Method for producing 1, 2-dihydropyridine-2-one compound
Inventors
Arimoto, Itaru • Nagato, Satoshi • Sugaya, Yukiko • Urawa, Yoshio • Ito, Koichi • Naka, Hiroyuki • Omae, Takao • Kayano, Akio • Nishiura, Katsutoshi
Assignees
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Publication Number
US-8772497-B2
Publication Date
2014-07-08
Expiration Date
Abstract
The present inventions provide a method for commercially producing a 1,2-dihydropyridine-2-one compound represented by the following formula (III-a) wherein the ring A represents an optionally substituted 2-pyridyl group, the ring B represents an optionally substituted phenyl group, and the ring C represents an optionally substituted phenyl group. Further, the invention provides crystals of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one and production processes therefore.
Core Innovation
The disclosure relates to the crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate, defined by powder X-ray diffraction, infrared absorption spectrum, and 13C Solid State Nuclear Magnetic Resonance. The hydrate crystals are identified by characteristic diffraction peaks at specified diffraction angles and by absorption peaks at specified wavenumbers in an infrared absorption spectrum (KBr method).
The document describes a process for producing crystals of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate by crystallizing 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one with crystallization solvents selected from alcoholic solvents, alkylketone solvents, and water. The resulting hydrate crystals are further defined by powder X-ray diffraction peaks, infrared absorption peaks (KBr method), and 13C Solid State Nuclear Magnetic Resonance peaks or spectra shown in figures.
The hydrate crystals are distinguishable from non-hydrate crystals by powder X-ray diffraction peak patterns, infrared absorption peak determination, and 13C solid-state NMR chemical shift tables. The crystal forms and their production are stated to enable industrial production in good yield and high purity.
The hydrate crystal forms are suitable as active ingredients for neurodegenerative disease therapeutics/prophylaxis. The disclosure also presents crystal forms and characterization used to support specific crystal forms including hydrate and anhydrous crystals.
Claims Coverage
The provided independent claims cover multiple distinct characterizations of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate crystals. The inventive features are defined using powder X-ray diffraction peak sets, infrared absorption peak sets (KBr method), 13C solid-state NMR peak sets, spectral figures, and a process claim for producing the hydrate crystals by crystallization with specified solvent categories and defined hydrate characterization outcomes. In total, the main inventive features are crystal-form identification and characterization, and a crystallization process leading to the defined hydrate crystal form.
Hydrate crystal characterized by PXRD peak at 2θ=8.7°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a diffraction peak at a diffraction angle (2θ±0.2°) of 8.7° in a powder X-ray diffraction.
Hydrate crystal characterized by PXRD peak at 2θ=12.5°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a diffraction peak at a diffraction angle (2θ±0.2°) of 12.5° in a powder X-ray diffraction.
Hydrate crystal characterized by PXRD peaks at 2θ=8.7° and 12.5°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 8.7° and 12.5° in a powder X-ray diffraction.
Hydrate crystal characterized by IR (KBr) peak at 1588±1 cm−1
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having an absorption peak at a wavenumber of 1588±1 cm−1 in an infrared absorption spectrum (KBr method).
Hydrate crystal characterized by IR (KBr) peaks at 1588±1 cm−1 and 751±1 cm−1
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 1588±1 cm−1 and 751±1 cm−1 in an infrared absorption spectrum (KBr method).
Hydrate crystal characterized by 13C solid-state NMR peaks around 146.7 ppm and around 123.3 ppm
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 146.7 ppm and around 123.3 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.
Crystallization process producing the defined hydrate using alcoholic, alkylketone, and/or water solvents
A process for producing a crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate, the process comprising the step of crystallizing 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one with an aid of one or two crystallization solvents selected from the group consisting of an alcoholic solvent, an alkylketone solvent, and water, wherein the hydrate has defined PXRD and IR and/or 13C solid-state NMR peak features.
Hydrate crystal characterized by PXRD peaks at 2θ=7.78°, 8.70°, and 24.19°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70° and 24.19° in a powder X-ray diffraction.
Hydrate crystal characterized by PXRD peaks at 2θ=7.78°, 8.70°, 9.52°, 12.45°, and 24.19°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45° and 24.19° in a powder X-ray diffraction.
Hydrate crystal characterized by PXRD peaks at 2θ=7.78° through 26.43°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45°, 15.24°, 17.54°, 23.26°, 24.19°, 25.44° and 26.43° in a powder X-ray diffraction.
Hydrate crystal characterized by PXRD peaks at 2θ=7.78° through 28.87°
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having diffraction peaks at diffraction angles (2θ±0.2°) of 7.78°, 8.70°, 9.52°, 12.45°, 14.59°, 15.24°, 15.60°, 16.18°, 17.54°, 19.98°, 21.04°, 21.42°, 23.26°, 24.19°, 25.44°, 25.82°, 26.43°, 27.31°, 27.86° and 28.87° in a powder X-ray diffraction.
Hydrate crystal characterized by IR (KBr) peaks at 1661.37, 1482.03, 1282.43, 899.63, and 784.89 cm−1
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 1661.37±1 cm−1, 1482.03±1 cm−1, 1282.43±1 cm−1, 899.63±1 cm−1 and 784.89±1 cm−1 in an infrared absorption spectrum (KBr method).
Hydrate crystal characterized by IR (KBr) peaks at multiple wavenumbers
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having absorption peaks at wavenumbers of 3406.64±1 cm−1, 2217.74±1 cm−1, 1661.37±1 cm−1, 1619.91±1 cm−1, 1588.09±1 cm−1, 1566.88±1 cm−1, 1550.49±1 cm−1, 1482.03±1 cm−1, 1434.78±1 cm−1, 1369.21±1 cm−1, 1318.11±1 cm−1, 1282.43±1 cm−1, 1249.65±1 cm−1, 1157.08±1 cm−1, 1099.23±1 cm−1, 899.63±1 cm−1, 879.38±1 cm−1, 784.89±1 cm−1, 751.14±1 cm−1, 730.89±1 cm−1, 697.14±1 cm−1, 606.50±1 cm−1, 557.33±1 cm−1 and 505.26±1 cm−1 in an infrared absorption spectrum (KBr method).
Hydrate crystal characterized by 13C solid-state NMR peaks around 146.7 ppm, 139.4 ppm, 132.7 ppm, 123.3 ppm, 120.8 ppm, and 118.4 ppm
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 146.7 ppm, around 139.4 ppm, around 132.7 ppm, around 123.3 ppm, around 120.8 ppm and around 118.4 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.
Hydrate crystal characterized by 13C solid-state NMR peaks around 159.8 ppm, 150.8 ppm, and multiple other chemical shift values including 108.8 ppm
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having peaks at chemical shifts of around 159.8 ppm, around 150.8 ppm, around 146.7 ppm, around 139.4 ppm, around 136.6 ppm, around 134.9 ppm, around 132.7 ppm, around 129.0 ppm, around 127.8 ppm, around 126.5 ppm, around 125.8 ppm, around 123.3 ppm, around 120.8 ppm, around 118.4 ppm, around 114.6 ppm and around 108.8 ppm in a 13C Solid State Nuclear Magnetic Resonance spectrum.
Hydrate crystal characterized by a PXRD pattern shown in FIG. 4
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a powder X-ray diffraction pattern shown in FIG. 4.
Hydrate crystal characterized by an infrared spectrum shown in FIG. 1
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having an infrared spectrum (KBr method) shown in FIG. 1.
Hydrate crystal characterized by a 13C solid-state NMR spectrum shown in FIG. 8
A crystal of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate having a 13C Solid State NMR spectrum shown in FIG. 8.
Overall, the independent claim set provides comprehensive identification coverage of the hydrate crystal through multiple independent characterization modalities: PXRD peak positions, IR absorption peak positions (KBr method), 13C solid-state NMR peak positions, and spectral figures. A further independent process claim ties production of the hydrate to crystallizing the compound using crystallization solvents from alcoholic solvent, alkylketone solvent, and water categories.
Stated Advantages
Improving industrial yield and purity by addressing by-product formation including boron-carbon bond cleavage and nitrile hydrolysis.
Industrial production in good yield and high purity.
Developing stable, uniform crystal forms for pharmaceutical use, including hydrate polymorphs.
Suitability of the crystal forms as active ingredients for neurodegenerative disease therapeutics/prophylaxis.
Documented Applications
Therapeutic uses including Parkinson’s disease, multiple sclerosis, epilepsy, and AMPA receptor antagonism.
Neurodegenerative disease therapeutics/prophylaxis as active ingredients.
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