Solid dispersion product containing N-aryl urea-based compound
A technology for solid dispersions and products, which can be used in medical preparations containing active ingredients, organic active ingredients, chemical/physical processes, etc., and can solve problems such as low bioavailability
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Embodiment 1
[0259] Example 1N-[(4R)-6-fluoro-2,2-dimethyl-3,4-dihydro-2H-benzopyran-4- Base] N'-(1-methyl-1H-indazol-4-yl)urea
Embodiment 1A
[0260] Example 1A: 6-fluoro-2,2-dimethylchroman-4-one
[0261] In a 500 mL round bottom flask was added 1-(5-fluoro-2-hydroxyphenyl)ethanone (20.0 g, 130 mmol, Aldrich Chemical), propan-2-one (19.0 mL, 260 mmol) in methanol (150 mL) and pyrrolidine (21.5 mL, 260 mmol) to give an orange solution. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was poured into EtOAc (200 mL), washed with 1N HCl (50 mL), saturated NaHCO 3 (50 mL) and brine (50 mL). The organic fraction was dried (Na 2 SO 4 ), filtered and concentrated to give an orange residue which was purified by silica gel chromatography (gradient elution, 0-20% EtOAc / hexanes) to give the title compound as a white solid (14.2 g, 73.1 mmol, 56%). MS (DCI / NH 3 )m / z208(M+NH 4 ) +
Embodiment 1B
[0262] Example 1B: (S)-6-fluoro-2,2-dimethylchroman-4-ol
[0263] Methyl tert-butyl ether (34 mL), (R)-diphenyl(pyrrolidin-2-yl)methanol (1.10 g, 4.35 mmol) and borane-N,N-diethylaniline complex ( A solution of 18.5 mL, 104 mmol) was heated to 45°C, then EXAMPLE 1A (16.9 g, 87.0 mmol) in methyl tert-butyl ether (136 mL) was added via addition funnel over 75 min. After the addition was complete, LCMS indicated complete reaction. After stirring at 45 °C for an additional 15 min, the reaction mixture was cooled to 10 °C and treated with MeOH (85 mL) for 10 min while maintaining the temperature ≤ 15 °C (H 2release). After stirring at ambient temperature for 30 min, 2N HCl (85 mL) was added and the reaction mixture was stirred for 10 min. Methyl tert-butyl ether (170 mL) was added and the reaction mixture was partitioned. The organic portion was washed with 2N HCl (85 mL) and brine (35 mL). The aqueous extract was back extracted with methyl tert-butyl ether (85 mL). The com...
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