Trimethylacetamide → HCID 90410317, compound

HRID 626601Notes

Reaction equation

HRID 626601 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl>[CH2:37]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[O:30])[CH2:36][CH2:35]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1

Participants

6

Reactant 3

HCID 12957TrimethylacetamideHCID 65578Oxalyl chlorideHCID 90410008HCID 90410008, compound

Product 1

HCID 90410317HCID 90410317, compoundYield 32.4%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirring suspension of trimethylacetamide (0.115 g, 1.141 mmol) in 1,2-dichloroethane (5 mL) at RT was added oxalyl chloride (0.100 mL, 1.141 mmol). The mixture was stirred 1 h at RT and then at 90° C. for 1 h. The mixture was cooled to RT and added slowly to a stirring solution of N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-benzylpiperazine-1-carboxamide (0.355 g, 0.878 mmol) in CH2Cl2 (15 mL). Solids precipitated and the suspension was stirred overnight at RT. DIEA (0.6 mL) was added and the resulting solution stirred 45 min. It was washed with H2O (2×), brine (1×), dried (MgSO4), and evaporated. The crude product was purified by silica gel chromatography (0-6% MeOH/CH2Cl2) and then re-purified by silica gel chromatography (0-10% MeOH/EtOAc) to afford 4-benzyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.151 g, 32%) as an off-white brittle foam. 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.24 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.28-7.26 (m, 5H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.46 (s, 2H), 3.40 (m, 4H), 2.31 (t, J=4.7 Hz, 4H), 1.21 (s, 9H); MS (ESI) m/z: 532.3 (M+H+).

Workup

  1. waitat 90° C. for 1 h
  2. temperatureThe mixture was cooled to RT
  3. customSolids precipitated
  4. stirringthe suspension was stirred overnight at RT
  5. additionDIEA (0.6 mL) was added
  6. stirringthe resulting solution stirred 45 min
  7. washIt was washed with H2O (2×), brine (1×)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by silica gel chromatography (0-6% MeOH/CH2Cl2)
  11. customre-purified by silica gel chromatography (0-10% MeOH/EtOAc)

Sources & evidence

ORD record
ord-2387ce4a647644c98a7d1d6bb232eba0
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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