morpholin-4-yl(piperidin-4-yl)methanone

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+. heating The mixture was filtered through a phase separator the resin washed with methanol The solvent was removed by evaporation the residue was dissolved in methylene chloride The solution washed twice with a saturated solution of NaHCO3 The organic phase was filtered through a phase separator the solvent was removed by evaporation The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+. heating The mixture was filtered through a phase separator the resin washed with methanol The solvent was removed by evaporation the residue was dissolved in methylene chloride The solution washed twice with a saturated solution of NaHCO3 The organic phase was filtered through a phase separator the solvent was removed by evaporation The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: General procedure C was followed using morpholino(piperidin-4-yl)methanone (21 mg, 0.12 mmol), 3,4,5-trichloropyridine (23 mg, 0.12 mmol), triethylamine (32 μL, 0.23 mmol) and NMP (1 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (15 mg, 35%), m.p. 172-174° C.; umax (CHCl3)/cm−1 3006, 2858, 1632, 1559, 1448, 1116, 1020; m/z (ESI) C15H20Cl2N3O2 requires 344.0927, found [M+H]+ 344.0929. The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+. heating The mixture was filtered through a phase separator the resin washed with methanol The solvent was removed by evaporation the residue was dissolved in methylene chloride The solution washed twice with a saturated solution of NaHCO3 The organic phase was filtered through a phase separator the solvent was removed by evaporation The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol)