Organic Syntheses, Coll. Vol. 3, p.774 (1955); Vol. 20, p.81 (1940).
The solution, filtered to remove the drying agent, is placed in a 4-l. beaker
and warmed to 50°. The beaker is then exposed to direct sunlight (Note 7)
, and 450 g. (2.81 moles) of bromine
is added with stirring (Note 8)
as fast as it is used. The reaction starts slowly but accelerates rapidly, and considerable heat is evolved. The temperature of the solution should be kept below 55° (Note 9)
. The bromination usually requires 20–30 minutes. At the conclusion of the reaction, the flask is cooled for 15 minutes in an ice-salt bath
, and the mercuric bromide
is separated by filtration. The chloroform
is removed by distillation under reduced pressure through a 20-in. column
, and the residue is fractionally distilled under reduced pressure from a modified Claisen flask
. The yield is 480–510 g.
based on the mercuric acetate
) of a product boiling at 70–80° at 6 mm.
This material contains 5–10% of methyl α,β-dibromopropionate
, which is not readily removed. Since the impurity causes no trouble in the synthesis of serine
, the crude bromo ester is used in succeeding steps (Note 10)
B. α-Bromo-β-methoxypropionic acid
. Eight hundred grams of the bromo ester
and 1 l. of 0.5 N sodium hydroxide
are placed in a 5 l. three-necked flask
equipped with an efficient stirrer and a separatory funnel
, and cooled with running tap water. The stirrer is started, and 800 ml. of 5 N sodium hydroxide
is added during the course of 2 hours. After the addition is complete, the solution is stirred for 1 hour and then neutralized with an equivalent quantity of sulfuric acid (Note 11)
. The neutralized solution is extracted once with a 1-l. portion, and three times with 500-ml. portions, of ether
. The ether
extracts are combined, washed once with a cold saturated solution of sodium sulfate
, and dried over anhydrous sodium sulfate
; the ether
is removed by distillation (Note 12)
. There remains 700–750 g.
of crude bromo acid which is used without purification in the preparation of serine (Note 13)
. One-half (350–375 g.) of the crude bromomethoxypropionic acid
prepared from the saponification of 800 g. of methyl α-bromo-β-methoxypropionate
is heated with 3.5 l. of concentrated ammonium hydroxide
in a glass-lined autoclave (Note 14)
for 10–15 hours at 90–100°, and the solution from the bomb is concentrated to a thick syrup under reduced pressure (Note 15)
. Two liters of water is added, and the solution is concentrated to dryness. The cake is dissolved in 1.5 l. of 48% hydrobromic acid
and refluxed for 2.5 hours. The resulting dark solution is concentrated to a volume of about 500 ml. and then cooled under the tap. The precipitated ammonium bromide
is removed by filtration, and the filtrate is concentrated to a thick syrup (Note 16)
. One liter of water is added, and the solution is again concentrated to a thick syrup. The syrupy residue is dissolved in 375 ml. of warm water, and ammonium hydroxide
is added carefully until a faint odor of ammonia
persists after vigorous shaking. One and one-half liters of absolute ethanol
is then added slowly (Note 17)
, and the mixture is allowed to stand overnight. The crude serine
is filtered and the filtrate discarded. The precipitate is dissolved in 500 ml. of boiling water (Note 18)
, heated on the steam cone for 10 minutes with 10–15 g. of Darco (Note 19)
, and then filtered. Five hundred milliliters of absolute ethanol
is added to the filtrate slowly with stirring. The mixture is cooled to 0° and is kept at this temperature for 1 hour with occasional stirring to ensure formation of a finely divided precipitate (Note 20)
. The serine
is filtered, washed with ethanol
, and air-dried. The precipitates from several runs may be combined and recrystallized as above from 50% ethanol
until a white product is obtained (one or two recrystallizations).
All the filtrates should be combined and evaporated to dryness under reduced pressure, and the residue should be recrystallized as above. The last concentrates (including filter paper and Darco
washings), if quite dark, may be precipitated from 70% ethanol
before recrystallizing. By this process a nearly quantitative recovery may be effected.
If the methyl acrylate
solution has stood for some time, it is advisable to use a 10% excess, since the solution slowly deteriorates. A low yield of bromo ester is usually caused by insufficient methyl acrylate
Six hundred and forty-eight grams (3 moles) of mercuric oxide
and 345 ml. (360 g., 6 moles) of acetic acid
may be used just as satisfactorily as mercuric acetate
. The solution of these substances should be cooled in an ice bath and vigorously shaken for several minutes after the reagents have been mixed, since the reaction of mercuric oxide
with acetic acid
produces considerable heat.
At this time there is still a small amount of undissolved mercuric acetate
(and mercuric oxide
, if used). Longer standing does not improve the yield.
All solutions of the mercury compounds should be handled with care, as they are extremely vesicant to some individuals.
The brominations proceed more smoothly if the chloroform
solution is washed free of methanol
The bromination may be carried out just as satisfactorily with the light from two No. 2 Photoflood lamps. These lamps should be mounted in suitable reflectors as near the surface of the solution as possible. The time required may be slightly longer.
An efficient mechanical stirrer
is required. Near the end of the bromination the precipitate of mercuric bromide
becomes quite heavy.
The temperature may be controlled by passing tap water through an 8-mm. glass cooling coil mounted in the beaker. The bromination proceeds rapidly at 45–55°, rather slowly at 35–40°, and practically ceases below 30°.
The crude ester may be used directly in the preparation of serine
. However, greater ease of purification and slightly better yields make it advantageous to prepare the free acid. Pure methyl α-bromo-β-methoxypropionate
is obtained by fractionally distilling the crude material under reduced pressure through a Widmer column
. From 100 g. of crude material there is obtained 80–90 g.
of pure ester, b.p. 73–75°/6 mm.
It is advisable to keep the temperature below 30° during both the hydrolysis and neutralization.
The acid should not be heated for long periods. The last traces of ether
should be removed under reduced pressure.
The crude bromo acid on standing 2–3 days may deposit an amorphous solid which is probably a polymerization product of α-bromoacrylic acid
. If this is removed before the bromo acid is aminated, the subsequent purification of serine
is much easier.
The checkers employed a simple autoclave, constructed as follows: A piece of 10-in. steam pipe 11 in. long and threaded at both ends was closed at one end by a standard pipe cap. A standard flange was screwed to the other end, and a blank companion flange seating on an "ammonia gasket" provided the closure for the top of the autoclave. A Pyrex battery jar 10 in. high and 8.5 in. in diameter fitted loosely in the pipe and was protected from breakage due to contact with the sides and bottom of the pressure vessel by rings made of rubber tubing. The battery jar was covered with a loosely fitting germinating dish to prevent condensate from the top from dripping into the reaction mixture. After the bromo acid had been introduced into the battery jar, concentrated ammonia
was poured into the annular space between the jar and the pipe to provide better heat transfer. The autoclave was heated in a wash tub containing water which was kept boiling by a steam coil.
All the concentrations under reduced pressure required in this preparation were carried out with the aid of an efficient water pump
The distillate may be redistilled at atmospheric pressure to recover the hydrobromic acid
Absolute ethanol (200 ml.)
is added to the warm (60–70°) solution, and the sides of the flask are scratched to induce crystallization; the remainder of the ethanol
is then added in large portions with stirring over a period of 1 hour.
is soluble in water to the extent of 50 g. per liter at 25°, 200 g. at 80°, and approximately 30 g. at 5–10°. The presence of impurities, however, will increase its solubility greatly.
is not so satisfactory as Darco
Slow precipitation tends to give large crystals with resulting inclusion of colored impurities.
The yield is directly dependent upon the quality of the methyl acrylate
has been prepared by the Strecker method from glycol aldehyde1
and from ethoxyacetaldehyde2,3,4
by the condensation of ethyl formate
with ethyl hippurate
followed by reduction and hydrolysis,5,6
from the reaction product of chloromethyl ether
with ethyl sodium phthalimidomalonate
by amination of α-bromo-β-methoxypropionic acid
with subsequent demethylation,8
by hydrolysis of 5-(methoxymethyl) hydantoin
by hydrolysis of ethyl α-acetamido-β-hydroxypropionate
by hydrogenolysis of N-benzylserine
and by reduction of the 2,4-dinitrophenylhydrazone of hydroxypyruvic acid
This preparation is referenced from:
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