Sodium Hydroxide → Enalapril Maleate

HRID 1758853Notes

Reaction equation

HRID 1758853 reaction equation
[NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[O:14]=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[H][H].[OH-:31].[Na+]>[Ni].C(O)C.C(OCC)(=O)C.O>[C:8]([OH:10])(=[O:9])/[CH:7]=[CH:11]\[C:12]([OH:14])=[O:31].[CH2:19]([O:18][C:16]([C@@H:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:17])[CH3:20]

Participants

9

Reactant 4

HCID 14798Sodium HydroxideHCID 83525L-Alanyl-L-prolineHCID 562087Ethyl alpha-oxobenzenebutanoateHCID 178418361HCID 178418361, compound2×

Product 1

HCID 5388961Enalapril Maleate

Reagents, catalysts & solvents 4

HCID 935NickelCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3 g. of L-alanyl-L-proline, 5 g of ethyl 2-oxo-4-phenyl-butanoate, 13 g. of 3A molecular sieves, and 3.6 g. of Raney nickel in 85 ml of ethanol is hydrogenated at 25° C. and at 40 psig of hydrogen until uptake of hydrogen ceases. The solids are filtered, washed with 80 ml. of ethanol and the filtrates are combined. Assay by high pressure liquid chromatography shows an 87:13 ratio of diastereoisomers in favor of the desired product. Ethanol is removed under vacuum to afford an oil which is dissolved in 60 ml. of water and 20 ml. of ethyl acetate. The pH of the stirred two-phase mixture is adjusted to 8.6 with 50% NaOH. The layers are separated and the water phase is extracted with 2×20 ml more of ethyl acetate. The water phase is adjusted to pH 4.25 with hydrochloric acid, 12 g. of NaCl is dissolved in the water, and product is extracted with 5× 12 ml of ethyl acetate. The extracts are combined and dried with Na2SO4. The desired product, N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline, is crystallized as its maleate salt by addition of 1.86 g. of maleic acid. After stirring for 4 hours, the salt is filtered, washed with ethyl acetate and dried to afford 5.2 g. of pure product, m.p. 150°-151° C.

Workup

  1. additionA mixture of 3 g
  2. filtrationThe solids are filtered
  3. washwashed with 80 ml
  4. customEthanol is removed under vacuum
  5. customto afford an oil which
  6. dissolutionis dissolved in 60 ml
  7. customThe layers are separated
  8. extractionthe water phase is extracted with 2×20 ml more of ethyl acetate
  9. dissolutionof NaCl is dissolved in the water, and product
  10. extractionis extracted with 5× 12 ml of ethyl acetate
  11. dry with materialdried with Na2SO4
  12. customThe desired product, N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline, is crystallized as its maleate salt by addition of 1.86 g
  13. filtrationthe salt is filtered
  14. washwashed with ethyl acetate
  15. customdried
  16. customto afford 5.2 g

Sources & evidence

ORD record
ord-d2e4e732d8fe43b980d8b4c8f0e9dc59
Source dataset
uspto-grants-1983_02
Patent number
US04374829

Reaction notes

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