Organic Syntheses, CV 3, 813
Submitted by Herbert E. Carter and Harold D. West.
Checked by Nathan L. Drake and William A. Stanton.
1. Procedure
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. (
88–93% 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.
B.
dl-Threonine. 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. (
85–90% based on the
formyl-dl-O-methylthreonine) of pure
dl-threonine, melting with decomposition at
234–235° (Note
14).
2. Notes
2. The
crotonic acid was obtained from the Niacet Chemical Company and used without purification.
3. 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.
4. 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.
5. 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.
6. 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.
7. All the concentrations under reduced pressure required in this preparation may be carried out at the pressure provided by an efficient
water pump.
8. 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.
9. If a mixture of
dl-threonine and
dl-allothreonine 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.
10. 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.
12. Crude
dl-allothreonine 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.
dl-Allothreonine of this purity melts at
242–243°.
13. Constant-boiling
hydrobromic acid can be recovered by fractionating the distillate at atmospheric pressure.
14. 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.
3. Discussion
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved