2-(5-broMo-3-Methoxypyridin-2-yl)acetonitrile synthesis

Yield:-

Reaction Conditions:

with lithium hexamethyldisilazane in tetrahydrofuran at 18 - 25;

Steps:

7

The 2-[5-(6,7-dimethoxyquinazolin-4-yloxy)-3-methoxypyridin-2-yl]acetic acid used as a starting material was prepared as follows :-Under an atmosphere of argon, a IM solution of lithium hexamethyldisilazane in THF (80 ml) was added dropwise to a stirred mixture of 5-bromo-2-chloro-3-methoxypyridine (International Patent Application WO 01/81347, within Example 10 thereof; 8 g), acetonitrile (4.1 ml) and THF (80 ml) that had been cooled to 18°C. Additional acetonitrile (4.1 ml) and IM lithium hexamethyldisilazane solution (80 ml) were added in turn. The reaction mixture was allowed to warm to ambient temperature and poured into a stirred mixture of water (300 ml) and diethyl ether (300 ml). The aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 4: 1 to 1 : 1 petroleum ether and diethyl ether as eluent. There was thus obtained 2-(5-bromo- 3-methoxypyridin-2-yl)acetonitrile (4.8 g); ¹H NMR: (CDCl₃) 3.85 (s, 2H), 3.91 (s, 3H), 7.35 (d, IH), 8.25 (d, IH); Mass Spectrum: M+H⁺ 227 and 229.

References:

WO2007/99317,2007,A1 Location in patent:Page/Page column 109-110