Hydrochloric Acid → 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole

Participants

Reaction Steps

To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (1 g) and triethylamine (0.29 mL) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.13 mL), and the mixture was stirred at room temperature for 1 hour. 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. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (1.12 g). This material was dissolved in acetonitrile (7 mL)-ethanol (7 mL). To the solution were added benzyl 3-benzylaminopropionate (1.27 g) and sodium iodide (240 mg), and the mixture was stirred at 60° C. for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. 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: dichloromethane/methanol 30/1-20/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-benzyloxycarbonylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (1.3 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.65 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(2-carboxyethylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole (0.95 g). This material was dissolved in 1,4-dioxane (10 mL). To the solution were added sodium hydrogen carbonate (0.45 g) and water (10 mL), and the mixture was stirred for 15 minutes. To the reaction mixture was added benzyloxycarbonyl chloride (0.23 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added benzyloxycarbonyl chloride (0.23 mL), and the mixture was stirred at room temperature for 3 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. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyloxycarbonyl-N-(2-carboxyethyl)amino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole (0.86 g). To a solution of the obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyloxycarbonyl-N-(2-carboxyethyl)amino]-propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.17 g) in N,N-dimethylformamide (3 mL) were added L-serine amide hydrochloride (37 mg), 1-hydroxybenzotriazole (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg) and triethylamine (0.11 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, 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: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N-benzyloxycarbonyl-N-{2-[(S)-1-carbamoyl-2-hydroxyethylcarbamoyl]ethyl}amino)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole (81 mg). This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (38 mg).

Provenance & Evidence