Lithium Hydroxide → 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

HRID 449594Notes

Reaction equation

HRID 449594 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][C:30]([OH:34])([CH3:33])[CH2:29][CH2:28]4)=[O:26])=[CH:21][N:20]=3)[C:15](=[O:35])[N:14]([CH3:36])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:37]1[N:46]=[CH:45][C:44]2[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=2)[C:38]1=[O:52])(=O)C.[Li+].[OH-]>O1CCOCC1>[C:47]([C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([F:51])[CH:41]=1)[C:38](=[O:52])[N:37]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][C:30]([OH:34])([CH3:33])[CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[C:15](=[O:35])[N:14]([CH3:36])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:46]=[CH:45]2)([CH3:48])([CH3:49])[CH3:50]

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 667425262-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate

Product 1

HCID 566556666-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-oneYield 14%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (62 mg, 87.4 μmol) was combined with dioxane (5 ml) and 1M LiOH (1 ml) to give a brown solution. The reaction mixture was stirred at 25° C. for 5 h. The crude reaction mixture was concentrated in vacuo and partitioned between DCM and water. The aqueous layer was back-extracted with DCM (2×25 mL). The organic layers were combined, washed with sat NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 8% MeOH in DCM), isolated as an off-white powder and dried under vacuum for 3 hrs at 25° C. The material was repurified by flash chromatography (silica gel, 24 g, 0% to 4% MeOH in DCM) to afford 0.008 g (14%) of the title compound as a white solid. (M+H)+=668 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.69 (s, 1H), 8.39-8.47 (m, 2H), 8.29 (d, J=2.3 Hz, 1H), 7.75 (dd, J=8.5, 2.1 Hz, 1H), 7.43-7.70 (m, 5H), 6.99 (d, J=8.7 Hz, 1H), 4.43 (br. s., 2H), 3.91 (s, 3H), 3.20-3.87 (m, 4H), 1.65 (br. s., 6H) 1.43 (s, 9H).

Workup

  1. customto give a brown solution
  2. customThe crude reaction mixture
  3. concentrationwas concentrated in vacuo
  4. custompartitioned between DCM and water
  5. extractionThe aqueous layer was back-extracted with DCM (2×25 mL)
  6. washwashed with sat NaCl (1×10 mL)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by flash chromatography (silica gel, 24 g, 0% to 8% MeOH in DCM)
  10. customisolated as an off-white powder
  11. customdried under vacuum for 3 hrs at 25° C
  12. customThe material was repurified by flash chromatography (silica gel, 24 g, 0% to 4% MeOH in DCM)

Sources & evidence

ORD record
ord-25320d058272495d95ad0535a75966ed
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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