Process for preparing AG-10, its intermediates, and salts thereof
Inventors
Chand, Pooran • Gupta, Yogesh Kumar • Kumawat, Rakesh Kumar • Alhamadsheh, Mamoun • Zamboni, Robert
Assignees
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Publication Number
US-10513497-B2
Publication Date
2019-12-24
Expiration Date
Abstract
Provided herein are improved processes for the preparation of a compound of Formula IX (AG-10). Also provided herein are pharmaceutically acceptable salts of Formula I and Formula Ib as well as crystalline types of Formula IX (AG-10). The processes described herein provide improved yields and efficiency, while the pharmaceutically acceptable salts and crystalline forms provide unexpected pharmacokinetic properties. Other features and aspects of the present disclosure will be apparent to a person of skill in the art upon reading the remainder of the specification.
Core Innovation
The document relates to an improved synthetic route toward AG-10, identified as the compound of Formula IX. The route forms a hydroxyl-containing ketone intermediate of Formula IV from compounds of Formula II and Formula III, including interconversion among tautomeric and cyclized forms of Formula IVa, Formula IVb, and Formula IVc. The intermediate is then converted to a hydrazine-derived intermediate of Formula V, and the hydroxyl group is replaced with a halogen or sulfonate substituent to form Formula VI.
Formula VI is coupled with a fluorinated phenolic ester derivative of Formula VII to form Formula VIII, and the ester-linked intermediate of Formula VIII is converted to the carboxylic acid of Formula IX. The document also states that pharmaceutically acceptable salts of Formula Ia and Formula Ib exist and provides characterization context for crystalline forms of Formula IX, including HCl salt and free base forms.
Crystalline form characterization is centered on Formula IX, particularly Crystalline Form Type A of Formula IX. The characterization includes X-ray powder diffraction peak sets, differential scanning calorimetry, thermal gravimetric analysis, and dynamic vapor sorption water uptake, together with a purity constraint that the form is substantially free of other crystalline or amorphous forms of Formula IX.
Claims Coverage
The claim coverage is directed to Crystalline Form Type A of Formula IX as its HCl salt, with the core identification defined by a specific XRPD peak set. Dependent claims further constrain the crystalline form using additional thermal, sorption, and compositional limitations.
Crystalline form type a of formula ix as its hcl salt defined by xrpd peaks
A crystalline Form Type A of Formula IX as its HCl salt, characterized by an X-ray powder diffraction pattern comprising peaks at 12.0, 21.8, 25.9, 26.7, and 27.9 degrees 2θ (±0.2 degrees 2θ).
Crystalline form type a defined by substantially matching xrpd pattern to fig. 31
A crystalline Form Type A of Formula IX as its HCl salt, characterized by an X-ray powder diffraction pattern substantially matching FIG. 31.
Crystalline form type a defined by dsc endothermic peaks
A crystalline Form Type A of Formula IX as its HCl salt, characterized by differential scanning calorimetry endothermic peaks at about 211–214 and 237–239°C.
Crystalline form type a defined by tga weight loss
A crystalline Form Type A of Formula IX as its HCl salt, characterized by a weight loss of about 0.7% to about 1.9% when heated to about 150°C as measured by thermal gravimetric analysis.
Crystalline form type a defined by dynamic vapor sorption water uptake
A crystalline Form Type A of Formula IX as its HCl salt, characterized by a water uptake of about 1.6% at 25°C/80% relative humidity after a dynamic vapor sorption cycle including pre-equilibration at 0% RH.
Crystalline form type a substantially free of other forms
A crystalline Form Type A of Formula IX as its HCl salt that is substantially free of other crystalline or amorphous forms of Formula IX.
Overall, the claim coverage is directed to Crystalline Form Type A of Formula IX as an HCl salt, with the core identification defined by a specific XRPD peak set. Dependent claims further constrain the crystalline form using additional thermal, sorption, and compositional limitations.
Stated Advantages
Improved Cmax for the HCl salt versus the zwitterion/Na salt.
Improved bioavailability for the HCl salt versus the zwitterion/Na salt.
Documented Applications
Pharmacokinetic evaluation comparing the HCl salt (Formula Ia) to the zwitterion/Na salt, reporting improved Cmax and exposure.
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