4-Methylmorpholine → HCID 12017812, compound

HRID 990333Notes

Reaction equation

HRID 990333 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.O.Cl.[NH2:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]>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:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]

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 18418744HCID 18418744, compound

Product 1

HCID 12017812HCID 12017812, compoundYield 72%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.39 g, 1.5 mmol, Example 1, 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-methylmorpholine (0.66 mL, 6.0 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.60 g, 1.6 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of 3-(3-amino-propyl)-1-methyl-3-phenyl-1,3-dihydro-indol-2-one monohydrochloride monohydrate (0.49 g, 1.5 mmol) in dry DMF (7 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 a white solid. Recrystallization from EtOAc-hexanes afforded 0.56 g (72%) of the pure titled compound as a white powder: mp 181-182° C. APCI-MS m/z 519.1 (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 a white solid
  11. customRecrystallization from EtOAc-hexanes

Sources & evidence

ORD record
ord-b70a44c491da4fc2853c2e5657f223ea
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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