N,N'-Dicyclohexylurea → (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic Acid Benzyl Ester

HRID 273476Notes

Reaction equation

HRID 273476 reaction equation
C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][C:27]([C@@H:29]1[CH2:37][C@H:36]2[C@H:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[NH:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.[C:48]([C@@H:53]([NH:57][C@H:58]([C:60](O)=[O:61])[CH3:59])[CH2:54][CH2:55][CH3:56])([O:50][CH2:51][CH3:52])=[O:49].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(=O)NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH3:56][CH2:55][CH2:54][C@H:53]([NH:57][C@H:58]([C:60]([N:30]1[C@@H:29]([C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:37][C@H:36]2[C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:61])[CH3:59])[C:48]([O:50][CH2:51][CH3:52])=[O:49]

Participants

8

Reactant 6

HCID 4277N,N'-DicyclohexylureaHCID 8471TriethylamineHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 10015159(2S)-2-[[(2S)-1-ethoxy-1-oxopentan-2-yl]amino]propanoic acidHCID 115465001H-Indole-2-carboxylic acid, octahydro-, phenylmethyl ester, (2S,3aS,7aS)-, 4-methylbenzenesulfonate (1:1)

Product 1

HCID 71751530(2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)butyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic Acid Benzyl EsterYield 94%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
25 °C

Procedure

Triethyl amine (14 g, 0.1238 moles) was added to a suspension of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid-benzyl ester para toluene sulfonate (20 g, 0.0464 moles) in ethyl acetate (240 g), under stirring at 25° C. in one lot. Then 1-hydroxybenzotriazole (24 g, 0.1776 moles), N-[(S)-1-carbethoxybutyl]-(S)-alanine (30 g, 0.1382 moles) were added to the reaction mixture at 25° C., under stirring, followed by dicyclohexyl carbodiimide (28 g, 0.1357 moles) at ambient temperature. The reaction mixture was stirred, keeping the temperature in the range of 15-20° C. for 3 hrs, when the TLC and the HPLC indicated a completion of the reaction. The reaction mixture was then filtered to remove the precipitated dicyclohexyl urea. The filtrate was washed with water (100 ml, twice). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford a viscous oil, which was still contaminated with dicyclohexyl urea. The oil was redissolved in ethyl acetate (100 ml) and the solution was cooled to 2-5° C. under stirring for 1 hr. The precipitated dicyclohexyl urea was again filtered off and the filtrate was concentrated under reduced pressure to afford 20 g (94%) of perindopril benzyl ester as an oil.

Workup

  1. stirringunder stirring
  2. stirringThe reaction mixture was stirred
  3. customin the range of 15-20° C.
  4. customfor 3 hrs
  5. customa completion of the reaction
  6. filtrationThe reaction mixture was then filtered
  7. customto remove the precipitated dicyclohexyl urea
  8. washThe filtrate was washed with water (100 ml
  9. dry with materialThe organic layer was dried over sodium sulphate
  10. concentrationconcentrated under reduced pressure
  11. customto afford a viscous oil, which
  12. temperaturethe solution was cooled to 2-5° C.
  13. stirringunder stirring for 1 hr
  14. filtrationThe precipitated dicyclohexyl urea was again filtered off
  15. concentrationthe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-567b78b982984f769d894b2e586de759
Source dataset
uspto-grants-2008_11
Patent number
US07456296B2

Reaction notes

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