Diisopropylethylamine → (S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxamide

HRID 75121

Reaction equation

HRID 75121 reaction equation
[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]3=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=12)=[O:19])[C:22]([NH:24][CH3:25])=[O:23]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 445856(2S)-2-Amino-N,3,3-trimethylbutanamideHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 253421753-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxylic acid2×

Product 1

HCID 46234937(S)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxamideYield 89.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxylic acid (Intermediate B1) (100 mg, 0.390 mmol) was dissolved in DCM (10 mL) in a 40 mL screw-cap vial. (S)-2-amino-N,3,3-trimethylbutanamide (59.1 mg, 0.410 mmol) and DIEA (204 μl, 1.171 mmol) were added, followed by TBTU (132 mg, 0.410 mmol), and the reaction was stirred for 3 hours. LCMS showed complete consumption of starting material. The solution was extracted with saturated aqueous sodium bicarbonate (10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (10 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to a brown oil which was purified by flash chromatography (silica gel, 25% Hex/EtOAc to 100% EtOAc). Fractions were combined to yield the desired (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxamide as a white solid (133 mg, 89%). LCMS (+ESI) m/z 383.2 [MH]+. 1H-NMR (CDCl3) δ 7.90 (d, 1H), 7.45-7.55 (m, 5H), 5.90 (m, 1H), 4.30 (d, 1H), 4.05 (m, 2H), 3.40 (m, 2H), 2.80 (d, 3H), 1.90 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.10 (s, 9H).

Workup

  1. customscrew-cap vial
  2. customconsumption of starting material
  3. extractionThe solution was extracted with saturated aqueous sodium bicarbonate (10 mL)
  4. customthe organic layer was removed
  5. extractionThe aqueous layer was extracted with DCM (10 ml)
  6. dry with materialThe combined organic extracts were dried with anhydrous sodium sulfate
  7. filtrationfiltered
  8. customevaporated under reduced pressure to a brown oil which
  9. customwas purified by flash chromatography (silica gel, 25% Hex/EtOAc to 100% EtOAc)

Sources & evidence

ORD record
ord-8b0e62b1b7984dd4984dfc3122c5d81f
Source dataset
uspto-grants-2014_09
Patent number
US08835422B2

Linked notes

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