Diisopropylethylamine → 2-methyl-2-propanyl 4-[({(2S,4S)-1-{[4-(N,N'-bis{[(2-methyl-2-propanyl)oxy]carbonyl}carbamimidoyl)-1-piperazinyl]carbonyl}-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoate

HRID 1053827Notes

Reaction equation

HRID 1053827 reaction equation
[CH3:1][C:2]([O:5][C:6](=[O:23])[NH:7][C:8](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])[CH3:3].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][N:52]([C@@H:55]2[CH2:59][NH:58][C@H:57]([C:60]([NH:62][C:63]3[CH:75]=[CH:74][C:66]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[CH:65][CH:64]=3)=[O:61])[CH2:56]2)[CH2:51][CH2:50]1)(=[O:48])=[O:47]>C1COCC1>[CH3:19][C:18]([O:17][C:16]([NH:15][C:8]([N:9]1[CH2:10][CH2:11][N:12]([C:25]([N:58]2[CH2:59][C@@H:55]([N:52]3[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]3)[CH2:56][C@H:57]2[C:60]([NH:62][C:63]2[CH:75]=[CH:74][C:66]([C:67]([O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:68])=[CH:65][CH:64]=2)=[O:61])=[O:27])[CH2:13][CH2:14]1)=[N:7][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:23])=[O:22])([CH3:21])[CH3:20]

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 68635492[tert-Butoxycarbonylimino(piperazin-1-yl)methyl]carbamic acid tert-butyl esterHCID 1181076652-methyl-2-propanyl 4-[({(2S,4S)-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoate

Product 1

HCID 1317363042-methyl-2-propanyl 4-[({(2S,4S)-1-{[4-(N,N'-bis{[(2-methyl-2-propanyl)oxy]carbonyl}carbamimidoyl)-1-piperazinyl]carbonyl}-4-[4-(methylsulfonyl)-1-piperazinyl]-2-pyrrolidinyl}carbonyl)amino]benzoateYield 39%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of the compound prepared in Example 28 (0.05 g, 0.15 mmol) in THF (10 mL), triphosgene (0.054 g, 0.182 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.456 mmol) were added at 0° C. and the reaction mixture warmed to room temperature. After stirring for 1 h, the reaction mixture was concentrated to dryness and the crude residue was dissolved in THF. To this mixture, the compound prepared in Example 6 (0.065 g, 0.152 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.456 mmol) were added at 0° C., and the reaction warmed to room temperature. After stirring for 4 h, the mixture was diluted with ice cold water and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 40 g, 20-60% ethyl acetate/hexanes) provided the title compound (0.045 g, 39%) as a white solid.

Workup

  1. concentrationthe reaction mixture was concentrated to dryness
  2. dissolutionthe crude residue was dissolved in THF
  3. temperaturethe reaction warmed to room temperature
  4. stirringAfter stirring for 4 h
  5. additionthe mixture was diluted with ice cold water
  6. extractionextracted with ethyl acetate (2×50 mL)
  7. washThe organic layer was washed with brine
  8. customdried
  9. concentrationconcentrated
  10. customPurification by flash chromatography (silica gel, 40 g, 20-60% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-545d0b8e43bb43399692eedb274dd9d9
Source dataset
uspto-grants-2016_07
Patent number
US09394250B2

Reaction notes

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