Organic Syntheses, Coll. Vol. 3, p.813 (1955); Vol. 20, p.101 (1940).
A. α-Bromo-β-methoxy-n-butyric acid.
In a 5-l. flask
are placed 3 l. of methanol
, 640 g. (2 moles) of mercuric acetate (Note 1)
, and 172 g. (2 moles) of crotonic acid (Note 2)
. The flask is warmed on a steam cone and shaken vigorously until the mercuric acetate
dissolves (about 10 minutes). The solution is allowed to stand at room temperature for 48 hours (Note 3)
, then the precipitate is filtered, washed twice with 300-ml. portions of methanol
, and air-dried. The yield is 625–650 g. (Note 4)
. This material is powdered and dissolved in a solution of 360 g. (3 moles) of potassium bromide
in 2 l. of water, and the solution is placed in a 4-l. beaker
, which is cooled in an ice bath
and exposed to direct sunlight (Note 5)
. A solution of 320 g. (2 moles) of bromine
and 360 g. (3 moles) of potassium bromide
in 600 ml. of water is added with stirring during 20–40 minutes, a large excess of bromine
being avoided. After 10–15 minutes' standing, any excess bromine
is destroyed with sodium bisulfite
. The bromo acids are isolated as follows: The solution is extracted once with 300 ml. of ether
to remove a small amount of lachrymatory material and, after acidification with 400 ml. of 40% hydrobromic acid
, is extracted again with six 800-ml. portions of ether
. The ether
extracts are combined, washed once with a small volume of cold water, and dried over anhydrous sodium sulfate
. The ether
is removed by distillation, leaving the crude bromo acid mixture.
The yield of crude bromo acids is 350–370 g.
based on the crotonic acid
used in the first step). This material is used without purification in the preparation of aminomethoxybutyric acid
The crude bromo acids may be freed from impurities by fractionation under reduced pressure. The fraction distilling below 125°/10 mm. (105°/3 mm.) is discarded; the remainder distils at 125–128°/10 mm. (105–107°/3 mm.) and consists of a mixture of stereoisomeric acids. The yield is 75–85%
based on the crotonic acid
used in the first step.
One hundred and seventy-five grams of crude bromomethoxybutyric acid
is heated with 2 l. of concentrated ammonium hydroxide
for 6 hours at 90–100° in a glass-lined autoclave (p. 777) (Note 6)
, The solution is concentrated to a thick gum under reduced pressure (Note 7)
, water is added, and the solution is reconcentrated under reduced pressure. The residue is allowed to stand under acetone
with frequent shaking (Note 8)
until the material has crystallized completely (1–2 days). The acetone
is decanted, and the residue dissolved in 1 l. of 85–90% formic acid (Note 9)
. The solution is warmed to 45°, and 350 g. (330 ml.) of acetic anhydride
is added with stirring during 10 minutes. The heat of reaction causes the temperature of the solution to rise to 70–80°, and the temperature of the mixture is maintained within this range for about 15 minutes. The solution is next evaporated to dryness under reduced pressure. The residue is dissolved, while being warmed on the steam bath
, in the minimum amount of water (Note 10)
, and the solution is cooled overnight in the icebox
. The crystals are filtered and air-dried. This material is a mixture of formyl derivatives (Note 11)
. One recrystallization from 150 ml. of hot water yields about 25 g.
of practically pure formyl-dl-O-methylthreonine
melting at 174–176°
. An additional 3–5 g.
is obtained by working up the filtrates. The yield is 25% (Note 12)
Twenty-five grams (0.16 mole) of formyl-dl-O-methylthreonine
is refluxed for 2 hours with 360 ml. of constant-boiling hydrobromic acid
. The solution is concentrated under reduced pressure (Note 13)
. Sufficient water is added to dissolve all the residue, and the solution is reconcentrated under reduced pressure. The gummy residue is next dissolved in 450 ml. of absolute ethanol
, and concentrated ammonium hydroxide
is added until the odor of ammonia
persists after vigorous shaking. The solution is cooled in the icebox overnight, and the crystals are filtered and dissolved in 3 volumes of hot water (about 5 ml. of water per gram of crude material). Seven volumes of absolute ethanol
are added, and the solution is cooled to room temperature with scratching of the flask to induce crystallization. It is then cooled in an icebox overnight. The crystals are filtered and washed twice with 90-ml. portions of absolute ethanol
and once with ether
. The yield is 18–20 g.
based on the formyl-dl-O-methylthreonine
) of pure dl-threonine
, melting with decomposition at 234–235° (Note 14)
The crotonic acid was obtained from the Niacet Chemical Company
and used without purification.
It is advisable to scratch the flask with a glass rod
after 3–4 hours. This usually initiates precipitation of the addition product in a finely divided form. If this is not done, the addition product may crystallize slowly on the sides of the flask in a cake which is removed only with the greatest difficulty. It is also advantageous to stir the mixture mechanically for several hours after crystallization begins in order to prevent caking.
The exact yield cannot be calculated, since the structure of the addition product is unknown. The yield is almost quantitative, however, since only a small amount of mercury
remains in the filtrate.
The bromination can be carried out equally successfully under the illumination of two No. 2 Photoflood lamps in suitable reflectors placed directly above the surface of the liquid. Under these conditions, however, the addition of the bromine
requires 10–15 minutes longer.
According to the submitters the amination can be carried out in ordinary 500-ml. glass bottles if the temperature does not exceed 85°. The time of heating should then be extended to 8–10 hours.
All the concentrations under reduced pressure required in this preparation may be carried out at the pressure provided by an efficient water pump
The material, if allowed to stand without shaking, solidifies to a hard cake. The shaking furthers extraction of certain gummy impurities which interfere with the separation to be carried out later.
If a mixture of dl-threonine
is desired instead of dl-threonine
alone, the residue may be dissolved directly in 1.2 l. of 48% hydrobromic acid
and refluxed for 2 hours. After removal of the hydrobromic acid
under reduced pressure, the gummy residue is dissolved in warm water, and concentrated ammonium hydroxide
is added slowly until a faint odor of ammonia
persists after vigorous shaking. The solution is concentrated until crystals appear, and 3–4 volumes of ethanol
is added. The acids are recrystallized by dissolving in the minimum amount of hot water (4–5 ml. per gram) and adding 4–5 volumes of ethanol
. The solution is allowed to cool and permitted to stand overnight at room temperature.
If, after solution is complete on the steam bath, 10% more water is added, the quality of the product is better, but the yield is slightly less.
may be obtained from the mother liquors by concentrating them to dryness, refluxing the residue with 10 volumes of 48% hydrobromic acid
, and working up the solution as described for dl-threonine
. The product contains a small amount of dl-threonine
which can be largely removed by three or four recrystallizations from 50% ethanol
of this purity melts at 242–243°
Constant-boiling hydrobromic acid
can be recovered by fractionating the distillate at atmospheric pressure.
The melting points obtained by the checkers were consistently 3–4° above those given. The melting points of these compounds vary with the method of determination.
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