6-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ylamine → gamma-Secretase modulator 6

関与物質

反応条件

反応手順

6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.892 g, 4.37 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.20 g, 4.37 mmol), Sodium tert-butoxide (0.630 g, 6.55 mmol), rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.272 g, 0.44 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.200 g, 0.22 mmol) were added to a microwave vial followed by toluene (16 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100°C and stirred overnight. The reaction was completed. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 60:40 as gradient. The product was obtained as yellow foam 1.55 g with a purity 96-99% depending on wavelength (96% on 220nm). Preparative purification with Gilson prep was performed, 30-70% gradient was used. The material was collected manually. The fractions were pooled together, concentrated in vacuo then treated with DCM and sat NaHCO3 solution. The phases were separated. The aqueous layer was extracted with DCM 2 more times than once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam and was dried overnight in a vacuum oven at 50°C. According to 1H-NMR 1.5 % ethyl acetate was present in the sample. **Ethyl acetate should be avoided for extraction!** The sample was dissolved in DCM and concentrated in vacuo then the process was repeated 2 more times. The product was dried in a vacuum oven overnight at 50°C.

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