A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1950, 30, 7
DOI: 10.15227/orgsyn.030.0007
Submitted by M. S. Dunn and B. W. Smart1.
Checked by H. T. Clarke and W. Pearlman.
1. Procedure
A. Triethyl α-phthalimidoethane-α,α,β-tricarboxylate. Three hundred and twenty-seven grams (1.0 mole) of diethyl sodium phthalimidomalonate2 and 735 g. (6.0 moles) of ethyl chloroacetate (b.p. 144–145°) are placed in a 2-l. Claisen flask fitted with a reflux condenser and rubber stoppers. The mixture is heated under reflux in an oil bath at 150–160° for 2.25 hours. The excess ethyl chloroacetate is removed by distillation at 30 mm. until the heating bath temperature reaches 150° and no more distillate is obtained (Note 1). The brown residual mass is cooled and then extracted with 1250 ml. of ether. The oil dissolves, leaving a solid residue which is separated by filtration and washed with 750 ml. of ether. The combined ether extracts are distilled to remove ether, and the residual oil is heated on a steam bath under reduced pressure (35 mm.) to remove traces of ethyl chloroacetate. The yield of triethyl α-phthalimidoethane-α,α,β-tricarboxylate, dried at 45° for 48 hours, is 373–389 g. (95–99%) (Note 2).
B. DL-Aspartic acid. A mixture of 383 g. of the above crude product, 1 l. of concentrated hydrochloric acid, 1 l. of glacial acetic acid, and 1 l. of water is boiled under reflux in a 5-l. round-bottomed flask for 2–3 hours. The reflux condenser is then replaced by a fractionating column, and the mixture is slowly distilled until the temperature at the head of the column has risen to 108°. This requires about 13 hours. The distillate amounts to 1.5 l. (Note 3).
The residual mixture is allowed to cool, and the phthalic acid which crystallizes is removed by filtration and washed with 350 ml. of 1% hydrochloric acid (Note 4). The combined filtrate and washings are distilled nearly to dryness on a steam bath under reduced pressure; the bulk of the hydrochloric and acetic acids remaining is removed by slowly adding 300 ml. of water through a dropping funnel while the distillation under reduced pressure is continued. The dark brown residue is warmed on a steam bath with 700 ml. of water, is allowed to cool, and is filtered to remove a small amount of black insoluble matter. The filtrate is decolorized with 2 g. of Norit, 200 ml. of hot water being used to wash the Norit. The volume of the combined filtrate and washings, amounting to about 1.2 l., is measured accurately, and a small portion is analyzed for chloride (Note 5). An amount of pyridine corresponding exactly to the chloride content is added, diluted with 500 ml. of 95% ethanol. The DL-aspartic acid, which crystallizes at once, is separated by filtration after the mixture has stood for 24 hours at room temperature and is washed with 50–100 ml. of cold water (Note 6).
The crude DL-aspartic acid, amounting to 58–60 g., is recrystallized from 600 ml. of hot water and yields 54 g. of pure DL-aspartic acid. The mother liquors on evaporation to about 90 ml. yield an additional 2–3 g. (Note 7). The total yield of pure colorless DL-aspartic acid is 56–57 g. (42–43%) (Note 8).
2. Notes
1. From 490 to 536 g. of ethyl chloroacetate (b.p. 144–145°) is recovered by the distillation.
2. Although this product cannot be purified by distillation, it contains almost the theoretical amount of nitrogen as shown by Kjeldahl analysis.
3. During the first few hours the distillate contains ethyl acetate; the distillate obtained during the first hour, amounting to 137 ml., distils below 99° and on saturation with sodium chloride yields 115 ml. of crude ethyl acetate.
4. The phthalic acid so obtained is brown and weighs 140–150 g.
5. The total amount of chloride found should be less than 1 mole.
6. The mother liquor contains too little DL-aspartic acid to justify its recovery. When the filtrate and washings are evaporated to a syrup and treated with 500 ml. of 95% ethanol, the pyridine hydrochloride dissolves completely, leaving 8–9 g. of crude glycine which yields little or no sparingly soluble DL-aspartic acid on treatment with a minimum quantity of cold water.
7. The final mother liquor from the recrystallization of DL-aspartic acid yields a small quantity (about 0.5 g.) of glycine.
8. The purity of the recrystallized DL-aspartic acid was established by nitrogen analysis by the Kjeldahl and Van Slyke methods. The decomposition point of this product is 325–348°.
3. Discussion
The above method for the preparation of DL-aspartic acid is a modification of one described by Dunn and Smart.3 Other methods are: the decomposition of acid ammonium malate by heat;4 the racemization of active aspartic acid5 and active asparagine;6 the reaction of maleic and fumaric acids with ammonia in a closed tube;7 the reduction of oxalacetic ester oxime;8 the reduction of silver fumarate by hydroxylamine hydrochloride;9 the reduction of nitrosuccinic ester;10 the catalytic reduction and amination of oxalacetic acid;11 the hydrolysis of triethyl α-aminoethane-α,α,β-tricarboxylate;12 the hydrolysis of β,β-dicarbethoxy-β-acetylaminopropionic acid;13 the hydrolysis of dimethyl (carbethoxy)formamidomalonate;14 the oxidation of β-(2-furyl)-α-alanine by potassium permanganate;15 and the hydrolysis of diethyl α-acetyl-α-aminosuccinate.16

References and Notes
  1. University of California, Los Angeles, California.
  2. Org. Syntheses Coll. Vol. 2, 384 (1943).
  3. Dunn and Smart, J. Biol. Chem., 89, 41 (1930).
  4. Dessaignes, Compt. rend., 30, 324 (1850); 31, 432 (1850); Wolff, Ann., 75, 293 (1850).
  5. Michael and Wing, Ber., 17, 2984 (1884); Am. Chem. J., 7, 278 (1885).
  6. Piutti, Ber., 19, 1691 (1886).
  7. Engel, Compt. rend., 104, 1805 (1887); 106, 1734 (1888); Stadnikoff, Ber., 44, 44 (1911).
  8. Piutti, Gazz. chim. ital., 17, 519 (1887).
  9. Tanatar, Ber., 29, 1477 (1896).
  10. Schmidt and Widmann, Ber., 42, 497 (1909).
  11. Knoop and Oesterlin, Z. physiol. Chem., 148, 294 (1925).
  12. Keimatsu and Kato, J. Pharm. Soc. Japan, 49, 111 (1929) [C. A., 24, 70 (1930)].
  13. Warner and Moe (to General Mills, Inc.), U. S. pat. 2,523,744 [C. A., 45, 5718 (1951)].
  14. Meek, Minkowitz, and Miller, J. Org. Chem., 24, 1397 (1959).
  15. Takahashi, Nippon Kagaku Zasshi, 76, 735 (1955) [C. A., 51, 17758 (1957)].
  16. Takizawa, Science Repts. Research Insts. Tôhoku Univ., Ser. A, 4, 316 (1952) [C. A., 48, 1959 (1954)].

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

maleic and fumaric acids

nitrosuccinic ester

ethanol (64-17-5)

hydrochloric acid (7647-01-0)

acetic acid (64-19-7)

ammonia (7664-41-7)

ethyl acetate (141-78-6)

ether (60-29-7)

potassium permanganate (7722-64-7)

sodium chloride (7647-14-5)

nitrogen (7727-37-9)

Norit (7782-42-5)

pyridine (110-86-1)

Ethyl chloroacetate (105-39-5)

Hydroxylamine hydrochloride (5470-11-1)

Glycine (513-29-1)

phthalic acid (88-99-3)

pyridine hydrochloride (628-13-7)

diethyl sodium phthalimidomalonate

asparagine (70-47-3)

DL-Aspartic acid (617-45-8)

aspartic acid (56-84-8)

silver fumarate

oxalacetic acid (328-42-7)

Triethyl α-phthalimidoethane-α,α,β-tricarboxylate (76758-31-1)

triethyl α-aminoethane-α,α,β-tricarboxylate

β,β-dicarbethoxy-β-acetylaminopropionic acid

dimethyl (carbethoxy)formamidomalonate


diethyl α-acetyl-α-aminosuccinate