1,2,4-trifluoro-5-methylsulfonylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (0.040 g, 0.13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 0.053 g, 0.25 mmol) and Na2CO3 (0.040 g, 0.38 mmol) were dissolved in DMF (1 mL) and heated at 130° C. overnight. The reaction was concentrated and the residue was purified using preparative TLC (100% EtOAc) to afford (S)-3-((2,5-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (0.018 g, 0.035 mmol, 28% yield) as yellow solid. Mass spectrum (apci) m/z=508.3 (M+H). The reaction was concentrated the residue was purified

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid. The reaction was concentrated purified over silica gel (25-75% EtOAc in hexanes)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid. The reaction was concentrated purified over silica gel (25-75% EtOAc in hexanes)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.5, 7.9 mmol) (Preparation E, Step D), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (3.3 g, 16 mmol), and Na2CO3 (2.5 g, 24 mmol) in DMSO (20 mL) was degassed using nitrogen and was stirred at 130° C. for 18 hours in a sealed tube. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.6 g, 5.1 mmol, 65%). extracted with EtOAc (3×100 mL) The combined organic layers were washed with brine dried over MgSO4 filtered then concentrated in vacuo The material was purified over silica gel (100% EtOAc)

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

実験手順: To a solution of 2,4,5-trifluorobenzenesulfinic acid (34 g, 173 mmol), in DMF (200 mL), was added iodomethane (21.6 mL, 347 mmol), and N-ethyl-N-isopropylpropan-2-amine (60.5 mL, 347 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was concentrated and partitioned between water and ethyl acetate and extracted with CH2Cl2. The combined organic layers were concentrated and purified over silica gel (15-100% EtOAc in hexanes) to afford 1,2,4-trifluoro-5-(methylsulfonyl)benzene (25.8 g, 123 mmol, 71% yield) as yellow solid. The reaction was concentrated partitioned between water and ethyl acetate extracted with CH2Cl2 The combined organic layers were concentrated purified over silica gel (15-100% EtOAc in hexanes)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (0.040 g, 0.13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 0.053 g, 0.25 mmol) and Na2CO3 (0.040 g, 0.38 mmol) were dissolved in DMF (1 mL) and heated at 130° C. overnight. The reaction was concentrated and the residue was purified using preparative TLC (100% EtOAc) to afford (S)-3-((2,5-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (0.018 g, 0.035 mmol, 28% yield) as yellow solid. Mass spectrum (apci) m/z=508.3 (M+H). The reaction was concentrated the residue was purified

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (0.040 g, 0.13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 0.053 g, 0.25 mmol) and Na2CO3 (0.040 g, 0.38 mmol) were dissolved in DMF (1 mL) and heated at 130° C. overnight. The reaction was concentrated and the residue was purified using preparative TLC (100% EtOAc) to afford (S)-3-((2,5-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (0.018 g, 0.035 mmol, 28% yield) as yellow solid. Mass spectrum (apci) m/z=508.3 (M+H). The reaction was concentrated the residue was purified

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid. The reaction was concentrated purified over silica gel (25-75% EtOAc in hexanes)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.0 g, 13 mmol), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (Preparation C, 4.2 g, 20 mmol) and Na2CO3 (2.9 g, 27 mmol) were dissolved in DMF (30 mL) and heated at 130° C. overnight. The reaction was concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol, 70% yield) as yellow solid. The reaction was concentrated purified over silica gel (25-75% EtOAc in hexanes)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.5, 7.9 mmol) (Preparation E, Step D), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (3.3 g, 16 mmol), and Na2CO3 (2.5 g, 24 mmol) in DMSO (20 mL) was degassed using nitrogen and was stirred at 130° C. for 18 hours in a sealed tube. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.6 g, 5.1 mmol, 65%). extracted with EtOAc (3×100 mL) The combined organic layers were washed with brine dried over MgSO4 filtered then concentrated in vacuo The material was purified over silica gel (100% EtOAc)

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

実験手順: To a solution of 2,4,5-trifluorobenzenesulfinic acid (34 g, 173 mmol), in DMF (200 mL), was added iodomethane (21.6 mL, 347 mmol), and N-ethyl-N-isopropylpropan-2-amine (60.5 mL, 347 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was concentrated and partitioned between water and ethyl acetate and extracted with CH2Cl2. The combined organic layers were concentrated and purified over silica gel (15-100% EtOAc in hexanes) to afford 1,2,4-trifluoro-5-(methylsulfonyl)benzene (25.8 g, 123 mmol, 71% yield) as yellow solid. The reaction was concentrated partitioned between water and ethyl acetate extracted with CH2Cl2 The combined organic layers were concentrated purified over silica gel (15-100% EtOAc in hexanes)