METHYL-2-BROMO-4-BROMOMETHYLBENZOATE

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

Procedure: This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H). This compound was produced The crude material was purified by flash chromatography through silica gel

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

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

Procedure: A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound. All the solvents are evaporated off the residue is purified by chromatography over silica gel

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

Procedure: A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound. All the solvents are evaporated off the residue is purified by chromatography over silica gel

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

Procedure: This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H). This compound was produced The crude material was purified by flash chromatography through silica gel

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

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

Procedure: This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H). This compound was produced The crude material was purified by flash chromatography through silica gel

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

Procedure: Using methyl 2-bromo-4-bromomethylbenzoate (500 mg) and isothiazolidine 1,1-dioxide (216 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (312 mg) was obtained. by the reaction and treatment in the same manner as in Preparation Example 42

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

Procedure: Using methyl 2-bromo-4-bromomethylbenzoate (500 mg) and isothiazolidine 1,1-dioxide (216 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (312 mg) was obtained. by the reaction and treatment in the same manner as in Preparation Example 42

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

Procedure: This compound was produced using similar methods as that used in Step 4, example 6, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.28 g, 0.91 mmol) and 1,2-dimethyl-1H-indole-3-carbaldehyde oxime (0.18 g, 0.96 mmol). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (50/50 with 1% formic acid) followed by HPLC (65% acetonitrile in 0.1% trifluoroacetic acid solution) and one final recrystallization from ethyl acetate/hexanes to give 2-bromo-4-[({[(1E)-(1,2-dimethyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]benzoic acid (0.16 g, 45%) as a white solid. mp=165-166° C. 1H NMR (400 MHz, DMSO-d6); δ 13.34 (bs, 1H), 8.53 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.75 (d, 1H), 7.51 (d, 1H), 7.44 (d, 1H), 7.16 (t, 1H), 7.08 (t, 1H), 5.17 (s, 2H), 3.67 (s, 3H), 2.47 (s, 3H). Mass spec; (ES+) m/z 401.1, (ES−) m/z 399.0. Elemental analysis; Calculated for C19H17BrN2O3: C, 56.87; H, 4.27; N, 6.98. Found: C, 56.84; H, 4.3; N, 6.92. This compound was produced The crude material was purified by flash chromatography through silica gel recrystallization from ethyl acetate/hexanes

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

Procedure: To a solution of 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.50g, 1.62 mmol) and 1-benzyl-1H-indole-3-carbaldehyde oxime (0.43 g, 1.70 mmol) in acetone (50 mL) was added cesium carbonate (2.12 g, 6.49 mmol). The mixture was heated to reflux for 6 hours and allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give an off-white solid. This solid was recrystallized one time from ethyl acetate/hexanes (1/6) to give 4-[({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]-2-bromobenzoic acid methyl ester (0.26 g, 34%) as off-white crystals. 1H NMR (400 MHz, CDCl3); δ 8.12 (s, 1H), 7.76 (m, 4H), 7.68 (s, 1H), 7.35 (d, 1H), 7.28 (m, 3H), 7.23 (m, 2H), 7.11 (d, 2H), 5.33 (s, 2H), 5.27 (s, 2H), 3.90 (s, 3H). The mixture was heated to reflux for 6 hours The mixture was partitioned between ethyl acetate and brine the layers were then separated The aqueous layer was extracted with one additional portion of ethyl acetate dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The crude material was purified by flash chromatography through silica gel to give an off-white solid This solid was recrystallized one time from ethyl acetate/hexanes (1/6)

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

Procedure: A solution of methyl 2-bromo-4-(bromomethyl)benzoate (4.57 g; 14.84 mmol) in 50 mL of methanol is added dropwise to a well-stirred solution of ammonia in methanol (7M; 315 mL) at ambient temperature, and the solution is then stirred for 3 hours. All the solvents are evaporated off and the residue is purified by chromatography over silica gel using dichloromethane-methanol as eluants to yield the title compound. All the solvents are evaporated off the residue is purified by chromatography over silica gel