4-(bromomethyl)-2-fluorobenzonitrile

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: N-Bromosuccinimide and AIBN were added to a carbon tetrachloride solution of 2-fluoro-4-methylbenzonitrile, followed by heating under reflux to obtain 4-(bromomethyl)-2-fluorobenzonitrile. By allowing this to react with morpholine in DMF in the presence of potassium carbonate, 2-fluoro-4-(morpholin-4-ylmethyl)benzonitrile was obtained. In DMF and in the presence of potassium carbonate, this was allowed to react with cyclohexanamine at 160° C. for 30 minutes while carrying out microwave irradiation. By post-treating the reaction liquid, 2-(cyclohexylamino)-4-(morpholin-4-ylmethyl)benzonitrile was obtained. by heating under reflux

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

Procedure: To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product. The reaction was heated to reflux for 30 minutes The solution was concentrated in vacuo to one-third the original volume poured into EtOAc washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane)

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

Procedure: 2-Amino-3-(4-cyano-3-fluoro-phenyl)-propionic acid ethyl ester. In a 1.0 L flask, a mixture of ethyl 2-(diphenylmethyleneamino)acetate (267 g, 1.0 mol) and the catalyst Bu4NBr (32 g, 0.1 mol) in CH3CN (1000 mL) was treated sequentially with 4-(bromomethyl)-2-fluorobenzonitrile (232 g) and K2CO3 (276 g, 2 mol). The mixture was then stirred for 24 hrs at room temperature. The mixture was filtered and concentrated to give ethyl 3-(4-cyano-3-fluorophenyl)-2-(diphenylmethyleneamino)propanoate (400 g, 100% yield) as a yellow oil. The crude was treated with 2M HCl (600 mL) in THF (400 mL) overnight, and then extracted with EtOAc (3×200 mL). The water phase was basified with a saturated Na2CO3 to pH 10 and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield the title compound (153 g, yield 65% for the last three steps). The crude was not further purified and used straightly in next step. The mixture was filtered concentrated

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

Procedure: Compound 10 was prepared in a similar manner to compound 1 from 4-(bromomethyl)-2-fluorobenzonitrile to afford a white solid (90 mg, 36%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.23 (s, 1H), 7.70-7.67 (m, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m, 3H), 6.78-6.74 (m, 1H), 6.71-6.68 (m, 1H), 5.50 (d, J=14.5 Hz, 1H), 5.17 (s, 2H), 5.15 (d, J=14.5 Hz, 1H). MS (ESI): m/z 503 [M++1]. HPLC: 95.84%.

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

Procedure: 4-Bromomethyl-2-fluoro-benzonitrile (3.44 g, 16.0 mmol) and imidazole (5.47 g, 80.3 mmol) were dissolved in DMF (40 mL) and stirred at ambient temperature for 2 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc (300 mL) and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (silica gel, 1-2% CH3OH/CH2Cl2). The DMF was removed in vacuo the residue was partitioned between EtOAc (300 mL) and aqueous saturated NaHCO3 solution The organic layer was separated washed with NaHCO3 solution, H2O, brine dried (MgSO4) Filtration and concentration to dryness

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

Procedure: N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified chromatography (silica gel, 5-10% EtOAc/hexane. The solution was cooled to −20° C. After the addition then left to warm to ambient temperature overnight extracted with EtOAc the organic layer separated washed with brine dried (MgSO4) Filtration and concentration to dryness

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

Procedure: N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified by chromatography (silica gel, 5-10% EtOAc/hexane. The solution was cooled to −20° C. After the addition then left to warm to ambient temperature overnight extracted with EtOAc the organic layer separated washed with brine dried (MgSO4) Filtration and concentration to dryness

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

Procedure: N-Bromosuccinimide (6.6 g, 0.037 mol) was dissolved in CH2Cl2 (150 mL), cooled to 0° C. and treated with dimethylsulfide (3.27 mL, 0.0446 mol). The solution was cooled to −20° C. and then treated dropwise with a solution of 2-fluoro-4-hydroxymethylbenzonitrile (3.74 g, 0.0248 mol) in CH2Cl2 (30 mL). After the addition, the reaction mixture was stirred at 0° C. for 2 h then left to warm to ambient temperature overnight. The reaction mixture was added to ice/H2O, extracted with EtOAc, the organic layer separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound which was purified by chromatography (silica gel, 5-10% EtOAc/hexane. The solution was cooled to −20° C. After the addition then left to warm to ambient temperature overnight extracted with EtOAc the organic layer separated washed with brine dried (MgSO4) Filtration and concentration to dryness