Methane → Perindopril

HRID 1180213Notes

Reaction equation

HRID 1180213 reaction equation
C(OC([CH:6]([CH2:19][CH3:20])[CH2:7][N:8]([C:14]([O:16]CC)=O)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=O)C.ClCCl.[NH:24]1[CH:32]2[CH:27]([CH2:28]CC[CH2:31]2)[CH2:26][CH:25]1[C:33]([OH:35])=[O:34].[C:36](N)([CH3:39])(C)C.C.[CH2:42]1COC[CH2:43]1>C(OCC)(=O)C>[CH3:28][CH2:27][CH2:26][C@H:25]([NH:24][C@H:32]([C:14]([N:8]1[C@H:9]([C:11]([OH:13])=[O:12])[CH2:10][C@H:6]2[C@@H:7]1[CH2:36][CH2:39][CH2:20][CH2:19]2)=[O:16])[CH3:31])[C:33]([O:35][CH2:42][CH3:43])=[O:34]

Participants

8

Reactant 6

HCID 297MethaneHCID 6344DichloromethaneHCID 6385Tert-ButylamineHCID 8028Tetrahydrofuran2×HCID 3274680Octahydroindole-2-carboxylic acidHCID 86598454N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

Product 1

HCID 107807PerindoprilYield 55%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (10.1 g, 35 mmol) in dichloromethane (35 mL) thionyl chloride (4.2 mL, 6.9 g, 58 mmol) was added in drops at 0-5° C. It was stirred at ambient temperature for 2-3 h. The solvent was evaporated to give a reddish oil. The residue was dissolved in THF (37.5 mL) and it was added to a suspension of perhydroindole-2-carboxylic acid (4.7 g, 28 mmol) in THF (37.5 mL). The suspension was refluxed with stirring for 4-4.5 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (120 mL), t-butylamine (2.8 mL, 1.95 g, 27 mmol) in ethyl acetate (60 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (6.8 g, 55%).

Workup

  1. customThe solvent was evaporated
  2. customto give a reddish oil
  3. temperatureThe suspension was refluxed
  4. stirringwith stirring for 4-4.5 h until a brownish solution
  5. customwas formed
  6. customAfter evaporation of the solvent the residue
  7. dissolutionwas dissolved in ethyl acetate (120 mL)
  8. customresulting in separation of a crystalline mass
  9. temperatureThe mixture was heated until a solution
  10. customwas formed
  11. customThe crystalline product obtained
  12. temperatureafter cooling
  13. filtrationwas filtered

Sources & evidence

ORD record
ord-a9e1b820a5b54a1b9f7dcfc5c4749402
Source dataset
uspto-grants-2007_10
Patent number
US07279595B2

Reaction notes

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