反应详情

3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 11.2 g, 25 mmol) was dissolved in methanol (50 mL) together with triethylamine (3.5 mL, 25 mmol). Together with another portion of triethylamine (3.5 mL, 25 mmol) the solution was transferred to a flask containing 1-acetyl-4-azetidin-3-ylpiperazine dihydrochloride (see WO 96/05193; 8.4 g, 32.6 mmol). The mixture was stirred at RT for 45 min and then sodium triacetoxyborohydride (8.0 g, 37.6 mmol) was added by installments during one hour. The reaction mixture was stirred at RT for 45 min. Water (0.45 mL) was added and then most of the solvent was removed by evaporation. The residue was dissolved in toluene (56 mL) and then an aqueous 10% solution of NaOH (55 mL) was added while heating to 40° C. The mixture was stirred vigorously at 45° C. for 5 min. The aqueous layer was separated off and the organic solution was left in the hood overnight. After several attempts to crystallize the product from different solvents the compound was purified by means of silica gel chromatography (ammonia saturated methanol-methylene chloride 1% to 10%). There was obtained 8.3 g (54%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): 1.4-1.8 (cm, 2H), 2.0 (s, 3H), 2.1-3.8 (cm, 21H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 614 (M+1)+.

1. stirringThe reaction mixture was stirred at RT for 45 min
2. custommost of the solvent was removed by evaporation
3. dissolutionThe residue was dissolved in toluene (56 mL)
4. additionan aqueous 10% solution of NaOH (55 mL) was added
5. temperaturewhile heating to 40° C
6. stirringThe mixture was stirred vigorously at 45° C. for 5 min
7. customThe aqueous layer was separated off
8. waitthe organic solution was left in the hood overnight
9. customAfter several attempts to crystallize the product from different solvents the compound
10. customwas purified by means of silica gel chromatography (ammonia saturated methanol-methylene chloride 1% to 10%)