Diisobutylaluminumhydride → N-(7-(5-fluoro-4-(hydroxymethyl)-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468967

Reaction equation

HRID 468967 reaction equation
[H-].C([Al+]CC(C)C)C(C)C.[CH:11]1([C:14]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([C:27]2[C:36]([CH3:37])=[CH:35][C:30]([C:31](OC)=[O:32])=[C:29]([F:38])[CH:28]=2)[CH:21]=3)=[O:15])[CH2:13][CH2:12]1>C1COCC1>[F:38][C:29]1[C:30]([CH2:31][OH:32])=[CH:35][C:36]([CH3:37])=[C:27]([C:22]2[CH:21]=[C:20]3[C:25]([CH:26]=[C:17]([NH:16][C:14]([CH:11]4[CH2:13][CH2:12]4)=[O:15])[N:18]=[CH:19]3)=[CH:24][CH:23]=2)[CH:28]=1

Participants

4

Reactant 2

HCID 21225700DiisobutylaluminumhydrideHCID 67974657Methyl 4-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-2-fluoro-5-methylbenzoate

Product 1

HCID 67974756N-(7-(5-fluoro-4-(hydroxymethyl)-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamideYield 57.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

Diisobutylaluminum hydride (1.0 mol/L) in THF (1.1 mL, 1.06 mmol) was added dropwise to a solution of methyl 4-[3-(cyclopropanecarbonylamino)-7-isoquinolyl]-2-fluoro-5-methyl-benzoate (100 mg, 0.26 mmol) in THF (1 mL) cooled at −15° C. The reaction mixture warmed to room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid solution in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (52 mg, 56%). 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.69 (dd, J=8.5, 1.6 Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 7.11 (d, J=10.7 Hz, 1H), 5.26 (s, 1H), 4.58 (s, 2H), 2.26 (s, 3H), 2.13-2.03 (m, 1H), 0.92-0.77 (m, 4H). LCMS (Method E): RT=4.595 min, M+H+=351.2.

Workup

  1. temperatureThe reaction mixture warmed to room temperature
  2. customthe reaction mixture was quenched with saturated aqueous ammonium chloride
  3. additiondiluted with ethyl acetate (50 mL)
  4. washwashed with 1.0M citric acid solution in water (20 mL)
  5. customThe organic layer was separated
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto provide a residue that
  10. customwas purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 minutes)
  11. customevaporated in vacuo

Sources & evidence

ORD record
ord-6a4993c777f4464cbf5471b39ceb7674
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Linked notes

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