Hydrochloric Acid → P-Anisidine

温度

65 °C

To a solution of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.33 g) in 1-methyl-2-pyrrolidone (5 mL) was added potassium phthalimide (0.26 g), and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-chloro-N-[6-methoxy-5-nitropyrimidin-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-yl]-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.26 g). To this material were added tetrahydrofuran (8 mL), methanol (3 mL) and 10% platinum-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the suspension of the residue in tetrahydrofuran (6 mL) was added triphosgene (50 mg) at room temperature. To the mixture was added sodium hydride (55%, 64 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/9) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-7,9-dihydro-8H-purin-8-one (0.1 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added hydrazine monohydrate (0.039 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (71 mg).

1. extractionthe resulting mixture was extracted with ethyl acetate
2. washThe extract was washed with water and brine
3. dry with materialdried over anhydrous sodium sulfate
4. customthe solvent was removed under reduced pressure
5. filtrationcollected by filtration
6. customThe collected solids were dried under reduced pressure

ORDレコード

ord-1c66459191e343ce8fe2f01de265e2c8

出典データセット

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08217069B2