6-Hydroxynicotinic Acid

[5006-66-6]  · C6H5NO3  · 6-Hydroxynicotinic Acid  · (MW 139.12)

(building block for the synthesis of pyridine derivatives useful as agrochemicals, pharmaceuticals, liquid crystals; metal complexing agent)

Physical Data: mp 314-316 °C (dec); pKa1 3.8, pKa2 10.8.

Solubility: sol DMSO, DMF, aq. NaOH; sol 0.6 g L-1 at 20 °C in water, 4 g L-1 in methanol; insol nonpolar organic solvents.

Form Supplied in: off-white solid, &egt;98% purity; impurities: max. 0.5% nicotinic acid, 0.3% water.

Analysis of Reagent Purity: HPLC, Karl Fischer (H2O).

Preparative Methods: industrially, through bacterial oxidation of nicotinic acid1 or 3-cyanopyridine;2 from coumalic acid and NH3.3

Handling, Storage, and Precautions: LD50 (oral, rat) >5000 mg kg-1; no special precautions are necessary.

Reactivity.

6-Hydroxynicotinic acid displays reactivity patterns typical for both pyridones4a and pyridinecarboxylic acids.4b The carboxyl function can be transformed without affecting the pyridone moiety. Esters can be prepared either by the normal Fischer esterification procedure or through various known activation methods5a (e.g. N,N-Carbonyldiimidazole),5b including selective chlorination with Thionyl Chloride.5c The same methods can be used to prepare amides or hydrazides of 6-hydroxynicotinic acid (eq 1).

6-Hydroxynicotinic acid chloride can also be hydrogenated to the corresponding aldehyde or alcohol under Rosenmund conditions.6a,b Moreover, the carboxyl group can be converted into a trifluoromethyl group using Sulfur Tetrafluoride.7

As a pyridone, 6-hydroxynicotinic acid undergoes N-alkylation (eq 2) in good yields (typically, 70 and 84% for R1 = Me and Bn, respectively)8a,b and O-acylation (eq 2), as well as substitution by strong electrophiles in the ortho position (eq 3) under mild conditions (0 °C). In this case, the carboxyl group can be easily substituted by a second electrophile, particularly under basic conditions.

Halogens (Cl2, Br2, I2) or hypohalites, as well as nitric acid, have been used as electrophiles to produce a variety of disubstituted pyridones, e.g. E1 = Cl,9a Br,9b NO2,9c E1 = E2 = Cl,9d I,9e NO29f (eq 3). Such pyridones, like 6-hydroxynicotinic acid itself, can be converted into chloro-10a,b,c or bromopyridines10d through halodehydroxylation. Subsequently, the halopyridines can be engaged in nucleophilic substitutions with alcohols, amines, phenols, thiols, fluoride, and silicon11 or carbon nucleophiles, to produce diversely substituted pyridines (eq 4). Finally, 6-hydroxynicotinic acid can take part as the diene in Diels-Alder cycloadditions with electron-deficient dienophiles.12

Applications.

6-Hydroxynicotinic acid has been used as a complexing agent to elute metal-bound proteins in affinity chromatography of enzymes.13 A few important synthetic derivatives of 6-hydroxynicotinic acid are illustrated below. Optically active esters of type (1) (eqs 1 and 2) (R1 = aryl, R2 = chiral alkyl) are used as components of liquid crystals and optical switching devices.14 A large number of patents describe the preparation and use of chloropyridines of general structure (2) (X = primary or secondary amine) as insecticides.15 Compounds (2) have been prepared on an industrial scale from the corresponding alcohol (2) (X = OH) derived from 6-chloronicotinic acid chloride16 (eq 4). The compound (3), also derived from 6-chloronicotinic acid, represents a class of nicotinamide analogs useful for the treatment of psoriasis in humans.17

A great variety of 6-hydroxy- or 6-aminonicotinic amides have shown potentially useful biological activities.18 2,3,5-Trichloropyridine has been prepared on a large scale from 6-hydroxynicotinic acid (eqs 3 and 4) as an intermediate for the production of herbicides19 of structure (4). A further application of the ring chlorination (eq 3) is illustrated by the synthesis of growth-stimulating agents (5) via 5,6-dichloronicotinic acid.20a,b The N-alkylation of 6-hydroxynicotinic acid or derivatives (eq 2) has served notably to prepare nucleoside analogs (e.g. 6).21

Related Reagents.

2-Ethoxypyridine 1-Oxide; N-Hydroxypiperidine; 3-Hydroxypyridine; 2-Hydroxypyridine; Pyridine; Pyridine N-Oxide; 2-Pyridinethiol.


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3. Boyer, J. H.; Schoen, W. OS 1956, 36, 44.
4. (a) Tieckelmann, H. In The Chemistry of Heterocyclic Compounds; Weissberger, A.; Taylor, E. C., Eds.; Wiley: 1974; Vol. 14, Suppl. Part 3, Chapter 12, p 597. (b) Pollak, P. I.; Windholz, M. ibid., Chapter 10, p 257.
5. (a) MOC 1985, E5/1. (b) Hoffmann, S.; Witkowski, W.; Schubert, H. ZC 1974, 14, 154 (CA 1974, 81, 136 565). (c) Meyer H., M 1901, 22, 440.
6. (a) Werbitzky, O.; Studer, P. (Lonza AG) Eur. Patent 569 947, 1993 (CA 1994, 120, 134 302). (b) Mosettig, E.; Mozingo, R. OR 1949, 4, 362.
7. Bailey, T. D. (Reilly) U.S. Patent. Appl. 4 230 864, 1980 (CA 1981, 94, 121 342).
8. (a) Chung, N. M.; Tieckelmann, H., JOC 1970, 35, 2517. (b) Mukherjee, R.; Chatterjee, A. T 1966, 22, 1461.
9. (a) Burson, R. L. (Dow Chemical) Eur. Patent 136 593, 1985 (CA 1985, 103, 104 856). (b) Thompson, W. J.; Gaudino, J. JOC 1984, 49, 5237. (c) Berrie, A. H.; Newbold, G. T.; Spring, F. S. JCS 1951, 2590. (d) Quarroz, D. (Lonza AG) Eur. Patent 206 293, 1986 (CA 1987, 107, 39 618). (e) Tchitchibabin, A. E., Kirsanov, A. W. CB 1924, 57, 1161.
10. (a) Forrest, H. S.; Walker, J. JCS 1948, 1939. (b) Quarroz, D. (Lonza AG) Swiss Patent 664 754, 1988 (CA 1989, 110, 7953). (c) Shvekhgeimer, M. G.; Kobrakov, K. I.; Sychev, S. S.; Promonenkov, V. K. KGS 1987, 1082 (CA 1988, 109, 37 714). (d) Quallich, G. J.; Fox, D. E.; Friedmann, R. C.; Murtiashaw, C. W. JOC 1992, 57, 761.
11. Effenberger, F.; Krebs, A.; Willrett, P. CB 1992, 125, 1131.
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15. Kristiansen, O.; Gsell, L.; Maienfisch, P. (Ciba-Geigy) Eur. Patent 483 052, 1992 (CA 1992, 117, 90 281); Uneme, H.; Higuchi, N.; Minamida, I.; Okauchi, T. (Takeda) Jpn. Patent 0 459 763, 1992 (CA 1992, 117, 48 541); Mete, A.; Chan, L. C. (Shell) Eur. Patent 425 030, 1991 (CA 1991, 115, 135 921); Diehr, H. J. (Bayer) Ger. Patent 3 830 238, 1990 (CA 1990, 113, 115 302).
16. Carlson, L. A.; Hedbom, C.; Helgstrand, E.; Misiorny, A.; Sjöberg, B.; Stjernström, N. E.; Westin, G. Acta Pharm. Suec. 1972, 9, 411.
17. Yu, R. J.; Van Scott, E. J. U.S. Patent 4 258 052, 1981 (CA 1981, 95, 49 414).
18. E.g. anti-angina: Nagano, H.; Sakai, K.; Kamiyama, H. (Chuga Pharm. Ltd) Jpn. Patent 62 286 968, 1987 (CA 1988, 108, 150 164); antimicrobial: El-Naggar, A. M.; El-Haddad, A. F.; Badie, M. F.; Latif, M. S.; Gommaa, A. M. Afinidad 1983, 40, 379; antihypertensive: Bergmann, R.; Gericke, R. JMC 1990, 33, 492.
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20. (a) Lindel, H.; Hallenbach, W.; Bonse, G.; Böshagen, H.; Stoltefuss, J.; Berschauer, F.; de Jong, A.; Scheer, M. (Bayer) Ger. Patent 3 615 293, 1987 (CA 1988, 108, 112 249. (b) Kuo, D. L. T 1992, 48, 9233.
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Jean-Paul Roduit

Lonza, Visp, Switzerland



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