2-chloro-4-iodoaniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (1 molar equivalent) in anhydrous tetrahydrofuran under a nitrogen atmosphere is added a commercially available lithium diisopropylamide solution (Aldrich, 2.0 M in tetrahydrofuran/heptane/ethylbenzene, 1 molar equivalent). After stirring for 5 minutes, a solution comprised of 4-dimethylsulfamoyl-2-fluoro-benzoic acid (1 molar equivalent) in tetrahydrofuran is added. The cold bath is removed and the reaction mixture is stirred for 2 hours. The reaction mixture is then partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford a product which may be purified by chromatography of recrystallization from an appropriate solvent like chloroform or heptane-ethanol. To a stirring cold (−78° C.) solution is added The cold bath is removed the reaction mixture is stirred for 2 hours The reaction mixture is then partitioned between diethyl ether and dilute aqueous hydrochloric acid The organic phase is washed with brine dried over magnesium sulfate concentrated in vacuo to afford a product which may be purified by chromatography of recrystallization from an appropriate solvent like chloroform or heptane-ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (0.143 g, 5.64×10−4 mol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere was added a commercially available lithium diisopropylamide solution (Aldrich, 2.0 M in tetrahydrofuran/heptane/ethylbenzene, 0.300 ml, 6.0×10−4 mol). After stirring for 5 minutes, a solution comprised of 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid methyl ester (0.15 g, 5.0×10−4 mol) in tetrahydrofuran (10 ml) was added via syringe. The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then partitioned between diethyl ether (125 ml) and saturated aqueous sodium bicarbonate (125 ml). The aqueous bicarbonate phase was extracted with an additional portion (125 ml) of diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was crystallized from heptane-ethyl acetate to afford 0.060 g of an off-white powder; 23% yield; mp 154-156° C.; 1H-NMR (400 MHz; CDCl3) δ9.74 (s, 1H), 8.30 (d, 1H, J=7.1 Hz), 7.72 (s, 1H), 7.49 (d, 1H, J=8.3 Hz), 6.73-6.69 (m, 1H), 3.92 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ−123.90 (d), −139.55 (d). To a stirring cold (−78° C.) solution was added via syringe The cold bath was removed the reaction mixture was stirred for 2 hours The reaction mixture was then partitioned between diethyl ether (125 ml) and saturated aqueous sodium bicarbonate (125 ml) The aqueous bicarbonate phase was extracted with an additional portion (125 ml) of diethyl ether The combined organic phases were dried over anhydrous magnesium sulfate concentrated in vacuo to give a yellow oil The oil was crystallized from heptane-ethyl acetate

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-iodoaniline (5 g) was dissolved in DCM (100 ml) and cooled to 0-5° C. in an ice bath. Pyridine (2.1 ml) was added followed by dropwise addition of 2-acetoxy-2-methylpropanoyl chloride (3.44 ml) and the mixture was allowed to warm to ambient temperature over 15 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography eluting with 10-50% ethyl acetate/hexane to give the title compound (7.5 g) as a solid. Mp 156-158° C.; NMR (CDCl3): 1.7 (s, 6H), 2.2 (s, 3H), 7.6 (d, 1H), 7.7 (d, 1H), 8.2 (d, 1H), 8.4 (s, 1H); MS (ESP−): 380. to warm to ambient temperature over 15 hours The solvent was removed by evaporation the residue was purified by flash chromatography eluting with 10-50% ethyl acetate/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 2-chloro-4-iodoaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 2-chloro-4-iodoaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in anhydrous THF (40 mL) at 0° C. was added LDA (16.2 mL, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirred at 0° C. for 15 min and then at room temperature for 1 h. After cooling the reaction mixture to 0° C. a solution of 2-chloro-4-iodo-phenylamine (3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition of PdCl2(dppf) (0.3 g, 0.4 mmol) and aq. K2CO3 (14 mL, 2.0 M). The mixture was warmed to room temperature and continued to stir overnight. The reaction was diluted with water and then extracted with ethyl acetate. The organic layers was dried, concentrated and triturated with chloroform to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.1 g, 64%) as an off-white solid. at room temperature for 1 h was added The mixture was warmed to room temperature to stir overnight extracted with ethyl acetate The organic layers was dried concentrated triturated with chloroform