3-Methylenecyclobutanecarboxylic acid → N-((3-chloropyrazin-2-yl)methyl)-3-methylenecyclobutanecarboxamide

HRID 643378Notes

Reaction equation

HRID 643378 reaction equation
C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.Cl.Cl.[Cl:23][C:24]1[C:25]([CH2:30][NH2:31])=[N:26][CH:27]=[CH:28][N:29]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH2:30][NH:31][C:18]([CH:16]2[CH2:15][C:14](=[CH2:13])[CH2:17]2)=[O:20])=[N:26][CH:27]=[CH:28][N:29]=1

Participants

7

Reactant 4

HCID 274753-Methylenecyclobutanecarboxylic acidHCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 42609650(3-Chloropyrazin-2-yl)methanamine dihydrochloride

Product 1

HCID 57681076N-((3-chloropyrazin-2-yl)methyl)-3-methylenecyclobutanecarboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

1,1′-Carbonyldiimidazole (CDI) (8.24 g, 50.81 mmol) and 3-methylenecyclobutanecarboxylic acid (5.70 g, 50.81 mmol) were dissolved in anhydrous THF (100 mL) and allowed to stir at 60° C. for 4 h. A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (10.0 g, 46.19 mmol) and diisopropylethylamine (DIPEA) (32.30 mL, 184.76 mmol) in anhydrous CH2Cl2 (150 mL) was added to the mixture and the reaction was allowed to stir at rt for 24 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc and the resulting solution washed with saturated NaHCO3 (aq.) water H2O and Brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude product, which was purified by chromatography over silica gel eluting with 50-70% EtOAc/hexane to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.92-2.94 (2H, m), 3.05-3.14 (2H, m), 4.60 (2H, d, J=4.24 Hz), 4.80-4.84 (2H, m), 6.75 (1H, brs), 8.33 (1H, d, J=4.22 Hz) and 8.45 (1H, d, J=2.54 Hz). MS (ES+): m/z 238 and 240 [MH+].

Workup

  1. stirringto stir at rt for 24 h
  2. concentrationThe mixture was concentrated in vacuo
  3. dissolutionthe residue dissolved in EtOAc
  4. washthe resulting solution washed with saturated NaHCO3 (aq.) water H2O and Brine
  5. dry with materialThe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto afford crude product, which
  9. customwas purified by chromatography over silica gel eluting with 50-70% EtOAc/hexane

Sources & evidence

ORD record
ord-a3426b6e5e424635b38f4e287b9eb577
Source dataset
uspto-grants-2010_04
Patent number
US07700594B2

Reaction notes

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