An efficient synthesis of 2,6-dichloro-5-fluoronicotinoyl acetate (1) has been accomplished in a single step using the Blaise reaction of ethyl bromoacetate with 3-cyano-2,6-dichloro-5-fluoropyridine (4). Use of methanesulfonic acid as an in situ activator of zinc removed the induction period of the Blaise reaction to render it safe and viable for a large-scale operation.A naphthyridine ring is embedded as a key structural unit of many potent quinolone antibiotics such as enoxacin, 2 tosufloxacin, 3 trovafloxacin, 4 and gemifloxacin (Scheme 1). 5 To construct this structural segment, most of the reported syntheses employed ethyl 2,6-dichloro-5-fluoronicotinoyl acetate (1) as a key starting material that was prepared from a common synthetic route, the reaction of an acetate enolate equivalent with 2,6-dichloro-5-fluoronicotinoyl chloride (2) (Scheme 2). The reaction of magnesium enolate of diethyl malonate with the nicotinoyl chloride 2 proceeded well to give the diester intermediate 3 (R ) OEt), which was partially hydrolyzed and decarboxylated to give 1. 6 However, this process is complicated with the selective partial hydrolysis of the diester intermediate 3: the formation of the methyl ketone impurity 7 via double decarboxylations was observed as a side product. A more advanced synthesis is the use of malonate monoester, 8 which clearly removed the problems of the selective hydrolysis of the diester intermediate. The last version employed the magnesium enolate of ethyl acetoacetate as an acetate enolate equivalent, and subsequent deacetylation of the formed intermediate 3 (R ) CH 3 ) afforded 1. 9 Although the current syntheses are well established and scalable, we describe here an alternative, single-step transformation of the nitrile group of the early intermediate 4 into the -keto ester functionality of 1, employing the Blaise reaction (Scheme 3). 10 As expected, slow addition of ethyl bromoacetate to a mixture of the 3-cyanopyridine 4 and activated zinc 11 in THF Miyamoto, T.; Minamida, A.; Nishimura, Y.; Egawa, H.; Nishimura, H. Castaldi, M. J.; Chan, S.; Fox, D. E.; Keltonic, T.; McGarry, J.; Hawkins, J. M.; Norris, T.; Rose, P. R.; Sieser, J. E.; Sitter, B. J. Watson, H., Jr. The reported yield of 1 from the acid chloride 2 is 74%. See: (a) Bouzard, D.; Di Cesare, P.; Essiz, M.; Jacquet, J. P.; Ledoussal, B.; Remuzon, P.; Kessler, R. E.; Fung-Tomc, J. J. Med. Chem. 1992, 35, 518. (b) Miyamoto, T.; Matsumoto, J.-I. Chem. Pharm. Bull. 1990, 38, 3211. (7) In an acid-catalyzed decarboxylation of 3 (R ) OEt), ca. 10% (area % by HPLC) of the methyl ketone impurity was usually formed in the reaction mixture. The analysis of the isolated 1 showed ca. 2% contamination of the methyl ketone impurity. 1 H NMR data of the methyl ketone impurity: (300 MHz) δ 7.57 (d, 1H, J ) 7.3 Hz), 2.71 (s, 3H). (8) The reported yield of 1 from the acid chloride 2 is 96%. See: (a) Refer to ref 2. (b) O'Neill, B. T.; Busch, F. R.; Lehner, R. S. EP 449445, 1991. (c) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. Synthesis...