4-[(4-fluorophenyl)methyl]piperidine;hydrochloride

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

実験手順: A solution of 4N hydrogen chloride in ethyl acetate (100 ml) was added to 1-tert-butoxycarbonyl-4-(4-fluorobenzyl)piperidine (39.9 g) and the solution was stirred for an hour at room temperature. The reaction mixture was concentrated under reduced pressure, then diethyl ether was added thereto. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (30.1 g). The reaction mixture was concentrated under reduced pressure diethyl ether was added The resulting precipitate was collected by filtration washed with diethyl ether dried under reduced pressure

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

実験手順: A solution of 4N hydrogen chloride in ethyl acetate (100 ml) was added to 1-tert-butoxycarbonyl-4-(4-fluorobenzyl)piperidine (39.9 g) and the solution was stirred for an hour at room temperature. The reaction mixture was concentrated under reduced pressure, then diethyl ether was added thereto. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (30.1 g). The reaction mixture was concentrated under reduced pressure diethyl ether was added The resulting precipitate was collected by filtration washed with diethyl ether dried under reduced pressure

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

実験手順: N-(t-butoxycarbonyl)-4-(4-fluorophenylmethyl)piperidine (11.2 g, 38.2 mmol) was dissolved in 4M HCl in dioxane (50 mL). The reaction was stirred for 15 min and then conc. in vacuo to a white solid. The solid was dissolved in 3% MeOH/CH2Cl2 in EtOAc/MeOH while warming once all solids were dissolved hexanes was added. The crystallization was allowed to cool to room temperature and then placed at 4° C. for 16 h. The white solids were filtered off to yield 8.4 g of product. MS (ESI) 194 (M−HCl+H). while warming once all solids was added The crystallization placed at 4° C. for 16 h The white solids were filtered off

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

実験手順: 78 ml of ethanol are placed in a 250 ml conical flask and 2 ml of a 5.3N methanolic solution of sodium methoxide are added. 2.29 g (0.01 mol) of 4-(4-fluorobenzyl)-piperidine hydrochloride are added and the mixture is stirred for 15 minutes. 1.38 g of potassium carbonate are then added, followed by 2.33 g (0.01 mol) of 2-bromo-4'-chloroacetophenone, and the mixture is heated under reflux for 2 hours. It is left to cool, the inorganic precipitate is filtered off, the filtrate is evaporated to dryness and the residual oil is taken up in 1N hydrochloric acid. Extraction is carried out with chloroform and the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness. 3.22 g of the crude hydrochloride remain in the form of an oil, which is used as such but which can be recrystallized from a mixture of acetone/diethyl ether (melting point=168° C.). the mixture is heated under reflux for 2 hours It is left to cool the inorganic precipitate is filtered off the filtrate is evaporated to dryness Extraction the organic phase is washed with water dried over sodium sulphate evaporated to dryness can be recrystallized from a mixture of acetone/diethyl ether (melting point=168° C.)

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

実験手順: 78 ml of ethanol are placed in a 250 ml conical flask and 2 ml of a 5.3N methanolic solution of sodium methoxide are added. 2.29 g (0.01 mol) of 4-(4-fluorobenzyl)-piperidine hydrochloride are added and the mixture is stirred for 15 minutes. 1.38 g of potassium carbonate are then added, followed by 2.33 g (0.01 mol) of 2-bromo-4'-chloroacetophenone, and the mixture is heated under reflux for 2 hours. It is left to cool, the inorganic precipitate is filtered off, the filtrate is evaporated to dryness and the residual oil is taken up in 1N hydrochloric acid. Extraction is carried out with chloroform and the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness. 3.22 g of the crude hydrochloride remain in the form of an oil, which is used as such but which can be recrystallized from a mixture of acetone/diethyl ether (melting point=168° C.). the mixture is heated under reflux for 2 hours It is left to cool the inorganic precipitate is filtered off the filtrate is evaporated to dryness Extraction the organic phase is washed with water dried over sodium sulphate evaporated to dryness can be recrystallized from a mixture of acetone/diethyl ether (melting point=168° C.)

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

実験手順: The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide (Example 180a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 169-171° C. (hexane)

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

実験手順: The title compound is prepared from 2-chloro-N-(4-nitro-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 120-123° C. (diethylether)

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

実験手順: The title compound is prepared from 2-chloro-N-(3-cyano-phenyl)-acetamide (Example 166a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 101-103° C. (diisopropylether)

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

実験手順: The title compound is prepared from 2-chloro-N-(4-cyano-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 113-116° C. (diethylether)

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

実験手順: The title compound is prepared from 2-chloro-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide (Example 143a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 178-180° C. (diethylether)

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

実験手順: A mixture of 0.91 g (4 mmol) of 2-chloro-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide, 0.7 g (4 mmol) of potassium iodide, 1.2 ml (8 mmol) of triethylamine, 0.7 g (3 mmol) of 4-(4-fluoro-benzyl)-piperidine hydrochloride and 50 ml of acetonitrile is refluxed for 20 hours. The reaction mixture is concentrated and 30 ml of water and 30 ml of chloroform are added to the residue. The organic layer is separated and the water phase is extracted three times with 10 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform methanol=97:3 as eluent to yield 0.3 g (26%) of the title compound. Melting Point: 232-234° C. (diethylether) is refluxed for 20 hours The reaction mixture is concentrated 30 ml of water and 30 ml of chloroform are added to the residue The organic layer is separated the water phase is extracted three times with 10 ml of chloroform The combined organic layers are dried over sodium sulfate concentrated the residue is purified by column chromatography

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

実験手順: The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (298 mg, 1.30 mmol), 2-(3-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (250 mg): mp 145-147° C. 1H NMR (CD3OD) 1.529 (m, 2 H), 1.821 (d, J=12.9 Hz, 2 H), 2.551 (d, J=6.3 Hz, 2 H), 3.003 (m, 2 H), 3.468 (m, 2 H), 3.541 (m, 2 H), 4.243 (t, J=5.4 Hz, 2 H), 6.369-6.422 (m, 3 H), 6.924-7.034 (m, 3 H), 7.120-7.167 (m, 2 H).