methyl 3-amino-2-bromobenzoate

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: 2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 mmol) (prepared from 2-amino-3-nitro-benzoic acid as described by Webber E. S., et al., see patent application number WO 01/16136 A2) and SnCl2 (42 g, 223 mmol) were refluxed in methanol (225 mL, 0.2 M) and H2O (5.3 g, 243 mmol) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 g) and dichloromethane (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5(a) (11.4 g) in 98% yield. The mixture was filtered the organic phase was washed with saturated aqueous sodium chloride The organic solution was dried over sodium sulfate filtered all volatiles were removed under reduced pressure

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

Procedure: 2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 mmol) (prepared from 2-amino-3-nitro-benzoic acid as described by Webber E. S., et al., see patent application number WO 01/16136 A2) and SnCl2 (42 g, 223 mmol) were refluxed in methanol (225 mL, 0.2 M) and H2O (5.3 g, 243 mmol) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 g) and dichloromethane (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5(a) (11.4 g) in 98% yield. The mixture was filtered the organic phase was washed with saturated aqueous sodium chloride The organic solution was dried over sodium sulfate filtered all volatiles were removed under reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 hours. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30° C. over 1 hour. The mixture was then heated at 50-60° C. for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35° C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above. The mixture was cooled to room temperature The resultant mixture was extracted three times with chloroform The extracts were washed with brine dried over sodium sulfate filtered concentrated

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

Procedure: Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through CELITE. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm−1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232. The catalyst was removed by filtration through CELITE

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate)