4-Methylmorpholine → HCID 59913951, compound

HRID 990335Notes

Reaction equation

HRID 990335 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.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[C:51]1([N:57]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH2:66][NH2:67])=[N:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[C:12](=[O:14])[NH:67][CH2:66][C:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:58]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7530182(2S)-2-(azepane-1-carbonylamino)-4-methylpentanoic acidHCID 18418689HCID 18418689, compound

Product 1

HCID 59913951HCID 59913951, compoundYield 48%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.45 g, 1.8 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N-methylmorpholine (0.68 mL, 6.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.70 g, 1.8 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of C-(1-phenyl-1H-indazol-3-yl)-methylamine monohydrochloride (0.45 g, 1.8 mmol) in dry DMF (8 mL) was added. After additional 20 minutes stirring at 0° C., the ice-water bath was removed, and the reaction mixture was stirred and allowed to warm up to ambient temperature for 15 minutes. The reaction mixture was poured into 50 mL of EtOAc; the resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo affording an amber oil which was further purified by flash chromatography (80% EtOAC in hexanes). Finally, recrystallization from EtOAc-Hexanes afforded 0.39 g (48%) of the pure titled compound as a off-white solid: mp 135-136° C. APCI-MS m/z 462.0 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringAfter additional 20 minutes stirring at 0° C.
  3. customthe ice-water bath was removed
  4. stirringthe reaction mixture was stirred
  5. temperatureto warm up to ambient temperature for 15 minutes
  6. additionThe reaction mixture was poured into 50 mL of EtOAc
  7. washthe resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine
  8. dry with materialwas dried over Na2SO4
  9. concentrationThe solution was concentrated in vacuo
  10. customaffording an amber oil which
  11. customwas further purified by flash chromatography (80% EtOAC in hexanes)
  12. customFinally, recrystallization from EtOAc-Hexanes

Sources & evidence

ORD record
ord-5b323092c6f04c38adf4f03623ee3246
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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