Sulfuric Acid → (5-Bromo-3-pyridinyl)methanol

The manner in which certain 5-substituted-3-pyridyl compounds of the present invention can be synthetically produced can vary. For example, 5-bromo-3-pyridyl compounds can be prepared using a combination of synthetic techniques known in the art. 5-Bromo-substituted analogs of 2-(3-pyridyl)-1-azabicyclo[2.2.1]heptane, 2-(3-pyridyl)-1-azabicyclo[2.2.2]octane, 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane, 7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane, 8-(3-pyridyl)-1-azabicyclo[3.2.1]octane and 7-(3-pyridyl)-1-azabicyclo[3.2.2]nonanc can all be prepared using synthetic methodology outlined in Scheme 1 and the corresponding 5-bromo intermediates. 5-Bromonicotinic acid, which is commercially available from Aldrich, is a convenient starting material for the synthesis of 5-bromo-3-(aminomethyl)pyridine, which is the precursor of the 5-bromo analog of A. The 5-bromonicotinic acid is converted to the mixed anhydride with ethyl chloroformate and reduced with lithium aluminum hydride in tetrahydrofuran at −78° C., to afford 5-bromo-3-(hydroxymethyl)pyridine, as reported by Ashimori et al., Chem. Pharm. Bull. 38:2446 (1990). Alternatively, the 5-bromonicotinic acid is esterified in the presence of sulfuric acid and ethanol, and then the intermediate ester is reduced with sodium borohydride to yield 5-bromo-3-(hydroxymethyl)pyridine, according to the techniques reported in Natatis et al., Org. Prep. and Proc. Int. 24:143 (1992). The resulting 5-bromo-3-(hydroxymethyl)pyridine can then be converted to the 5-bromo-3-(aminomethyl)pyridine utilizing a modification of the techniques of Mitsunobu, Synthesis 1 (1981), or via treatment of 5-bromo-3-(hydroxymethyl)pyridine with thionyl chloride and reaction of the resulting 5-bromo-3-(chloromethyl)pyridine hydrochloride with aqueous ammonia/ethanol, according to North et al., WO 95/28400. 5-Bromo-3-(aminomethyl)pyridine can be converted to 3-(1-azabicyclo[2.2.2]oct-2-yl)-5-bromopyridine using methods described in U.S. Pat. No. 5,510,355 to Bencherif et al., the disclosures of which are hereby incorporated by reference in its entirety.

ORD record

ord-9f58c94b4f29410a9c80a9aa998e7b78

Source dataset

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07214686B2