Submitted by H. R. Snyder, J. S. Buck, and W. S. Ide.
Checked by John R. Johnson and P. W. Vittum.
1. Procedure
(
A)
Methyl Homoveratrate.—In a
3-l. round-bottomed flask are placed
1 l. of 10 per cent sodium hydroxide solution and
200 g. (0.65 mole) of the azlactone of α-benzoylamino-β-(3,4-dimethoxyphenyl) acrylic acid (m.p.
149–150°)
(p. 55). The flask is fitted with a
reflux condenser and immersed in an
oil bath so that the inner level is lower than the oil level of the bath (Note
1). The mixture is refluxed gently for six to seven hours, until the evolution of
ammonia is complete. The resulting solution contains the
sodium salts of 3,4-dimethoxyphenylpyruvic acid (Note
2) and
benzoic acid.
To the above aqueous solution, contained in a
2-l. wide-mouthed Erlenmeyer flask, is added
85 cc. of 40 per cent sodium hydroxide solution. The flask is equipped with a
mechanical stirrer and is cooled in an
ice-salt mixture. With stirring,
75 cc. of 30 per cent hydrogen peroxide (Merck's "Superoxol") diluted with 75 cc. of water is added at such a rate that the temperature does not rise above 15°. After standing for about ten hours at room temperature (preferably overnight) the solution is acidified by the cautious addition (Note
3) of
450 cc. of concentrated hydrochloric acid (sp. gr. 1.19). The warm acid solution is extracted with one
400-cc. portion and two 200-cc. portions of warm benzene. The combined
benzene extracts are dried over anhydrous
magnesium sulfate and filtered through a
cotton plug into a 3-l. round-bottomed flask.
The
benzene is removed by distillation,
1 l. of methyl alcohol (Note 4) containing 15 cc. of concentrated sulfuric acid is added, and the flask is fitted with an
efficient reflux condenser provided with a drying tube. After refluxing gently for five hours the condenser is set downward for distillation and the
methyl alcohol is distilled from a
steam bath. The residual liquid is cooled and shaken with 500 cc. of cold water. The mixture is transferred to a
separatory funnel and extracted with one
400-cc. portion and two 200-cc. portions of benzene. The combined extracts are washed twice with
100-cc. portions of 10 per cent sodium carbonate solution and finally with two 100-cc. portions of water. After the
benzene solution has been dried over anhydrous
magnesium sulfate, it is transferred to a
2-l. flask and the
benzene is distilled, using a steam bath. The residual mixture of
methyl benzoate and
methyl homoveratrate is transferred to a
250-cc. Claisen flask and distilled under reduced pressure. The first fraction, collected up to 100° at 16 mm., is
methyl benzoate (b.p.
87°/16 mm.) and weighs about
75 g. (
85 per cent of the theoretical amount). After a small intermediate fraction of 2–3 g., pure
methyl homoveratrate is collected at
176–178°/16 mm. or
129–131°/1 mm. The yield is
76–82 g. (
56–60 per cent of the theoretical amount based on the azlactone).
(
B)
Homoveratric Acid.—In a
500-cc. round-bottomed flask are placed
250 cc. of 10 per cent sodium hydroxide solution and
76 g. (0.36 mole) of methyl homoveratrate. The flask is fitted with a reflux condenser and the mixture is boiled gently. The saponification proceeds rapidly, and the ester layer disappears after about ten minutes. The mixture is refluxed gently for twenty minutes longer, after which the solution is cooled in an
ice bath and then poured slowly, with stirring, into a mixture of
125 cc. of concentrated hydrochloric acid and 350 g. of ice. Crystals of the
hydrate of homoveratric acid separate at once. After standing for about thirty minutes the crystalline product is filtered with suction and washed on the filter with two 25-cc. portions of ice water. The crystals are pressed thoroughly on the filter, pulverized, and allowed to stand overnight in a
vacuum desiccator containing soda lime (to remove residual
hydrochloric acid) and
calcium chloride. The yield in the saponification is almost quantitative and amounts to
70 g. (
55 per cent of the theoretical amount based on the original azlactone). This product melts at
96–97° and contains traces of
sodium chloride. For purification it is dissolved in
350 cc. of hot benzene and the solution is filtered. To the hot filtrate is added
150 cc. of hot ligroin (b.p.
70–80°), and the solution is covered with a
watch glass and allowed to cool slowly. After standing for several hours (preferably overnight) in a cool place, the crystals are filtered with suction and washed with a cold solution of
35 cc. of benzene and
15 cc. of ligroin, followed by
50 cc. of cold petroleum ether. The solvent is removed as completely as possible by pressing on the filter and finally by allowing the product to stand in a vacuum desiccator (Note
5). The purified
homoveratric acid weighs
65 g. (
51 per cent of the theoretical amount based on the original azlactone) and melts sharply at
98°.
2. Notes
1. The inner level is kept below that of the oil in order to avoid the otherwise uncontrollable bumping of the solution.
2.
3,4-Dimethoxyphenylpyruvic acid can be isolated from this solution in the following way (J. S. Buck and W. S. Ide). The aqueous solution of the sodium salts is saturated with
sulfur dioxide, while the temperature is maintained below 40°. The
benzoic acid precipitates and is filtered with suction and washed with a small quantity of water. The filtrate and washings are placed in a 3-l. round-bottomed flask provided with a mechanical stirrer and heated to boiling. Concentrated
hydrochloric acid is added cautiously, with stirring, until present in excess. The acid must be added carefully since the solution tends to become supersaturated with
sulfur dioxide, which is subsequently liberated with violence. A heavy precipitate of
3,4-dimethoxyphenylpyruvic acid separates; after the reaction mixture has cooled, this is filtered with suction, dried, and washed with two
50-cc. portions of ether. The yield of
3,4-dimethoxyphenylpyruvic acid is
110–116 g. (
76–80 per cent of the theoretical amount), and the product melts at
181–184°. It can be purified by crystallization from glacial
acetic acid.
An alternative procedure for the preparation of
homoveratric acid (J. S. Buck and W. S. Ide) consists in isolating the
pyruvic acid and subjecting it to the oxidation given in the second paragraph of part (
A). This variation obviates the esterification but in the hands of the checkers did not prove so satisfactory as the one described.
3. Large quantities of
carbon dioxide are evolved during the addition of the acid.
4. It is unnecessary to use especially dried
methyl alcohol. High-grade commercial
methanol is quite satisfactory.
5. Since the acid forms a hydrate it is advisable to minimize the exposure of the acid to atmospheric moisture.
3. Discussion
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