反应详情

A solution of 1-{[4-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester dihydrochloride (Example 22)(3.60 g, 7.25 mmol) and 5-allyloxy-2-tert-butoxycarbonylamino-pentanoic acid (the product of step 26E, 1.98 g, 7.25 mmol) in 75 ml of DMF was treated with HATU (3.31 g, 8.7 mmol) and N-methylmorpholine (2.79 ml, 25.4 mmol). The reaction mixture was stirred at rt under N2 for 4 h, and then quenched with pH 4 buffer (biphthalate). The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaCl, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (silica gel, 10–60% ethyl acetate/hexane) gave 3.91 g (˜79%) of 1-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester as a yellow collapsed foam: 1H NMR (500 MHz, METHANOL-D4) δ 1.05–1.16 (m, 1H), 1.32 (s, 9H), 1.37–1.50 (m, 3H), 1.51–1.67 (m, 3H), 1.68–1.84 (m, 2H), 2.17–2.30 (m, 1H), 2.32–2.50 (m, 1H), 2.58–2.73 (m, 1H), 2.80 (s, 1H), 3.33–3.52 (m, 2H), 3.86–3.95 (m, 5H), 4.00–4.06 (m, 1H), 4.07–4.22 (m, 3H), 4.23–4.38 (m, 1H), 4.58–4.67 (m, 1H), 5.04–5.17 (m, 2H), 5.18–5.34 (m, 2H), 5.65–5.94 (m, 3H), 7.07–7.28 (m, 3H), 7.82–7.92 (m, 1H), 7.96–8.13 (m, 1H). LC-MS (Method B, retention time: 1.75 min), MS m/z 681 (M++1).

1. customquenched with pH 4 buffer (biphthalate)
2. extractionThe resulting mixture was extracted with EtOAc
3. washThe organic phase was washed with sat. aq. NaCl
4. dry with materialdried (MgSO4)
5. concentrationconcentrated in vacuo
6. customto give the crude product