Sodium Hydroxide → 3-[({4-[(cyclohexyl{5-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoic acid

温度

100 °C

A solution of ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (400 mg) obtained in Example A194(4), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) synthesized above and tripotassium phosphate (223 mg) in N,N-dimethylformamide (4 mL) was stirred at 100° C. for 14 hr. 1,1-Dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) and tripotassium phosphate (112 mg) were further added to the mixture, and the mixture was stirred at 100° C. for 2 hr then at 120° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-34:66, v/v) to give a colorless amorphous form (200 mg). The colorless amorphous form (200 mg) was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 1N aqueous sodium hydroxide solution (0.64 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.64 mL) under ice-cooling and stirred at 0° C. for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (136 mg, 29%) as a colorless amorphous form.

1. stirringthe mixture was stirred at 100° C. for 2 hr
2. waitat 120° C. for 3 hr
3. extractionthe mixture was extracted with ethyl acetate
4. washThe organic layer was washed with saturated brine
5. dry with materialdried over anhydrous magnesium sulfate
6. filtrationAfter filtration
7. concentrationthe filtrate was concentrated
8. customv/v) to give a colorless amorphous form (200 mg)
9. stirringthe mixture was stirred at room temperature for 30 min
10. customThe solvent was evaporated under reduced pressure, water (4 mL)
11. additionwas added to the residue
12. temperaturecooling
13. stirringstirred at 0° C. for 30 min
14. filtrationThe resulting precipitate was collected by filtration
15. customdried

ORDレコード

ord-ddbc6fb2ef024355a1a6c0b3b8c7a92a

出典データセット

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08436043B2