2-broMo-5-iodobenzoic acid Methyl ester

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid methyl ester (4.33 g, 12.7 mmol) and tributyl(ethoxyvinyl)stannane (4.79 g, 13.3 mmol) in dioxane (56 ml) was added PdCl2(PPh3)2 (322 mg). The mixture was heated at 80° C. for 17 hours and was cooled to 0° C. Water (19 ml) was added, followed by slow addition of NBS (2.33 g, 12.9 mmol) over 10 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc=2/1) gave 2-bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester (3.48 g). was cooled to 0° C the solvent was removed under reduced pressure The mixture was diluted with EtOAc was washed with water and brine dried with sodium sulfate Concentration and purification by flash column chromatography (hexane/EtOAc=2/1)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g). The solvent and reagent were removed under reduced pressure the mixture was diluted with EtOAc The organic solution was washed with saturated sodium bicarbonate, water, and brine was dried with sodium sulfate Concentration

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

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid methyl ester (4.33 g, 12.7 mmol) and tributyl(ethoxyvinyl)stannane (4.79 g, 13.3 mmol) in dioxane (56 ml) was added PdCl2(PPh3)2 (322 mg). The mixture was heated at 80° C. for 17 hours and was cooled to 0° C. Water (19 ml) was added, followed by slow addition of NBS (2.33 g, 12.9 mmol) over 10 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc=2/1) gave 2-bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester (3.48 g). was cooled to 0° C the solvent was removed under reduced pressure The mixture was diluted with EtOAc was washed with water and brine dried with sodium sulfate Concentration and purification by flash column chromatography (hexane/EtOAc=2/1)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g). The solvent and reagent were removed under reduced pressure the mixture was diluted with EtOAc The organic solution was washed with saturated sodium bicarbonate, water, and brine was dried with sodium sulfate Concentration

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g). The solvent and reagent were removed under reduced pressure the mixture was diluted with EtOAc The organic solution was washed with saturated sodium bicarbonate, water, and brine was dried with sodium sulfate Concentration

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid methyl ester (4.33 g, 12.7 mmol) and tributyl(ethoxyvinyl)stannane (4.79 g, 13.3 mmol) in dioxane (56 ml) was added PdCl2(PPh3)2 (322 mg). The mixture was heated at 80° C. for 17 hours and was cooled to 0° C. Water (19 ml) was added, followed by slow addition of NBS (2.33 g, 12.9 mmol) over 10 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc=2/1) gave 2-bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester (3.48 g). was cooled to 0° C the solvent was removed under reduced pressure The mixture was diluted with EtOAc was washed with water and brine dried with sodium sulfate Concentration and purification by flash column chromatography (hexane/EtOAc=2/1)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture was heated at 55° C. for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2-bromo-5-iodo-benzoic acid methyl ester (10.5 g). The solvent and reagent were removed under reduced pressure the mixture was diluted with EtOAc The organic solution was washed with saturated sodium bicarbonate, water, and brine was dried with sodium sulfate Concentration

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

実験手順: A solution of methyl 2-bromo-5-iodobenzoate (2-2, 2.0 g, 5.87 mmol, 1.0 equiv), 5-methylpyridine-3-boronic acid (0.803 g, 5.87 mmol, 1.0 equiv), Cs2CO3 (6.69 g, 20.53 mmol, 3.5 equiv) and PdCl2(dppf) (0.429 g, 0.587 mmol, 0.1 equiv) was made in DMF (30 mL) and stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase column chromatography (25 to 75% EtOAc in hexanes) to afford the product (2-3) as a solid. ESI+ MS [M+H]+ C14H12BrNO2: 307.8 found, 307.1 required. The reaction mixture was partitioned between EtOAc and water The layers were separated the aqueous layer extracted with ethyl acetate The combined organics were washed with saturated sodium bicarbonate solution and brine dried over anhydrous sodium sulfate filtered concentrated The residue was purified by normal phase column chromatography (25 to 75% EtOAc in hexanes)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-5-iodobenzoic acid (2-1), 5.0 g, 15.3 mmol, 1.0 equiv) in methanol (45 mL) was added sulfuric acid (1.06 mL, 19.9 mmol, 1.3 equiv). The reaction mixture was stirred for 60 hours at 60° C., then heated to reflux and stirred 24 hours more. The reaction mixture was cooled, partitioned between EtOAc and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the product (2-2) as a white solid. ESI+ MS [M]+ C8H6BrIO2: 340.7 found, 340.9 required. heated to reflux stirred 24 hours more The reaction mixture was cooled partitioned between EtOAc and saturated sodium bicarbonate solution The layers were separated the aqueous layer extracted with ethyl acetate The combined organics were dried over anhydrous sodium sulfate filtered concentrated

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 in analogy to Example 92 starting from ethyleneurea (commercially available), bromo-5-iodo-benzoic acid methyl ester prepared as in Example 92, (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C26H20ClN3O4: 473, observed (M+H)+: 474.21H NMR (400 MHz, DMSO-d6) δppm 2.14 (dd, J=9.22, 4.93 Hz, 1 H) 2.41 (dd, J=7.96, 4.67 Hz, 1 H) 3.22-3.28 (m, 1 H) 3.43-3.49 (m, 1 H) 3.92-3.98 (m, 1 H) 6.19 (d, J=7.58 Hz, 1 H) 6.80 (t, J=7.71 Hz, 1 H) 6.85 (d, J=7.83 Hz, 1 H) 7.12 (t, J=8.34 Hz, 1 H) 7.22 (s, 1 H) 7.42 (q, J=8.59 Hz, 3 H) 7.64 (s, 1 H) 7.99 (t, J=2.02 Hz, 1 H) 8.13 (s, 1 H).