O-ethylhydroxylamine hydrochloride → N-Ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide

HRID 1500733ノート

反応式

HRID 1500733 の反応式
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]

参加物

5

反応物 3

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

生成物 1

HCID 44135982N-Ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide収率 19.1%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-9f53b3c62b5e43b2a3091b8ee22ceac3
出典データセット
uspto-grants-2015_12
特許番号
US09206174B2

反応ノート

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