Crystalline fosaprepitant dicyclohexylamine salt and its preparation
Inventors
Patel, Jigneshkumar Jasubhai • Muthiah, Raja Jeyakumar John
Assignees
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Publication Number
US-10544175-B2
Publication Date
2020-01-28
Expiration Date
Abstract
Dicyclohexylamine salt of fosaprepitant (fosaprepitant DCHA), a process for preparing fosaprepitant DCHA, and a use of fosaprepitant DCHA in the preparation of pharmaceutically acceptable fosaprepitant dimeglumine with high purity is provided. Fosaprepitant dimeglumine is prepared by treating fosaprepitant DCHA with an acid to form fosaprepitant, followed by adding N-methyl-D-glucamine to fosaprepitant.
Core Innovation
The invention provides a process for the preparation of fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia. The process starts from crystalline fosaprepitant di(dicyclohexylamine) salt of formula II, which is treated with an acid to obtain fosaprepitant of formula I, followed by salt formation with N-methyl-D-glucamine and isolation of fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia.
A key aspect is the use of a crystalline fosaprepitant di(dicyclohexylamine) salt of formula II defined by an X-ray powder diffraction pattern having specific peaks at about 4.52, 8.29, 13.17, 13.23, 18.31, and 22.51±0.2 2θ. This crystalline intermediate is then converted to fosaprepitant of formula I by acid treatment, and the resulting fosaprepitant is dissolved with N-methyl-D-glucamine in a first solvent to form the target salt of formula Ia.
The described approach is directed to improved product quality, including fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia having HPLC purity ≥99.0% and low heavy-metal (Pd) impurity. The crystalline intermediate and final product are characterized by crystallographic characterization (XRPD) and spectroscopic characterization (FTIR absorptions) for the intermediate and/or related materials.
Claims Coverage
The independent claim defines two inventive features centered on preparing fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia from a crystalline fosaprepitant di(dicyclohexylamine) salt intermediate defined by XRPD peaks, followed by acid treatment, salt formation with N-methyl-D-glucamine, and isolation. Dependent claims further refine the process by adding quantitative constraints, impurity limits, and characterization requirements.
Crystalline dicyclohexylamine salt-defined conversion to fosaprepitant
adding crystalline fosaprepitant di(dicyclohexylamine) salt of formula II in a solvent to form a solution and treating the solution with an acid to obtain fosaprepitant of formula I, wherein the crystalline fosaprepitant di(dicyclohexylamine) salt of formula (II) has a X-ray powder diffraction pattern with peaks at about 4.52, 8.29, 13.17, 13.23, 18.31, and 22.51±0.2 2θ
Salt formation with N-methyl-D-glucamine and isolation
dissolving fosaprepitant of formula I and N-methyl-D-glucamine in a first solvent to obtain a solution of fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia; and isolating fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia
Across the independent claim and its dependencies, the claim coverage focuses on preparing fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia by acid treatment of a crystalline fosaprepitant di(dicyclohexylamine) salt (formula II) defined by specified XRPD peaks, followed by dissolution with N-methyl-D-glucamine in a first solvent and isolation. Dependent claims further address product and intermediate quality via purity and impurity constraints and additional characterization.
Stated Advantages
fosaprepitant di(N-methyl-D-glucamine) salt of formula Ia has HPLC purity ≥99.0% (preferably up to 99.9%)
low heavy-metal (Pd) impurity
Documented Applications
EMEND for injection
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