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Publication Number
US-11078190-B2
Publication Date
2021-08-03
Expiration Date
Abstract
The present invention relates to crystalline forms of the compound represented by Structural Formula I, and compositions comprising crystalline forms of the compound represented by Structural Formula I described herein. The crystalline forms of the compound of Structural Formula I and compositions comprising the crystalline forms of the compound of Structural Formula I provided herein, in particular, single crystalline Form A, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders associated with CRM1 activity, including cancer. Also described herein are methods for preparing the compound of Structural Formula I and its single crystalline forms.
Core Innovation
The invention relates to crystalline forms of selinexor, designated as the compound of Structural Formula I, and synthetic methods for its preparation. The process involves a T3P-mediated coupling of compounds of Structural Formulas II and III, followed by crystallization as Form D and conversion to Form A. In-situ activation reduces double-bond isomerization and KF9 byproduct formation, improving yield and purity across scales up to kilogram quantities.
The disclosure characterizes crystalline Forms A through D using X-ray powder diffraction and thermal analysis, identifying Form A as the thermodynamically stable anhydrous form. Crystalline Form D is an acetonitrile solvate useful as an intermediate for obtaining Form A in high yield and purity. Pharmaceutical compositions containing Form A exhibit unimodal particle-size distributions and are provided for treating CRM1-associated disorders.
Claims Coverage
The relevant claims include seven independent claims: claims 1, 8, 9, 16, 17, 19, and 20, covering the crystalline Form D acetonitrile solvate, methods for preparing Forms D and A, and integrated synthetic routes.
Acetonitrile solvate of Form D
Claim 1 covers a single crystalline form of the compound of Structural Formula I that is an acetonitrile solvate of Form D, characterized by selected X-ray powder diffraction peaks.
Conversion of Form D to Form A by slurry processing
Claim 8 covers preparing and isolating crystalline Form A from Form D using an isopropanol-based slurry process [procedural detail omitted for safety], with crystalline forms identified by selected X-ray powder diffraction peaks.
Conversion of Form D to Form A by water addition and cooling
Claim 9 covers preparing and isolating crystalline Form A from crystalline Form D through an isopropanol-based conversion involving water addition and cooling [procedural detail omitted for safety], with forms identified by selected X-ray powder diffraction peaks.
Preparation of Form A by thermal or solvent maturation
Claim 16 covers preparing and isolating crystalline Form A from Form D by heating, solvent-system maturation, drying, or a combination of these operations [procedural detail omitted for safety], with Form A identified by selected X-ray powder diffraction peaks.
Preparation of the acetonitrile solvate of Form D
Claim 17 covers preparing and isolating solid particles of crystalline Form D as an acetonitrile solvate by dissolving the compound of Structural Formula I in an acetonitrile-containing solvent system and inducing particle formation [procedural detail omitted for safety], characterized by selected X-ray powder diffraction peaks.
Integrated preparation of Form A through Form D
Claim 19 covers preparing the compound of Structural Formula I from compounds of Structural Formulas II and III, forming and isolating crystalline Form D, and converting it to crystalline Form A by heating, solvent maturation, drying, or a combination of these operations [procedural detail omitted for safety].
Integrated preparation of Form A using slurry-based conversion
Claim 20 covers preparing the compound of Structural Formula I from compounds of Structural Formulas II and III, forming and isolating crystalline Form D, and converting Form D to Form A through an isopropanol-based slurry process [procedural detail omitted for safety], with crystalline forms identified by selected X-ray powder diffraction peaks.
The independent claims cover one crystalline Form D acetonitrile solvate and six methods directed to preparing Form D, converting Form D to Form A, or integrating compound synthesis with Form A preparation.
Stated Advantages
The in-situ activation process is reported to reduce double-bond isomerization and KF9 byproduct formation.
The process is reported to improve purity and yield, with the summary reporting about 80% overall yield and an example reporting greater than 99.5% UPLC purity.
The process is reported to scale to kilogram quantities.
Form A is identified as the most thermodynamically stable anhydrous crystalline form under the tested conditions.
Form D is presented as an advantageous intermediate for obtaining Form A in high yield and purity.
Documented Applications
Preparation of selinexor, including crystallization as Form D and conversion to crystalline Form A.
Preparation and characterization of crystalline Forms A, B, C, and D of the compound of Structural Formula I.
Pharmaceutical compositions containing Form A for use in CRM1-associated disorders, including cancer and wound healing.
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