1-benzyl-N-ethylpiperidin-4-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2,6-Difluoro-3-nitropyridine (5.00 g) is dissolved in acetonitrile (10 ml) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 6.81 g) dissolved in 10 ml of acetonitrile is added via cannula. Then an additional 58 ml of acetonitrile is added and the reaction is cooled to 0°. Then 5.1 g of potassium carbonate is added and the reaction is stirred 10 min and allowed to warm to 20°-25°. After 6 hrs, the reaction is poured into water, extracted with ethyl acetate, washed with saline and dried over sodium sulfate. Flash column chromatography (silica gel; 5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, NMR (300 MHz, CDCl3) 8.22, 7.37-7.23, 6.25, 3.66, 3.55, 3.50, 3.01, 2.10, 1.95, 1.83 and 1.09δ. is added via cannula the reaction is cooled to 0° to warm to 20°-25° After 6 hrs extracted with ethyl acetate washed with saline dried over sodium sulfate

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

Procedure: 2,6-Difluoro-3-nitropyridine (Recl. Trav. Chim., 95, 127-156 (1976) and Tetrahedron Lett., 28, 111-114 (1987), 2.4 g, 15.0 mmol) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 3.3 g, 15 mmol) are dissolved in 37.5 mmol of acetonitrile at 0°. Then solid potassium carbonate (2.49 g, 18 mmol) is added and the reaction is slowly warmed to 20°-25°. After the reaction is complete by TLC (ethyl acetate/hexane, (25/75)), it is poured into water and extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and concentrated under reduced pressure. Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, mp=99°-100°; NMR (300 MHz, CDCl3) 8.00, 7.13-7.04, 6.02, 3.43, 3.31, 3.28, 2.77, 1.85, 1.71, 1.63 and 0.86δ; CMR (75 MHz, CDCl3) 163.5, 160.2, 151.2, 140.9, 130.4, 128.9, 128.0, 126.9, 96.9, 62.6, 59.6, 52.9, 38.7, 29.3 and 14.0δ. the reaction is slowly warmed to 20°-25° extracted with ethyl acetate The organic phase is washed with saline dried over sodium sulfate concentrated under reduced pressure Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane)

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

Procedure: To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mmol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the title compound as a solid (38 g); 1H NMR (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219. the resulting mixture stirred at room temperature for 1 h the resulting mixture extracted with diethyl ether The organic extracts were dried (K2CO3) evaporated

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

Procedure: To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the sub-titled compound as a solid (38 g); NMR: (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2–7.4 (m, 5H); MS: 219 (MH+). the resulting mixture stirred at room temperature for 1 h the resulting mixture extracted with diethyl ether The organic extracts were dried (K2CO3) evaporated

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

Procedure: 2,6-Difluoro-3-nitropyridine (5.00 g) is dissolved in acetonitrile (10 ml) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 6.81 g) dissolved in 10 ml of acetonitrile is added via cannula. Then an additional 58 ml of acetonitrile is added and the reaction is cooled to 0°. Then 5.1 g of potassium carbonate is added and the reaction is stirred 10 min and allowed to warm to 20°-25°. After 6 hrs, the reaction is poured into water, extracted with ethyl acetate, washed with saline and dried over sodium sulfate. Flash column chromatography (silica gel; 5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, NMR (300 MHz, CDCl3) 8.22, 7.37-7.23, 6.25, 3.66, 3.55, 3.50, 3.01, 2.10, 1.95, 1.83 and 1.09δ. is added via cannula the reaction is cooled to 0° to warm to 20°-25° After 6 hrs extracted with ethyl acetate washed with saline dried over sodium sulfate

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

Procedure: 2,6-Difluoro-3-nitropyridine (Recl. Trav. Chim., 95, 127-156 (1976) and Tetrahedron Lett., 28, 111-114 (1987), 2.4 g, 15.0 mmol) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 3.3 g, 15 mmol) are dissolved in 37.5 mmol of acetonitrile at 0°. Then solid potassium carbonate (2.49 g, 18 mmol) is added and the reaction is slowly warmed to 20°-25°. After the reaction is complete by TLC (ethyl acetate/hexane, (25/75)), it is poured into water and extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and concentrated under reduced pressure. Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, mp=99°-100°; NMR (300 MHz, CDCl3) 8.00, 7.13-7.04, 6.02, 3.43, 3.31, 3.28, 2.77, 1.85, 1.71, 1.63 and 0.86δ; CMR (75 MHz, CDCl3) 163.5, 160.2, 151.2, 140.9, 130.4, 128.9, 128.0, 126.9, 96.9, 62.6, 59.6, 52.9, 38.7, 29.3 and 14.0δ. the reaction is slowly warmed to 20°-25° extracted with ethyl acetate The organic phase is washed with saline dried over sodium sulfate concentrated under reduced pressure Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane)

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

Procedure: 2,6-Difluoro-3-nitropyridine (Recl. Trav. Chim., 95, 127-156 (1976) and Tetrahedron Lett., 28, 111-114 (1987), 2.4 g, 15.0 mmol) and 1-benzyl-4-ethylaminopiperidine (EXAMPLE 11, 3.3 g, 15 mmol) are dissolved in 37.5 mmol of acetonitrile at 0°. Then solid potassium carbonate (2.49 g, 18 mmol) is added and the reaction is slowly warmed to 20°-25°. After the reaction is complete by TLC (ethyl acetate/hexane, (25/75)), it is poured into water and extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and concentrated under reduced pressure. Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gives the title compound, mp=99°-100°; NMR (300 MHz, CDCl3) 8.00, 7.13-7.04, 6.02, 3.43, 3.31, 3.28, 2.77, 1.85, 1.71, 1.63 and 0.86δ; CMR (75 MHz, CDCl3) 163.5, 160.2, 151.2, 140.9, 130.4, 128.9, 128.0, 126.9, 96.9, 62.6, 59.6, 52.9, 38.7, 29.3 and 14.0δ. the reaction is slowly warmed to 20°-25° extracted with ethyl acetate The organic phase is washed with saline dried over sodium sulfate concentrated under reduced pressure Purification via flash column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 2-methoxy-4-trifluoroacetylamino-5-chlorobenzoyl chloride (17.4 g; 0.055 moles) dissolved in anhydrous ethyl methyl ketone (75 ml) was added little by little to another solution of 1-benzyl-4-ethylamino-piperidine (10.9 g; 0.05 moles) and triethylamine (7.0 ml; 0.05 moles) in anhydrous ethyl methyl ketone (75 ml) at room temperature. On completion of the addition, the mixture was left at room temperature and stirred for 48 hours, and then the mixture was concentrated at reduced pressure, poured into water, and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo. The residue was recrystallized from a mixture of methanol and diethyl ether to give N-ethyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-trifluoroacetylamino-5-chlorobenzamide (17 g), m.p. 198°-200° C. On completion of the addition the mixture was left at room temperature the mixture was concentrated at reduced pressure poured into water extracted with chloroform The organic solution was dried (Na2SO4) the solvent removed in vacuo The residue was recrystallized from a mixture of methanol and diethyl ether

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

Procedure: To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mmol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the title compound as a solid (38 g); 1H NMR (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219. the resulting mixture stirred at room temperature for 1 h the resulting mixture extracted with diethyl ether The organic extracts were dried (K2CO3) evaporated