4-Methylmorpholine → (R)-tert-butyl 2-(6-fluoro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate

HRID 1968258Notes

Reaction equation

HRID 1968258 reaction equation
[C:1]([O:5][C:6](=[O:36])[C@H:7]([NH:11][CH2:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]2[N:20]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:21]=[C:22]([C:23]([OH:25])=O)[C:14]=12)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[F:19][C:18]1[C:13]2[CH2:12][N:11]([C@H:7]([CH:8]([CH3:10])[CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[C:23](=[O:25])[C:22]3=[CH:21][N:20]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[C:15]([C:14]=23)=[N:16][CH:17]=1

Participants

4

Reactant 3

HCID 79724-Methylmorpholine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 58293452(R)-4-((1-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Product 1

HCID 58293424(R)-tert-butyl 2-(6-fluoro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate

Procedure

Crude (R)-4-((l-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid was heated in HATU (2.60 g, 7.19 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) at reflux for 3 h. The reaction was incomplete by LC-MS. HATU (1.37 g, mmol, 3.79 mmol) and 4-methylmorpholine (1.091 g, 10.79 mmol) were added and the reaction mixture was stirred at reflux for 16 h. Following reaction, the mixture was washed with aqueous NaHCO3 (sat.) and extracted with DCM. The organics were washed with brine, dried over Na2SO4, and concentrated to a brown oil. Purification by silica column chromatography (EtOAc/DCM, 0-20%) afforded the title compound as a white foam. (0.933 g, 51.7%). 1H NMR (400 MHz, DMSO-d6) δ 0.80 (d, J=6.57 Hz, 3 H) 1.02 (d, J=6.57 Hz, 3 H) 1.39 (s, 9 H) 2.31-2.39 (m, 4 H) 4.77 (d, J=10.61 Hz, 1 H) 5.02 (d, J=7.58 Hz, 2 H) 7.46 (d, J=7.83 Hz, 2 H) 8.08 (d, J=8.34 Hz, 2 H) 8.29 (s, 1 H) 8.44 (d, J=2.78 Hz, 1 H). [M+H] calc'd for C25H28FN3O5S, 502; found, 502.3.

Workup

  1. temperatureat reflux for 16 h
  2. customreaction
  3. washthe mixture was washed with aqueous NaHCO3 (sat.)
  4. extractionextracted with DCM
  5. washThe organics were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to a brown oil
  8. customPurification by silica column chromatography (EtOAc/DCM, 0-20%)

Sources & evidence

ORD record
ord-5dfffc34be014df1b742af04e01f41f1
Source dataset
uspto-grants-2013_04
Patent number
US08420816B2

Reaction notes

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