| 90% |
With potassium carbonate In acetonitrile at 20℃; |
107.ii (ii)
To a solution of 1, 1-dimethylethyl 4- [ (cyclohexylmethyl) amino] piperidine-1- carboxylate (0.245 g, 0.840 mmole, 1.0 eq. ), 2-phenylbenzyl bromide (0.185 ml, 1.01 mmole, 1.2 eq. ) in dry acetonitrile (5 ml) was added anhydrous potassium carbonate (0.19 g, 1.35 mmole, 1.6 eq. ). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give a white solid. The white solid was taken up in dichloromethane (10 ml) and this washed with water (10 ml). The dichloromethane layer was passed through a hydrophobic frit then diluted with methanol (10 ml). This solution was loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material was eluted using 2N ammonia in methanol (50 ml). Concentration of the ammonia/methanol solution under vacuum yielded a colourless oil (0.344 g, 90%). To a solution of this oil (0.344 g, 0.74 mmole, 1.0 eq. ) in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 eq). The solution was stirred overnight at room temperature. Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2N ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil (0.298 g, 99%). The oil was taken up in methanol. To this solution was added a solution of fumaric acid (0.095 g, 0.08 mmole, 1 EQ) in methanol followed by diethyl ether and cyclohexane. The resulting precipitate was collected by filtration to give the title compound as a white solid (0.302 g, 76 %). ON (300 MHz, MEOD) 7. 58 (1H, d, ArH), 7.45-7. 29 (7H, m, ArH), 7.18 (1H, d, ArH), 6.70 (2H, s, fumarate CH), 3.64 (2H, s, CH2AR), 3.33-3. 32 (2H, m, NCH2), 2.79 (2H, dt, NCH2), 2.65-2. 54 (1H, m, NCH), 2.17 (2H, d, NCH2), 1.74-1. 47 (9H, m, CCH2), 1.28-1. 11 (4H, m, CH, CCH2), 0.78-0. 67 (2H, m, CH2) ; LCMS 12 min, Rt = 5.0 min, (M++1) = 363. |
| 90% |
With potassium carbonate In acetonitrile at 20℃; |
4A.ii
To a solution of 1, 1-dimethylethyl 4- [ (cyclohexylmethyl) amino] piperidine-1- carboxylate (0.245 g, 0.840 mmole, 1.0 eq. ), 2-phenylbenzyl bromide (0.185 ml, 1.01 mmole, 1.2 eq. ) in dry acetonitrile (5 ml) was added anhydrous potassium carbonate (0.19 g, 1. 35 mmole, 1.6 eq. ). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give a white solid. The white solid was taken up in dichloromethane (10 ml) and this washed with water (10 ml). The dichloromethane layer was passed through a hydrophobic frit then diluted with methanol (10 ml). This solution was loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material was eluted using 2N ammonia in methanol (50 ml). Concentration of the AMMONIALMETHANOL solution under vacuum yielded a colourless oil (0.344 g, 90%). To a solution of this oil (0.344 g, 0.74 mmole, 1.0 eq. ) in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 eq). The solution was stirred overnight at room temperature. Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2N ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil (0. 298 g, 99%). The oil was taken up in methanol. To this solution was added a solution OF FUMARIC acid (0.095 g, 0. 08 mmole, 1 eq) in methanol followed by diethyl ether and cyclohexane. The resulting precipitate was collected by filtration to give the title compound as a white solid (0.302 g, 76 %). 8H (300 MHz, MEOD) 7.58 (1H, d, ArH), 7.45-7. 29 (7H, m, ArH), 7.18 (1H, d, ArH), 6.70 (2H, s, fumarate CH), 3.64 (2H, s, CH2Ar), 3.33-3. 32 (2H, m, NCH2), 2.79 (2H, dt, NCH2), 2.65-2. 54 (1H, IN, NCH), 2.17 (2H, d, NCH2), 1.74-1. 47 (9H, m, CCH2), 1.28-1. 11 (4H, m, CH, CCH2), 0.78-0. 67 (2H, m, CH2) ; LCMS 12 min, Rt = 5.0 min, (M++1) = 363 |
| 90% |
With potassium carbonate In acetonitrile at 20℃; |
4A.ii
(ii) To a solution of 1,1-dimethylethyl 4- [ (cyclohexylmethyl) amino] piperidine-1- carboxylate (0.245 g, 0.840 mmole, 1.0 eq. ), 2-phenylbenzyl bromide (0.185 ml, 1. 01 mmole, 1.2 eq. ) in dry acetonitrile (5 ml) was added anhydrous potassium carbonate (0.19 g, 1.35 mmole, 1.6 eq. ). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to give a white solid. The white solid was taken up in dichloromethane (10 ml) and this washed with water (10 ml). The dichloromethane layer was passed through a hydrophobic frit then diluted with methanol (10 ml). This solution was loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml) then basic material was eluted using 2N ammonia in methanol (50 ml). Concentration of the ammonia/methanol solution under vacuum yielded a colourless oil (0.344 g, 90%). To a solution of this oil (0.344 g, 0.74 mmole, 1.0 eq. ) in dichloromethane (10 ml) was added trifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 EQ). The solution was stirred overnight at room temperature. Solvent and TFA were removed in vacuo. The resulting oil was taken up in methanol and loaded onto an SCX-2 (10 g) column. The column was washed with methanol (50 ml). Basic material was then eluted using 2N ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave a colourless oil (0.298 g, 99%). The oil was taken up in methanol. To this solution was added a solution of fumaric acid (0. 095 g, 0. 08 mmole, 1 EQ) in methanol followed by diethyl ether and cyclohexane. The resulting precipitate was collected by filtration to give the title compound as a white solid (0.302 g, 76 %). ON (300 MHz, MEOD) 7.58 (1H, d, ArH), 7.45-7. 29 (7H, m, ArH), 7.18 (1H, d, ArH), 6.70 (2H, s, fumarate CH), 3.64 (2H, s, CH2Ar), 3.33-3. 32 (2H, m, NCH2), 2.79 (2H, dt, NCH2), 2.65-2. 54 (1H, m, NCH), 2.17 (2H, d, NCH2), 1.74-1. 47 (9H, m, CCH2), 1. 28-1. 11 (4H, m, CH, CCH2), 0.78-0. 67 (2H, m, CH2); LCMS 12 min, Rt = 5.0 min, (M++1) = 363. |
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