Aldoxime → HCID 71008511, compound

HRID 1025597Notes

Reaction equation

HRID 1025597 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=N[OH:39])C.[Cl-].[In+3].[Cl-].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[C:25]([C:32]([NH2:33])=[O:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 7863AldoximeHCID 8857Ethyl AcetateHCID 159675indium(III)chlorideHCID 71008601HCID 71008601, compound

Product 1

HCID 71008511HCID 71008511, compoundYield 17.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A stirred solution of 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (610 mg, 783 μmol, Eq: 1.00), acetaldoxime (139 mg, 143 μl, 2.35 mmol, Eq: 3) and indium (III) chloride (8.66 mg, 39.1 μmol, Eq: 0.05) in toluene (25.2 ml) was heated to 110° C. and stirred for 3 h. The reaction mixture was poured into 15 mL EtOAc and extracted with sat NH4Cl (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes) gave 66 mgs of desired product with impurity. This material was re-purified by preparative reverphase HPLC in TFA. The desired product was neutralized with NaHCO3 (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo., extracted with ethyl acetate/methanol (9:1) to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (43 mgs, 12%) as white solid. 1H NMR (DMSO-d6) δ: 8.64 (dd, J=7.9, 1.6 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.82 (dd, J=13.2, 1.6 Hz, 1H), 7.66-7.78 (m, 3H), 7.63 (dd, J=7.3, 2.3 Hz, 1H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.18 (br. s., 1H), 4.72 (t, J=5.4 Hz, 1H), 4.11-4.34 (m, 2H), 1.44 (s, 9H). MS m/e 486.6 (M+H+).

Workup

  1. extractionextracted with sat NH4Cl (1×25 mL)
  2. dry with materialThe organic layers were dried over MgSO4
  3. concentrationconcentrated in vacuo
  4. customAfter removal of solvent and residue
  5. customwas separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-1263fe3c697b4ce98902c9e1cec2fb91
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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