m-Chloroperbenzoic acid → 2-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxide

HRID 337326Notes

Reaction equation

HRID 337326 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:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:49]>C(Cl)Cl.CO>[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:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N+:37]([O-:49])([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 2

HCID 70297m-Chloroperbenzoic acidHCID 712578706-tert-butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)phthalazin-1(2H)-one

Product 1

HCID 715138692-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxideYield 30.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a solution of 6-tert-butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)phthalazin-1(2H)-one (500 mg, 854 μmol, 1 equiv.) in DCM (10 ml) was added 3-chlorobenzoperoxoic acid (191 mg, 854 μmol, 1 equiv.). The reaction mixture was stirred for 18 h. The reaction mixture was diluted with methylene chloride and washed with 1.0 N NaOH (aq). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford a liquid that gradually hardened to a low melting, yellow solid under vacuum, overnight. The solid was dissolved in a minimum of methanol, diluted with methylene chloride and loaded onto a column. The crude material was purified by flash chromatography (silica gel, 40 g, 50% 60:10:1 DCM:MeOH:NH4 OH in DCM) to give 2-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H) -yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxide (158.5 mg, 263 μmol, 30.9% yield) as a yellow solid. (M+H)+=602 m/e. 1H NMR (300 MHz, METHANOL-d4) d ppm 1.47 (s, 9 H) 3.45 (s, 3 H) 3.74 (dt, J=12.46, 2.46 Hz, 1 H) 3.89 (s, 3 H) 4.07 (td, J=11.80, 4.72 Hz, 1 H) 4.25-4.43 (m, 1 H) 4.45-4.62 (m, 2 H) 4.61-4.85 (m, 3 H) 6.13 (s, 1 H) 7.54-7.79 (m, 2 H) 7.87 (d, J=1.51 Hz, 1 H) 8.07 (s, 1 H) 8.50 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H).

Workup

  1. washwashed with 1.0 N NaOH (aq)
  2. customThe layers were separated
  3. washthe organic layer was washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto afford a liquid that
  8. customgradually hardened to a low melting, yellow solid under vacuum, overnight
  9. customThe crude material was purified by flash chromatography (silica gel, 40 g, 50% 60:10:1 DCM:MeOH:NH4 OH in DCM)

Sources & evidence

ORD record
ord-e397fed7704246b382bcc9e20e611ae9
Source dataset
uspto-grants-2014_11
Patent number
US08889682B2

Reaction notes

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