反应详情

温度

25 °C

A suspension of the trifluoroacetic acid salt of 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (2.35 g, 5.8 mmol) in methanol (50 mL) was treated with N,N-diisopropylethylamine (1.5 mL, 8.6 mmol). The resulting mixture was stirred at 25° C. for 30 min. At this time, the reaction was treated with 4-fluoro-3-(trifluoromethyl)benzaldehyde (1.34 g, 6.96 mmol) followed by toluene (50 mL). The resulting mixture was stirred at 60° C. for 1 h and then concentrated in vacuo. Additional toluene (200 mL) was then added. The reaction mixture was stirred for 15 min and then concentrated in vacuo. This procedure was repeated a few times until the reaction mixture became homogenous when dissolved in toluene. After the final concentration to remove toluene, the reaction mixture was diluted with dichloroethane (100 mL) and then treated with acetic acid (351 mg, 5.8 mmol) and sodium triacetoxyborohydride (3.7 g, 17.4 mmol). The resulting reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 1:1 ethyl acetate/hexanes to 100% ethyl acetate) afforded (R)-3-(4-fluoro-3-trifluoromethyl-benzylamino)-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (1.44 g, 52.8%) as a foamy solid; ES-HRMS m/e calcd for C19H18F4N6O2S (M+H)+ 471.1221, found 471.1221.

1. stirringThe resulting mixture was stirred at 60° C. for 1 h
2. concentrationconcentrated in vacuo
3. additionAdditional toluene (200 mL) was then added
4. stirringThe reaction mixture was stirred for 15 min
5. concentrationconcentrated in vacuo
6. dissolutiondissolved in toluene
7. concentrationAfter the final concentration
8. customto remove toluene
9. additionthe reaction mixture was diluted with dichloroethane (100 mL)
10. customThe resulting reaction mixture
11. stirringto stir at 25° C. overnight
12. extractionextracted with ethyl acetate
13. washThe combined organics were washed with water
14. dry with materiala saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. washFlash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 1:1 ethyl acetate/hexanes to 100% ethyl acetate)