反応 #607483

反応方程式

123d

2-(4-(5-amino-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(hydroxymethyl)-pyridin-2-yl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

(1S,2S)-2-fluorocyclopropanecarboxylic acid

HATU

N,N-diisopropylethylamine

→

123

収率 73.0%

(1S,2S)—N-[5-[2-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2-yl)-3-(hydroxymethyl)-4-pyridyl]-1-methyl-2-oxo-3-pyridyl]-2-fluoro-cyclopropanecarboxamide

収率 73.0%

溶媒

DMF

反応条件

後処理

1. 1
   濃縮The reaction mixture was concentrated under vacuum
2. 2
   その他the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm)

実験手順

A solution of 123d, (1S,2S)-2-fluorocyclopropanecarboxylic acid (15 mg, 0.14 mmol, 1.3 equiv), HATU (65 mg, 0.17 mmol, 1.5 equiv) and N,N-diisopropylethylamine (60 uL, 0.33 mmol, 3.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 43 mg (73%) of 123 as an off white solid. LC-MS m/z: 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.49 (d, J=5.0 Hz, 1H), 5.03-4.73 (m, 1H), 4.89 (t, J=5.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.60 (s, 3H), 2.50-2.41 (m, 1H), 1.68-1.52 (m, 1H), 1.39 (s, 9H), 1.20-1.08 (m, 1H).

出典