methyl 5-bromo-2-fluorobenzoate

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: tert-Butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate was synthesized as described for INTERMEDIATE 6 (step A) using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Eastwood, P. R. Tetrahedron Lett., 41, 19, 2000, 3705-3708) and methyl 5-bromo-2-fluorobenzoate as starting material and PdCl2dppf.CH2Cl2 as a catalyst.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-fluorobenzoic acid (25 g, 0.11 mol), methyl iodide (8.5 mL, 0.14 mol), and potassium carbonate (31 g, 0.23 mol) in DMF (200 mL) was heated to 50° C. for 18 hr. The cooled reaction mixture was diluted with EtOAc (200 mL) and the organic phase was washed with a saturated aqueous NaCl solution (4×). The organic phase was then dried over sodium sulfate and evaporated to dryness to give 24g of methyl 5-bromo-2-fluorobenzoate as a yellow oil. Step B: The cooled reaction mixture the organic phase was washed with a saturated aqueous NaCl solution (4×) The organic phase was then dried over sodium sulfate evaporated to dryness

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

Procedure: Sequentially add tri-tert-butylphosphine (88 mg, 0.437 mmol) in anhydrous 1,4-dioxane (1 mL), diisopropylethylamine (1.5 mL, 8.74 mmol), 5-bromo-2-fluorobenzoic acid methyl ester, (prepared as described in PREPARATION 42), (1.69 g, 7.28 mmol) and a solution of 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.93 g, 7.28 mmol) in anhydrous 1,4-dioxane (4 mL), to a stirring mixture of dichloro(benzonitrile)palladium (II) (84 mg, 0.218 mmol) and copper (I) iodide (28 mg, 0.146 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen. Stir for 2 h and concentrate. Purify the residue twice by silica gel chromatography, eluting with 10:90 ethyl acetate:hexanes, to give the title compound as a white solid (0.9 g, 44%). concentrate Purify the residue twice by silica gel chromatography eluting with 10:90 ethyl acetate

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

Procedure: Sequentially add tri-tert-butylphosphine (88 mg, 0.437 mmol) in anhydrous 1,4-dioxane (1 mL), diisopropylethylamine (1.5 mL, 8.74 mmol), 5-bromo-2-fluorobenzoic acid methyl ester, (prepared as described in PREPARATION 42), (1.69 g, 7.28 mmol) and a solution of 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.93 g, 7.28 mmol) in anhydrous 1,4-dioxane (4 mL), to a stirring mixture of dichloro(benzonitrile)palladium (II) (84 mg, 0.218 mmol) and copper (I) iodide (28 mg, 0.146 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen. Stir for 2 h and concentrate. Purify the residue twice by silica gel chromatography, eluting with 10:90 ethyl acetate:hexanes, to give the title compound as a white solid (0.9 g, 44%). concentrate Purify the residue twice by silica gel chromatography eluting with 10:90 ethyl acetate

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

Procedure: Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%). at reflux overnight Concentrate dissolve the residue in ethyl acetate wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride dry (sodium sulfate) filter concentrate

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

Procedure: Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%). at reflux overnight Concentrate dissolve the residue in ethyl acetate wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride dry (sodium sulfate) filter concentrate

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

Procedure: Triphenylphosphine polymer bound (200 mg; 0.60 mmol; 0.15 eq.), palladium (II) acetate (60.17 mg; 0.27 mmol; 0.07 eq.) and DMF (12 mL) were first mixed in a microwave vial, purged with N2 and let stirring at RT for 2 h. The vial was then opened, zinc cyanide (469.70 mg; 4 mmol; 1 eq.) and methyl 5-bromo-2-fluorobenzoate, prepared from literature procedure starting from 5-bromo-2-fluorobenzoic acid (COMBI-BLOCKS; CA-4097) (932.15 mg; 4 mmol; 1 eq.), were added and the resulting mixture was purged once more and sealed. It was then heated in the microwave at 140° C. for 50 min. The reaction mixture was filtrated through a glass frit and the resin was washed with Et2O (3×10 mL). The combined organic solutions were washed with water (3×5 mL), once with NaCl sat. solution (10 mL) and then dried over magnesium sulfate. Evaporation of the solvents gave the title compound as a white solid (638 mg; 89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (dd, J=6.8, 2.2 Hz, 1H), 8.2-8.17 (m, 1H), 7.63 (dd, J=10.6. 8.6 Hz, 1H), 3.89 (s, 3H). GC/MS: 179. HPLC (Method A), Rt 2.74 min (purity: 93.9%). were first mixed in a microwave vial purged with N2 were added the resulting mixture was purged once more sealed It was then heated in the microwave at 140° C. for 50 min The reaction mixture was filtrated through a glass frit the resin was washed with Et2O (3×10 mL) The combined organic solutions were washed with water (3×5 mL), once with NaCl sat. solution (10 mL) dried over magnesium sulfate Evaporation of the solvents

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

Procedure: The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (165 mg, 0.55 mmol), methyl 5-bromo-2-fluorobenzoate (128 mg, 0.55 mmol), palladium acetate (12.3 mg, 0.05 mmol), BINAP (68.3 mg, 0.11 mmol) and cesium carbonate (536 mg, 1.65 mmol), to obtain 33 mg of the title compound as a yellow oily substance (14%).

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

Procedure: Triphenylphosphine polymer bound (200 mg; 0.60 mmol; 0.15 eq.), palladium (II) acetate (60.17 mg; 0.27 mmol; 0.07 eq.) and DMF (12 mL) were first mixed in a microwave vial, purged with N2 and let stirring at RT for 2 h. The vial was then opened, zinc cyanide (469.70 mg; 4 mmol; 1 eq.) and methyl 5-bromo-2-fluorobenzoate, prepared from literature procedure starting from 5-bromo-2-fluorobenzoic acid (COMBI-BLOCKS; CA-4097) (932.15 mg; 4 mmol; 1 eq.), were added and the resulting mixture was purged once more and sealed. It was then heated in the microwave at 140° C. for 50 min. The reaction mixture was filtrated through a glass frit and the resin was washed with Et2O (3×10 mL). The combined organic solutions were washed with water (3×5 mL), once with NaCl sat. solution (10 mL) and then dried over magnesium sulfate. Evaporation of the solvents gave the title compound as a white solid (638 mg; 89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.35 (dd, J=6.8, 2.2 Hz, 1H), 8.2-8.17 (m, 1H), 7.63 (dd, J=10.6. 8.6 Hz, 1H), 3.89 (s, 3H). GC/MS: 179. HPLC (Method A), Rt 2.74 min (purity: 93.9%). were first mixed in a microwave vial purged with N2 were added the resulting mixture was purged once more sealed It was then heated in the microwave at 140° C. for 50 min The reaction mixture was filtrated through a glass frit the resin was washed with Et2O (3×10 mL) The combined organic solutions were washed with water (3×5 mL), once with NaCl sat. solution (10 mL) dried over magnesium sulfate Evaporation of the solvents