ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (1) (1.0 equiv.) in acetonitrile (0.3M) and EtOH (0.5M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (3) as a white solid. The reaction was degassed flushed with N2 The reaction was flushed again with N2 After cooling to room temperature hexane was added the mixture was filtered through a pad of silica eluting with EA/Hex (1:1) until the product was completely eluted The filtrate was concentrated purified on Combiflash eluting with 0-15% EA in Hex

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

実験手順: To a solution of 2,6-dichloro-3-iodopyridine (3.0 g, 10.95 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2.476 g, 10.95 mmol), and Dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II) (0.357 g, 0.548 mmol) in THF (81 mL) was added 1M (aq) K2CO3 (54.8 mL, 54.8 mmol). A steady stream of N2 was bubbled through the resultant mixture for 5 minutes. Stirring was continued at ambient temperature for 2 h then the mixture was diluted with EtOAc and the organic layer washed successively with water (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-30% EtOAc/Hexanes as eluent to give the title compound as a tan solid. 1H NMR δ (ppm) (CHCl3-d): 7.95 (1H, d, J=16 Hz), 7.90 (1H, d, J=8.1 Hz), 7.35 (1H, d, J=8.1 Hz), 6.47 (1H, d, J=16 Hz), 4.32 (2H, q, J=7.15 Hz), 1.38 (3H, t, J=7.14 Hz). MS (M+H)+: 245. A steady stream of N2 was bubbled through the resultant mixture for 5 minutes the mixture was diluted with EtOAc the organic layer washed successively with water (1×) and brine (1×) The organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1 g of tert-butyl (2-bromobenzyl)carbamate, 1.12 g of ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate, 16 mg of palladium acetate, 72 mg of dicyclohexyl(2′,6′-dimethoxybiophenyl-2-yl)phosphine, 1.5 g of potassium phosphate, and 20 mL of toluene was stirred at 100° C. for 5 days. To the reaction mixture was added ether, followed by filtration through silica gel. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 412 mg of ethyl (2E)-3-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acrylate. followed by filtration through silica gel The filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1 g of tert-butyl (2-bromobenzyl)carbamate, 1.12 g of ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate, 16 mg of palladium acetate, 72 mg of dicyclohexyl(2′,6′-dimethoxybiophenyl-2-yl)phosphine, 1.5 g of potassium phosphate, and 20 mL of toluene was stirred at 100° C. for 5 days. To the reaction mixture was added ether, followed by filtration through silica gel. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 412 mg of ethyl (2E)-3-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acrylate. followed by filtration through silica gel The filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Then the reaction mixture was filtered through kieselguhr washed with hydrochloric acid (1 M) dried over magnesium sulphate filtered concentrated under reduced pressure Then the reaction mixture was added to ice-cold dilute hydrochloric acid extracted with ethyl acetate The organic phase was dried over sodium sulphate filtered concentrated to dryness under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid. The reaction was degassed flushed with N2 The reaction was flushed again with N2 After cooling to room temperature hexane was added the mixture was filtered through a pad of silica eluting with EA/Hex (1:1) until the product was completely eluted The filtrate was concentrated purified on Combiflash eluting with 0-15% EA in Hex

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.026 g, 0.056 mmol, Preparation #MM.1) and PdCl2(dppf)•DCM adduct (0.005 g, 0.006 mmol) in THF (1 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.052 g, 0.23 mmol) and Na2CO3 (0.021 g, 0.20 mmol) followed by water (0.25 mL). The reaction mixture was heated to about 65° C. After about 15 h, the reaction mixture was cooled to ambient temperature and directly purified by chromatography on silica gel (12 g) eluting with 20-80% EtOAc:DCM (1:1) in heptane to provide (E)-ethyl 3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate (0.045 g, 70%) as a yellow solid: LC/MS (Table 1, Method a) Rt=3.15 min; MS m/z: 493 (M+H)+. the reaction mixture was cooled to ambient temperature directly purified by chromatography on silica gel (12 g) eluting with 20-80% EtOAc:DCM (1:1) in heptane