反应详情

4-Methylmorpholine (0.98 mL, 8.9 mmol) was added to a suspension of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1.69 g, 4.45 mmol), 1-hydroxybenzotriazole monohydrate (0.68 g, 4.45 mmol) and 4-(4-isopropylpiperazin-1-yl)benzoic acid (82% wt., 1.41 g, 4.66 mmol) in dimethylformamide (8 mL). The suspension was sonicated for 3 minutes then added to (S)-2-amino-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethylpentan-1-one hydrochloride (prepared as above, assume 4.24 mmol). After 2.5 hours saturated sodium hydrogen carbonate solution (50 mL) was added then the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (50 mL), then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with methanol:dichloromethane mixtures 0:100 to 10:90 gave N—((S)-1-((3R,3aR,6R,6aS)-3-hydroxy-6-methoxydihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-isopropylpiperazin-1yl)benzamide as a pale yellow solid (1.77 g, 81%). TLC (Rf=0.10-0.15 double spot, MeOH:CH2Cl2 5:95), analytical HPLC main peak, Rt=10.16 min., HPLC-MS 517.4 [M+H]+, 1033.7 [2M+Na]+; [□]D19+28.85° (c=3.64, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 5:3; 0.98 (9H, s, C(CH3)3), 1.08 (3.78H, d, J=6.53 Hz, NCH(CH3)2 major), 1.09 (2.22H, d, J=6.52 Hz, NCH(CH3)2 minor), 1.58-1.67 (1.37H, m, CH2C(CH3)3), 1.76 (0.63H, dd, 9.43 Hz, CH2C(CH3)3 major), 2.64-2.69 (4H, m, CH2CH2NCH(CH3)2), 2.69-2.76 (1H, m, NCH(CH3)2), 3.18 (0.63H, dd, 9.63 Hz, NCH2CHOCH3 major), 3.27-3.33 (4H, m, CH2CH2NCH3), 3.37 (0.37H, brt, J=9.45 Hz, NCH2CHOCH3 minor), 3.46 (1.89H, s, OCH3 major), 3.48 (1.11H, s, OCH3 minor), 3.63 (0.63H, dd, 6.40 Hz, OCH2CHOH major), 3.74-3.78 (0.63H, m, CHOCH3 major), 3.79 (0.37H, dd, 4.09 Hz, OCH2CHOH minor), 3.92-3.96 (0.37H, m, CHOCH3 minor), 4.03-4.09 (1H, m, NCH2CHOCH3), 4.28-4.38 (3H, m, OCH2CHOHCH and 1×OCH2CHOH), 4.67 (0.37H, brt, J=4.59 Hz, OCHCHOCH3 minor), 4.72 (0.63H, brt, J=5.04 Hz, OCHCHOCH3 major), 4.97-5.03 (0.37H, m, CHCH2C(CH3)3 minor), 5.24-5.29 (0.63H, m, CHCH2C(CH3)3 major), 5.96 (0.63H, brs, OH major), 6.62 (0.37H, d, J=8.39 Hz, NH minor), 6.71 (0.63H, d, J=9.83 Hz, NH major), 6.82-6.87 (2H, m, aromatic CH), 7.66-7.70 (2H, m, aromatic CH); δC (125 MHz, CDCl3) 18.50 (CH(CH3)2, 29.79/29.91 (C(CH3)3), 30.71/30.75 (C(CH3)3), 46.18/47.10 (CH2C(CH3)3), 46.56 (NCH2CHOCH3), 47.82/48.30 (CHCH2C(CH3)3), 47.87/49.01 (NCH2CH2NCH(CH3)2), 48.40/48.44 (NCH2CH2NCH(CH3)2), 54.56/54.60 (NCH(CH3)2), 58.06/58.03 (OCH3), 69.93/70.56 (OCH2CHOHCH), 74.01/75.01 (OCH2CHOH), 76.35/79.85 (CHOH), 77.94/79.41 (CHOCH3), 78.54/80.45 (OCHCHOCH3), 113.92/114.06/128.52 and 128.73 (aromatic CH), 122.18/123.16 (aromatic quaternary), 153.53/153.80 (aromatic quaternary), 166.57/167.19 (NHC═O), 172.37/173.13 (CH2NC═O).

1. customThe suspension was sonicated for 3 minutes
2. extractionthe aqueous phase was extracted with dichloromethane (3×20 mL)
3. washThe combined organic layers were washed with brine (50 mL)
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. washFlash chromatography over silica, eluting with methanol