Diisopropylethylamine → tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

HRID 1486115Notes

Reaction equation

HRID 1486115 reaction equation
Cl.[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH2:13])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3].[C:33]([N:40]([CH3:46])[C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].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>CN(C=O)C.O>[C:2]([N:5]1[C@@H:11]([CH3:12])[C@H:10]([NH:13][C:43](=[O:44])[C@@H:41]([N:40]([CH3:46])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:42])[C:9](=[O:14])[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH3:26])[C:7]2[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:6]1=2)(=[O:4])[CH3:3]

Participants

7

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 72712775(3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride

Product 1

HCID 72712777tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 88%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a 0° C. solution of (3S,4S)-5-acetyl-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (162 mg, 361 μmol) in DMF (1.2 ml) was added Boc-N-methyl-L-alanine (80.7 mg, 397 μmol), N,N-diisopropylethylamine (250 μl, 1.44 mmol), and HBTU (151 mg, 397 μmol). The reaction was stirred at rt for 30 min, then diluted with H2O and the solids were collected by vacuum filtration, taken up in 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-((3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (189 mg, 88%) as a white solid. MS m/z 620 (MNa)+.

Workup

  1. filtrationthe solids were collected by vacuum filtration
  2. washwashed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-ca0cbe5a0a4c4aa8a63716fdef1cbbc0
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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