2-piperidin-1-ylphenol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-(piperidin-1-yl)phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2-piperidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (3.3 g, 97%) as a white solid; ESI-MS 412 [M+H+]; HPLC conditions (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity>98%. 1H-NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.08 (m, 4H), 5.99 (s, 1H), 5.52 (m, 1H), 2.93 (m, 4H), 2.35 (m, 1H), 2.12 (m, 1H), 1.60 (m, 13H), 1.16 (m, 2H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (55 wt. %, 1.04 g) was added to a solution of 2-piperidinophenol (3.4 g) in N,N-dimethylformamide (35 ml) in an ice bath under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 15 minutes. To the reaction mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.25 g) in small portions. This mixture was stirred at 60° C. for 2 hours. At the end of this time the solvent was evaporated and water added to the residue. The mixture was neutralized with concentrated hydrogen chloride and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using c-hexane/isopropyl ether=5/1 as the eluant to afford t-butyl N-[2-nitro-5-(2-piperidinophenoxy)phenyl]-N-methylcarbamate, of which Rf value was 0.27 in thin layer chromatography on a silica gel plate using c-hexane/isopropyl ether=5/1 as the eluant. A mixture of a solution of this product in toluene/methanol=7/3 (100 ml) and palladium on carbon (10%, 0.63 g) was vigorously stirred at room temperature under a hydrogen atmosphere for 14.5 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was washed with cooled methanol and n-hexane to give the title compound (4.2 g). This mixture was stirred at 60° C. for 2 hours At the end of this time the solvent was evaporated water added to the residue extracted with ethyl acetate The ethyl acetate layer was dried over sodium sulfate concentrated under reduced pressure The residue was purified by chromatography on a silica gel column

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 2-bromo-N-(3-(aminosulfonyl)phenyl)benzamide (0.10 g, 0.28 mmol), 2-(piperidin-1-yl)phenol (74 mg, 0.28 mmol), K3PO4 (0.12 g, 0.56 mmol), and CuI (53 mg, 0.28 mmol) in DMF (1 mL) and water (20 μL) was sealed in a glass tube and heated in a microwave oven at 150° C. for 15 min. The reaction was filtered and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-(piperidin-1-yl)phenoxy)-N-(3-(aminosulfonyl)phenyl)benzamide. LC/MS: m/z 452.0 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). was sealed in a glass tube The reaction was filtered purified by preparative reverse phase

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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.