反应详情

温度

120 °C

8-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (see Method 8; 43 mg, 0.17 mmol) was dissolved in methanol (3 mL) together with a few drops of water and acetic acid (0.2 mL). 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 80 mg, 0.18 mmol) dissolved in methanol (1 mL) was added to the former solution together with (polystyrylmethyl)-trimethylammonium cyanoborohydride (4.2 mmol/g, 47 mg, 0.25 mmol). The reaction mixture was heated to 120° C. for 5 min using microwave single node heating. The resin was filtered off and washed with methanol. The filtrate was concentrated by evaporation. The product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%). The solvent of the collected fractions was removed by evaporation followed by freeze-drying. The residue was partitioned between methylene chloride and aqueous NaHCO3. The two phases were separated by means of a phase separator column and then the solvent of the organic solution was removed by evaporation. There was obtained 50 mg (44%) of the title compound. 1H NMR (500 MHz, CD3OD): 1.5-1.7 (b, 1H), 1.7-2.0 (cm, 3H), 2.2-4.2 (cm, 21H), 4.5 (d, 1H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.

1. temperatureheating
2. filtrationThe resin was filtered off
3. washwashed with methanol
4. concentrationThe filtrate was concentrated by evaporation
5. customThe product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%)
6. customThe solvent of the collected fractions was removed by evaporation
7. customby freeze-drying
8. customThe residue was partitioned between methylene chloride and aqueous NaHCO3
9. customThe two phases were separated by means of a phase separator column
10. customthe solvent of the organic solution was removed by evaporation