Diisopropylethylamine → tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 1486086Notes

Reaction equation

HRID 1486086 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:9]([CH3:22])[N:8]([C:23](=[O:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:7]=2[CH:30]=1)#[N:2].[C:31]([N:38]([CH3:44])[C@H:39](C(O)=O)[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:21])[C@@H:39]([N:38]([CH3:44])[C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH3:40])[C@H:9]([CH3:22])[N:8]([C:23](=[O:29])[CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])[C:7]=2[CH:30]=1)#[N:2]

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 72713839tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate

Product 1

HCID 72713840tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 74.4%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A rt solution of tert-butyl(2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (137 mg, 314 μmol) in 4 M HCl in dioxane (1.57 ml) was stirred for 2 h. The reaction was concentrated, taken up in in DMF (1.05 ml), and Boc-N-methyl-L-alanine (70.2 mg, 345 μmol), N,N-diisopropylethylamine (217 μl, 1.26 mmol), and HBTU (131 mg, 345 μmol) were added at 0° C. The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (121.8 mg, 74%) as a white solid. MS m/z 544 (MNa)+.

Workup

  1. concentrationThe reaction was concentrated
  2. additionwere added at 0° C
  3. washwashed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-e4f7efff0dff4a16b10709ccdd2e6553
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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