4-bromo-2-chloro-1-isothiocyanatobenzene

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

Procedure: A mixture of 4-bromo-2-chloroaniline (30.0 g, 0.145 mol) in tetrahydrofuran (150 mL) and aqueous saturated sodium hydrogen carbonate (150 mL) was added thiophosgene (13.3 mL, 0.174 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a colorless solid (25.51 g, 0.103 mol, 71%). The mixture was extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with cold-n-hexane

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

Procedure: To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (7.67 g, 29.72 mmol) in tetrahydrofuran (200 mL) was added 4-bromo-2-chloro-1-isothiocyanatobenzene (8.86 g, 35.66 mmol). The reaction mixture was stirred at room temperature for 2.5 d. The starting material wasn't consumed completely. To the mixture was added 4-bromo-2-chloro-1-isothiocyanatobenzene (1.47 g, 5.91 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The solvent was removed by concentration. The residue was washed with diisopropyl ether to give a mixture contained the thiourea. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (200 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.41 g, 22.97 mmol) and triethylamine (3.50 mL, 25.27 mmol). The reaction mixture was stirred at 50° C. for 13 hrs. After cooling, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (9.08 g, 19.19 mmol, 65% (2 steps)). The starting material wasn't consumed completely The reaction mixture was stirred at room temperature for 5 hrs The solvent was removed by concentration The residue was washed with diisopropyl ether to give a mixture The mixture was subject to next step without further purification The mixture was dissolved into tetrahydrofuran (200 mL) The reaction mixture was stirred at 50° C. for 13 hrs After cooling extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with diisopropyl ether/ethyl acetate

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

Procedure: A mixture of 4-bromo-2-chloroaniline (30.0 g, 0.145 mol) in tetrahydrofuran (150 mL) and aqueous saturated sodium hydrogen carbonate (150 mL) was added thiophosgene (13.3 mL, 0.174 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a colorless solid (25.51 g, 0.103 mol, 71%). The mixture was extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with cold-n-hexane

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

Procedure: To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (7.67 g, 29.72 mmol) in tetrahydrofuran (200 mL) was added 4-bromo-2-chloro-1-isothiocyanatobenzene (8.86 g, 35.66 mmol). The reaction mixture was stirred at room temperature for 2.5 d. The starting material wasn't consumed completely. To the mixture was added 4-bromo-2-chloro-1-isothiocyanatobenzene (1.47 g, 5.91 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The solvent was removed by concentration. The residue was washed with diisopropyl ether to give a mixture contained the thiourea. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (200 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.41 g, 22.97 mmol) and triethylamine (3.50 mL, 25.27 mmol). The reaction mixture was stirred at 50° C. for 13 hrs. After cooling, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (9.08 g, 19.19 mmol, 65% (2 steps)). The starting material wasn't consumed completely The reaction mixture was stirred at room temperature for 5 hrs The solvent was removed by concentration The residue was washed with diisopropyl ether to give a mixture The mixture was subject to next step without further purification The mixture was dissolved into tetrahydrofuran (200 mL) The reaction mixture was stirred at 50° C. for 13 hrs After cooling extracted with ethyl acetate (×3) The combined organic layer was washed with brine (×1) dried over anhydrous magnesium sulfate filtered concentrated in vacuo The residue was washed with diisopropyl ether/ethyl acetate