Tetrahydrofuran → 3-(3-{[3-(t-Butoxycarbonylaminomethyl)-4-cyanophenylamino]-(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic Acid Methyl Ester

Temperature

65 °C

To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (2c))(101 mg) and THF (2.0 mL) there were added 3-hydrazinothiophene-2-carboxylic acid methyl ester (33.1 mg) and triethylamine (27.9 μL), and the mixture was stirred at 65° C. for 15 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off. DMF (2.0 mL) was added to the residue, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off, and methanol (5 mL) and acetic acid (52.1 μL) were added to the residue. Sodium cyanotrihydroborate (114 mg) was then added to the mixture and the mixture was stirred overnight at room temperature. Water (25 mL) and ethyl acetate (50 mL) were added to the mixture, and after sufficiently shaking the mixture, the organic layer was separated off. The organic layer was washed twice with water (25 mL) and once with saturated aqueous sodium chloride (25 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate mixture) to obtain the target compound (103 mg) as a colorless solid.

1. distillationThe solvent in the mixture was distilled off
2. additionDMF (2.0 mL) was added to the residue
3. stirringthe mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere
4. distillationThe solvent in the mixture was distilled off
5. additionmethanol (5 mL) and acetic acid (52.1 μL) were added to the residue
6. additionSodium cyanotrihydroborate (114 mg) was then added to the mixture
7. stirringthe mixture was stirred overnight at room temperature
8. additionWater (25 mL) and ethyl acetate (50 mL) were added to the mixture
9. stirringafter sufficiently shaking the mixture
10. customthe organic layer was separated off
11. washThe organic layer was washed twice with water (25 mL) and once with saturated aqueous sodium chloride (25 mL) in that order
12. dry with materialdried over anhydrous magnesium sulfate
13. filtrationThe mixture was filtered
14. customto obtain a filtrate
15. distillationthe solvent in the filtrate was distilled off under reduced pressure
16. customThe residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate mixture)

ORD record

ord-bdefa8d0e9664622810061fa10139e59

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07807690B2