Triethylamine → (2S)-N-((1S,2S)-3-{(2S,4S)-2-[N-(tert-butyl)carbamoyl]-4-chloropyrrolidinyl}-2-hydroxy-3-oxo-1-benzylpropyl)-3-carbamoyl-2-[(phenylmethoxy)carbonylamino]propanamide

HRID 1780235Notes

Reaction equation

HRID 1780235 reaction equation
Cl.[C:2]([NH:6][C:7](=[O:14])[C@@H:8]1[CH2:12][C@H:11]([Cl:13])[CH2:10][NH:9]1)([CH3:5])([CH3:4])[CH3:3].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:35]([OH:39])[C:36]([N:9]1[CH2:10][C@@H:11]([Cl:13])[CH2:12][C@H:8]1[C:7]([NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:14])=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 57125825(2S,3S)-3-(N2-benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acidHCID 67722329(4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride

Product 1

HCID 473123(2S)-N-((1S,2S)-3-{(2S,4S)-2-[N-(tert-butyl)carbamoyl]-4-chloropyrrolidinyl}-2-hydroxy-3-oxo-1-benzylpropyl)-3-carbamoyl-2-[(phenylmethoxy)carbonylamino]propanamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

680 mg (2.23 mmol) of (4S)-1-t-butoxycarbonyl-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Preparation 2) were treated with 10 ml of a 4N solution of hydrogen chloride in dioxane, in order to eliminate the t-butoxycarbonyl group and give (4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride. The whole of the hydrochloride thus obtained and 880 mg (1.99 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) were dissolved in 5 ml of dimethylformamide, and the solution was cooled with ice. 420 mg (2.58 mmol) of diethyl cyanophosphate, followed by 640 mg (6.40 mmol) of triethylamine, were then added to the ice-cooled mixture, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of citric acid and then extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 850 mg of the title compound as a colorless powder, melting at 107°-109° C.

Workup

  1. temperaturethe solution was cooled with ice
  2. temperaturecooled mixture
  3. concentrationAt the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure
  4. additionthe residue was mixed with a 10% w/v aqueous solution of citric acid
  5. extractionextracted with ethyl acetate
  6. extractionThe organic extract
  7. washwas washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order
  8. dry with materialafter which it was dried over anhydrous sodium sulfate
  9. customThe solvent was then removed by distillation under reduced pressure
  10. customthe residue was purified by preparative thin layer chromatography
  11. additionby volume mixture of methylene chloride and methanol as the developing solvent

Sources & evidence

ORD record
ord-f0b75d9522a04845a90692a068cb670e
Source dataset
uspto-grants-1997_05
Patent number
US05629406

Reaction notes

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