2,6-dichloro-4-iodoaniline

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

Procedure: The title compound was synthesized following the procedure in Example 155, Steps 1, 2, and 3 using 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3), 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (124 mg, 0.495 mmol) (Example 133, Step 3), and 2,6-dichloro-4-iodoaniline as the starting materials.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3) (200 mg, 0.770 mmol) and 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3)(193, 0.770 mmol) in THF (12 mL) were added 2,6-dichloro-4-iodoaniline (443 mg, 1.54 mmol) and sodium tert-butoxide (444 mg, 4.62 mmol) and the mixture was heated to 85° C. for 1 hr. After cooling to room temperature, the mixture was extracted with EtOAc. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Column chromatography (100% hexane to 100% EtOAc) provided 10-chloro-N-(2,6-dichloro-4-iodophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine and N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine. Most instances 10-chloro-N-(2,6-dichloro-4-iodophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine and N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine were carried on as a mixture, however, the mixtures can be separated and carried on separately. This mixture (282 mg) was taken up in methanol (5 mL) and 25% sodium methoxide (3 mL) and heated at 100° C. for 1 hr. After cooling to room temperature, the solution was concentrated and then taken up in EtOAc and washed with water. The organic layers were dried with MgSO4, filtered, and concentrated to afford the title compounds. After cooling to room temperature the mixture was extracted with EtOAc The organic layers were dried with MgSO4 filtered concentrated under reduced pressure

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

Procedure: The title compound was prepared according to the procedure in (Example 3, Method C, Step 4) using 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine and 2,6-dichloro-4-iodoaniline as the starting materials.

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

Procedure: 2,6-Dichloro-4-iodoaniline (10.4 g, 36.0 mmol) is dissolved in toluene (100 mL) and treated with 1.5 equivalents of phenylboronic acid (6.6 g, 54 mmol), and a catalytic amount of tetrakistriphenylphosphine palladium(0) (3.0 g, 2.6 mmol) as a solution in ethanol (20 mL). Sodium carbonate (40 mL of 2 M aqueous solution) is added and the reaction mixture stirred and heated to reflux temperature for 24 hours. After cooling to room temperature, the mixture is partitioned between Et2O (300 mL) and water (150 mL). The organic layer is washed with brine, dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-phenylaniline (m.p. 112–113° C.). heated to reflux temperature for 24 hours the mixture is partitioned between Et2O (300 mL) and water (150 mL) The organic layer is washed with brine dried (MgSO4) concentrated by rotary evaporator The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloroaniline (16.2 g, 0.1 mol) is suspended in a solution of sodium bicarbonate (8.6 g, 0.1 mol in 100 mL of water) and warmed to 60° C. Elemental iodine (25.4 g, 0.1 mol) is added portionwise and the resulting mixture stirred at 60° C. for 3 days. After cooling to room temperature, the reaction mixture is partitioned between CH2Cl2 (250 mL) and saturated sodium bisulfite solution (500 mL). The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) and the combined organic layers dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-iodoaniline (m.p. 100–102° C.). After cooling to room temperature the reaction mixture is partitioned between CH2Cl2 (250 mL) and saturated sodium bisulfite solution (500 mL) The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) the combined organic layers dried (MgSO4) concentrated by rotary evaporator The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc)