6-Bromomethyl-nicotinonitrile

Preparation 22; 3-Aminomethyl-6-(tert-butylthio)methyl-pyridine; 6-Bromomethyl-pyridine-S-carbonitrile; Dissolve 6-methyl-nicotinonitrile (2 g, 17 mmol) and NBS (3.01 g, 17 mmol) in anhydrous DCE (56 mL) under nitrogen. Add AIBN (277 mg, 1.7 mmol) and heat the mixture at 80°C for 1.5-2 h. Add another batch of AIBN (277 EPO Step 1: 5-Cyano-2-methylpyridine (1. 025 g, 8.68 mmol) was dissolved in carbon tetrachloride (50 ml). N-bromosuccinimide (1.7 g, 9.54 mmol) and benzoyl peroxide (75percent, 140 mg, 0.43 mmol) were added, and the mixture was heated to reflux in a heat block at 86°C. After 17 h, the reaction was filtered, rinsed with DCM and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 6- (bromomethyl)pyridine-3-carbonitrile as a brownish oil (0.69 g , 40percent).[0351] Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3- carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5) as eluent to yield 5 g (37percent) of 6-(bromomethyl)pyridine-3- carbonitrile as a beige solid.Into a 250-mE round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mE). N-l3romosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AII3N (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yieldS g (37percent) of 6-(bromomethyl) pyridine-3-carbonitrile as a beige solid.6-(Bromomethyl)nicotinonitrile (I-4)To a stirred solution of 6-methylnicotinonitrile (1.0 g, 8.47 mmol) in 1, 2-dichloroethane (30 mL) was added N-bromosuccinimide (NBS; 1.52 g, 8.54 mmol) and followed by 2, 2'-azobis(isobutyronitrile) (AIBN; 0.14 g, 0.85 mmol) at RT. The reaction mixture was then heated to 80° C. and stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10percent EtOAc/Hexane) afforded compound I-4 (0.6 g, 3.05 mmol, 36percent) as a colorless liquid. Compound SM (2.5 g, 21.2 mmol) was dissolved in CCl4 (40 mL) and NBS (3.77 g, 21.2 mmol) and AIBN (347.5 mg, 2.12 mmol) were added with stirring. Under nitrogen, the reaction was carried out at 85 ° C for 2 hours. TLC showed that there was no reaction finished. AIBN (347.5 mg, 2.12 mmol) was added and the reaction was continued at 85 ° C for 2 hours. Cool to room temperature, add H20 (100 mL) and extract with DCM (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 30: 1) to give the title compound (1.42 g, 34.1percent).Example 50 Example 50 Preparation 22; 3-Aminomethyl-6-(tert-butylthio)methyl-pyridine; 6-Bromomethyl-pyridine-S-carbonitrile; Dissolve 6-methyl-nicotinonitrile (2 g, 17 mmol) and NBS (3.01 g, 17 mmol) in anhydrous DCE (56 mL) under nitrogen. Add AIBN (277 mg, 1.7 mmol) and heat the mixture at 80°C for 1.5-2 h. Add another batch of AIBN (277 EPO A slurry of 6-methylnicotinonitrile (500 mg, 4.23 mmol), iV-brornosucciniinide (791mg, 4.44 mmol) and AIBN (208 mg, 1.270 mmol) in CC14 (5 mL) was heated at 85°C for 20hours. The mixture was concentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (40 g Si02) eluting with a gradient of 0-40percent EtOAc in hexanesto give the title compound as a light red oil (441 mg, 52.9percent). ‘H NMR (400 MHz, CDC13) ö ppm 4.58 (s, 2 H), 7.60 (dd, J=8.1, 0.8 Hz, 1 H), 7.99 (dd, J=8.1, 2.0 Hz, 1 H), 8.82 - 8.88(m, 1 H); ESI-MS m/z [M+Hj 197, 199.Step 1: 5-Cyano-2-methylpyridine (1. 025 g, 8.68 mmol) was dissolved in carbon tetrachloride (50 ml). N-bromosuccinimide (1.7 g, 9.54 mmol) and benzoyl peroxide (75percent, 140 mg, 0.43 mmol) were added, and the mixture was heated to reflux in a heat block at 86°C. After 17 h, the reaction was filtered, rinsed with DCM and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 6- (bromomethyl)pyridine-3-carbonitrile as a brownish oil (0.69 g , 40percent).[0351] Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3- carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5) as eluent to yield 5 g (37percent) of 6-(bromomethyl)pyridine-3- carbonitrile as a beige solid.Into a 250-mE round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mE). N-l3romosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AII3N (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yieldS g (37percent) of 6-(bromomethyl) pyridine-3-carbonitrile as a beige solid.6-(Bromomethyl)nicotinonitrile (I-4)To a stirred solution of 6-methylnicotinonitrile (1.0 g, 8.47 mmol) in 1, 2-dichloroethane (30 mL) was added N-bromosuccinimide (NBS; 1.52 g, 8.54 mmol) and followed by 2, 2'-azobis(isobutyronitrile) (AIBN; 0.14 g, 0.85 mmol) at RT. The reaction mixture was then heated to 80° C. and stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10percent EtOAc/Hexane) afforded compound I-4 (0.6 g, 3.05 mmol, 36percent) as a colorless liquid. Compound SM (2.5 g, 21.2 mmol) was dissolved in CCl4 (40 mL) and NBS (3.77 g, 21.2 mmol) and AIBN (347.5 mg, 2.12 mmol) were added with stirring. Under nitrogen, the reaction was carried out at 85 ° C for 2 hours. TLC showed that there was no reaction finished. AIBN (347.5 mg, 2.12 mmol) was added and the reaction was continued at 85 ° C for 2 hours. Cool to room temperature, add H20 (100 mL) and extract with DCM (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 30: 1) to give the title compound (1.42 g, 34.1percent).Example 50 Example 50

Molecular Weight:197.03
XLogP3:1.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:195.96361
Monoisotopic Mass:195.96361
Topological Polar Surface Area:36.7
Heavy Atom Count:10
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes