ethyl 1-benzylpiperidine-4-carboxylate

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

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

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

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: Ethylamine hydrochloride (6.59 g, 80.8 mmol) is dissolved in 40 ml dry toluene and cooled to 0°. Trimethylaluminum (2M in toluene, 40.4 ml, 80.8 mmol) is slowly added and after 30 min at 0° the mixture is warmed to 20°-25°. After one hr gas evolution has ceased. Then ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol) is added in 20 ml of toluene and the mixture is heated to 85° for 2 hr. The reaction is quenched cautiously with 5% hydrochloric acid, then adjusted to pH 8 with sodium hydroxide and extracted with chloroform. The extract is dried over sodium sulfate, filtered and evaporated to give the title compound; NMR (300 MHz, CDCl3) 7.32, 3.58, 3.27, 3.00, 2.0-2.2, 1.7-2.0 and 1.11δ. cooled to 0° is warmed to 20°-25° the mixture is heated to 85° for 2 hr The reaction is quenched cautiously with 5% hydrochloric acid extracted with chloroform The extract is dried over sodium sulfate filtered evaporated

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 7.8 parts of sodium amide 5% in benzene and 135 parts of methylbenzene was added dropwise a solution of 11.7 parts of benzeneacetonitrile in 45 parts of methylbenzene at 25° C. (cooling was necessary). After stirring for 30 minutes at 30° C., there was added dropwise a solution of 24.7 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 45 parts of methylbenzene at 30° C. Upon completion, stirring was continued overnight at 80° C. The reaction mixture was cooled, 12 parts of ethanol were added and the whole was poured into ice water. The layers were separated and the aqueous phase was neutralized with acetic acid. The oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 12 parts (38%) of α-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrile; mp. 191.9° C. (intermediate 5). (cooling was necessary) Upon completion, stirring was continued overnight at 80° C The reaction mixture was cooled The layers were separated The oily product was extracted with trichloromethane The extract was dried filtered evaporated The residue was crystallized from 4-methyl-2-pentanone

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluoro-benzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil. to reach room temperature stirred over night The reaction was quenched with ammonium chloride (aq, sat) partitioned between water and ethyl acetate The organic layer was washed with brine dried over magnesium sulphate filtrated concentrated The crude material was purified on silica (heptane/ethyl acetate)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluoro-benzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil. to reach room temperature stirred over night The reaction was quenched with ammonium chloride (aq, sat) partitioned between water and ethyl acetate The organic layer was washed with brine dried over magnesium sulphate filtrated concentrated The crude material was purified on silica (heptane/ethyl acetate)

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

Procedure: To a solution of diisopropylamine (5.68 mL, 0.040 mol) in 100 ml THF at −78° C. was added nBuli (1.6M solution in hexane, 25.9 mL, 0.041 mol) drop-wise. The reaction mixture was warmed to −5° C. and stirring was continued for 30 mins. A solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 mL) was added drop wise and stirring was continued for a further 3 hr followed by the addition of a solution of 1-bromo-2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 mL) at −5° C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted 1NHCl. The aqueous layers were then combined, made basic (with 1N NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+). stirring was continued for a further 3 hr to warm to room temperature stirring was continued overnight The reaction mixture was quenched with water concentrated in vacuo to give a brown residue which extracted 1NHCl extracted with ethyl acetate washed with brine dried (Na2SO4) filtered concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane)

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

Procedure: To a solution of diisopropylamine (5.68 mL, 0.040 mol) in 100 ml THF at −78° C. was added nBuli (1.6M solution in hexane, 25.9 mL, 0.041 mol) drop-wise. The reaction mixture was warmed to −5° C. and stirring was continued for 30 mins. A solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (5.00 g, 0.020 mol) in THF (20 mL) was added drop wise and stirring was continued for a further 3 hr followed by the addition of a solution of 1-bromo-2-methoxy-ethane (3.82 g, 0.040 mol) in THF (20 mL) at −5° C. The reaction mixture was then allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched with water and concentrated in vacuo to give a brown residue which was diluted with ethyl acetate and extracted 1NHCl. The aqueous layers were then combined, made basic (with 1N NaOH) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane) to give 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 84%) as a brown oil. MS (ESI): 306.3 (MH+). stirring was continued for a further 3 hr to warm to room temperature stirring was continued overnight The reaction mixture was quenched with water concentrated in vacuo to give a brown residue which extracted 1NHCl extracted with ethyl acetate washed with brine dried (Na2SO4) filtered concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 AcOEt/heptane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about −78° C. followed by the addition of n-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0° C. and stirred for about 30 min and then cooled to about −40° C. To the mixture was added a solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between −40 to −30° C. The mixture was stirred for about 1 h at about −10° C. before being cooled to about −78° C. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about −65 and −78° C. The mixture was then stirred for about 1 h at about −78° C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl 1-benzyl-4-fluoropiperidine-4-carboxylate (7.13 g, 66%): LC/MS (Table 2, Method h) Rt=2.21 min; MS m/z: 266 (M+H)+. The mixture was warmed to about 0° C. cooled to about −40° C is kept between −40 to −30° C The mixture was stirred for about 1 h at about −10° C. before being cooled to about −78° C the mixture between about −65 and −78° C The mixture was then stirred for about 1 h at about −78° C The mixture was poured into a separatory funnel was added The aqueous layer was extracted with EtOAc (3×25 mL) the combined organic extracts were washed with brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1)