反应详情

温度

25 °C

In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (83 mg, 88%) as a white foam: [α]30589=−88.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.32 (m, 10H, 5×CH2), 3.34 (brs, 5H, OCH2 and SO2CH3), 3.95 (m, 1H, ArCHCO), 4.02 (t, J=6.5 Hz, 2H, NCH2), 4.56 (t, J=4.7 Hz, 1H, OH), 6.41 (s, 1H, Ar), 7.56 (s, 1H, Ar), 7.61 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1 H, NH).

1. customIn a round bottom flask was placed
2. customtransferred to a separatory funnel
3. washwashed with a saturated aqueous sodium bicarbonate solution (10 mL)
4. dry with materiala 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customPurification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)