An Improved Procedure for the Large Scale Preparation of 5-Bromo-2-Hydroxynicotinic Acid [5-Bromo-3-Carboxy-2(1H)-Pyridone]

Abstract

Bromination of 2-hydroxynicotinic acid is conveniently carried out on a large scale using sodium hypobromite generated from sodium bromide and commercial bleach solution. This procedure safely provides high yields of pure 5-bromo-2-hydroxynicotinic acid [5-bromo-3-carboxy-2(1H)-pyridone], without use of hazardous elemental bromine.

Key words

bromine - electrophilic aromatic substitution - pyridine - bromination - hypobromite - combinatorial chemistry

References

• 1 Zou J.-W. Li J.-B. Zhu L.-G. Yu Q.-S. Lin R.-S. Gaodeng Xuexiao Huaxue Xuebao  1999,  20:  1784 ; Chem. Abstr. 2000, 132, 78260
• 2 Tee OS. Paventi M. J. Am. Chem. Soc.  1982,  104:  4142 
• 3 Repolles Moliner J, Pubill Coy F, Cabeza Lorente L, and Malet Falco C. inventors; Patent WO  9215608.  ; Chem. Abstr. 1993, 81446
• 4 Friary RJ, Schwerdt JH, and Ganguly AK. inventors; US Patent 5 034  531.  ; Chem. Abstr. 1991, 115, 232221
• 5 Cale AD. Gero TW. Walker KR. Lo YS. Welstead WJ. Jaques LW. Johnson AF. Leonard CA. Nolan JC. Johnson DN. J. Med. Chem.  1989,  32:  2178 
• 6a Gero TW. Jaques LW. Mays RP. Reid DH. Shamblee DA. Lo YS. Synth. Commun.  1989,  19:  553 
• 6b Lo YS. inventors; US Patent  4 960 896.  ; Chem. Abstr. 1991, 114, 164023
• 8a Senanayake CH. Fredenburgh LE. Reamer RA. Larsen RD. Verhoeven TR. Reider PJ. J. Am. Chem. Soc.  1994,  116:  7947 
• 8b The use of N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin in aqueous alkali has been reported for the bromination of electron rich aromatics: Auerbach J. Weissman SA. Blacklock TJ. Angeles MR. Hoogsteen K. Tetrahedron Lett.  1993,  34:  931 
• 9 Fieser LF. Fieser M. Reagents for Organic Synthesis   Vol. 1:  Wiley; New York: 1967.  p.1083 
• 11 Kornblum N. Coffey GP. J. Org. Chem.  1966,  31:  3447 

7

The reaction of elemental Br₂ with NaOH solutions to produce NaOBr is highly exothermic, and requires careful temperature control to avoid thermal decomposition.

10

Product 1 is easily separated from unreacted starting material 2 during the acidic aqueous workup. On the other hand, separation of 1 from dibrominated material 3 requires several triturations and is much less efficient.