3-amino-4-chlorophenol

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:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A heat gun-dried 100-mL round bottomed flask equipped with a magnetic stir bar was charged with potassium phosphate (5.91 g, 27.9 mmol), picolinic acid (0.171 g, 1.393 mmol), copper(I) iodide (0.133 g, 0.697 mmol), 3-amino-4-chlorophenol (2.0 g, 13.93 mmol), dimethylsulfoxide (27.9 mL), and iodobenzene (3.41 g, 16.72 mmol). The resulting mixture was heated to 80° C. After 15 h, the reaction mixture was subjected to an aqueous workup to afford the crude product, which was then purified by flash chromatography to afford pure 2-chloro-5-phenoxyaniline (2.61 g, 85%). MS (ESI, pos. ion) m/z 220 [M+1]. A heat gun-dried 100-mL round bottomed flask equipped with a magnetic stir bar to afford the crude product, which was then purified by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 4-chloro-3-nitrophenol (6.0 g, 34.6 mmol) and acetic acid (60 mL). Iron powder (325 mesh) (19.31 g, 346 mmol) was added, and the mixture was heated at 100° C. for 30 min. The mixture was cooled to room temperature and diluted with water (40 mL). The mixture was then filtered through a pad of Celite and rinsed with water. The filtrate was then extracted with ethyl acetate, and the combined extracts were concentrated under reduced pressure. Heptane (ca. 100 mL) was added to the filtrate and then removed under reduced pressure in order to remove residual acetic acid and water. This was repeated. The residue was dissolved in acetonitrile and concentrated under reduced pressure. The resulting solid was suspended in heptane and concentrated under reduced pressure to afford 3-amino-4-chlorophenol (4.38 g, 88%) as a pale purple/amber solid. MS (ESI, pos. ion) m/z 144 [M+1]. A 100-mL round bottomed flask equipped with a magnetic stir bar The mixture was cooled to room temperature The mixture was then filtered through a pad of Celite rinsed with water The filtrate was then extracted with ethyl acetate the combined extracts were concentrated under reduced pressure Heptane (ca. 100 mL) was added to the filtrate removed under reduced pressure in order to remove residual acetic acid and water The residue was dissolved in acetonitrile concentrated under reduced pressure concentrated under reduced pressure

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

Procedure: A solution of 3-amino-4-chlorophenol (1.00 g, 7.0 mmol) and cesium carbonate (3.38 g, 10.4 mmol) in DMF (20 mL) were heated at 80 C for 1 hr. The chloroquinazoline (1.61 g, 7.2 mmol) was added and the mixture heated for an additional hour. The mixture was poured into water (300 mL) and extracted with EtOAc twice. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography eluting with EtOAc/hexane (30-70%), the main peak collected and triturated with DCM to afford 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline. 1H NMR (300 MHz, DMSO d6) δ 3.96 (s, 6H), 5.55 (s, 2H), 6.45 (t, 1H), 6.76 (d, 1H), 7.25 (d, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.55 (s, 1H); LC-MS (ESI) m/z 332 (M+H)+ the mixture heated for an additional hour extracted with EtOAc twice The combined extracts were washed with brine dried with magnesium sulfate filtered concentrated The residue was purified eluting with EtOAc/hexane (30-70%) the main peak collected triturated with DCM

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

Procedure: A solution of sodium nitrite (2.07 g, 30.0 mmol) in water (6.0 mL) was added dropwise to an ice cold slurry of 3-amino-4-chlorophenol (4.30 g, 30.0 mmol) and hydrochloric acid (37% aqueous, 9.0 mL) and the mixture stirred for 45 min. Tin (II) chloride (15.4 g, 81.0 mmol) in water (18.0 mL) and hydrochloric acid (37% aqueous, 18.0 mL) was added dropwise and the reaction stirred overnight. The mixture was cooled in an ice/water bath, diluted with water and neutralised by addition of NaOH (1M aq). The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was passed through an acidic ion-exchange cartridge (SCX-2), washing with methanol and eluting with 2M ammonia in methanol. The basic fraction was evaporated in vacuo then purified by FCC, using 3-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.30 g, 27%). 1H NMR (300 MHz, d6-DMSO): 4.12 (2H, br s), 6.03 (1H, dd, J=8.5, 2.9 Hz), 6.26 (1H, s), 6.63 (1H, d, J=2.7 Hz), 6.93 (1H, d, J=8.5 Hz), 9.22 (1H, s). the reaction stirred overnight The mixture was cooled in an ice/water bath The aqueous layer was then extracted with EtOAc (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo washing with methanol eluting with 2M ammonia in methanol The basic fraction was evaporated in vacuo then purified by FCC

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

Procedure: A solution of 3-amino-4-chlorophenol (1.00 g, 7.0 mmol) and cesium carbonate (3.38 g, 10.4 mmol) in DMF (20 mL) were heated at 80 C for 1 hr. The chloroquinazoline (1.61 g, 7.2 mmol) was added and the mixture heated for an additional hour. The mixture was poured into water (300 mL) and extracted with EtOAc twice. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography eluting with EtOAc/hexane (30-70%), the main peak collected and triturated with DCM to afford 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline. 1H NMR (300 MHz, DMSO d6) δ 3.96 (s, 6H), 5.55 (s, 2H), 6.45 (t, 1H), 6.76 (d, 1H), 7.25 (d, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.55 (s, 1H); LC-MS (ESI) m/z 332 (M+H)+ the mixture heated for an additional hour extracted with EtOAc twice The combined extracts were washed with brine dried with magnesium sulfate filtered concentrated The residue was purified eluting with EtOAc/hexane (30-70%) the main peak collected triturated with DCM

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

Procedure: 4-chloro-3-(4-methylpiperazin-1-yl)phenol Compound 14B is prepared according to the same procedure as 13A, using the following reactants: 14A (1.1 g, 10.1 mmol); 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.96 g, 10.1 mmol); sodium carbonate (535 mg, 5.05 mmol) in 1-butanol (40 ml).

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

Procedure: 4-chloro-3-(4-methylpiperazin-1-yl)phenol Compound 14B is prepared according to the same procedure as 13A, using the following reactants: 14A (1.1 g, 10.1 mmol); 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.96 g, 10.1 mmol); sodium carbonate (535 mg, 5.05 mmol) in 1-butanol (40 ml).