Org. Synth. 1956, 36, 44
DOI: 10.15227/orgsyn.036.0044
6-HYDROXYNICOTINIC ACID
[Nicotinic acid, 6-hydroxy-]
Submitted by J. H. Boyer and W. Schoen
1.
Checked by T. L. Cairns and W. J. Linn.
1. Procedure
A.
Methyl coumalate. In a
500-ml. round-bottomed flask provided with a
thermometer is placed
139 ml. of concentrated sulfuric acid. To the acid is added, with swirling,
50 g. (0.36 mole) of pulverized coumalic acid (
p. 201) in small portions. The reaction is slightly exothermic, and the mixture is maintained between 20° and 30° by occasional immersion of the flask into an
ice bath.
Methanol (70 ml.) is then added in small portions with frequent swirling, and the temperature is held between 25° and 35°. The mixture is heated on a
steam bath for 1 hour, cooled to about 40°, and poured slowly with stirring into 800 ml. of water in a
2-l. beaker while the temperature is maintained below 40° by an ice bath
(Note 1). Anhydrous
sodium carbonate is added in small portions with stirring until the mixture is slightly alkaline
(Note 2). The precipitated ester is freed of inorganic salts by slurrying four times with 100-ml. portions of cold water, filtered, and air-dried overnight. The yield of
methyl coumalate, m.p.
68–70°, is
17.5–24.5 g. (
32–45%). This crude product is used for the preparation of
6-hydroxynicotinic acid.
B. 6-Hydroxynicotinic acid. In a 500-ml. beaker provided with a thermometer, magnetic stirring, and external cooling is placed 117 ml. of 14% ammonium hydroxide. With stirring, 45 g. (0.29 mole) of methyl coumalate is added over a period of 10 minutes, during which time the solution is kept below 20°. Stirring is continued for an additional 45 minutes at about 20° (Note 3).
A solution of 600 ml. of approximately 17% aqueous sodium hydroxide is placed in a 2-l. beaker and heated almost to the boiling point. At the end of the 45-minute period, the ammoniacal solution is added to the hot sodium hydroxide solution, and the mixture is heated rapidly to the boiling point. After it has boiled vigorously for 5 minutes, the stirred solution is cooled in an ice bath to room temperature. With the temperature held below 30°, concentrated hydrochloric acid is added with stirring until the solution is strongly acid (Note 4). The heavy, yellow, microcrystalline solid which separates after stirring and cooling for about an hour is collected on a Büchner funnel, washed twice with water, and dried at 80°. The yield of bright yellow 6-hydroxynicotinic acid, m.p. 299–300° (dec., uncor.), is 29–37 g. (72–91%) (Note 5).
2. Notes
1.
A turbid, brown solution containing a small amount of fine precipitate is obtained.
2.
A small amount of curdy, brown precipitate is obtained at first. About
220 g. of anhydrous sodium carbonate is required.
3.
Most of the ester dissolves; a turbid, red solution is formed.
4.
About 250 ml. of acid is required.
5.
The product is sufficiently pure for further synthetic work; a purer product may be obtained by recrystallization from
50% aqueous acetic acid.
3. Discussion
The procedure for preparing
methyl coumalate is based on a method described by von Pechmann.
2 Methyl coumalate has also been prepared by direct esterification of the reaction mixture from
malic acid and fuming
sulfuric acid3 and from
coumalyl chloride and
methanol.
4The procedure for preparing
6-hydroxynicotinic acid is also based on a method described by von Pechmann.
5 6-Hydroxynicotinic acid has also been prepared by decarboxylation of
6-hydroxy-2,3-pyridinedicarboxylic acid;
6,7 by heating
6-hydrazinonicotinic acid or its hydrazide with
hydrochloric acid;
8 by the action of
carbon dioxide on the
sodium salt of α-pyridone at 180–200° and 20 atm.;
9 by heating the nitrile of
6-chloronicotinic acid with alcoholic
sodium hydroxide or
hydrochloric acid;
10 from
6-aminonicotinic acid;
11,12 by the prolonged action of concentrated
ammonium hydroxide on
methyl coumalate;
3 and by carbonating
2-hydroxypyridine in the presence of
potassium carbonate.
13
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
potassium carbonate (584-08-7)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
methanol (67-56-1)
sodium hydroxide (1310-73-2)
sodium carbonate (497-19-8)
carbon dioxide (124-38-9)
ammonium hydroxide (1336-21-6)
malic acid (617-48-1)
Coumalic acid (500-05-0)
6-Hydroxynicotinic acid,
Nicotinic acid, 6-hydroxy- (5006-66-6)
Methyl coumalate (6018-41-3)
coumalyl chloride
6-hydrazinonicotinic acid
6-chloronicotinic acid (5326-23-8)
6-aminonicotinic acid (3167-49-5)
2-hydroxypyridine (142-08-5)
6-hydroxy-2,3-pyridinedicarboxylic acid
sodium salt of α-pyridone
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