反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.
实验步骤: To a solution of 3-amino-6-bromopyrazine-2-carboxylic acid (4.0 g, 18 mmol) in DMF, HATU (10.4 g, 27.5 mmol), N,N-diisopropylethylamine (8.5 mL, 27.5 mmol) and (S)-3-amino-1-N-Boc-piperidine (4.0 g, 20 mmol, commercially available from Astatech and Arch Corporation) were added. The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3×, 200 mL), washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3: 400 (MH+). This material was taken up in ethylene glycol dimethyl ether (150 mL), and triethylamine (4.6 mL, 45 mmol), Pd(dppf)2Cl2 (2.3 g, 2.75 mmol), 3-carboxyphenylboronic acid (3.6 g, 21.8 mmol) and water (15 mL) were added. The reaction was refluxed at 85° C. and monitored by LCMS. The reaction was complete after 3 h. The solvent was removed under reduced pressure to afford a brown solid. The crude product was purified by silica gel chromatography to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5: 442 (MH+). A portion of this intermediate (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), and HATU (62.7 mg, 0.165 mmol), N,N-diisopropylethylamine (29 μL, 0.16 mmol) and 2-phenylbenzylamine (24.2 mg, 0.132 mmol) were added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The crude product was purified by preparative HPLC and lyophilized to afford a white solid (MS (ESI-LCMS) for C35H38N6O4: 607 (MH+). This material was dissolved in methanol (2 mL), and 4M HCl in dioxane (2 mL) was added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was complete after 1 h. The solvents were removed under reduced pressure to afford a yellow gel product. The yellow gel product was dissolved in acetonitrile-water (2 mL), frozen and lyophilized to afford a yellow solid: 1H NMR (400 MHz, d6-DMSO): δ 9.25 (t, 1H), 9.05 (d, 1H), 8.95 (s, 1H), 8.9 (d, 1H), 8.85 (d, 1H), 8.6 (s, 1H), 8.35 (d, 1H), 7.9 (d, 1H), 7.6 (t, 1H), 7.5-7.3 (m, 8H), 7.25 (m, 1H), 4.5 (d, 2H), 4.35 (m, 1H), 3.25 (m, 2H), 3.05 (m, 1H), 2.75 (m, 1H), 1.95-1.7 (m, 4H). MS (EI) for C30H30N6O2: 507 (MH+).
extracted with ethyl acetate (3×, 200 mL)
washed with 5% LiCl (3×, 100 mL) and brine (3×, 100 mL)
dried over anhydrous sodium sulfate
filtered
concentrated in vacuo
to afford a brown solid (MS (ESI-LCMS) for C15H22BrN5O3
The reaction was refluxed at 85° C.
The reaction was complete after 3 h
The solvent was removed under reduced pressure
to afford a brown solid
The crude product was purified by silica gel chromatography
to afford a yellow solid (MS (ESI-LCMS) for C22H27N5O5
The reaction was stirred at room temperature
The reaction was complete after 1 h
The crude product was purified by preparative HPLC
to afford a white solid (MS (ESI-LCMS) for C35H38N6O4
The reaction was stirred at room temperature
The reaction was complete after 1 h
The solvents were removed under reduced pressure
to afford a yellow gel product
frozen
to afford a yellow solid
来源 ID: ord-cab60588182040a3bbff54ec18927e16