Preparation of vadadustat [I(A)] and roxadustat [I(B)] via the disclosed intermediates and synthetic processes.
Synthesis of hydroxypyridine-glycine derivatives, including protected and arylated intermediates across the (a3), [I(A)], (b3-1), and (bI-1) families on an industrial scale.
Industrial processing of crystal type I of compound (a3-1-A).
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