methyl 3-bromo-5-[(dimethylamino)methyl]benzoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 3-bromo-5-formylbenzoate (200 mg, 0.82 mmol), methanol (3 mL), 2.0 M dimethylamine solution in THF (0.3 mL, 6 mmol), zinc dichloride (30 mg, 0.22 mmol), and sodium cyanoborohydride (200 mg, 3.2 mmol) was stirred at 0° C. for 1 h. The mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound. the aqueous layer was extracted with EtOAc (15 mL×3) The combined organic layers were dried over anhydrous MgSO4 concentrated The residue was purified by silica gel chromatography

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

Procedure: Methyl 3-bromo-5-[(dimethylamino)methyl]benzoate (0.30 g, 1.1 mmol, from Step A) was dissolved in tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.555 g, 13.2 mmol) in water (6 mL) was added. After stirring for 3 hours, the mixture was rotovapped to remove THF and reduce the volume of water. The mixture was diluted with an equivalent volume of acetonitrile and filtered. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation to afford a white solid. Yield: 0.26 g (91%); LC-MS: 258.0, 260.0 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 7.86 (dd, 1H), 7.76 (dd, 1H), 7.43 (dd, 1H), 3.38 (s, 2H), 2.14 (s, 6H). to remove THF The mixture was diluted with an equivalent volume of acetonitrile filtered The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) Solvent was removed from fractions containing desired product by rotary evaporation to afford a white solid

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

Procedure: To a solution of methyl 3-bromo-5-formylbenzoate (1.8 g, 7.4 mmol, prepared as described in WO 2003048111 from dimethyl 5-bromoisophthalate, Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0 M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol). This mixture was stirred for 15 minutes, followed by the addition of sodium triacetoxyborohydride (4.7 g, 22 mmol). The resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the product was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford a light yellow oil. Yield: 1.87 g (93%); LC-MS: 272.0, 274.0 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.89 (dd, 1H), 7.69 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H). The resulting mixture was stirred overnight the product was extracted with ethyl acetate The combined organic extracts were washed twice with water, once with brine dried over sodium sulfate filtered concentrated to afford a light yellow oil

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

Procedure: 1.0M Diisobutylaluminum hydride in hexanes (6.2 mL, 6.2 mmol) was added dropwise to a solution of methyl 3-bromo-5-[(dimethylamino)methyl]benzoate (0.50 g, 1.8 mmol, from Step A) in tetrahydrofuran (10 mL) at −78° C. After stirring for 2 hours, the mixture was quenched with saturated potassium sodium tartrate solution and was allowed to warm to room temperature. Ethyl acetate was added and the mixture was then stirred until a biphasic solution formed. The ethyl acetate layer was washed with water (3×), followed by brine, was dried over sodium sulfate and concentrated to give a light yellow oil (0.41 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.41 (dd, J=1.7 Hz, 1H), 7.37 (dd, J=1.8 Hz, 1H), 7.24 (dd, J=1.4, 0.7 Hz, 1H), 4.65 (s, 2H), 3.37 (s, 2H), 2.22 (s, 6H). LCMS (M+H)+: 244.0, 246.0. the mixture was quenched with saturated potassium sodium tartrate solution Ethyl acetate was added the mixture was then stirred until a biphasic solution formed The ethyl acetate layer was washed with water (3×) was dried over sodium sulfate concentrated

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

Procedure: To a solution of methyl 3-bromo-5-formylbenzoate (1.8 g, 7.4 mmol, prepared as described in WO2003/048111 starting from dimethyl 5-bromoisophthalate (Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol) and the reaction was stirred for 15 min. Sodium triacetoxyborohydride (4.7 g, 22 mmol) was then added and the resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product as a light yellow oil (1.87 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.08-8.03 (m, 1H), 7.90-7.87 (m, 1H), 7.70-7.67 (m, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H); LCMS (M+H)+: 272.0, 274.0. the resulting mixture was stirred overnight the resulting mixture was extracted with ethyl acetate The organic extract was washed twice with water, once with brine dried over sodium sulfate filtered concentrated