2-Amino-4-methylpyridine → ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate

HRID 626607Notes

Reaction equation

HRID 626607 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH3:10]>COCCOC>[CH3:16][C:14]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[C:13]=1[C:12]([O:11][CH2:9][CH3:10])=[O:18]

Participants

4

Reactant 2

HCID 15332-Amino-4-methylpyridineHCID 11858Ethyl 2-chloroacetoacetate

Product 1

HCID 682232ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylateYield 78%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Procedure

In this specific example of synthesis of ND-8454, a solution of 2-amino-4-picoline (10.0 g, 91.5 mmol) and ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 mL of 1,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered and solids (2-amino-4-picoline hydrochloride salt) was collected and washed with hexanes. The filtrate liquor was concentrated in vacuo and residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2×) and brine. The organic phase was collected, dried over sodium sulfate (Na2SO4), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 20% ethyl acetate:CH2Cl2 solvent system to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate as a tan solid. mp 59-61° C.; 1H NMR (300 MHz, CDCl3) 9.14 δ(d, J=7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J=7.1, 1.7 Hz, 1H), 4.40 (q, J=7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1.42 (t, J=7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calcd. for C12H15N2O2, 219.1155; found 219.1128. Retention time=1.4 minutes (mobile phase: 60% water:acetonitrile).

Workup

  1. temperatureheated for 36 h
  2. temperatureat reflux
  3. filtrationThe reaction mixture was filtered
  4. customsolids (2-amino-4-picoline hydrochloride salt) was collected
  5. washwashed with hexanes
  6. concentrationThe filtrate liquor was concentrated in vacuo and residue
  7. dissolutionwas dissolved in CH2Cl2
  8. washwashed with 5% acetic acid solution (2×) and brine
  9. customThe organic phase was collected
  10. dry with materialdried over sodium sulfate (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customCrude material obtained
  14. customwas purified by silica gel column chromatography with a 20% ethyl acetate

Sources & evidence

ORD record
ord-3bbcbfc0e94840968d4763ee6939bce0
Source dataset
uspto-grants-2016_04
Patent number
US09309238B2

Reaction notes

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