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Stage #1: With trifluoroacetic acid In toluene; acetonitrile at 35℃; Stage #2: With sodium tetrahydroborate In methanol; toluene; acetonitrile at -10 - 20℃; for 1 h; Stage #3: With ammonia; water In methanol; toluene; acetonitrile
Example AS; a. Preparation of intermediate compound 15; CF3COOH (16.8 ml; 5 eq) was added at room temperature to a solution of phenylhydrazine (3.2 ml; 1.1 eq) in toluene/CH3CN (49/1) (50 ml). The mixture was heated at 35 °C. A solution of 1-(phenylmethyl)-4-piperidinecarboxaldehyde (6 g; 0.03 mol) in toluene/CH3CN (49/1) (10 ml) was added slowly. The mixture was heated at 35 °C overnight, then cooled down to -10 °C. Methanol (7 ml) was added then NaBH4 (1.7 g; 1.5 eq) was added portionwise. The mixture was stirred at room temperature for 1 hour. NH40H 10 percent was added, the mixture was extracted with EtOAc, dried over MgS04, filtered and evaporated. The residue (10 g) was purified by column chromatography over silica gel (75 g Si02 35-70 μm; eluent : 98/2 CH2Cl2/MeOH). Yield: 3.3 g of intermediate compound 15 (40 percent)
With n-butyllithium; sodium chloride; ammonium chloride; diisopropylamine; In tetrahydrofuran; hexane; ethyl acetate;
1(4) 1-Methyl-3-[3-(1-benzyl-4-piperidyl)acryloyl] indole 7 ml of a 15% w/v solution of butyllithium in hexane were added to a solution of 1 g of diisopropylamine in 10 ml of dry tetrahydrofuran, whilst stirring, and at a temperature of -10C. The mixture was then stirred whilst ice-cooling for 10 minutes, after which it was cooled to -78C. A solution of 1.8 g of 1-methyl-3-acetylindole [prepared as described in step (1)] in 10 ml of dry tetrahydrofuran was then added and the mixture was stirred for 30 minutes. A solution of 2.7 g of 1-benzyl-4-piperidinecarbaldehyde [prepared as described in step (3) above] in 20 ml of dry tetrahydrofuran was then added to the mixture. The reaction mixture was then stirred, first at 0C for 3 hours and then at room temperature for 2 hours. At the end of this time, an aqueous solution of ammonium chloride was added to the mixture. The organic layer was then removed and the aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was then combined with the organic layer removed in the previous step, and the resulting solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of ethyl acetate and hexane in proportions of from 1: 9 to 10: 0 by volume as the eluent, to give 3.1 g of the title compound as an oil, with an Rf value of 0.40, using ethyl acetate as developing solvent.
dimethyl (E)-(2-(1-benzylpiperidin-4-yl)vinyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With sodium hydride; In toluene; at 20 - 40℃; for 16h;Inert atmosphere;
[00313] Sodium hydride (2.16 g, 54.11 mmol) was carefully added to a stirred solution of bis(dimethoxyphosphoryl)methane (11.42 g, 49.19 mmol) in toluene (100 mL) at room temperature. The reaction mixture was then placed under an atmosphere of nitrogen and a solution of 1- benzylpiperidine-4-carbaldehyde (10 g, 49.19 mmol) in toluene (50 mL) was slowly added keeping the temperature below 40 C. The resulting mixture was left to stir at room temperature for 16 h and then quenched by the addition of aqueous saturated ammonium chloride solution. The organic phase was separated, washed with brine, dried (Mg504) and evaporated to dryness. Chromatography (120 g 5i02 5 to 100% gradient of EtOAc in hexanes) provided dimethyl (E)-(2-(1-benzylpiperidin-4- yl)vinyl)phosphonate (6.2 g, 16%) as a colorless oil.
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