Ethylmorpholine → L-Proline

HRID 569889Notes

Reaction equation

HRID 569889 reaction equation
[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N1C=CN=C1)(N1C=CN=C1)=O.SCC(CC(OC)=O)C([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([OH:53])=[O:52])=O.C(N1CCOCC1)C>CN(C)C=O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[NH:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([OH:53])=[O:52]

Participants

7

Reactant 4

HCID 7525EthylmorpholineHCID 682631,1'-CarbonyldiimidazoleHCID 539411441-[3-Mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-prolineHCID 86742077HCID 86742077, compound

Product 2

HCID 145742L-ProlineHCID 86742077HCID 86742077, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
-10 °C

Procedure

A solution of 10 mmoles of Nα -pyro-L-glutamyl-Nε -tert-butyloxycarbonyl-L-lysyl-β-alanine in redistilled dimethylformamide (DMF) is cooled in an ice-dry ice-acetone bath at -20° C. To this solution is added a cold solution of 10 mmoles of 1,1'-carbonyldiimidazole in DMF. The solution is stirred at -10° C. for two hours and then mixed with a cold solution of 10 mmoles of N-[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-proline (from Example 82) in DMF which is neutralized with N-ethyl morpholine. The reaction mixture is stirred at -10° C. for an additional hour and then slowly warmed to room temperature. The solvent is removed under reduced pressure to 40° C. and ethyl acetate is added to the residue. The mixture is cooled in an ice water bath and washed with 1N citric acid and then three times with saturated NaCl solution. The solvent is removed with a rotary evaporator after drying over anhydrous MgSO4. The product is purified by LH-20 column chromatography using a 1.2 cm by 95 cm column and eluted with THF:isopropanol, 3:7 (parts by volume). The peak fractions are pooled and the solvent is removed under reduced pressure yielding the product Nα -[(3-[Nα -pyro-L-glutamyl-Nε -tertbutyloxycarbonyl-L-lysyl-β-alanine]-thio-2-(methoxycarbonylmethyl)propanoyl]-L-proline. The tert-butyloxycarbonyl protecting group is removed as described in Example 94 to yield the named product.

Workup

  1. stirringThe reaction mixture is stirred at -10° C. for an additional hour
  2. temperatureslowly warmed to room temperature
  3. customThe solvent is removed under reduced pressure to 40° C. and ethyl acetate
  4. additionis added to the residue
  5. temperatureThe mixture is cooled in an ice water bath
  6. washwashed with 1N citric acid
  7. customThe solvent is removed with a rotary evaporator
  8. dry with materialafter drying over anhydrous MgSO4
  9. customThe product is purified by LH-20 column chromatography
  10. washeluted with THF
  11. customthe solvent is removed under reduced pressure

Sources & evidence

ORD record
ord-f520eb82c406498a90af35761cbb956f
Source dataset
uspto-grants-1988_03
Patent number
US04734420

Reaction notes

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