Diisopropylethylamine → (s)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-amide

HRID 990357Notes

Reaction equation

HRID 990357 reaction equation
[N:1]1([C:8]([NH:10][C@@H:11]([CH3:15])[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.[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[CH2:58][CH2:59][CH2:60][NH2:61])=[CH:53][CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[CH2:58][CH2:59][CH2:60][NH:61][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH3:15])=[O:14])=[CH:53][CH:52]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12968581(s)-2-[(Azepane-1-carbonyl)-amino]-propanoic acidHCID 18418679HCID 18418679, compound

Product 1

HCID 53939331(s)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-amideYield 65.6%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-2-[(Azepane-1-carbonyl)-amino]-propanoic acid (0.300 g, 1.40 mmol) 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 (0.732 mL, 4.20 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.531 g, 1.40 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.412 g, 1.40 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 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 an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexanes) to afford 0.42 g (65%) of the pure titled compound as a white foam: mp 29-49° C. APCI-MS m/z 458.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 10 minutes at 0° C.
  3. custom40 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 an viscous oil
  8. customThe crude product was further purified by flash chromatography (70% EtOAc in hexanes)

Sources & evidence

ORD record
ord-c29b7777b13f423d84a1bc555c07dae4
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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