Diisopropylethylamine → (s)-Azepane-1-carboxylic acid {1-[4-(9h-fluoren-9-yl)-piperazine-1-carbonyl]-3-methyl-butyl}-amide

HRID 990373Notes

Reaction equation

HRID 990373 reaction equation
[N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:54]1([CH:60]2[C:72]3[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=3[C:66]3[C:61]2=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.C(OCC)C>[CH:62]1[C:61]2[CH:60]([N:54]3[CH2:59][CH2:58][N:57]([C:12]([C@@H:11]([NH:10][C:8]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:56][CH2:55]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 27461801-(9H-fluoren-9-yl)piperazine DihydrochlorideHCID 7530182(2S)-2-(azepane-1-carbonylamino)-4-methylpentanoic acid

Product 1

HCID 12017814(s)-Azepane-1-carboxylic acid {1-[4-(9h-fluoren-9-yl)-piperazine-1-carbonyl]-3-methyl-butyl}-amideYield 37%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-2-[(Azepane-1-carbonyl)-amino]4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.816 mL, 4.68 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 9-piperazinofluorene dihydrochloride (0.293 g, 1.17 mmol, Maybridge Chemical Co. Ltd., Tintagel Cornwall, U.K.) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane containing 1% MeOH to provide 0.21 g (37%) of the pure titled compound as a white foam: mp 63-73° C. APCI-MS m/z 489.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 20 minutes at 0° C.
  3. custom20 minutes at ambient temperature, reaction mixture
  4. washthe resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL)
  5. dry with materialwas dried over Na2SO4
  6. concentrationThe solution was concentrated in vacuo
  7. customaffording a viscous oil
  8. customThe crude product was further purified by flash chromatography (50% EtOAc in hexane containing 1% MeOH

Sources & evidence

ORD record
ord-a9d7a3eb69ab403f8839d24c8a77bc3c
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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