反应详情

温度

70 °C

(5-Chloro-N-(2,4-dimethoxybenzyl)-4-({3-[(2E)-3-(dimethylamino)prop-2-enoyl]-2′-(trifluoromethyl)biphenyl-4-yl}oxy)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 44, 563 mg, 0.724 mmol) in ethanol (10 mL) was slowly added a solution of tert-butyl 3-hydrazinoazetidine-1-carboxylate (Preparation 36, 603 mg, 3.22 mmol) in ethanol (10 mL) and acetic acid (0.25 mL) at 0° C. under nitrogen. The reaction was heated to 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was neutralised to pH7 with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and concentrated in vacuo to afford a yellow oil. The oil was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (1.74 g). The oil was partially purified by silica gel column chromatography (0%-10% methanol in dichloromethane gradient elution) to afford the title compound as a solid (228 mg) of 52% purity via LCMS. The compound was used without further purification in the next step.

1. temperaturecooled to room temperature
2. concentrationconcentrated in vacuo
3. customto afford a yellow oil
4. customThe oil was partitioned between water (100 mL) and ethyl acetate (100 mL)
5. extractionThe aqueous layer was then extracted with ethyl acetate (2×100 mL)
6. washThe combined organic layers were washed with brine (2×100 mL)
7. dry with materialdried over anhydrous sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo