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

HRID 1486041Notes

Reaction equation

HRID 1486041 reaction equation
Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C@H:4]1[CH3:23].[C:24]([N:31]([CH3:37])[C@H:32]([C:34](O)=[O:35])[CH3:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].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)C=O.C(OCC)(=O)C>[CH3:37][N:31]([C@@H:32]([CH3:33])[C:34]([NH:2][C@H:3]1[C@H:4]([CH3:23])[N:5]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[NH:8][C:9]1=[O:10])=[O:35])[C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29]

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 90082357(3S,4S)-3-amino-4-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one hydrochloride

Product 1

HCID 90082481tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamateYield 96%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a room temperature solution of (3S,4S)-3-amino-4-methyl-5-(tetrahydro-2H-pyran-4-carbonyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one hydrochloride (173 mg, 509 μmol) in N,N-dimethylformamide (2 ml) was added Boc-N-methyl-L-alanine (114 mg, 560 μmol), N,N-diisopropylethylamine (440 μl, 2.55 mmol), and HBTU (212 mg, 560 μmol). The reaction was stirred at room temperature for 2 h. After this time, the reaction was diluted with ethyl acetate (20 mL), washed with a saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous layer was then extracted with ethyl acetate (3×10 mL) and the combined organics were washed with a saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and the filterate concentrated in vacuo. The crude material was purified using an Initelliflash 280 system (4 g silica gel column Varian brand, 20-90% ethyl acetatehexanes) to afford tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (238 mg, 96%): LC-MS m/z 487 [M−H]−.

Workup

  1. washwashed with a saturated aqueous sodium bicarbonate solution (20 mL)
  2. extractionthe aqueous layer was then extracted with ethyl acetate (3×10 mL)
  3. washthe combined organics were washed with a saturated aqueous sodium chloride solution (20 mL)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationthe filterate concentrated in vacuo
  7. customThe crude material was purified

Sources & evidence

ORD record
ord-089ae7d0828f401da92a5fe1e2f17156
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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