Lithium Hydroxide → 6-tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]phthalazin-1-one

HRID 407661Notes

Reaction equation

HRID 407661 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:38]2[N:47]=[CH:46][C:45]3[C:40](=[C:41]([F:52])[CH:42]=[C:43]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:44]=3)[C:39]2=[O:53])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:48]([C:43]1[CH:44]=[C:45]2[C:40](=[C:41]([F:52])[CH:42]=1)[C:39](=[O:53])[N:38]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:31]6[CH2:34][O:33][CH2:32]6)[CH2:27][C@@H:26]5[CH3:35])=[CH:21][N:20]=4)[C:15](=[O:36])[N:14]([CH3:37])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:47]=[CH:46]2)([CH3:50])([CH3:49])[CH3:51]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86683947(S)-(2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)methyl Acetate

Product 1

HCID 866839486-tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridyl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]phthalazin-1-oneYield 97.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 22597222Tetrahydrofuran 2-propanolSolvent

Conditions

Temperature
30 °C

Procedure

A mixture of 117d (110 mg, 0.15 mmol) and lithium hydroxide (65 mg, 1.5 mmol) in THF/i-propanol (5/3 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 117 (100 mg, 95%) as a yellow solid. MS-ESI: [M+H]+ 682.4. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 8.60 (s, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=5.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.34 (s, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.73-4.55 (m, 5H), 3.92 (m, 4H), 3.73-3.74 (m, 1H), 3.55-3.53 (m, 1H), 3.16-3.15 (m, 2H), 2.64-2.39 (m, 4H), 1.44 (s, 9H), 1.09-1.07 (m, 3H).

Workup

  1. customThe mixture was evaporated under reduced pressure
  2. extractionthe residue was extracted with ethyl acetate (2×20 mL)
  3. extractionThe combined ethyl acetate extract
  4. concentrationwas concentrated under reduced pressure
  5. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-3db7a4b9f51a4fba887ee193043562dc
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

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