Hydrochloric Acid → L-Phenylalanine, L-alpha-aspartyl-, 2-methyl ester, hydrochloride (1:1)

HRID 653549Notes

Reaction equation

HRID 653549 reaction equation
[ClH:1].Cl.[NH2:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7].[CH3:23]O>>[ClH:1].[CH3:23][O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH2:3]

Participants

4

Reactant 3

HCID 313Hydrochloric Acid3×HCID 887MethanolHCID 12800346L-Aspartyl-L-phenylalanine Hydrochloride

Product 1

HCID 134600L-Phenylalanine, L-alpha-aspartyl-, 2-methyl ester, hydrochloride (1:1)

Procedure

L-Phenylalanine (7.4 g, 0.045 mole) was stirred in 90 ml of water. The pH of this solution was adjusted to 10.2 (0°-2° C.) with 50% NaOH. Then a solution of pure NCA (8.3 g, 0.048 mole) in 8 ml of THF was added in 15 min. with vigorous stirring. The pH was maintained at 10.0-10.2 by the addition of 7N NaOH solution. The reaction mixture was then stirred at 0°-2° C. for 2 hr (pH 10.0-10.2). Sufficient 37% hydrochloric acid (9.7 g) was added at the end of the hold period to neutralize the NaOH. The solution was then warmed to 25° C. Liquid chromatography indicated an 80-82% yield of aspartyl ester based on L-phenylalanine. This clear solution was extracted twice with 50 ml portions of ethyl acetate. To the aqueous solution, 4.2 g of 37% HCl (0.043 mole) was added. The solution was concentrated under vacuum to a total weight of 31.1 g. Another 8.4 g (0.085 mole) of 37% HCl was added and the reaction slurry was held at 40° C. for 6 h to convert the aspartyl ester to α-L-aspartyl-L-phenylalanine hydrochloride. Solid (NaCl) was collected at 40° C. and washed with 2.6 g (0.026 mole) of 37% HCl and 7.5 g of methanol. Seed crystals were added to the combined filtrate and washings. The resulting solution was stirred at ambient temperature for 68 hours. The thick slurry was cooled to 0°-2° C. and the solid was collected by filtration and washed with 7 ml of cold water. The dry weight of α-APM.HCl was 9 g (55% yield based on L-phenylalanine). Product identity was confirmed by LC analysis.

Workup

  1. extractionThis clear solution was extracted twice with 50 ml portions of ethyl acetate
  2. concentrationThe solution was concentrated under vacuum to a total weight of 31.1 g
  3. customSolid (NaCl) was collected at 40° C.
  4. additionSeed crystals were added to the combined filtrate and washings
  5. temperatureThe thick slurry was cooled to 0°-2° C.
  6. filtrationthe solid was collected by filtration
  7. washwashed with 7 ml of cold water

Sources & evidence

ORD record
ord-25c517c62c2244879c7356606077c56d
Source dataset
uspto-grants-1987_06
Patent number
US04677220

Reaction notes

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