反应详情

1-(Methoxycarbonyl)-2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (5.629 g, 16.99 mmol) (reference compound 13) was dissolved in methyl THF (120 mL) and di(1H-imidazol-1-yl)methanone (4.13 g, 25.49 mmol) added. The suspension was stirred at room temperature under nitrogen for 3 h 45 min (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (5.21 g, 30.58 mmol) was suspended in methyl THF (120 mL) and magnesium chloride (2.91 g, 30.58 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3.5 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase extracted with water, satd NaHCO3 and water. The organic layer was evaporated and traces of water were azeotropically removed by MeCN to yield a brown oil. The diastereoisomers were separated in 2 runs on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.474 g, 7%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)phenyl)-piperidine-1-carboxylate (3.532 g, 52%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.26 (t, 3H), 1.72-2.22 (m, 3H), 2.29 (ddd, 1H), 2.83-2.96 (m, 1H), 3.29-3.49 (m, 3H), 3.64 (s, 3H), 4.07-4.23 (m, 3H), 4.92-5.06 (m, 1H), 7.32 (d, 2H), 7.58 (d, 2H). MS m/z 402 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.13-1.26 (m, 3H), 1.43-1.60 (m, 1H), 1.64-1.85 (m, 1H), 1.95 (dt, 1H), 2.44-2.61 (m, 2H), 2.73-2.85 (m, 1H), 3.39 (s, 2H), 3.70 (s, 3H), 3.99-4.36 (m, 3H), 5.59 (br. s, 1H), 7.28 (d, 2H), 7.56 (d, 2H). MS m/z 402 (M+H)+

1. stirringThe suspension was stirred at 50° C. under nitrogen for 3.5 h
2. additionThe beige suspension in flask 1 was now added to the white suspension in flask 2
3. stirringThe resulting beige suspension was stirred under nitrogen at room temperature for 23 h
4. additionadded
5. customThe phases were separated
6. extractionthe organic phase extracted with water
7. customThe organic layer was evaporated
8. customtraces of water were azeotropically removed by MeCN
9. customto yield a brown oil
10. customThe diastereoisomers were separated in 2