Diethyl Ether → HCID 70156176, compound

HRID 990368Notes

Reaction equation

HRID 990368 reaction equation
[CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[N:34]2[CH2:35][CH2:36][N:37]([C:9](=[O:11])[C@@H:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:38][CH2:39]2)=[CH:45][CH:44]=1

Participants

6

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 11401906HCID 11401906, compound

Product 1

HCID 70156176HCID 70156176, compoundYield 89.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.200 g, 0.880 mmol, Example 21, Step A) 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 (0.389 mL, 1.76 mmol) and solid O-benzotriazol-1-yl-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (0.334 g, 0.880 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.254 g, 0.880 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 90 minutes at ambient temperature, reaction mixture was mixed with 50 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 (30% EtOAC in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.39 g (78%) of the pure titled compound as a white solid; mp 171-182° C. APCI-MS m/z 498.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 10 minutes at 0° C.
  3. custom90 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 (30% EtOAC in hexanes)
  9. dissolutionThe free amine was dissolved in 5 mL of ethyl ether
  10. additiontreated with ethereal HCl
  11. concentrationSubsequent concentration in vacuo
  12. customdrying under vacuum

Sources & evidence

ORD record
ord-ce3e6c8b11754a92857e227b5430f39b
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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