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

HRID 2076222Notes

Reaction equation

HRID 2076222 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

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 8028TetrahydrofuranSolvent

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

Sources & evidence

ORD record
ord-cfdeffa19c134924a128443b47e4aded
Source dataset
uspto-grants-2011_04
Patent number
US07923456B2

Reaction notes

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