4-Methylmorpholine → (R)-tert-Butyl 3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate

HRID 1968283Notes

Reaction equation

HRID 1968283 reaction equation
C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[C:16]([O:20][C:21](=[O:27])[C@@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:37]=[C:38]([C:39](O)=[O:40])[C:31]=12)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.C1COCC1.CCOC(C)=O>[CH3:26][CH:24]([CH3:25])[C@@H:22]([N:23]1[C:39](=[O:40])[C:38]2=[CH:37][N:36]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[C:32]3[C:31]2=[C:30]([CH:35]=[CH:34][N:33]=3)[CH2:28]1)[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27]

Participants

9

Reactant 5

HCID 79724-Methylmorpholine2×HCID 5049666Sodium triacetoxyborohydrideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 45108216H-D-Val-OtBu hydrochlorideHCID 582934364-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Product 1

HCID 67224983(R)-tert-Butyl 3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Sodium triacetoxyborohydride (603 mg, 2.85 mmol) and D-valine-tert-butyl ester HCl salt (597 mg, 2.85 mmol) were combined in DCM (15 mL). The reaction mixture was stirred for 20 min at room temperature and then cooled to 0° C. 4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (700 mg, 2.03 mmol) was added, and the solution was stirred for 1 h. The solution was concentrated in vacuo to give a white foam, which was re-dissolved in THF (40 mL). HATU (1.16 g, 3.05 mmol) and N-methylmorpholine (339 μL, 3.05 mmol) were added, and the reaction mixture was stirred at 52° C. for 2 h. Additional HATU (580 mg, 1.53 mmol) and N-methylmorpholine (170 μL, 1.53 mmol) were added, and the reaction mixture was stirred for an additional 2 h at 52° C. The solution was subsequently cooled, diluted with EtOAc, and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (1:2:2 EtOAc/Hexanes/DCM) gave the title compound as a yellow oil, which solidified upon sitting (840 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J=7.0 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H), 1.42 (s, 9H), 2.25-2.34 (m, 1H), 2.35 (s, 3H), 4.77-5.14 (m, 3H), 7.05 (d, J=5.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 8.05-8.10 (m, 3H), 8.45 (d, J=5.0 Hz, 1H). [M+H] calc'd for C25H29N3O5S, 484; found, 484.

Workup

  1. temperaturecooled to 0° C
  2. stirringthe solution was stirred for 1 h
  3. concentrationThe solution was concentrated in vacuo
  4. customto give a white foam, which
  5. stirringthe reaction mixture was stirred at 52° C. for 2 h
  6. stirringthe reaction mixture was stirred for an additional 2 h at 52° C
  7. temperatureThe solution was subsequently cooled
  8. washwashed with brine
  9. dry with materialThe organics were dried over MgSO4
  10. concentrationconcentrated in vacuo
  11. customPurification by silica gel chromatography (1:2:2 EtOAc/Hexanes/DCM)

Sources & evidence

ORD record
ord-1e7d43c3dfde4f56816e81dd3e515b74
Source dataset
uspto-grants-2013_04
Patent number
US08420816B2

Reaction notes

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