3-Bromo-4-cyanopyridine

Preparation of 3-bromoisonicotinonitrile: (Z)-3-bromoisonicotinaldehyde oxime (4975 mg, 24.75 mmol) was suspended in THF with triethylamine (13.80 mL, 98.99 mmol) and cooled to 0° C. in an ice bath. POCl3- Bromo-4-cyanopyridine (34). 3-Bromopyridine-4-carboxamideCompound32 (687 mg, 3.4 mmol) was stirred at reflux withPOClStep 2 [0184] To a suspension of Compound (2) (3.05 g) in dichloromethane (60 ml), were added triethylamine (6.31 ml) and trifluoroacetic anhydride (2.57 ml) at 0° C. and the mixture was stirred for 1 hour. After addition of water and dichloromethane to the mixture, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by chromatography to afford Compound (3)(2.61 g). [0185] 1008731 Step B: Preparation of 3-bromoisonicotinonitrile: Charged a round bottomed flask plus stir bar with 3-bromoisonicotinaldehyde oxime (24.4 g, 121 mmol), anhydrous THF (200 mL), and Et3N (68 mL, 486 mmol). Cooled in an ice bath under N2, and then added POC13 (11.7 mL, 127 mmol) dropwise. Continued stirring in the ice bath for 3 hours. The mixture was partitioned between EtOAc (400 mL) and saturated aqueous NaHCO3 (400 mL). Separated phases. Re-extracted aqueous with EtOAc (2 x 150 mL). The combined organic phases were dried (Na2504), filtered, and concentrated. Triturated crude with pentane (100- 150 mL), and filtered pink solids. Concentrated the mother liquor. Triturated the resulting solids with more pentane (50-75 mL) to obtain a second crop. Pooled the first and second crops (which contained some triethyl amine hydrochloride by NMR) and partitioned the combined crops between 10percent EtOAc in Et20 (150 mL) and water (50 mL). Neutralized the aqueous layer with saturated aqueous NaHCO3 (50-100 mL). Separated phases, and reextracted aqueous phase with more 10percent EtOAc in Et20 (2 x 50 mL). The combined organic phases were dried (Mg504), filtered, and concentrated to provide desired product as a solid. Yield: 19.7 g (87percent).

3-Bromo-4-cyanopyridine is used in the synthesis of nicotinic receptor ligands which have application towards diseases such as nicotinic addiction,, neurodegenerative and cognitive disorders. It is also used in the synthesis of orally bioavailable cannabinoid receptor 2 agonists for use as analgesic and anti-inflammatory agents.