Chloroacetaldehyde → Methyl imidazo(1,2-a)pyridine-7-carboxylate

HRID 910266Notes

Reaction equation

HRID 910266 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][CH:14]=O.C(=O)([O-])O.[Na+]>CCO>[N:1]1[CH:13]=[CH:14][N:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=12

Participants

5

Reactant 3

HCID 33ChloroacetaldehydeHCID 236984Methyl 2-aminopyridine-4-carboxylateHCID 516892Sodium Bicarbonate

Product 1

HCID 15096964Methyl imidazo(1,2-a)pyridine-7-carboxylate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Methyl 2-aminoisonicotinate (5.64 g) and chloroacetaldehyde (6.1M, 12.2 mL) were dissolved in EtOH. To this solution, sodium hydrogen carbonate (6.23 g) was added and heated to 80 degrees. After stirring for 2 hours, the reaction mixture was evaporated and treated with water, extracted ethyl acetate, washed with brine, dried over sodium sulfate, then evaporated under reduced pressure to give methyl imidazo[1,2-a]pyridine-7-carboxylate (4.42 g). This compound (4.42 g) was dissolved in acetic acid. To this solution, formaldehyde (37%, 13.2 mL) and sodium acetate (7.82 g) were added and heated to 105 degrees. After stirring for 3 hours, the reaction mixture was treated with water, and NaOH aq., then the precipitate was filtered off. The filtrate was extracted with EtOAc-n-BuOH (×2), dried over sodium sulfate, then evaporated under reduced pressure to give methyl 3-(hydroxymethyl)imidazo[1,2-a]pyridine-7-carboxylate (2.22 g). This compound (2.22 g) was dissolved in N,N-dimethylformamide, to the solution, diphenylphosphoryl azide (6.14 g) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.40 g) were added. After stirring for 2 hours at room temperature, the reaction mixture was evaporated, and then treated with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-(azidomethyl)imidazo[1,2-a]pyridine-7-carboxylate (1.91 g). This compound (1.91 g) was dissolved in THF (30 mL) and water (3 mL). To this solution, triphenylphosphine (4.33 g) was added and heated to 70 degrees. After stirring for 1.5 hours, the reaction mixture was evaporated and treated with 1N HCl. The water phase was washed with EtOAc (×2) to give methyl 3-(aminomethyl)imidazo[1,2-a]pyridine-7-carboxylate 2 hydrochloride (1.98 g).

Workup

  1. temperatureheated to 80 degrees
  2. customthe reaction mixture was evaporated
  3. additiontreated with water
  4. extractionextracted ethyl acetate
  5. washwashed with brine
  6. dry with materialdried over sodium sulfate
  7. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-0871826d2fbb40fcb9f6193075008b13
Source dataset
uspto-grants-2011_09
Patent number
US08022061B2

Reaction notes

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