Potassium Carbonate → Ethyl 6-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)picolinate

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A mixture of 78.56 g (249.4 mmol) of (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid, 59.9 g (249.4 mol) of ethyl 6-(chloromethyl)-2-pyridinecarboxylate hydrochloride, 137.68 g (997.7 mol) of potassium carbonate and 28.89 g (24.95 mmol) of tetrakis(triphenylphoshine)palladium(0) in 1:1 toluene/ethanol (1840 ml) was stirred and heated at 90° C. under argon for 2 hours. Cooled, diluted with water/ether and filtered. Organic phase was washed with 2M hydrochloric acid and water, dried overnight (sodium sulphate), filtered and evaporated. Dissolved in dichloromethane, filtered to remove some insoluble material and the filtrate applied to a large column on the Biotage 75 and eluted with 15% ethyl acetate in hexane. Some purification but lower spot started to elute with product so eluent changed to ethyl acetate/hexane (1:1) and all fractions containing product combined and evaporated. Redissolved in dichloromethane and biotaged (chromatographed) again on same size column eluting with 4 litres of (3:1) dichloromethane/hexane changing to 5% ethanol in dichloromethane to remove the remaining product. Evaporated in vacuo and recrystallised from ethanol (1 litre) cooling to 20° C. in an ice bath then filtering off immediately to give 46 g of product. MLS (mother liquors) were left over the weekend when more solid separated which was filtered off but TLC showed this to be impurity and leaving very of this in the filtrate. MLS evaporated and recrystallised from ethanol (140 ml) to give 9.4 g of product. NMR and LC/MS of both products identical. (total yield of 55.4 g).

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