2-Fluoro-4-iodoaniline → 5-(2-Fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester

HRID 2063981Notes

Reaction equation

HRID 2063981 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1Cl)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[O:13]

Participants

5

Reactant 3

HCID 1856942-Fluoro-4-iodoanilineHCID 2733832Lithium HexamethyldisilazideHCID 58324565Methyl 5-chloroimidazo[1,5-a]pyridine-6-carboxylate

Product 1

HCID 591401365-(2-Fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl esterYield 83.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred suspension 2-fluoro-4-iodo aniline (53.95 g, 0.256 mol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (62.0 g, 0.253 mol) in THF (500 mL) under nitrogen at −78° C., a solution of lithium bis(trimethylsilyl) amide (544 mL, 1M solution, 0.544 mol) was added dropwise over 1 hr, maintaining the temperature below −65° C., giving a red/brown solution. After stirring for 30 minutes at −78° C. the reaction mixture was allowed to warm to −30° C. and then quenched with addition water (100 mL). The solvent was removed in vacuo, before diluting with water (500 ml) and the mixture was extracted with 2-methyltetrahydrofuran (2×500 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was triturated tert-butyl methyl ether (600 mL) to yield product as yellow/brown solid (87.2 g 83%). LCMS (Method B): RT=3.54 min, [M+H]+=412.

Workup

  1. temperaturemaintaining the temperature below −65° C.
  2. customgiving a red/brown solution
  3. temperatureto warm to −30° C.
  4. customquenched with addition water (100 mL)
  5. customThe solvent was removed in vacuo
  6. additionbefore diluting with water (500 ml)
  7. extractionthe mixture was extracted with 2-methyltetrahydrofuran (2×500 mL)
  8. washThe combined organic extracts were washed with water
  9. dry with materialbrine, dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe resultant residue was triturated tert-butyl methyl ether (600 mL)

Sources & evidence

ORD record
ord-87c976d33e6a4c5b917a0ef2dc10279d
Source dataset
uspto-grants-2012_10
Patent number
US08288408B2

Reaction notes

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