4-[2-(Trifluoromethyl)phenoxy]piperidine hydrochloride

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

実験手順: Into a 100-mL flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (3.80 g, 19.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (6.90 g, 24.5 mmol) and 2-propanol (25 mL). The suspension was treated with N,N-diisopropylethylamine (8.6 mL, 49 mmol) and stirred at room temperature for 10 min and then heated to 100° C. for 16 h. After this time, the mixture was cooled to room temperature, poured into a 250-mL separatory funnel containing saturated aqueous NH4Cl (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude solid was triturated in diethyl ether to yield the title compound as an off-white solid. MS (ESI, Q+) m/z 403, 405 (M+1 for 35Br and 37Br). Into a 100-mL flask equipped with a magnetic stirbar heated to 100° C. for 16 h After this time, the mixture was cooled to room temperature poured into a 250-mL separatory funnel the mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over MgSO4 filtered the solvent was evaporated under reduced pressure The crude solid was triturated in diethyl ether

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

実験手順: A solution of 4-(2-trifluoromethylphenoxy)piperidine hydrochloride (42 mg, 0.15 mmol), 3-chlorophenyl isocyanate (36 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) was stirred in dichloromethane (2 mL) at room temperature for overnight. The reaction mixture was diluted with dichloromethane and the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which was 98% pure by LCMS analysis (15.7 mg, 26%). the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine The organic fraction was dried over MgSO4 filtered concentrated The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (5.5 g, 2.2 mmol) in DMF (50 mL) was added 5-bromo-1,3,4-thiadiazol-2-amine (3.3 g, 2.2 mmol) and K2CO3 (9.1 g, 6.6 mmol). The reaction was heated at 80° C. with stirring overnight. After cooling, the salt was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with EtOAc to afford the title compound. After cooling the salt was removed by filtration the filtrate was evaporated in vacuo The residue was triturated with EtOAc

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

実験手順: Into a 100-mL flask equipped with a magnetic stirbar was added 5-bromo-2-chloropyrimidine (3.80 g, 19.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (6.90 g, 24.5 mmol) and 2-propanol (25 mL). The suspension was treated with N,N-diisopropylethylamine (8.6 mL, 49 mmol) and stirred at room temperature for 10 min and then heated to 100° C. for 16 h. After this time, the mixture was cooled to room temperature, poured into a 250-mL separatory funnel containing saturated aqueous NH4Cl (125 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude solid was triturated in diethyl ether to yield the title compound as an off-white solid. MS (ESI, Q+) m/z 403, 405 (M+1 for 35Br and 37Br). Into a 100-mL flask equipped with a magnetic stirbar heated to 100° C. for 16 h After this time, the mixture was cooled to room temperature poured into a 250-mL separatory funnel the mixture was extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over MgSO4 filtered the solvent was evaporated under reduced pressure The crude solid was triturated in diethyl ether

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

実験手順: A solution of 4-(2-trifluoromethylphenoxy)piperidine hydrochloride (42 mg, 0.15 mmol), 3-chlorophenyl isocyanate (36 mg, 0.30 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) was stirred in dichloromethane (2 mL) at room temperature for overnight. The reaction mixture was diluted with dichloromethane and the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which was 98% pure by LCMS analysis (15.7 mg, 26%). the solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine The organic fraction was dried over MgSO4 filtered concentrated The compound was purified by radial silica gel chromatography (1:20 to 1:2 ethyl acetate:hexanes) to afford the product which

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

実験手順: The intermediate 1f is synthesised according to the procedure described for the synthesis of 1a from 2-chloro-5-(trifluoromethyl)phenol and trans-(2-hydroxymethyl-cyclopropyl)-carbamic acid tert-butyl ester and, the amine function deprotection step is carried out in an HCl solution (4N in dioxane). 1f is isolated in solid form with a 95% yield. The intermediate 1f is synthesised

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

実験手順: Compound 70 is prepared from intermediate 4c and from 4-(2,4,5-trichloro-phénoxy)-piperidine (obtained following the method described for intermediate 1a) applying synthesis method 7 (yield: 46%). obtained synthesis method 7 (yield: 46%)

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

実験手順: Compound 68 is prepared from intermediate 4c and from 4-(5-fluoro-2-methyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 46%). obtained synthesis method 7 (yield: 46%)

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

実験手順: Compound 67 is prepared from intermediate 4c and from 4-(3-fluoro-5-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 42%). obtained synthesis method 7 (yield: 42%)

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

実験手順: Compound 60 is prepared from intermediate 4c and from 4-(4-fluoro-3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 51%). obtained synthesis method 7 (yield: 51%)

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

実験手順: Compound 59 is prepared from intermediate 4c and from 4-o-tolyloxy-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 50%). obtained synthesis method 7 (yield: 50%)

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

実験手順: Compound 58 is prepared from intermediate 4c and from 4-(3-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 36%). obtained synthesis method 7 (yield: 36%)