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 1627162Notes

Reaction equation

HRID 1627162 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-((1-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-6cf97a556bd3447bbb2189c6e2018dce
Source dataset
uspto-grants-2014_07
Patent number
US08785429B2

Reaction notes

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