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Lithium Hexamethyldisilazide → 5-(4-Bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamide

HRID 2064040
Notes
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Reaction equation

HRID 2064040 reaction equation
CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[N:9]3[CH:20]=[N:21][CH:22]=[C:8]3[CH:7]=[N:6][C:5]=2[C:3]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:4])=[C:13]([F:19])[CH:14]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamineHCID 591401755-(4-Bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester

Product 1

HCID 591401825-(4-Bromo-2-fluorophenylamino)-N-(2-(vinyloxy)ethoxy)-imidazo[1,5-a]pyrazine-6-carboxamideYield 89.6%

Reagents, catalysts & solvents 1

HCID 8028
Tetrahydrofuran
Solvent

Procedure

To a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (150 mg, 0.41 mmol) and O-(2-vinyloxy-ethyl)hydroxylamine (127 mg, 1.23 mmol, 3.0 eq) in anhydrous THF (7.5 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.23 mmol, 3.0 eq.), and the reaction, mixture was stirred at room temperature. After 1 h the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 5% methanol in dichoromethane) to give an oil. Crystallization from DCM—ether—hexane afforded the desired product as a pale orange solid (160.2 mg, 89.4%). LCMS (method C): RT=2.53 min, [M+H]+=437/439.

Workup

  1. customthe reaction, mixture
  2. customAfter 1 h the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate
  3. additiondiluted with ethyl acetate
  4. customThe organic layer was isolated
  5. washwashed with water and brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give an oil
  10. customCrystallization from DCM—ether—hexane

Sources & evidence

ORD record
ord-e802a57b1c514e728b4c607746ee1bbf
Source dataset
uspto-grants-2012_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08288408B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes