3,5-dichlorobenzene-1,2-diamine

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

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

Procedure: A mixture of 2,4-dichloro-6-nitroaniline (7.7 g, 37.2 mmol) and SnCl2 (21.6 g, 111.6 mmol) were mechanically stirred under a nitrogen atmosphere. Hydrochloric acid (38.5 ml) was added and the mixture was warmed at 75°-80° C. for 2 h. The mixture was cooled (ice bath) and neutralized (pH=9) with 50% potassium hydroxide solution followed by extraction with ether (3×150 ml). The combined organic extracts was dried over sodium hydroxide pellets and filtered. The solvent was evaporated leaving 6.2 g of intermediary 1,2-diamino-3,5-dichlorobenzene, which was dissolved in 200 ml of methanol and stirred under cooling in an ice bath. Hydrochloric acid (2.90 ml) was added followed by addition of glyoxylic acid monohydrate (3.9 g, 42.4 mmol). The ice bath was removed and stirring was continued for 16 h. The precipitate was filtered off, washed with cold methanol and dried to afford 6.0 g isomeric mixture (6:1, 1H-NMR) of 6,8-dichloroquinoxalin-2(1H)-one and 5,7-dichloroquinoxalin-2(1H)-one, respectively. The isomeric mixture was recrystallized from 2-methoxyethanol (100 ml) to afford 3.4 g of 6,8 -dichloroquinoxalin-2-(1H)-one. M.p. 228°-229° C. 1H-NMR (DMSO-d6):δ7.88 (m, 2H), 8.30 (s, 1H), 12.20 (s, 1H). the mixture was warmed at 75°-80° C. for 2 h followed by extraction with ether (3×150 ml) The combined organic extracts was dried over sodium hydroxide pellets filtered The solvent was evaporated

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

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

Procedure: The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646. was heated to reflux under N2 for 6 h the pale yellow shiny solid collected by vacuum filtration rinsed with EtOH (20 mL) and air dried to give 286 mg (44%) mp 326°-328° C. (dec) Lit 337°-340° C.

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

Procedure: 3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2 °2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming ) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4). All the starting material had reacted poured into 40 mL crushed ice was added (foaming ) The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate the combined organic extracts washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated to yield a pale orange oil which crystallized to yield 789 mg (93%)

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

Procedure: The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646. was heated to reflux under N2 for 6 h the pale yellow shiny solid collected by vacuum filtration rinsed with EtOH (20 mL) and air dried to give 286 mg (44%) mp 326°-328° C. (dec) Lit 337°-340° C.

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

Procedure: A mixture of 2,4-dichloro-6-nitroaniline (7.7 g, 37.2 mmol) and SnCl2 (21.6 g, 111.6 mmol) were mechanically stirred under a nitrogen atmosphere. Hydrochloric acid (38.5 ml) was added and the mixture was warmed at 75°-80° C. for 2 h. The mixture was cooled (ice bath) and neutralized (pH=9) with 50% potassium hydroxide solution followed by extraction with ether (3×150 ml). The combined organic extracts was dried over sodium hydroxide pellets and filtered. The solvent was evaporated leaving 6.2 g of intermediary 1,2-diamino-3,5-dichlorobenzene, which was dissolved in 200 ml of methanol and stirred under cooling in an ice bath. Hydrochloric acid (2.90 ml) was added followed by addition of glyoxylic acid monohydrate (3.9 g, 42.4 mmol). The ice bath was removed and stirring was continued for 16 h. The precipitate was filtered off, washed with cold methanol and dried to afford 6.0 g isomeric mixture (6:1, 1H-NMR) of 6,8-dichloroquinoxalin-2(1H)-one and 5,7-dichloroquinoxalin-2(1H)-one, respectively. The isomeric mixture was recrystallized from 2-methoxyethanol (100 ml) to afford 3.4 g of 6,8 -dichloroquinoxalin-2-(1H)-one. M.p. 228°-229° C. 1H-NMR (DMSO-d6):δ7.88 (m, 2H), 8.30 (s, 1H), 12.20 (s, 1H). the mixture was warmed at 75°-80° C. for 2 h followed by extraction with ether (3×150 ml) The combined organic extracts was dried over sodium hydroxide pellets filtered The solvent was evaporated

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

Procedure: The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646. was heated to reflux under N2 for 6 h the pale yellow shiny solid collected by vacuum filtration rinsed with EtOH (20 mL) and air dried to give 286 mg (44%) mp 326°-328° C. (dec) Lit 337°-340° C.

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

Procedure: 3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2 ·2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4). All the starting material had reacted poured into 40 mL crushed ice was added (foaming!) The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate the combined organic extracts washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated to yield a pale orange oil which crystallized to yield 789 mg (93%)

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

Procedure: The title compound (Leeson, P. D. et al., J. Med. Chem 34: 1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ 7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O: 229.9650, found 229.9646. was heated to reflux under N2 for 6 h the pale yellow shiny solid collected by vacuum filtration rinsed with EtOH (20 mL) and air dried to give 286 mg (44%) mp 326°-328° C. (dec) Lit 337°-340° C.

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

Procedure: 3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2.2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ 3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4). All the starting material had reacted poured into 40 mL crushed ice was added (foaming!) The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate the combined organic extracts washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated to yield a pale orange oil which crystallized to yield 789 mg (93%)

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

Procedure: The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646. was heated to reflux under N2 for 6 h the pale yellow shiny solid collected by vacuum filtration rinsed with EtOH (20 mL) and air dried to give 286 mg (44%) mp 326°-328° C. (dec) Lit 337°-340° C.