Diisopropylethylamine → (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-2-methyl-propyl)-amide

HRID 990359Notes

Reaction equation

HRID 990359 reaction equation
[N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:17])[CH3:16])[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.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[F:71][C:68]1[CH:67]=[CH:66][C:65]([CH:58]([C:55]2[CH:56]=[CH:57][C:52]([F:51])=[CH:53][CH:54]=2)[N:59]2[CH2:60][CH2:61][N:62]([C:12]([C@@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH:15]([CH3:17])[CH3:16])=[O:14])[CH2:63][CH2:64]2)=[CH:70][CH:69]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12968580(s)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-butanoic acid

Product 1

HCID 59913945(S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-2-methyl-propyl)-amideYield 82%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-butyric acid (0.26 g, 1.1 mmol, Example 26, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.40 g, 1.1 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.31 g, 1.1 mmol) was then added. After additional 90 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.45 g (82%) of the pure titled compound as a white foam; mp 72-82° C. APCI-MS m/z 513.2 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter additional 90 minutes stirring at 0° C.
  3. customreaction mixture
  4. washthe resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationThe solution was concentrated in vacuo
  7. customaffording a viscous oil
  8. customThe crude product was further purified by flash chromatography (60% EtOAc in hexane)

Sources & evidence

ORD record
ord-10934d99316844009d704587cd50ae1d
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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