O-tritylhydroxylamine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a solution of the crude 2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxyphenyl)-ethoxycarbonyl))-4-piperidinyl]acetic acid (0.66 mmol) in methylene chloride (35 ml) is added O-tritylhydroxylamine (547 mg, 1.98 mmol), N-methylmorpholine (0.44 ml, 3.97 mmol), 1-hydroxy-7-azabenzotriazole (90 mg, 0.66 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.86 mmol). The reaction mixture is stired at room temperature for 18 hours, diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel chromatography (2% to 4% methanol in methylene chloride) to provide N-(trityl-oxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxy-phenyl)-ethoxycarbonyl))-4-piperidinyl]acetamide. washed with water The aqueous layer is extracted with ethyl acetate the combined organic layers are washed with brine dried over sodium sulfate concentrated in vacuo The crude product is purified by silica gel chromatography (2% to 4% methanol in methylene chloride)

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: WSC.HCl (683 mg, 3.49 mmol) was dissolved in water (1 mL) and the pH was adjusted to 4.8. The compound of Example 55 (300 mg, 0.582 mmol) was dissolved in the same amount of THF and added to the former solution. O-Trityl hydroxylamine (505 mg, 1.746 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The water phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, a saturated sodium hydrogen carbonate solution, and brine. The solvent was evaporated, following drying over sodium sulfate, and the crude was flashed with 30% ethyl acetate in hexanes. 1H NMR(CDCl3, 400 MHz: 1.32(s, 9H); 1.50(m, 1H); 1.74(m, 1H); 2.32(m, 6H); 2.53(m, 2H); 3.46(m, 2H); 7.00(m, 1H); 7.16-7.57(m, 30H); FAB: 774(MH+). added to the former solution The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate The water phase was extracted several times with ethyl acetate The recombined organic layer was washed with brine The solvent was evaporated following drying over sodium sulfate

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

実験手順: WSC.HCl (683 mg, 3.49 mmol) was dissolved in water (1 mL) and the pH was adjusted to 4.8. The compound of Example 55 (300 mg, 0.582 mmol) was dissolved in the same amount of THF and added to the former solution. O-Trityl hydroxylamine (505 mg, 1.746 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The water phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, a saturated sodium hydrogen carbonate solution, and brine. The solvent was evaporated, following drying over sodium sulfate, and the crude was flashed with 30% ethyl acetate in hexanes. 1H NMR(CDCl3, 400 MHz: 1.32(s, 9H); 1.50(m, 1H); 1.74(m, 1H); 2.32(m, 6H); 2.53(m, 2H); 3.46(m, 2H); 7.00(m, 1H); 7.16-7.57(m, 30H); FAB: 774(MH+). added to the former solution The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate The water phase was extracted several times with ethyl acetate The recombined organic layer was washed with brine The solvent was evaporated following drying over sodium sulfate

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

実験手順: To a solution of the compound of example 64 (1.10 g, 4.19 mmol) and HOBt (0.70 g, 5.03 mmol) in DMF (5 mL) were added O-trityl hydroxylamine (1.82 g, 6.28 mmol) and DIC (800 μL), respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (1N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, saturated sodium bicarbonate, and brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed with 20-30% ethyl acetate in hexanes. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.58, 2.14, 2.47(3m, 7H); 3.69(s, 3H); 7.34(m, 15H); 7.88(d, broad, 1H). The reaction mixture was partitioned between HCl (1N, excess) and ethyl acetate The aqueous phase was extracted several times with ethyl acetate The recombined organic layer was washed with brine, saturated sodium bicarbonate, and brine The solvent was evaporated following drying over sodium sulfate

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

実験手順: A solution of the title compound of Example 1, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (304 mg, 0.593 mmol) and NMM (0.330 mL, 3.00 mmol) in 10 mL of dichloromethane is treated with 1-hydroxy-7-azabenzotriazole (89 mg, 0.654 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) at RT. After stirring for 30 min, O-tritylhydroxylamine (489 mg, 1.776 mmol) is added, and the reaction is stirred for 16 h. The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water. The organic solution is washed with 30 mL of 1M aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 4/6—ethyl acetate/hexane) affords 293 mg (64%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide as a waxy solid: NMR(CDCl3) 0.62-0.76 (br m, 1H), 1.08-1.24 (br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J=8.7), 5.31 (d, 1H, J=9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J=8.4), 7.59 (d, 2H, J=8.5), 7.70 (d, 4H, J=8.3), 7.91 (d, 2H, J=8.3), 8.27 (s, 1H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M++1). the reaction is stirred for 16 h The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water The organic solution is washed with 30 mL of 1M aqueous NaHCO3 dried over anhydrous Na2SO4 concentrated

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

実験手順: A solution of benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester (2.592 g, 10.97 mmol), O-trityl -hydroxylamine (3.020 g, 10.97 mmol), EDC (3.150 g, 16.48 mmol), HOBt (1.482 g, 10.97 mmol) and DIEA (4.80 mL, 27.6 mmol) in anhydrous THF (100 mL) was allowed to stir at rt for one week and then concentrated. To the residue was added MeOH (10 mL) and water (100 mL). The syrup obtained was washed with water (10 mL) and triturated with water (90 mL) to give 2-trityloxycarbamoyl-benzo[b]thiophene-5-carboxylic acid methyl ester as a pale solid. MS (EI): cal'd 243.1 (M-benzothiophene moiety+H+), exp 243.2 (M-benzothiophene moiety+H+). concentrated To the residue was added MeOH (10 mL) and water (100 mL) The syrup obtained was washed with water (10 mL) triturated with water (90 mL)

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

実験手順: A solution of benzo[b]thiophene-2,5-dicarboxylic acid 5-methyl ester (2.592 g, 10.97 mmol), O-trityl -hydroxylamine (3.020 g, 10.97 mmol), EDC (3.150 g, 16.48 mmol), HOBt (1.482 g, 10.97 mmol) and DIEA (4.80 mL, 27.6 mmol) in anhydrous THF (100 mL) was allowed to stir at rt for one week and then concentrated. To the residue was added MeOH (10 mL) and water (100 mL). The syrup obtained was washed with water (10 mL) and triturated with water (90 mL) to give 2-trityloxycarbamoyl-benzo[b]thiophene-5-carboxylic acid methyl ester as a pale solid. MS (EI): cal'd 243.1 (M-benzothiophene moiety+H+), exp 243.2 (M-benzothiophene moiety+H+). concentrated To the residue was added MeOH (10 mL) and water (100 mL) The syrup obtained was washed with water (10 mL) triturated with water (90 mL)

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

実験手順: To a stirred solution of 40.1 mg (0.09 mmol) of 8 in 5 mL of dry CH2Cl2 was added sequentially 140 mg (0.37 mmol) of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 49.5 mg (0.37 mmol) of HOBt, and 91 uL (0.55 mmol) of DIEA. The resulting solution was stirred at room temperature for 10 min followed by adding 50.5 mg (0.18 mmol) of O-tritylhydroxylamine. After stirring at the same temperature for 30 min, the solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc/Hex 1:4) to give O-trityl hydroxyamic acid of 8 in a quantitative yield. The resulting oily product was treated with 5 mL of 1:2 mixture of AcOH/2,2,2-trifluoroethanol at room temperature for 24 h. After evaporation of the solvent in vacuo, the residue was dissolved in CH2Cl2 and washed with 10 mL of a saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/EtOAc 1:9) to give 12.7 mg (54% over two steps) of 9 as a bright yellow powder: mp˜150° C. (decomp); 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 11.68 (brs, 1H), 8.95 (brs, 1H), 7.99 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 7.70 (m, 3H), 7.66-7.48 (m, 6H), 7.38 (t, J=7.0 Hz, 1H), 7.08 (s, 1H), 3.41 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 167.1, 147.9, 142.3, 141.6, 138.1, 136.9, 133.3, 133.2, 132.8, 132.1, 131.4, 131.0, 129.8, 129.7, 129.0, 127.7, 126.2, 121.1, 120.7, 113.9, 99.9, 33.2; IR (KBr) cm−1 3422-3241, 2902, 1596, 1433, 1322. After stirring at the same temperature for 30 min the solvent was removed in vacuo the residue was purified by flash chromatography (EtOAc/Hex 1:4) to give O-trityl hydroxyamic acid of 8 in a quantitative yield After evaporation of the solvent in vacuo the residue was dissolved in CH2Cl2 washed with 10 mL of a saturated NaHCO3 solution The organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by flash chromatography (MeOH/EtOAc 1:9)

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

実験手順: To a stirred solution of 40.1 mg (0.09 mmol) of 8 in 5 mL of dry CH2Cl2 was added sequentially 140 mg (0.37 mmol) of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 49.5 mg (0.37 mmol) of HOBt, and 91 uL (0.55 mmol) of DIEA. The resulting solution was stirred at room temperature for 10 min followed by adding 50.5 mg (0.18 mmol) of O-tritylhydroxylamine. After stirring at the same temperature for 30 min, the solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc/Hex 1:4) to give O-trityl hydroxyamic acid of 8 in a quantitative yield. The resulting oily product was treated with 5 mL of 1:2 mixture of AcOH/2,2,2-trifluoroethanol at room temperature for 24 h. After evaporation of the solvent in vacuo, the residue was dissolved in CH2Cl2 and washed with 10 mL of a saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/EtOAc 1:9) to give 12.7 mg (54% over two steps) of 9 as a bright yellow powder: mp˜150° C. (decomp); 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 11.68 (brs, 1H), 8.95 (brs, 1H), 7.99 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 7.70 (m, 3H), 7.66-7.48 (m, 6H), 7.38 (t, J=7.0 Hz, 1H), 7.08 (s, 1H), 3.41 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 167.1, 147.9, 142.3, 141.6, 138.1, 136.9, 133.3, 133.2, 132.8, 132.1, 131.4, 131.0, 129.8, 129.7, 129.0, 127.7, 126.2, 121.1, 120.7, 113.9, 99.9, 33.2; IR (KBr) cm−1 3422-3241, 2902, 1596, 1433, 1322. After stirring at the same temperature for 30 min the solvent was removed in vacuo the residue was purified by flash chromatography (EtOAc/Hex 1:4) to give O-trityl hydroxyamic acid of 8 in a quantitative yield After evaporation of the solvent in vacuo the residue was dissolved in CH2Cl2 washed with 10 mL of a saturated NaHCO3 solution The organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by flash chromatography (MeOH/EtOAc 1:9)