Trimethylacetamide → HCID 90403369, compound

HRID 1049369Notes

Reaction equation

HRID 1049369 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[CH:24]=1.CCN(C(C)C)C(C)C>ClCCCl.O1CCOCC1>[CH3:14][C:15]1[N:20]=[C:19]([NH:21][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)[CH:24]=1

Participants

7

Reactant 4

HCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 90403180HCID 90403180, compound

Product 1

HCID 90403369HCID 90403369, compoundYield 56.1%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 2,2,2-trimethylacetamide (0.040 g, 0.400 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.035 mL, 0.400 mmol), stirred at RT for 5 min, then warmed to 80° C. for 0.5 h. The solution was cooled to RT, added to a mixture of 6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (0.10 g, 0.266 mmol) and DIEA (0.2 mL, 1.145 mmol) in dioxane (4 mL) and stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with 1N NaOH, then brine, dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, and the resulting solid was collected via filtration and dried to afford N-((6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (75 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (br s, 1H), 10.40 (br s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.94-7.87 (m, 3H), 7.65 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.65 (dd, J=5.6, 2.4 Hz, 1H), 3.21 (t, J=4.6 Hz, 4H), 2.44 (br s, 4H), 2.27 (s, 3H), 2.21 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 503.3 (M+H+).

Workup

  1. temperaturewarmed to 80° C. for 0.5 h
  2. temperatureThe solution was cooled to RT
  3. stirringstirred at RT for 3 h
  4. additionThe mixture was treated with satd
  5. extractionNaHCO3, extracted with EtOAc (3×)
  6. washthe combined organics were washed with 1N NaOH
  7. dry with materialbrine, dried over Na2SO4
  8. concentrationconcentrated to dryness
  9. additionThe material was treated with MeCN
  10. filtrationthe resulting solid was collected via filtration
  11. customdried

Sources & evidence

ORD record
ord-493d318f42364bb9877b587ecd7085db
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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