Water → furan-2-carboxylic acid N-hydroxysuccinimide ester

참여 물질

반응 단계

2-Furanecarboxylic acid (2.0 g), 2.26 g of N-hydroxysuccinimide and 3.76 g of the water-soluble carbodiimide hydrochloride were stirred overnight at room temperature in tetrahydrofuran (THF for short)/methylene chloride. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from isopropanol to give 2.8 g of N-(2-furoyloxy)succinimide (melting point 126°-127° C.). To a solution of 1.79 g of the resulting succinimide and 2.0 g of N6 -benzyloxycarbonyl-L-lysine in THF/water was added 2.9 g of triethylamine, and the mixture was stirred overnight at room temperature. THF was evaporated under reduced pressure, and the residual solution was adjusted to pH 2-3 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (CHP20P column; 30%→60% acetonitrile/water gradient) to give 2.3 g of N2 -(2-furoyl)-N6 -benzyloxycarbonyl-L-lysine [α]D25 : -4.6° (methanol). An aliquote (1.35 g) of this product and 1.0 g of the diester A were dissolved in methylene chloride, and 0.66 g of the water-soluble carbodiimide hydrochloride was added. The mixture was stirred overnight at room temperature. The reaction mixture was washed successively with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was reprecipitated from ether/ethanol to give 1.8 g of ethyl 1-[N2 -(2-furoyl)-N6 -benzyloxycarbonyl-L-lysyl-01 -ethyl-gamma-D-glutamyl]indoline-2(S)-carboxylate (mp: 120°-123° C.). To a solution of 1.65 g of the resulting ethyl ester in dioxane was added 6.85 ml of 1N-NaOH, and the mixture was stirred at room temperature for 1 hour. The mixture was then acidified with 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from petroleum ether/ethyl acetate, and collected by filtration to give 1.50 g of 1-[N2 -(2-furoyl)-N6 -benzyloxycarbonyl-L-lysyl-gamma-D-glutamyl]indoline-2(S)-carboxylic acid. To a methanol solution of 1.35 g of this product were added 0.35 g of ammonium formate and 0.4 g of 10% palladium carbon, and the mixture was stirred at room temperature for 7 hours. The catalyst was removed, and methanol was evaporated under reduced pressure. Ethyl acetate was then added, and the mixture was extracted with 10% hydrochloric acid. The extract was chromatographed on a column of CHP20P using acetonitrile/water (0%→60% gradient) as an eluent to give a fraction containing about 70% of the desired product. The fraction was purified by column chromatography [a column of ODS-Q3 (a product of Wako Pure Chemical Co., Ltd.) having a diameter of 4 cm and a length of 30 cm; acetonitrile/1% trifluoroacetic acid=1/9)] to give 0.65 g of a powder. The powder was further chromatographed on a column of CHP20P (0%→60% acetonitrile/water gradient), and concentrated to dryness under reduced pressure. The residue was dissolved in water, and lyophilized to give 0.3 g of the captioned compound.

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