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

HRID 1486127Notes

Reaction equation

HRID 1486127 reaction equation
Cl.Cl.[NH2:3][C@@H:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][C:14]=2[CH:23]2[CH2:25][CH2:24]2)[C:8]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:7]=2[N:6]([C:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[C@H:5]1[CH3:40].[C:41]([N:48]([CH3:54])[C@H:49]([C:51](O)=[O:52])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].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.CCOC(C)=O>[C:30]([C:28]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:11])[C@@H:4]([NH:3][C:51](=[O:52])[C@@H:49]([N:48]([CH3:54])[C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH3:50])[C@H:5]([CH3:40])[N:6]([C:32]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])[C:7]=2[CH:29]=1)#[N:31]

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 90082427(3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride

Product 1

HCID 118292686tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamateYield 77.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 0° C. solution of (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (60 mg, 103 μmol) in DMF (343 μl) was added Boc-N-methyl-L-alanine (23.0 mg, 113 μmol), N,N-diisopropylethylamine (89.1 μl, 515 μmol), and HBTU (43.0 mg, 113 μmol). 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-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55.3 mg, 77%) as a white solid. MS m/z 695 (MH)+.

Workup

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

Sources & evidence

ORD record
ord-6b282e741e5643b38e0cb7a4f363af23
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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