Processes for the preparation of a kinase inhibitor
Inventors
DeMorin, Frenel • Shah, Khalid • Shakya, Sagar • Wang, Yong • Xu, Wei
Assignees
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Publication Number
US-12497367-B2
Publication Date
2025-12-16
Expiration Date
Abstract
The present invention relates to processes for the synthetic preparation of c-Met inhibitors of Formula I, or pharmaceutically acceptable salts thereof. The present invention further relates to processes for the synthetic preparation of the c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to processes for the synthetic preparation of Compound 1·hemifumarate. The invention further relates to large scale processes for the synthetic preparation of the c-Met inhibitor, Compound 1 and Compound 1·hemifumarate.
Core Innovation
The document describes synthetic processes for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof. The preparation comprises contacting a compound of Formula II with a compound of Formula III in the presence of a solvent and a base. The transformation is defined by a leaving group (LG) on Formula III and by variable substituent definitions used across Formula I, including R1, R2, R3, R4, and R5a/R5b/R5c.
The leaving group LG is selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound. The process includes defined selection rules for the substituents of Formula I, where R1 is selected from halo, C1-6 alkyl, C1-6 alkoxy, and C3-6 cycloalkyl; R2 and R3 are each independently selected from halo and C1-6 alkyl; and R4 is selected from halo, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, and C3-6 heteroaryl.
The document further defines R5a, R5b, and R5c, including optional substitution patterns and the possibility that R5a and R5b together form a C3-6 heterocycloalkyl with the nitrogen to which they are attached. In addition, w, x, y, and z are each independently an integer from 0 to 4. The process optionally further comprises contacting the compound of Formula I with an acid to produce a pharmaceutically acceptable salt, and salt formation is exemplified by hemifumarate.
The document also describes related intermediates and additional conversion steps involving further compounds, including Compound 4 and intermediates associated with Formula IV/V/VI and beyond. These additional steps include formation of acyl chloride type intermediates using oxalyl chloride and thionyl chloride, and they include definitions for leaving-group options for LG' in related transformations. The document identifies preferred embodiments for solvent systems and base choices, including inorganic bases and solvent mixtures, and it describes downstream operations such as separation and filtration in the context of the overall synthetic workflow.
Claims Coverage
The partial content identifies three independent claims, which recite a process for preparing a Formula I compound or a pharmaceutically acceptable salt by contacting Formula II with Formula III, a process for preparing Compound 1 by contacting Compound 4 with Formula III', and a multi-step process for preparing Compound 1 with intermediate formation and separation steps. The main inventive features are the defined LG-enabled contacting steps, the structured substituent-selection rules, and the staged Compound 1 route.
Process of contacting Formula II with Formula III for preparing Formula I
A process for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising contacting a compound of Formula II with a compound of Formula III in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound, and wherein R1, R2, R3, R4, R5a, R5b, R5c, R', and w, x, y, and z are defined by the stated structural-selection rules.
Process for preparing Compound 1 via contacting Compound 4 with Formula III'
A process for preparing Compound 1 or a pharmaceutically acceptable salt thereof comprising contacting Compound 4 with a compound of Formula III' in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound, and wherein the process optionally further comprises contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt of Compound 1.
Multi-step preparation of Compound 1 with intermediate formation and phase separation
A process for preparing Compound 1 or a pharmaceutically acceptable salt thereof comprising reacting Compound 3 with 4-aminophenol in the presence of dimethylacetamide and sodium t-pentoxide to provide Compound 4; reacting Compound 6 with oxalyl chloride in the presence of tetrahydrofuran and a catalytic amount of dimethylformamide to produce Compound 7; adding the second reaction mixture to a third reaction mixture comprising a solvent that is approximately 2:1 tetrahydrofuran:water, a base that is K2CO3, and Compound 4, over a period of at least 30 minutes to create a fourth reaction mixture wherein the temperature of the fourth reaction mixture is maintained below approximately 27°C during the addition; heating to form separate phases, discarding the aqueous phase, heating the organic phase, filtering, adding water, stirring, and isolating Compound 1 as a solid product, optionally contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt.
Across the independent claims, the claim coverage centers on defined leaving-group-enabled contacting steps and a specific multi-step Compound 1 route that includes intermediate formation, staged combination of reaction mixtures, phase separation, filtration, and isolation, with optional acid salt formation.
Stated Advantages
Improved yield and purity with 20% water/EtOH versus higher-solvent cases.
Reportedly high yield (>95% and examples including 97%) and high purity (e.g., >99% by UPLC) for the hemifumarate salt preparation.
Documented Applications
Preparation of Compound 1-hemifumarate (a pharmaceutically acceptable salt) from Compound 1 using fumaric acid under specified conditions.
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