| 94% |
With hydrogenchloride; triethylamine In tetrahydrofuran at 70℃; for 0.25 h; Microwave irradiation |
A mixture of isonipecotic acid 1 (129 mg, 1.0 mmol), benzoyl chloride 2 (140 mg, 1.0 mmol) and Et3N (0.32 mL, 2.5 mmol) in THF (5 mL) was stirred under microwave irradiation (120 W) at 70 °C for 15 min. The reaction mixture was acidified using 1 M HCl (10 mL) and extracted with dichloromethane (3 * 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 5percent ethyl acetate in hexane, followed by 80percent ethyl acetate in hexane as eluent to yield 3 (94percent) as white solid. Mp 136-138 °C. 1H NMR (400 MHz, CDCl3) δ 1.71-1.85 (m, 3H), 2.03-2.06 (m, 1H), 2.59 (tt, 1H, J = 10.4, 4.1 Hz), 3.04-3.12 (m, 2H), 3.72-3.76 (m, 1H), 4.48-4.52 (m, 1H), 7.36-7.44 (m, 5H), 11.16 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ 40.4, 41.4, 46.8, 126.7, 128.3, 129.6, 135.3, 170.7, 178.3. HRMS (ESI): calcd for C13H14NO3 [M-H]-, 232.0973; found, 232.0979. |
| 85% |
Stage #1: With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22 h;
Stage #2: With hydrogenchloride In water at 0℃; |
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol,1.0 equiv) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol, 5.0 equiv) were added, and the mixture was cooled to 0°C. A solution of benzoyl chloride (8.980 mL, 77.425 mmol, 1.0 equiv) in THF (35mL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mLseparating funnel and washed with EtOAc (3 × 150 mL). The aqueous phase was cooled to 0 °C and adjusted to pH 1-2 with 6 M aq HCl. The white precipitate was collected in a Büchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 12 as a white solid (85percentyield). This product was used in the next step without further purification. Rf = 0.55 (MeCN-H2O-MeOH= 3:1:1); mp 118–122 °C. IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1169,1014, 791, 731, 707, 628, 577. cm-1. 1H NMR (400 MHz,DMSO-d6): δ = 1.49 (2 H, bs), 1.83 (2 H, bd, J = 45.68 Hz), 2.52–2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1H, bs), 7.34–7.46 (5 H, m), 12.32 (1 H, bs). 13C NMR (100 MHz,DMSO-d6): δ = 27.62, 28.24, 40.06, 40.74, 46.38, 126.61, 128.38, 129.31,136.23, 168.96, 175.481. HRMS (ESI+): m/z calcd for C13H16NO3: 234.1130; found 231.1125. Anal. Calcd for C13H15NO3: C,66.94; H, 6.48; N, 6.00. Found C, 67.22; H, 6.78; 6.22. |
| 85% |
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22 h; |
To a 250-mL round-bottomed flask equipped with a stirring bar, isonipecotic acid (10.000 g, 77.425 mmol) was added. THF (80 mL), H2O (80 mL) and K2CO3 (53.504 g, 387.121 mmol) were added, and the mixture was cooled to 0 °C. A solution of benzoyl chloride (8.980 imL, 77.425 mmol) in THF (35 imL) was added drop-wise. The reaction mixture was allowed to warm to r.t. and then stirred for 22 h. The reaction mixture was transferred into a 500-mL separating funnel and washed with EtOAc (3 χ 150 ml_). The aqueous phase was cooled to 0 °C and adjusted to pH 1 -2 with 6 M aq HCI. The white precipitate was collected in a Buchner funnel under suction filtration, and then dried in vacuo at room temperature in the presence of NaOH, P2O5 and silica gel to constant mass to produce 15.369 g of 1 -benzoylpiperidine-4-carboxylic acid. This product was used in the next step without further purification.Product appearance: white solid.Yield: 85percent.Melting point: 1 18-122 °C . TLC: Rf = 0.55 (MeCN-H2O-MeOH = 3:1 :1 ) .IR (ATR): 2857, 2359, 1730, 1612, 1447, 1207, 1 169, 1014, 791 , 731 , 707, 628, 577. cm"1 (0361) [0333] 1H NMR (400 MHz, DMSO-d6): δ = 1 .49 (2 H, bs), 1 .83 (2 H, bd, J = 45.68 Hz), 2.52-2.57 (1 H, m), 3.01 (2 H, bd, J = 52.08 Hz), 3.52 (1 H, bs), 4.31 (1 H, bs), 7.34-7.46 (5 H, m), 12.32 (1 H, bs).13C NMR (100 MHz, DMSO-d6): δ = 27.62, 28.24, 40.06, 40.74, 46.38, (0363) 126.61 , 128.38, 129.31 , 136.23, 168.96, 175.48.HRMS (ESI+): m/z calculated for C13H16NO3: 234.1 130; found 231 .1 125. CHN analysis: Calculated for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: (0366) C, 67.22; H, 6.78; N, 6.22. |
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