Lithium Hydroxide → [6-(3,5-Dimethyl-isoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-ylmethyl]-carbamic acid tert-butyl ester

HRID 908267Notes

Reaction equation

HRID 908267 reaction equation
[Li+].[OH-].[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N:15][CH:16]=[C:17](Br)[CH:18]=2)([CH3:6])([CH3:5])[CH3:4].[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1.OC(C(O)(C)C)(C)C>>[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][C:11]1[NH:12][C:13]2[C:14]([N:20]=1)=[N:15][CH:16]=[C:17]([C:27]1[C:23]([CH3:22])=[N:24][O:25][C:26]=1[CH3:31])[CH:18]=2)([CH3:6])([CH3:5])[CH3:4]

Participants

5

Reactant 4

HCID 3939Lithium HydroxideHCID 6425PinacolHCID 27343463,5-Dimethylisoxazole-4-boronic acidHCID 22308601tert-butyl N-({6-bromo-1H-imidazo[4,5-b]pyridin-2-yl}methyl)carbamate

Product 1

HCID 58024801[6-(3,5-Dimethyl-isoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-ylmethyl]-carbamic acid tert-butyl esterYield 69%

Conditions

Temperature
120 °C

Procedure

To a dry 20 mL microwave vessel equipped with a stir bar, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (125 mg, 0.153 mmol) and LiOH (110 mg, 4.58 mmol) were combined. The vessel was capped with septa and purged three times with vacuum and nitrogen. The mixture was suspended into degassed, 10:1 dioxane: H2O (2.5 mL). To the suspension, (6-Bromo-1H-imidazo[4,5-b]pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (500 mg, 1.528 mmol), 3,5-dimethylisoxazole-4-boronic acid (323 mg, 2.292 mmol) and pinacol (271 mg, 2.292 mmol) were added. The reaction mixture was purged again with vacuum and nitrogen three times and sealed using a microwave crimped septa. The reaction vessel was placed in a microwave reactor and heated at 120° C. for 2.5 hrs. The reaction was complete based on LC/MS (M+1=344). The resulting brown suspension was concentrated under reduced pressure to dryness and reconstituted with 20 mL of 10% MeOH-DCM. 30 g of 230-400 mesh SiO2 was then added and the resulting slurry was stirred vigorously. Removed solvent under reduced pressure and packed compound absorbed on silica into a 40 g SIM cartridge. Purified crude using SiO2 flash chromatography (120 g ISCO cartridge; 230-400 mesh SiO2) equilibrated with 10% MeOH-DCM containing 0.5% triethylamine to give 360 mg of the title compound as an amber oil (69%).

Workup

  1. customTo a dry 20 mL microwave vessel equipped with a stir bar
  2. customThe vessel was capped with septa and
  3. custompurged three times with vacuum and nitrogen
  4. custominto degassed
  5. customThe reaction mixture was purged again with vacuum and nitrogen three times
  6. customsealed
  7. customThe reaction vessel was placed in a microwave reactor
  8. concentrationThe resulting brown suspension was concentrated under reduced pressure to dryness
  9. addition30 g of 230-400 mesh SiO2 was then added
  10. customabsorbed on silica into a 40 g SIM cartridge
  11. customPurified crude

Sources & evidence

ORD record
ord-9aeb90921dfb42138cb9277155159e49
Source dataset
uspto-grants-2011_09
Patent number
US08017605B2

Reaction notes

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