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).