5-chloro-2-fluorobenzamidine synthesis

Yield:674793-32-9 73%

Reaction Conditions:

Stage #1: 5-chloro-2-fluorobenzonitrilewith n-butyllithium;1,1,1,3,3,3-hexamethyl-disilazane in hexanes;diethyl ether at 0 - 20; for 2.08333 h;
Stage #2: with hydrogenchloride;water in hexanes;diethyl ether at 0; for 0.5 h;
Stage #3: with sodium hydroxide in hexanes;diethyl ether;water; pH=14;Product distribution / selectivity;

Steps:

1

Amidine intermediates suitable for preparing certain compounds of formula (I) can be synthesized using lithium bis(trimethylsilyl)amide:To a stirred O⁰C solution of 1,1,1,3,3,3-Hexamethyldisilazane (63 mL, 0.3 mol) in dry diethyl ether was added dropwise n-Butyl lithium (2M in hexanes, 150 mL, 0.3 mol). A white suspension formed, to which was added 2-Fluoro-5-chlorobenzonitrile (21.0 g, 0.14 mol) over 5 min. The resultant orange mixture was allowed to warm to r.t. and stirred for 2h. The mixture was cooled to O⁰C and the reaction quenched by the addition of 3M HCl (aq.) (240 mL). The mixture was stirred for 0.5h before water (600 mL) was added. The purple organic layer was discarded and the aqueous layer basified to pH 14 with satd. NaOH (aq.). The aqueous layer was extracted with CHCl₃ (5x100 mL) and the organic extracts dried over Na₂SO₄. Evaporation yielded the desired product as a yellow solid (16.2g, 73% yield).

References:

WO2006/100310,2006,A1 Location in patent:Page/Page column 28