Hydrochloric Acid → AHPBA 38a

HRID 1780242Notes

Reaction equation

HRID 1780242 reaction equation
Cl.C(OC(N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C(N1C[C@@H](Cl)C[C@H]1C(NC(C)(C)C)=O)=O)=O)CC(=O)N)=O)C1C=CC=CC=1.Cl.[NH2:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51].[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91](O)=[O:92].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CO.CN(C)C=O>[N:81]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)[N:84]=[CH:83][C:82]=1[C:91]([NH:47][C@H:48]([C:53]([NH:55][C@@H:56]([CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)[C@H:57]([OH:73])[C:58]([N:60]1[CH2:71][C@@H:70]([Cl:72])[CH2:69][C@H:61]1[C:62]([NH:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:92]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 96695Quinoxaline-2-carboxylic acidHCID 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]propanamideHCID 67722833(4S)-1-[(2S,3S)-3--asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloroprolinamide hydrochloride

Product 1

HCID 473135AHPBA 38a

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

0.6 ml of 1N aqueous hydrochloric acid was added to a solution of 300 mg (0.48 mmol) of (4S)-1-[(2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Example 1) in methanol, and a stream of hydrogen was bubbled through the mixture at atmospheric pressure for 3 hours in the presence of 60 mg of 10% w/w palladium-on-charcoal, to remove the benzyloxycarbonyl group. The whole of the resulting (4S)-1-[(2S,3S)-3--asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloroprolinamide hydrochloride and 99 mg (0.57 mmol) of 2-quinoxalinecarboxylic acid were dissolved in 5 ml of dimethylformamide, and 93 mg (0.57 mmol) of diethyl cyanophosphate and 144 mg (1.44 mmol) of triethylamine under ice-cooling were added to this solution. The resulting mixture was stirred for 3 hours, after which it was concentrated by evaporation under reduced pressure. The residue was mixed with a 10% w/v aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting 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 140 mg of the title compound as a colorless powder, melting at 132°-134° C.

Workup

  1. customa stream of hydrogen was bubbled through the mixture at atmospheric pressure for 3 hours in the presence of 60 mg of 10% w/w palladium-on-charcoal
  2. customto remove the benzyloxycarbonyl group
  3. additionwere added to this solution
  4. concentrationafter which it was concentrated by evaporation under reduced pressure
  5. additionThe residue was mixed with a 10% w/v aqueous solution of sodium hydrogencarbonate
  6. extractionextracted with ethyl acetate
  7. extractionThe organic extract
  8. washwas washed with a saturated aqueous solution of sodium chloride
  9. dry with materialdried over anhydrous sodium sulfate
  10. customThe solvent was removed by distillation under reduced pressure
  11. customthe resulting residue was purified by preparative thin layer chromatography
  12. additionby volume mixture of methylene chloride and methanol as the developing solvent

Sources & evidence

ORD record
ord-77ff33a2152b46c6aa39344f0b0c9602
Source dataset
uspto-grants-1997_05
Patent number
US05629406

Reaction notes

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