2-piperidin-4-ylphenol

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: 4-(2-Hydroxyphenyl piperidine. 1-Benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine was subjected to a procedure similar to that described in Example 10 sub-part c. to give 4-(2-hydroxyphenyl)piperidine as a brown solid (0.36 g); NMR (CDCl3): 1.7-1.9 (m,4), 2.77-2.86 (m,2), 2.99-3.04 (m,1), 3.23 (d,2, J=12), 4.17 (s,2), 6.72 (d,1, J=8), 6.84 (t,1, J=7), 7.05 (m,1); MS: m/z=178(M+1). This material was used in the next step without further purification.

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 4-(2-methoxyphenyl)piperidine (Fluka, 5 g, 26.1 mmol) in 48% hydrobromic acid (45 mL) was heated to 100° C. for 3 days. The mixture was then allowed to cool down to rt and it was concentrated under reduced pressure to give 2-(piperidin-4-yl)phenol as a light pink solid which was used directly in the next step. M+H=178.1. it was concentrated under reduced pressure

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

Procedure: A solution of the hydrobromide salt of 2-piperidin-4-yl-phenol Compound 3a (5.00 g, 19.37 mmol) in water (400 mL) was made basic to pH 8 by the addition of NaHCO3. A solution of O(Boc)2 (4.22 g, 19.36 mmol) in THF (80 mL) was added and the mixture was stirred at r.t. over night. CH2Cl2 (500 mL) was added and the organic layer was isolated and dried. The crude product was purified by chromatography to provide 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester Compound 2a (4.56 g, 85%) as a white powder 1H NMR δ 1.50 (s, 9H), 1.60 (m, 2H), 1.85 (bd, J=19.5 Hz, 2H), 2.82 (bm, 2H), 3.04 (m, 1H), 4.23 (bs, 2H), 6.7˜7.2 (m, 4H). the organic layer was isolated dried The crude product was purified by chromatography

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

Procedure: A solution of 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine (1.22 g) in 20 mL of tetrahydrofuran was treated with 10% palladium on carbon catalyst (0.12 g) and hydrogenated at the atmospheric pressure for 16 hours. Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid; MS: 178; NMR: 1.8-1.9 (m, 4), 2.7-2.8 (m, 2), 3.0 (m, 1), 3.2 (d, J=12, 2), 5.4 (br, 2), 6.7 (d, J=8, 1), 6.8 (t, J=7, 1), 7.0-7.1 (m, 1), 7.1 (d, J=7, 2). Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid

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

Procedure: A solution of 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine (1.22 g) in 20 mL of tetrahydrofuran was treated with 10% palladium on carbon catalyst (0.12 g) and hydrogenated at the atmospheric pressure for 16 hours. Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid; MS: 178; NMR: 1.8-1.9 (m, 4), 2.7-2.8 (m, 2), 3.0 (m, 1), 3.2 (d, J=12, 2), 5.4 (br, 2), 6.7 (d, J=8, 1), 6.8 (t, J=7, 1), 7.0-7.1 (m, 1), 7.1 (d, J=7, 2). Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid

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

Procedure: A solution of 1-benzyloxycarbonyl-4-(2-benzyloxyphenyl)piperidine (1.22 g) in 20 mL of tetrahydrofuran was treated with 10% palladium on carbon catalyst (0.12 g) and hydrogenated at the atmospheric pressure for 16 hours. Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid; MS: 178; NMR: 1.8-1.9 (m, 4), 2.7-2.8 (m, 2), 3.0 (m, 1), 3.2 (d, J=12, 2), 5.4 (br, 2), 6.7 (d, J=8, 1), 6.8 (t, J=7, 1), 7.0-7.1 (m, 1), 7.1 (d, J=7, 2). Upon filtration and evaporation of the filtrate the named product was obtained (0.36 g) as a solid

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

Procedure: Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(2-hydroxyphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography, eluting with dichloromethane:methanol, followed by conversion to the hydrochloride salt gave a white solid; mp 205°-210° C.; MS: 511; NMR (CD3OD): 1.7-2.3 (m, 6), 2.7 (s, 1), 2.8-3.1 (m, 6), 3.2-3.8 (m, 5), 6.7-6.8 (m, 2), 7.0 (t, J=7, 3), 7.2 (br, 2), 7.4 (br, 2), 7.4 (br, 4), 7.5-7.7 (m, 2), 9.5 (s, 10), 10.5 (s, 1). Analysis for C29H32Cl2N2O2 ·1.0 HCl·0.75 H2O: Calculated: C, 62.04; H, 6.19; N, 4.99; Found: C, 62.24; H, 6.15; N, 5.08. that described in Example 1 (alternative preparation) Chromatography, eluting with dichloromethane gave a white solid

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

Procedure: A solution of 4-(2-methoxyphenyl)piperidine (Fluka, 5 g, 26.1 mmol) in 48% hydrobromic acid (45 mL) was heated to 100° C. for 3 days. The mixture was then allowed to cool down to rt and it was concentrated under reduced pressure to give 2-(piperidin-4-yl)phenol as a light pink solid which was used directly in the next step. M+H=178.1. it was concentrated under reduced pressure