Yield:1065076-45-0 97%

Reaction Conditions:

with acetic acid;zinc at 70;Product distribution / selectivity;Reflux;Clemmensen Reaction;

Steps:

2

Intermediate 2 (via Clemensen reduction)4-Ethyl-5-fluoroguaiacol (D2)A solution of l-(2-fluoro-4-hydroxy-5-methoxyphenyl)ethanone (18.0 g; 97.7 mmol; 1 eq; which may be prepared as hereinbefore described for Dl) in glacial acetic acid (800 ml_) is stirred at 70°C before adding added zinc dust (63.9 g ; 977 mmol; 10 eq). The resulting grey heterogeneous mixture is then heated at reflux and stirred overnight using a mechanical stirrer. After this period, zinc has aggregated and conversion rate reaches 90% according to the ¹H NMR analysis of a crude aliquot. Therefore, the zinc metal is removed by filtration on a fritted glass and fresh zinc dust (6.4 g; 98 mmol) is added to the resulting limpid yellow filtrate. The solution is heated at reflux overnight until completion of the reaction. The solution is filtered on a fritted glass and basified until pH 11-12 is reached with a saturated aqueous solution of potassium carbonate ( 1.5 L) and with additional solid potassium carbonate if needed . The resulting aqueous layer is then extracted with ethyl acetate (1.0 L), dried over sod iu m su l ph ate or by azeotropic tol uene d isti l l ation , fi ltered a nd concentrated under vacuum to afford the pure title compound (16.1 g; 94.7 mmol; 97%) as a pale yellow oil. It should be noted that the title compound is a volatile product and should be kept in the fridge under Argon away from light (darkens with oxygen and/or UV exposure).

References:

WO2011/26529,2011,A1 Location in patent:Page/Page column 14