反应详情

(3Z)-3-(3,5-Dimethyl-4-carboxy-1H-pyrrol-2-ylmethylidene)-5-fluoro-1,3-dihydro-2H-indol-2-one (120 mg, 0.40 mmol), prepared as described in published PCT Application WO01/60814, and BOP (221 mg, 0.50 mmol) were suspended in DMF (5 mL) with good stirring at room temperature and triethylamine (134 μL, 0.96 mmol) was added. After 10-15 min., to the homogeneous reaction mixture was added the 4-(morpholin-4-yl)piperidine (85 mg, 0.50 mmol) all at once. The reaction mixture was stirred for 48 h (might be done much earlier), then transferred to a funnel containing chloroform-isopropanol (5/1) and 5% aq. LiCl. The cloudy-orange organic phase was separated, washed with additional 5% aq LiCl (2×), 1 M aq NaOH (3×), satd aq NaCl (1×), and then dried (Na2SO4) and evaporated to yield the crude product (96.3% pure; trace hexamethylphosphoramide (HMPA) by 1HNMR). This crude product was then further purified by passage through a very short column (3 cm) of silica gel (5 to 15% gradient of MeOH in dichloromethane (DCM)) where a trace of faster moving 3E-isomer was removed. The pure fractions were evaporated and recrystallized overnight from a satd EtOAc soln which was diluted with Et2O (˜3-fold) and chilled at 0° C. The mother liquor was decanted to yield after full vacuum the desired compound as orange crystals (153 mg 85%).

1. stirringThe reaction mixture was stirred for 48 h (might be done much earlier)
2. customtransferred to a funnel
3. customThe cloudy-orange organic phase was separated
4. washwashed with additional 5% aq LiCl (2×), 1 M aq NaOH (3×)
5. dry with materialdried (Na2SO4)
6. customevaporated
7. customto yield the crude product (96.3% pure; trace hexamethylphosphoramide (HMPA) by 1HNMR)
8. customThis crude product was then further purified by passage through a very short column (3 cm) of silica gel (5 to 15% gradient of MeOH in dichloromethane (DCM)) where a trace
9. customwas removed
10. customThe pure fractions were evaporated
11. customrecrystallized overnight from a satd EtOAc soln which
12. additionwas diluted with Et2O (˜3-fold)
13. temperaturechilled at 0° C
14. customThe mother liquor was decanted