| 67% |
Stage #1: 2-methyl-3-(4-(tert-pentyl)phenyl)propanal; cis-2,6-dimethylmorpholine With acetic acid In ethanol at 0 - 20℃; for 0.5h;
Stage #2: With sodium tetrahydroborate In ethanol at -15 - 0℃; for 3h;
Stage #3: With hydrogenchloride In di-isopropyl ether; ethyl acetate at 0℃; for 1h; |
1.c
3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propionaldehyde (109.63 g ; 0.50 mol) obtained at the previous step were dissolved in absolute ethanol (500 mL). To the ethanol solution was added at 0°C (ice/water) AcOH (30 mL, 0.5 mol) and cis-2,6-dimethylmorpholine (69.108 g, 0.60 mol) and the reaction was stirred at RT for 30 min. It was then cooled to (-15°C) and NaBH4 (15.93 g, 0.42 mol) was added in portions during 1 h. Stirring was continued at 0°C for 2 h and the reaction was quenched by drop-wise addition of NaOH solution in water (30 g, 0.75 mol, /100 mL H2O) to pH=12. The reaction was then partitioned between H2O (2 L) and hept/EtOAc (9/1) (2x1 L). The organic phases were combined, washed with the H2O (1L), and dried over MgSO4. After evaporation of the solvents, the residue (147.14 g) was dissolved in iPr2O (500 mL) and cooled to 0°C. To this solution was added the solution of HCl gas in EtOAc (150 ml, ~4M) drop-wise (30 min) and with stirring. White precipitate that was formed during HCl addition was filtered 30 min after completion of the addition. It was washed with iPr2O (300 mL) and was dried in vacuo at 40°C during 48 h providing 118.79 g of cis-4-{3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propyl}-2,6-dimethyl-morpholine hydrochloride as white powder. (67% yield) (Melting Point = 205.9°C) 1H NMR (400 MHz, CDCl3) δ: 0.63 (3H, t, J = 7.39 Hz), 1.12 (3H, d, J = 6.30 Hz), 1.13 (3H, d, J = 6.32 Hz), 1.24 (6H, s), 1.26 (3H, d, J = 6.65 Hz), 1.59 (2H, q, J = 7.49 Hz), 2.05 (1H, q, J = 10.77 Hz), 2.26 (1H, q, J = 10.80 Hz), 2.27-2.35 (1H, m), 2.56-2.66 (2H, m), 2.76-2.89 (2H, m), 3.22 (2H, t, J = 13.28 Hz), 4.36-4.44 (1H, m), 4.46-4.54 (1H, m), 7.06 (2H, d, J = 8.22 Hz), 7.23 (2H, d, J = 8.22 Hz), 12.55 (1H, b) |
| 64% |
Stage #1: 2-methyl-3-(4-(tert-pentyl)phenyl)propanal; cis-2,6-dimethylmorpholine With acetic acid In ethanol; N,N-dimethyl-formamide at 0 - 20℃; for 0.25h;
Stage #2: With sodium tetrahydroborate In ethanol; N,N-dimethyl-formamide at -5 - 3℃; for 3.5h;
Stage #3: With hydrogenchloride In di-isopropyl ether; ethyl acetate at 0℃; for 1h; |
2
Through a mixture of (1,1-dimethyl-propyl)-4-iodo-benzene (137.07 g, 050 mol), palladium(II) acetat (1.122 g, 5 mmol) and sodium bicarbonate (50.40 g, 0.60 mol) in dry DMF (500 mL) was bubbled nitrogen for 10 min. Then 2-methyl-prop-2-en-1-ol (54.083 g, 0.75 mol) was added and nitrogen bubbled for another ten minutes. The reaction mixture was heated under nitrogen for 9 h at 100°C. The reaction was cooled (0°C)and was filtered through a thin layer of Celite. The Celite was then washed with cold DMF (300 mL). To DMF solution was added EtOH (abs. 700 mL) followed by AcOH (30 mL) and cis-2,6-dimethylmorpholine (73.9 mL). After 15 min stirring at RT, the reaction was cooled to -5°C and NaBH4 (15.93 g, 0.42 mol) was added in portions over 1h 30 min so that temperature did not exceed 2-3°C. Stirring was continued at 0°C for 1 h and the reaction was quenched by drop-wise addition of NaOH solution in water at 0°C (30 g, 0.75 mol, /100 mL H2O) to pH=12. The reaction was then partitioned between H2O (2 L) and Hept/EtOAc (9/1) (2x1 L). The organic phases were combined, washed with the H2O (1L), and dried over MgSO4. After evaporation of the solvents, the residue (147.14 g) was dissolved in iPr2O (500 mL) and cooled to 0°C. To this solution was added the solution of HCl gas in EtOAc (150 ml, ~4M) drop-wise (30 min) and with stirring. White precipitate was formed during HCl addition and was filtered 30 min after completion of the addition. It was washed with iPr2O (300 mL) and was dried in vacuo at 40°C during 48 h providing 112.34 g of cis-4-{3-[4-(1,1-dimethylpropyl)-phenyl]-2-methyl-propyl}-2,6-dimethyl-morpholine hydrochloride as white powder. (64% yield) (Melting Point = 205.8°C) 1H NMR (400 MHz, CDCl3) δ: 0.63 (3H, t, J = 7.39 Hz), 1.12 (3H, d, J = 6.30 Hz), 1.13 (3H, d, J = 6.32 Hz), 1.24 (6H, s), 1.26 (3H, d, J = 6.65 Hz), 1.59 (2H, q, J = 7.49 Hz), 2.05 (1H, q, J = 10.77 Hz), 2.26 (1H, q, J = 10.80 Hz), 2.27-2.35 (1H, m), 2.56-2.66 (2H, m), 2.76-2.89 (2H, m), 3.22 (2H, t, J = 13.28 Hz), 4.36-4.44 (1H, m), 4.46-4.54 (1H, m), 7.06 (2H, d, J = 8.22 Hz), 7.23 (2H, d, J = 8.22 Hz), 12.55 (1H, b) |
| 64% |
Stage #1: 2-methyl-3-(4-(tert-pentyl)phenyl)propanal; cis-2,6-dimethylmorpholine With acetic acid In methanol at 0 - 20℃; for 0.5h;
Stage #2: With hydrogen In methanol at 37℃;
Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages; |
3
First step: Same as example 1Second step: 3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propionaldehyde (100.56 g, 0,46 mol) obtained as described in example 1-b) was dissolved in absolute methanol (500 mL). To the methanol solution cooled at 0°C (ice/water) was added AcOH (30 mL, 0.50 mol) and cis-2,6-dimethylmorpholine (69.108, 0.60 mol) and the reaction was stirred at room temperature for 30 min. It was then placed under nitrogen and Pd/C 10% (5.00 g) added to it. nitrogen was replaced with hydrogen and the reaction was heated at 37°C under hydrogen pressure. At the end of the reduction. the reaction mixture was filtered through Celite. The Celite was washed with MeOH (200 mL), then aqueous NaOH solution was added to the methanolic reaction mixture until pH=12. The reaction mixture was partitioned with Hept/EtOAc (9/1) (2x1 L), the organic phase was washed with water (1 L) and was dried over MgSO4. After evaporation of the solvents, the residue (144.32 g) was dissolved in iPr2O (500 mL) and cooled to 0°C. To this solution was added a solution of HCl gas in EtOAc (150 ml, ~4M) drop-wise (30 min) and with stirring. White precipitate formed during HCl in EtOAc addition was filtered 30 min after completion of the addition. It was washed with iPr2O (300 mL) and was dried in vacuo at 40°C during 48 h providing 112.65 g of cis-4-{3-[4-(1,1-dimethyl-propyl)-phenyl]-2-methyl-propyl}-2,6-dimethyl-morpholine hydrochloride as white powder. (64% yield) (Melting Point = 205.7°C) 1H NMR (400 MHz, CDCl3) δ: 0.63 (3H, t, J = 7.39 Hz), 1.12 (3H, d, J = 6.30 Hz), 1.13 (3H, d, J = 6.32 Hz), 1.24 (6H, s), 1.26 (3H, d, J = 6.65 Hz), 1.59 (2H, q, J = 7.49 Hz), 2.05 (1H, q, J = 10.77 Hz), 2.26 (1H, q, J = 10.80 Hz), 2.27-2.35 (1H, m), 2.56-2.66 (2H, m), 2.76-2.89 (2H, m), 3.22 (2H, t, J = 13.28 Hz), 4.36-4.44 (1H, m), 4.46-4.54 (1H, m), 7.06 (2H, d, J = 8.22 Hz), 7.23 (2H, d, J = 8.22 Hz), 12.55 (1H, b) |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
