Diisopropylethylamine → (S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

HRID 990353Notes

Reaction equation

HRID 990353 reaction equation
[CH3:1][CH:2]([CH3:16])[CH2:3][C@H:4]([N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.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.[ClH:50].[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[CH2:59][CH2:60][CH2:61][NH2:62])=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[ClH:50].[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([C:63]2[CH:64]=[CH:65][C:66]([F:69])=[CH:67][CH:68]=2)[CH2:59][CH2:60][CH2:61][NH:62][C:5](=[O:7])[C@@H:4]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:3][CH:2]([CH3:1])[CH3:16])=[CH:54][CH:53]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 15458710(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acidHCID 18418679HCID 18418679, compound

Product 1

HCID 86758552(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochlorideYield 64.8%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.300 g, 1.31 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 (0.684 mL, 3.93 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.496 g, 1.31 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.390 g, 1.31 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 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 hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.432 g (63%) of the pure titled compound as a white foam; mp 75-92° C. APCI-MS m/z 473.4 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter stirring for, sequentially, 15 minutes at 0° C.
  3. custom30 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 hexane)
  9. additiontreated with ethereal HCl
  10. concentrationSubsequent concentration in vacuo
  11. customdrying under vacuum

Sources & evidence

ORD record
ord-87dc9395dbc243d8bee01a7bacc8bb9a
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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