Lithium Hydroxide → 6-tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]phthalazin-1-one

HRID 407810Notes

Reaction equation

HRID 407810 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:34]2[N:43]=[CH:42][C:41]3[C:36](=[C:37]([F:48])[CH:38]=[C:39]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:40]=3)[C:35]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:31]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:44]([C:39]1[CH:40]=[C:41]2[C:36](=[C:37]([F:48])[CH:38]=1)[C:35](=[O:49])[N:34]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:31]=[C:22]5[CH2:23][N:24]([CH:27]6[CH2:30][O:29][CH2:28]6)[CH2:25][CH2:26][N:21]5[N:20]=4)[C:15](=[O:32])[N:14]([CH3:33])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:43]=[CH:42]2)([CH3:47])([CH3:45])[CH3:46]

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 86684068(2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-3-yl)methyl Acetate

Product 1

HCID 712577926-tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-(oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2-yl]amino]-6-oxo-pyridazin-3-yl]-2-pyridyl]phthalazin-1-oneYield 27.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 22597222Tetrahydrofuran 2-propanolSolvent

Procedure

A mixture of 155d (117 mg, 0.175 mmol) and lithium hydroxide.water (73.5 mg, 1.75 mmol) in i-propanol/THF (1:1, 8 mL) and water (1 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (6 mL). It was then extracted with dichloromethane (3×50 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 155 (30 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 628.3. 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.79-7.77 (m, 1H), 7.61 (d, J=4.5 Hz, 1H), 6.04 (s, 1H), 7.61-7.60 (m, 1H), 4.61-4.59 (m, 2H), 4.50-4.45 (m, 4H), 4.01-3.99 (m, 2H), 3.78 (s, 3H), 3.69-3.65 (m, 1H), 3.54 (s, 2H), 2.79-2.76 (m, 2H), 1.39 (s, 9H).

Workup

  1. customThe mixture was evaporated under reduced pressure
  2. additionthe residue was diluted with water (6 mL)
  3. extractionIt was then extracted with dichloromethane (3×50 mL)
  4. extractionThe combined dichloromethane extract
  5. concentrationwas concentrated under reduced pressure
  6. customthe residue was purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-48d4be3e45d544edb2d984d0b45c5b2a
Source dataset
uspto-grants-2014_06
Patent number
US08754077B2

Reaction notes

Loading…