Hydrochloric Acid → Ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate

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Reaction Steps

1.7 g of an oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature of about 10° C. 9.8 g of ethyl 6-methyl-3-oxo-6-heptenoate in 25 cm3 of anhydrous dimethylformamide are subsequently added. The suspension is stirred for 30 minutes and the temperature is allowed to return to about 20° C., followed by the addition of 11.6 g of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone. The reaction mixture is stirred for 4 hours at a temperature of about 20° C. and is then poured into 250 cm3 of water. The aqueous phase, which is acidified by the addition of 25 cm3 of aqueous 1N hydrochloric acid solution, is extracted twice with 200 cm3 of dichloromethane. The organic phases are combined and washed twice with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue is purified by chromatography on silica [eluent:ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After crystallization in diisopropyl ether, 9.4 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate (mixture of A and B forms) are thus obtained, melting at 125° C.

Provenance & Evidence