3-Bromo-2-cyanopyridine

Off-White Crystals

3-Bromo-pyridine 1-oxide (9.4 g, 54 mmol) is dissolved in acetonitrile (60 mL) and triethylamine (15 mL) is added followed by trimethylsilyl cyanide (21.7 mL, 163 mmol). The mixture is heated to 100 Intermediate 3 3-Bromo-pyridine-2-carbonitrile Alternate Procedure:A 50 L three-neck round bottom flask is equipped with a mechanical stirrer, thermocouple, nitrogen inlet, efficient reflux condenser, and drying tube (do not set up drying tube during addition of trimethyl silylcyanide). The flask is charged with 3778 g (about 20 mol) crude 3-bromopyridine-N-oxide (prepared, for example, essentially as described in the Alternate Procedure for Intermediate 2), acetonitrile (19 L) and triethylamine (6.667 L, 50 mol). The reaction mixture is heated to a gentle reflux of about 70-73° C., then neat trimethyl silylcyanide (6.667 L, 50 mol) is added via the addition funnel in 10-15 minute intervals, over a total of 3 h. After addition of each portion of trimethyl silylcyanide, the reaction proceeds toward strong reflux (if vapors escape, additional trimethylsilylcyanide may be needed to drive the reaction to completion). Once the addition is complete, the reaction mixture is stirred at reflux for 20 h with adjustment of heating rate as necessary to maintain the reflux. The reaction progress is monitored by TLC (heptane EtOAc 1:1). Once the reaction is deemed complete the reaction mixture is cooled to 0-10° C. A solution of 50percent aqueous NaOH (7.2 kg) in water (9 L) is added in a stream over 30 min and an exotherm results. The temperature rises to 20-25° C. and the reaction is stirred for 30 min at 15-25° C. The reaction mixture is transferred to a separatory funnel and the organic layer is separated. The organic layer is washed with brine (4 L) and the combined aqueous layers are extracted with EtOAc (3.x.3 L). The combined organic layers are washed with brine (3 L), treated with charcoal, dried over magnesium sulfate, filtered, and concentrated. The resulting solids (about 3.8 kg) are dissolved in EtOAc (25 L, using some heat), dried over magnesium sulfate, charcoal, filtered and concentrated. The resulting tan/brown solids are dissolved in ethanol (7 L) with heating. The resulting solution is transferred to a pail and allowed to stand at room temperature overnight. After this time the solids are collected by filtration and washed with cold ethanol on a filter (2.x.1 L, -20° C.). The solids are dissolved in EtOAc (20 to 25 L), the solution dried over magnesium sulfate, treated with charcoal to remove the color, and then filtered. The filter cake is washed with EtOAc (2.x.2 L) and the filtrates combined and concentrated to dryness. The residual solids (2.7 kg) are co-evaporated with EtOH (1 L). Then the solids are dissolved in EtOH (6 L) using heating. A clear solution forms at about 70° C. and the solution is then cooled to 0-5° C. and stirred for 2 h at this temperature. The solids are collected by filtration, washed with cold ethanol (2.x.1 L, 0-5° C.), and then heptane (1 L, 0-5° C.), and dried in a vacuum oven at 40° C.(b) 14.1: 3-Bromo-pyridine-2-carbonitrile. To a solution of 3-bromo-pyridine (5.0 g, 0.032 mol) in trifluoro acetic anhydride (25 mL) at 0 C, was slowly added nitric acid (4 mL, 0.064 mol). The reaction mixture was stiiTcd at room temperature for 1 hom- and then cooled to 0 C. A solution of potassium cyanide (10.0 g, 0.16 mol) and sodium acetate (13.0 g, 0.16 mol) in water (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours and to it was then added dichloromethane and water. The organic layer was separated and the aqueous layer was further extracted with dichloromethane (3x). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel to give 3-bromo-pyridine-2-cai'bonitrile (1.0 g, 17 %).A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100 C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid. 1H NMR (acetone d-6): delta 9.04 (d, 1H), 8.91 (d, 1H), 8.45 (d, 1H), 7.86 (dd, 1H), 7.53-7.62 (m, 2H), 7.35 (t, 1H), 6.65 (br, 2H). LRMS [M+H]=196.1A solution of 2-(7EXAMPLE 3 3-Bromopicolinamide, prepared as in Example 2(4 g.) is heated with 100 ml. of acetic anhydride on a steam bath. The mixture is then concentrated and worked up by diluting and triturating with water. The solid is dried and sublimed to give

Molecular Weight:183.01
XLogP3:1.6
Hydrogen Bond Acceptor Count:2
Exact Mass:181.94796
Monoisotopic Mass:181.94796
Topological Polar Surface Area:36.7
Heavy Atom Count:9
Complexity:137
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes