1-Hydroxybenzotriazole → 3-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-4-{[4-(3-(N-benzyloxycarbonyl-N-[2-(4-benzylpiperazin-1-yl)carbonyl-2-(methyl)propyl]amino)propoxy)-2-methylphenyl]methyl}-5-isopropyl-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 (0.25 mL) in dichloromethane (5 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). The obtained 3-(2,3,4,6-tetra-O-acetyl-(β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.36 g) was dissolved in 2-propanol (2 mL)-acetonitrile (2 mL). To the solution were added benzyl 3-amino-2,2-di-(methyl)propionate (0.26 g) and sodium iodide (75 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 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=1/5-dichloromethane/methanol=20/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-benzyloxycarbonyl-2-(methyl)propylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.35 g). This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (0.1 g), 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 give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-carboxy-2-(methyl)propylamino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole (0.31 g). This material was dissolved in tetrahydrofuran (4 mL). To the solution were added triethylamine (0.094 mL) and N-(benzyloxycarbonyloxy)-succinimide (64 mg), and the mixture was stirred at room temperature overnight. 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, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-{N-benzyloxycarbonyl-N-[2-carboxy-2-(methyl)propyl]amino}propoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.3 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-carboxy-2-(methyl)-propyl]amino}propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.1 g) in N,N-dimethylformamide (2 mL) were added 1-benzylpiperazine (26 mg), 1-hydroxybenzotriazole (17 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg) and triethylamine (0.064 mL), and the mixture was stirred at room temperature for 6 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=40/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-{N-benzyloxycarbonyl-N-[2-(4-benzylpiperazin-1-yl)carbonyl-2-(methyl)propyl]amino}propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (45 mg). This material was dissolved in tetrahydrofuran (4 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. To the reaction mixture was added methanol (2 mL), 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. The residue was dissolved in methanol (2 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) and preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) successively to give the title compound (12 mg).

Provenance & Evidence