Ethyl chloroformate → (5-Bromo-3-pyridinyl)methanol

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Reaction Steps

The required aldehyde, 5-bromopyridine-3-carboxaldehyde, can be prepared from 5-bromonicotinic acid (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc.). The 5-bromonicotinic acid can be treated with ethyl chloroformate producing the mixed anhydride, which can be reduced with lithium aluminum hydride in tetrahydrofuran (THF) at −78° C., to afford 5-bromo-3-hydroxymethylpyridine, as reported by A. Ashimori et al., Chem. Pharm. Bull. 38(9): 2446-2458 (1990). Alternatively, the 5-bromonicotinic acid can be esterified in the presence of sulfuric acid and ethanol, and the intermediate ethyl ester can be reduced with an excess of sodium borohydride to yield 5-bromo-3-hydroxymethylpyridine, according to the techniques reported in C. F. Nutaitis et al., Org. Prep. and Proc. Int. 24:143-146 (1992). The resulting 5-bromo-3-hydroxymethylpyridine can then be converted to 5-bromo-3-pyridinecarboxaldehyde by Swern oxidation using oxalyl chloride and dimethylsulfoxide according to the methods of M. J. Stocks et al., Tetrahedron Lett. 36(36): 6555-6558 (1995) and A. J. Mancuso et al., J. Org Chem. 44(23): 4148-4150 (1979). The aldehyde, 4-bromopyridine-3-carboxaldehyde can be synthesized according to methodology described by Chin et al. PCT WO 94/29893 or by methodology described by Ojea et al., Synlett. 6: 622-624 (1995). 6-Bromopyridine-3-carboxaldehyde can be prepared according to procedures described in Windschief and Voegtle, Synthesis 1: 87-92 (1994) or Fey et al German Patent No. 93/4320432.

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