tert-butyl piperazine-1-carboxylate;hydrochloride

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (0.75 mmol), 5-bromo-2-fluoropyridine (0.90 mmol), (R)-2,2′-bis(diphenylphosphino)-1, 1′-binaphthyl (0.038 mmol), palladium acetate (0.038 mmol) and cesium carbonate (1.8 mmol) in toluene is stirred at 80° C. for 7 h and then 100° C. for 4 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 43% yield. Rf=0.61 (n-hexane:AcOEt=1:1) 100° C. for 4 h The mixture is extracted with AcOEt The organic layer is washed with water dried over magnesium sulfate concentrated The crude product is purified by silica gel column chromatography to give the product in 43% yield

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (0.75 mmol), 5-bromo-2-fluoropyridine (0.90 mmol), (R)-2,2′-bis(diphenylphosphino)-1, 1′-binaphthyl (0.038 mmol), palladium acetate (0.038 mmol) and cesium carbonate (1.8 mmol) in toluene is stirred at 80° C. for 7 h and then 100° C. for 4 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 43% yield. Rf=0.61 (n-hexane:AcOEt=1:1) 100° C. for 4 h The mixture is extracted with AcOEt The organic layer is washed with water dried over magnesium sulfate concentrated The crude product is purified by silica gel column chromatography to give the product in 43% yield

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

実験手順: To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 ml) at 0° C. was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (0.75 mmol), 5-bromo-2-fluoropyridine (0.90 mmol), (R)-2,2′-bis(diphenylphosphino)-1, 1′-binaphthyl (0.038 mmol), palladium acetate (0.038 mmol) and cesium carbonate (1.8 mmol) in toluene is stirred at 80° C. for 7 h and then 100° C. for 4 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 43% yield. Rf=0.61 (n-hexane:AcOEt=1:1) 100° C. for 4 h The mixture is extracted with AcOEt The organic layer is washed with water dried over magnesium sulfate concentrated The crude product is purified by silica gel column chromatography to give the product in 43% yield

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

実験手順: To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 ml) at 0° C. was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

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

実験手順: To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 ml) at 0° C. was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d6) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4 (332.15); C: 57.82, H: 6.07, N: 16.86. found (%); C: 57.76, H: 6.11, N: 16.80. The mixture was cooled to room temperature extracted with ethyl acetate (100 mL) the organic layer was washed with brine (20 mL) dried over Na2SO4 evaporated

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4(332.15); C, 57.82; H, 6.07; N, 16.86. found (%); C, 57.76; H, 6.11; N, 16.80. The mixture was cooled to room temperature extracted with ethyl acetate (100 mL) the organic layer was washed with brine (20 mL) dried over Na2SO4 evaporated

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

実験手順: To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 mL) at 0° C. was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

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

実験手順: To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 ml) at 0° C. was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of piperazine-1-carboxylic acid tert-butyl ester hydrochloride (0.75 mmol), 5-bromo-2-fluoropyridine (0.90 mmol), (R)-2,2′-bis(diphenylphosphino)-1, 1′-binaphthyl (0.038 mmol), palladium acetate (0.038 mmol) and cesium carbonate (1.8 mmol) in toluene is stirred at 80° C. for 7 h and then 100° C. for 4 h, and poured into water. The mixture is extracted with AcOEt. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give the product in 43% yield. Rf=0.61 (n-hexane:AcOEt=1:1) 100° C. for 4 h The mixture is extracted with AcOEt The organic layer is washed with water dried over magnesium sulfate concentrated The crude product is purified by silica gel column chromatography to give the product in 43% yield