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Diisopropylethylamine → (3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester

HRID 1268616
Notes
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Reaction equation

HRID 1268616 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2N=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@H:58]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH2:59][NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([C@@H:43]([C:42](=[O:57])[N:41]([C@H:58]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH2:59][NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH3:40])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)[CH3:56])([CH3:2])([CH3:3])[CH3:4]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 10847814(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acidHCID 54203801N-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamideHCID 178516469CID 294631

Product 1

HCID 59057141(3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl esterYield 82.6%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (352 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). Hydroxy-7-azabenzotriazole (197 mg, 1.45 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol) was added. The solution was stirred for 15 min at 0° C. A solution of N-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide (598 mg, 1.32 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.23 ml, 1.32 mmol) were added successively. The solution was stirred for 18 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and extracted with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (2:1) as eluent to give 740 mg of (3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester.

Workup

  1. stirringThe solution was stirred for 18 h, while it
  2. temperaturewas warming up to room temperature
  3. extractionextracted with 1 N hydrochloric acid
  4. extractionThe aqueous phase was extracted with ethyl acetate (50 ml)
  5. washThe combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml)
  6. dry with materialdried over magnesium sulfate
  7. customThe solvent was removed in vacuo
  8. customThe crude product was purified by flash chromatography on silica (60 g)

Sources & evidence

ORD record
ord-4bbc82a945384484a347aacc83ac0d9a
Source dataset
uspto-grants-2003_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06555570B2

Reaction notes

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