| 28% |
Stage #1: 4-acetylmorpholine With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: 4-phenylindan-1-one In tetrahydrofuran at -78℃; for 4h; Inert atmosphere; Further stages; |
1.b b) Synthesis of 4-(2-(7-phenyl-1 H-inden-3-yl)ethyl)morpholine maleate
To 4 mL of THF cooled to -78 <€, a solution of LDA (1 .5 M in THF, 2 mL, 2.95 mmol) was added, under argon atmosphere. Then, /V-acetylmorpholine (274 μ, 2.36 mmol) was added and the resulting mixture was stirred at -78 ' for 1 h. Finally, a solution of 4-phenyl-2,3-dihydro-1 H-inden-1 -one (246 mg, 1 .18 mmol) in THF (10 mL) was added, and the resulting mixture was kept at -78 ' for 4 h. The reaction mixture was acidified with 1 N HCI and extracted with EtOAc. The organic extracts were dried over Na2S04 and evaporated to dryness. To a solution of the previous residue in CH2CI2 (12 mL) p-toluenesulfonic acid (30 mg, 0.12 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was basified with saturated NaHC03 aqueous solution and extracted with CH2CI2. The organic extract was dried over Na2S04 and evaporated to dryness. To a solution of the previous residue in THF (15 mL) cooled to 0 <€, AIH3-NMe2Et (0.5 M in toluene, 4.8 mL, 2.38 mmol) was added and the resulting mixture was stirred for 5 h. EtOAc:H20 (40 mL, 1 :1 ) was added to the reaction mixture and the resulting suspension was filtered through Celite. The layers were separated and the aqueous phase was extracted with EtOAc. The organic extract, after being dried over Na2S04, was evaporated to dryness. A solution of the previous residue in 37% HCLEtOH (30 mL, 1 :1 ) was refluxed overnight. The reaction mixture was evaporated to dryness, dissolved in water, basified with KOH, and extracted with EtOAc. The organic layers were dried with Na2S04 and evaporated to dryness. Purification of the residue by silica gel column chromatography (hexane:EtOAc mixtures of increasing polarity as eluent) afforded the desired product (100 mg, 28%). The product was converted into the corresponding maleate salt by adding maleic acid (39 mg, 0.33 mmol) in acetone (0.6 mL), followed by filtration of the resulting solid and drying under vacuum. 1 H-NMR (DMSO-de, 300 MHz) δ: 7.60 (dd, J=8.4, 1 .5 Hz, 2H), 7.50-7.44 (m, 4H), 7.40 (m, 1 H), 7.26 (dd, J=6.0, 2.4 Hz, 1 H), 6.40 (s, 1 H), 6.04 (s, 2H), 3.79 (m, 4H), 3.47 (s, 2H), 3.31 (m, 8H), 2.95 (m, 2H) ppm. ESI(+)-HRMS: 306.1852 [M+H]+. |
| 28% |
Stage #1: 4-acetylmorpholine With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: 4-phenylindan-1-one In tetrahydrofuran at -78℃; for 4h; Further stages; |
1.b b) Synthesis of 4-(2-(7-phenyl-1H-inden-3-yl)ethyl)morpholine maleate
b) Synthesis of 4-(2-(7-phenyl-1H-inden-3-yl)ethyl)morpholine maleate To 4 mL of THF cooled to -78 °C, a solution of LDA (1.5 M in THF, 2 mL, 2.95 mmol) was added, under argon atmosphere. Then, N-acetylmorpholine (274 μL, 2.36 mmol) was added and the resulting mixture was stirred at -78 °C for 1 h. Finally, a solution of 4-phenyl-2,3-dihydro-1H-inden-1-one (246 mg, 1.18 mmol) in THF (10 mL) was added, and the resulting mixture was kept at -78 °C for 4 h. The reaction mixture was acidified with 1 N HCl and extracted with EtOAc. The organic extracts were dried over Na2SO4 and evaporated to dryness. To a solution of the previous residue in CH2Cl2 (12 mL) p-toluenesulfonic acid (30 mg, 0.12 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was basified with saturated NaHCO3 aqueous solution and extracted with CH2Cl2. The organic extract was dried over Na2SO4 and evaporated to dryness. To a solution of the previous residue in THF (15 mL) cooled to 0 °C, AlH3-NMe2Et (0.5 M in toluene, 4.8 mL, 2.38 mmol) was added and the resulting mixture was stirred for 5 h. EtOAc:H2O (40 mL, 1:1) was added to the reaction mixture and the resulting suspension was filtered through Celite. The layers were separated and the aqueous phase was extracted with EtOAc. The organic extract, after being dried over Na2SO4, was evaporated to dryness. A solution of the previous residue in 37% HCl:EtOH (30 mL, 1:1) was refluxed overnight. The reaction mixture was evaporated to dryness, dissolved in water, basified with KOH, and extracted with EtOAc. The organic layers were dried with Na2SO4 and evaporated to dryness. Purification of the residue by silica gel column chromatography (hexane:EtOAc mixtures of increasing polarity as eluent) afforded the desired product (100 mg, 28%). The product was converted into the corresponding maleate salt by adding maleic acid (39 mg, 0.33 mmol) in acetone (0.6 mL), followed by filtration of the resulting solid and drying under vacuum. 1H-NMR (DMSO-d6, 300 MHz) δ: 7.60 (dd, J=8.4, 1.5 Hz, 2H), 7.50-7.44 (m, 4H), 7.40 (m, 1H), 7.26 (dd, J=6.0, 2.4 Hz, 1H), 6.40 (s, 1H), 6.04 (s, 2H), 3.79 (m, 4H), 3.47 (s, 2H), 3.31 (m, 8H), 2.95 (m, 2H) ppm. |
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