反应详情

温度

45 °C

Into a 1-L Atlas jacketed reactor were added 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylic acid (49.08 g, 263.02 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (70 g, 219.19 mmol), 4-dimethylaminopyridine (5.41 g, 43.84 mmol), toluene (600 mL) and diisopropylethylamine (95.56 mL, 547.96 mmol). The reaction mixture was heated to 45° C. and stirred for 10 min until most of the solids were dissolved. 1-Propanephosphonic acid cyclic anhydride (195.70 mL, 328.78 mmol, 50% solution in ethyl acetate) was added and the temperature was increased to 110° C. The reaction mixture was stirred for 19 h before adding more 1-propanephosphonic acid cyclic anhydride solution (25 mL). The mixture was stirred at 110° C. for 5 h. The mixture was concentrated to a low volume via distillation with jacket temperature at 80° C. A mixture of ethanol:water (1:1, 1000 mL) was added to keep the temperature around 70° C. Once the addition was complete, the mixture was cooled to 15° C. over a period of 2 h and left granulating for 18 h. The solids were filtered and rinsed with a mixture of ethanol:water (1:1, 750 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 18 h to afford (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (72 g). 1H NMR (500 MHz, CDCl3) δ 1.50-1.66 (m, 4H), 1.82-2.05 (m, 11H), 2.53-2.61 (m, 1H), 3.00-3.20 (m, 2H), 3.34-3.42 (m, 1H), 3.49 (t, 2H), 6.32 (d, 1H), 7.61 (s, 1H), 7.68 (s, 1H), 8.21 (d, 1H), 11.01 (s, 1H); MS (ES+) (M+H) 488; HPLC retention time: 7.520 min (Method: Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase B: 0.1 M phosphoric acid (H3PO4) in water; Mobile Phase D: acetonitrile; Gradient: 80%-10% Mobile Phase B until 7.00 min; hold until 10.00 min; rapid ramp of 80% Mobile Phase B until 10.1 min; equilibrate until 12.1 min; Flow: 0.8 mL/min; Column Temperature: 30° C.; DAD1A, Sig=254 nm).

1. dissolutionwere dissolved
2. temperaturethe temperature was increased to 110° C
3. stirringThe reaction mixture was stirred for 19 h
4. stirringThe mixture was stirred at 110° C. for 5 h
5. concentrationThe mixture was concentrated to a low volume via distillation with jacket temperature at 80° C
6. additionA mixture of ethanol:water (1:1, 1000 mL)
7. additionwas added
8. customthe temperature around 70° C
9. additionOnce the addition
10. temperaturethe mixture was cooled to 15° C. over a period of 2 h
11. waitleft
12. waitgranulating for 18 h
13. filtrationThe solids were filtered
14. washrinsed with a mixture of ethanol:water (1:1, 750 mL)
15. customdried in a vacuum oven at 40° C. with a nitrogen
16. waitbleed for 18 h