(2S)-2-amino-3-methylbutanamide

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g, 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were mixed with 1-methoxy-2-propanol (8 ml) and heated with stirring at reflux for 48 hours. The solvent was removed under reduced pressure, the residue was partitioned between water and ethyl acetate, the phases were separated, the aqueous phase was washed 3 times with ethyl acetate and basified with 50% NaOH. A precipitate formed that was filtered off and dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS (APCI) M/z=243.6 [M+H]+. heated at reflux for 48 hours The solvent was removed under reduced pressure the residue was partitioned between water and ethyl acetate the phases were separated the aqueous phase was washed 3 times with ethyl acetate A precipitate formed that was filtered off dried in air

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H). Solvent was removed by rotary evaporation the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H). Solvent was removed by rotary evaporation the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1). at reflux for 2 hours The solid material was collected by filtration washed with acetone (2×25 mL) The crude product was dissolved in water (60 mL) treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g) The mixture was stirred for 15 minutes The resin was removed by filtration The filtrate was poured into EtOH (250 mL) The solid product, after the completion of the precipitation was collected by filtration dried in vacuo to afford compound EQ (1.6 g, 51%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g, 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were mixed with 1-methoxy-2-propanol (8 ml) and heated with stirring at reflux for 48 hours. The solvent was removed under reduced pressure, the residue was partitioned between water and ethyl acetate, the phases were separated, the aqueous phase was washed 3 times with ethyl acetate and basified with 50% NaOH. A precipitate formed that was filtered off and dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS (APCI) M/z=243.6 [M+H]+. heated at reflux for 48 hours The solvent was removed under reduced pressure the residue was partitioned between water and ethyl acetate the phases were separated the aqueous phase was washed 3 times with ethyl acetate A precipitate formed that was filtered off dried in air

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g, 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were mixed with 1-methoxy-2-propanol (8 ml) and heated with stirring at reflux for 48 hours. The solvent was removed under reduced pressure, the residue was partitioned between water and ethyl acetate, the phases were separated, the aqueous phase was washed 3 times with ethyl acetate and basified with 50% NaOH. A precipitate formed that was filtered off and dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS (APCI) M/z=243.6 [M+H]+. heated at reflux for 48 hours The solvent was removed under reduced pressure the residue was partitioned between water and ethyl acetate the phases were separated the aqueous phase was washed 3 times with ethyl acetate A precipitate formed that was filtered off dried in air

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H). Solvent was removed by rotary evaporation the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1). at reflux for 2 hours The solid material was collected by filtration washed with acetone (2×25 mL) The crude product was dissolved in water (60 mL) treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g) The mixture was stirred for 15 minutes The resin was removed by filtration The filtrate was poured into EtOH (250 mL) The solid product, after the completion of the precipitation was collected by filtration dried in vacuo to afford compound EQ (1.6 g, 51%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H). Solvent was removed by rotary evaporation the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.75 g (10 mmoles) Ac-Gly-Gly-OH and 1.73 g (15 mmoles) HONSu were dissolved in 25 ml acetonitrile and cooled to 0° C. 2.46 g DCC (12 mmoles) were then added, the mixture allowed to warm to room temperature and stirred for 2 hours until complete formation of the active ester. After filtering off the DCU, 1.16 g of Val-NH2 free base (10 mmoles) in 25 ml H2O at pH 8 were added slowly and pH maintained above 7. At completion of the reaction the acetonitrile was removed under vacuum and a small residue filtered off from the aqueous phase. The product was then purified by reverse phase HPLC using water/ethanol/acetic acid buffers. to warm to room temperature were added slowly pH maintained above 7 was removed under vacuum a small residue filtered off from the aqueous phase The product was then purified by reverse phase

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride 13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to a solution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide (0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 66 h. Solvent was removed by rotary evaporation and the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) to give the desired product 14 as a white powder (0.41 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79 (m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H). Solvent was removed by rotary evaporation the residue was purified by flash silica gel chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (15:1:0.1

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.75 g (10 mmoles) Ac-Gly-Gly-OH and 1.73 g (15 mmoles) HONSu were dissolved in 25 ml acetonitrile and cooled to 0° C. 2.46 g DCC (12 mmoles) were then added, the mixture allowed to warm to room temperature and stirred for 2 hours until complete formation of the active ester. After filtering off the DCU, 1.16 g of Val-NH2 free base (10 mmoles) in 25 ml H2O at pH 8 were added slowly and pH maintained above 7. At completion of the reaction the acetonitrile was removed under vacuum and a small residue filtered off from the aqueous phase. The product was then purified by reverse phase HPLC using water/ethanol/acetic acid buffers. to warm to room temperature were added slowly pH maintained above 7 was removed under vacuum a small residue filtered off from the aqueous phase The product was then purified by reverse phase