Maleic Acid → Enalapril Maleate

HRID 51212Notes

Reaction equation

HRID 51212 reaction equation
[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32]>O>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32].[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]

Participants

4

Reactant 2

HCID 444266Maleic AcidHCID 5388962Enalapril

Product 1

HCID 5388961Enalapril Maleate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

This solution containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline was added to a solution of 10.66 g (92 mmol) of maleic acid in 20 ml of H2O, with stirring at an inner temperature of 60° C. over 1 hour. The stirring was continued for 1 hour under the same conditions and, then, the inner temperature was cooled down to 5° C. over 3 hours, and the stirring was continued for further 2 hours. The deposited crystal was taken out by filtration under reduced pressure, and quickly washed three times with 80 ml of H2O cooled to 0 to 3° C. The resulting crystal had a good filterability and a glossy and excellent crystal form; In the case of forming the salt at an inner temperature of 30° C., the resulting salt was slurry in the form of whip and had a poor filterability and a form of fine crystal. The resulting wet crystal was dried under reduced pressure (20 to 50° C., 30→1 mmHg), to obtain 42.05 g (85 mmol) of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate. The purity was at least 99% and the contents of the diketopiperazine derivative (3), carboxy derivative (4) and N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (5) were respectively at most 0.05% by weight. The yield from N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine.N-carboxyanhydride was 89%.

Workup

  1. waitThe stirring was continued for 1 hour under the same conditions
  2. temperaturethe inner temperature was cooled down to 5° C. over 3 hours
  3. waitthe stirring was continued for further 2 hours
  4. filtrationThe deposited crystal was taken out by filtration under reduced pressure
  5. washquickly washed three times with 80 ml of H2O
  6. temperaturecooled to 0 to 3° C
  7. customIn the case of forming the salt at an inner temperature of 30° C.
  8. customThe resulting wet crystal was dried under reduced pressure (20 to 50° C., 30→1 mmHg)

Sources & evidence

ORD record
ord-c45bdcc404bd4f068399bf8c698c40e8
Source dataset
uspto-grants-2004_03
Patent number
US06713628B2

Reaction notes

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