ethyl (3R)-piperidine-3-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution containing 5-propargyl-10,11-dihydro-5H-dibenzo[b,f]azepine (2.45 g, 10.5 mmol, prepared similarly as described in U.S. Pat. No. 3,354,178 (1967)), (R)-3-piperidinecarboxylic acid ethyl ester (1.7 g, 10.8 mmol), paraformaldehyde (0.65 g) and a trace of cuprous chloride in dioxane (25 ml) was heated at reflux temperature for 5 h and left standing overnight. The mixture was filtered and the solvent evaporated. The remaining oil was purified by column chromatography on silica gel (40 g) using chloroform as eluent, affording 3.5 g (83%) of (R)-1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-butyn-1-yl)-3-piperidinecarboxylic acid ethyl ester. prepared similarly at reflux temperature for 5 h left The mixture was filtered the solvent evaporated The remaining oil was purified by column chromatography on silica gel (40 g)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the above iodide (1.80 g, 0.0044 mol), (R)-3-piperidinecarboxylic acid ethyl ester (0.69 g, 0.0044 mol) and anhydrous potassium carbonate (1.82 g, 0.0132 mol) in 2-butanone (30 ml) was heated to 50° C. for 6 h. After cooling, the mixture was diluted with ether (50 ml) and water (50 ml) and the phases were separated. The organic phase was washed with water (30 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the oily residue (2.1 g) was purified by gradient column chromatography on silica gel (40 g) using benzene and ethyl acetate as eluents. The benzene/ethyl acetate (9:1) fraction afforded 1.50 g (77%) of (R)-1-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-benzyl)-3-piperidinecarboxylic acid ethyl ester. After cooling the phases were separated The organic phase was washed with water (30 ml) dried (MgSO4) The solvent was evaporated in vacuo the oily residue (2.1 g) was purified by gradient column chromatography on silica gel (40 g)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylate (0.4 g), (R)-piperidine-3-carboxylic acid ethyl ester (0.165 g), BOP (0.537 g) and DIPEA (0.56 mL) were added to DMF (3 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, dried under reduced pressure, and purified by flash chromatography (DCM/MeOH) to give 39.6 mg of (R)-1-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarbonyl)-piperidine-3-carboxylic acid ethyl ester, MP=175.0-177.0° C. the resulting precipitate was collected by filtration washed with water dried under reduced pressure purified by flash chromatography (DCM/MeOH)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-3-nitropyridin-2-amine (0.8 g, 4.64 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (1.0 g, 5.16 mmol) and triethylamine (1.56 g, 15.48 mmol) in acetonitrile (20 mL) at room temperature. The reaction mixture was stirred at 80° C. for 3 h. The mixture was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 10-50% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.0 g). MS (ES+) (M+H) 295.22. The mixture was partitioned between ethyl acetate and water The organics were dried over sodium sulfate concentrated under reduced pressure The crude material was purified via column chromatography (100-200 mesh silica gel, 10-50% ethyl acetate in petroleum ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-3-nitropyridin-2-amine (1.25 g, 7.22 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (2.0 g, 10.32 mmol) and triethylamine (2.87 mL, 20.65 mmol) in acetonitrile (25 mL) at room temperature. The reaction mixture was stirred for 3 h at 80° C., then was cooled and was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-25% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (2 g). MS (ES+APCI) (M+H) 295.0; LCMS retention time 5.246 min (Method R1). was cooled was partitioned between ethyl acetate and water The organics were dried over sodium sulfate filtered concentrated under reduced pressure The crude material was purified via column chromatography (100-200 mesh silica gel, 0-25% ethyl acetate in petroleum ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-3-nitropyridin-2-amine (1.25 g, 7.22 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (2.0 g, 10.32 mmol) and triethylamine (2.87 mL, 20.65 mmol) in acetonitrile (25 mL) at room temperature. The reaction mixture was stirred for 3 h at 80° C., then was cooled and was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-25% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (2 g). MS (ES+APCI) (M+H) 295.0; LCMS retention time 5.246 min (Method R1). was cooled was partitioned between ethyl acetate and water The organics were dried over sodium sulfate filtered concentrated under reduced pressure The crude material was purified via column chromatography (100-200 mesh silica gel, 0-25% ethyl acetate in petroleum ether)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-ethyl piperidine-3-carboxylate (1 g, 6.33 mmol) in dimethylsulfoxide (15 mL) were added 2-amino-3-nitro-6-chloropyridine (1.098 g, 6.33 mmol) and triethylamine (1.921 g, 18.99 mmol) at room temperature. The mixture was heated to 100° C. for 18 h, then was poured into ice water and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (100-200 mesh silica, 30% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (650 mg, 93.5%). MS (ES+APCI) (M+H) 295.1; LCMS retention time 2.832 min (Method G). extracted with ethyl acetate The organic layer was dried filtered concentrated under reduced pressure The crude material was purified via flash chromatography (100-200 mesh silica, 30% ethyl acetate in petroleum ether)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (500 mg, 2 mmol) was combined with (R)-piperidine-3-carboxylic acid ethyl ester (0.51 g, 3.2 mmol) in methanol (10 mL, 200 mmol) and acetic acid (9.2 μL, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmol) was then added and the reaction was stirred overnight at room temperature. The reaction was then quenched with water and extracted three times with ethyl acetate. Organics were combined and dried over MgSO4. Solids were removed via filtration and 10 g of silica gel was added. All solvent was then removed and the resulting silica gel was loaded onto a 24 g column and the product was eluted using a gradient of 0-60% ethyl acetate/hexanes and then dried under vacuum to give the title compound as a colorless oil. EDI-MS: 438.1 (M+H)+. The reaction was then quenched with water extracted three times with ethyl acetate dried over MgSO4 Solids were removed via filtration and 10 g of silica gel was added All solvent was then removed the product was eluted dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(−)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%). LC/MS 6.76 min, [M+1]+ 417. LC/MS 6.76 min, [M+1]+ 417

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(−)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%). LC/MS 6.76 min, [M+1]+ 417. LC/MS 6.76 min, [M+1]+ 417

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yl-oxy)ethanol (16 g, 60 mmol) and triethylamine (15.1 g, 149 mmol) in dry toluene (75 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (13.7 g, 119 mmol) in dry toluene (75 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1.5 h at 5° C. Water was added (100 ml) and the mixture was stirred at room temperature for 0.5 h. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts was washed with brine, dried (Na2SO4) and filtered. To the filtrate was added ethyl (R)-3-piperidinecarboxylate (10.3 g, 66 mmol) and potassium carbonate (9.9 g, 72 mmol) and the mixture was heated at reflux temperature for 6 days. Another portion of ethyl (R)-3-piperidinecarboxylate (5.3 g) was added and the mixture was heated at reflux temperature for another 24 h. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) and then extracted with a 5% aqueous citric acid solution (4×30 100 ml). Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH was measured at 8.5. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 9.4 g (39 %) of (R)-N-(2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. the temperature below 10° C When addition the mixture was stirred at room temperature for 0.5 h The phases were separated the aqueous phase was extracted with a small portion of toluene The combined organic extracts was washed with brine dried (Na2SO4) filtered the mixture was heated at reflux temperature for 6 days the mixture was heated at reflux temperature for another 24 h extracted with ethyl acetate (2×200 ml) The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) extracted with a 5% aqueous citric acid solution (4×30 100 ml) Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH The phases were separated the organic phase was dried (Na2SO4) The solvent was evaporated in vacuo

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yl-oxy)ethanol (16 g, 60 mmol) and triethylamine (15.1 g, 149 mmol) in dry toluene (75 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (13.7 g, 119 mmol) in dry toluene (75 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1.5 h at 5° C. Water was added (100 ml) and the mixture was stirred at room temperature for 0.5 h. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts was washed with brine, dried (Na2SO4) and filtered. To the filtrate was added ethyl (R)-3-piperidinecarboxylate (10.3 g, 66 mmol) and potassium carbonate (9.9 g, 72 mmol) and the mixture was heated at reflux temperature for 6 days. Another portion of ethyl (R)-3-piperidinecarboxylate (5.3 g) was added and the mixture was heated at reflux temperature for another 24 h. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) and then extracted with a 5% aqueous citric acid solution (4×30 100 ml). Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH was measured at 8.5. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 9.4 g (39 %) of (R)-N-(2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. the temperature below 10° C When addition the mixture was stirred at room temperature for 0.5 h The phases were separated the aqueous phase was extracted with a small portion of toluene The combined organic extracts was washed with brine dried (Na2SO4) filtered the mixture was heated at reflux temperature for 6 days the mixture was heated at reflux temperature for another 24 h extracted with ethyl acetate (2×200 ml) The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) extracted with a 5% aqueous citric acid solution (4×30 100 ml) Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH The phases were separated the organic phase was dried (Na2SO4) The solvent was evaporated in vacuo