Sodium hydride → Tert-butyl 2-((tert-butoxycarbonyl)(5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)amino)acetate

HRID 1772691Notes

Reaction equation

HRID 1772691 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C.CCOC(C)=O>[C:22]([O:21][C:20]([N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:9]3[CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=[C:8]3[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:12][CH:11]=2)=[CH:18][N:17]=1)[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:26])([CH3:23])([CH3:25])[CH3:24]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 79177tert-Butyl bromoacetateHCID 117732286tert-Butyl (5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)carbamate

Product 1

HCID 117728174Tert-butyl 2-((tert-butoxycarbonyl)(5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)amino)acetate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Compound 48a (200.0 mg, 0.450 mmol) was treated with 60% sodium hydride (19.2 mg, 0.48 mmol) in DMF (5 mL) for 15 min. tert-Butyl bromoacetate (25.6 mg, 0.25 mmol) was then added, and the resulting mixture was stirred for 5 h at rt. The reaction was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give tert-butyl 2-((tert-butoxycarbonyl)(5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)amino)acetate as an off-white solid, which was subsequently deprotected with TFA following the methods described in the Example 47, Step B to afford the title compound 107 as an off-white solid after trituration with ether. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.84-3.93 (m, 4H), 4.27 (s, 2H), 4.31-4.39 (m, 4H), 5.66 (s, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.39-7.45 (m, 1H), 7.66 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.95-8.01 (m, 2H), 8.12-8.18 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H25N7O4: 512.2 [M+H]. found 512.2.

Workup

  1. additionwas then added
  2. washwashed with water
  3. washThe organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes)

Sources & evidence

ORD record
ord-4cd33cabbaab4c86b01927191f8fb2e8
Source dataset
uspto-grants-2016_02
Patent number
US09249163B2

Reaction notes

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