A. Methyl α-bromo-β-methoxypropionate. In a 5-l. flask is placed 450 g. of a 60% solution of methyl acrylate in methanol (Note 1) containing 3.1 moles of methyl acrylate (Note 2). To this solution are added 180 g. of methanol and 960 g. (3 moles) of mercuric acetate (Note 3). The mixture is allowed to stand at room temperature for 3 days with occasional shaking (Note 4). The flask is cooled in an ice bath, and a solution of 360 g. (3 moles) of potassium bromide in 1.2 l. of water is added with stirring during 15 minutes. The heavy oil that separates is extracted with 2.4 l. of chloroform (Note 5), and the aqueous layer is again extracted with 600 ml. of chloroform. The chloroform solutions are combined, washed three times with water, and carefully dried over anhydrous magnesium sulfate (Note 6).

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. (81–86% 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).

C. dl-Serine. 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 ether, 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.

The over-all yield is 30 to 40% of the theoretical amount based on the mercuric acetate (Note 21).