4-Methylmorpholine → (S)-2-Dimethylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

HRID 990347Notes

Reaction equation

HRID 990347 reaction equation
[CH3:1][N:2]([CH3:11])[C@@H:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O.CN1CCOCC1.[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C@@H:3]([N:2]([CH3:1])[CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:23][CH:22]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11658330(2S)-2-(dimethylamino)-4-methylpentanoic acidHCID 18418679HCID 18418679, compound

Product 1

HCID 86758548(S)-2-Dimethylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochlorideYield 30.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (S)-2-dimethylamino-4-methyl-pentanoic acid (433 mg, 2.72 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (809 mg, 2.72 mmol) in dry DMF (12 mL) was treated with Triton® B (1.80 mL, 3.96 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.). The clear solution was cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.03 g, 2.72 mmol) was then added. After stirring at 0° C. for 30 minutes, the cooling bath was removed, and the stirring was continued at ambient temperature for 15 minutes. After this period, the reaction mixture was mixed with 60 mL of diethyl ether, white precipitate forms and was removed by filtration. The filtrate was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (5% MeOH in 1:1 EtOAc/hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 361 mg (30%) of the pure titled compound as a white foam; mp 60-72° C. APCI-MS m/z 403.3 (MH+).

Workup

  1. customthe cooling bath was removed
  2. waitthe stirring was continued at ambient temperature for 15 minutes
  3. waitAfter this period
  4. additionthe reaction mixture was mixed with 60 mL of diethyl ether, white precipitate forms
  5. customwas removed by filtration
  6. washThe filtrate was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL)
  7. dry with materialwas dried over Na2SO4
  8. concentrationThe solution was concentrated in vacuo
  9. customaffording a viscous oil
  10. customThe crude product was purified by flash chromatography (5% MeOH in 1:1 EtOAc/hexanes)
  11. dissolutionThe free amine was dissolved in 5 mL of ethyl ether
  12. additiontreated with ethereal HCl

Sources & evidence

ORD record
ord-9abfcf6122e34874870befce8b6252a8
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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