33% |
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Example 45 Synthesis of ({4-cycloheptylamino-6-[((S)-1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile (143) To a mixture of cyanuric chloride (0.368 g, 2 mmol) in CH3CN at about -20° C. was added N-phenyl glycinonitrile (0.264 g, 2 mmol) in CH3CN followed by the addition of DIEA (0.35 mL, 2 mmol) and stirred for about 1 hour. The reaction mixture was then stirred at room temperature for about 1 hour. Then, cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture was stirred overnight at rt. Then, S-(-)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluding with 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide to yield 143, (0.300 g, 33percent) mp 53-55° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 6.9 min, 94.1percent purity; MS (ESI): m/z 449 (M+H, 100), 381 (1.2), 353 (16.2), 226 (19.9), 225 (54.3), 212 (20.5), 177 (18.3), 164 (9.6). |
33% |
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To a mixture of cyanuric chloride(0. 368 g, 2 mmol) inCH3CN atabout-20 C was added N-phenyl glycinonitrile (0.264 g, 2 mmol) inCH3CN followed by the addition of DIEA (0.35 mL, 2 mmol) and stirred for about 1 hour. The reaction mixture was then stirred at room temperature for about1 hour. Then, cycloheptylamine (0.25 mL, 2 mmol) and DIEA(0. 35 mL, 2 mmol) were added and the reaction mixture was stirred overnight at rt. Then,S- (-)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL,2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 96: 3: 1 methylene chloride: methanol:conc. ammonium hydroxide to yield 143, (0.300 g, 33percent) mp53-55 C ; HPLC: Inertsil ODS-3VC18, 40:30 : 30 [KH2P04 (0.01 M, pH 3. 2) : CH30H: CH3CN], 264 nm,Rt 6.9 min, 94.1percent purity; MS (ESI):m/z 449 (M+H, 100), 381 (1.2),353 (16.2), 226 (19.9), 225 (54.3), 212 (20.5), 177 (18. 3), 164 (9.6). |