O-ethylhydroxylamine hydrochloride → HCID 44135982, compound

HRID 1500733Notes

Reaction equation

HRID 1500733 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]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[CH2:24]([O:26][NH:27][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]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])[CH3:25]

Participants

5

Reactant 3

HCID 76850O-ethylhydroxylamine hydrochloride2×HCID 2733832Lithium Hexamethyldisilazide2×HCID 591401715-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester

Product 1

HCID 44135982HCID 44135982, compoundYield 19.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylamine hydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2 mmol, 3.0 eq). After stirring at room temperature for 16 h, additional O-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) and lithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and diluted with ethyl acetate (50 mL). 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 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to 15% methanol in ethyl acetate) to give an oil. Crystallization from DCM ether hexane afforded the title compound as a yellow solid (33.7 mg, 19.1%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H); LCMS (method D2): RT=1.24 min, [M+H]+=442.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 3 days
  2. customThe reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL)
  3. additiondiluted with ethyl acetate (50 mL)
  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-9f53b3c62b5e43b2a3091b8ee22ceac3
Source dataset
uspto-grants-2015_12
Patent number
US09206174B2

Reaction notes

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