Diisopropylethylamine → (R)-Azepane-1-carboxylic acid {1-(4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide

HRID 990360Notes

Reaction equation

HRID 990360 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.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([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])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=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 12017803(R)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid

Product 1

HCID 54422025(R)-Azepane-1-carboxylic acid {1-(4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amideYield 86%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(R)-2-[{Azepane-1-carbonyl)-amino]}-4-methyl-pentanoic acid (0.33 g, 1.3 mmol, Example 2, 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 (0.45 mL, 2.6 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.49 g, 1.3 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.37 g, 1.3 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 0.58 g (86%) of the pure titled compound as a white foam: mp 71-84° C. APCI-MS m/z 527.3 (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-0f0577fb3a7b46da9b6d8601bbfa5fa1
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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