Water → 6-tert-butyl-2-[4-[5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylamino)-1-methyl-6-oxo-3-pyridyl]-3-(hydroxymethyl)-2-pyridyl]-8-fluoro-phthalazin-1-one

HRID 1185244Notes

Reaction equation

HRID 1185244 reaction equation
C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[CH2:26][CH2:25][CH2:24][N:22]3[N:23]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[CH2:26][CH2:25][CH2:24][N:22]5[N:23]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:42])([CH3:40])[CH3:41]

Participants

5

Reactant 3

HCID 962WaterHCID 3939Lithium HydroxideHCID 86684090(2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate

Product 1

HCID 866840916-tert-butyl-2-[4-[5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylamino)-1-methyl-6-oxo-3-pyridyl]-3-(hydroxymethyl)-2-pyridyl]-8-fluoro-phthalazin-1-oneYield 33.7%

Reagents, catalysts & solvents 1

HCID 22722550Tetrahydrofuran water isopropanolSolvent

Procedure

To a solution of 162d (50 mg, 0.080 mmol) in THF/i-propanol/water (1/1/0.5 ml) was added lithium hydroxide (19 mg, 0.80 mmol) at room temperature. After the reaction was stirred for 2.5 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (15 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B: acetonitrile) to afford 162 (15 mg, 33.3%) as white solid. MS-ESI: [M+H]+ 556.3. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.55-7.47 (m, 4H), 7.26 (s, 1H), 5.74 (s, 1H), 4.47 (d, J=4.0 Hz, 2H), 4.07 (t, J=2.0 Hz, 2H), 3.70 (s, 3H), 2.87 (t, J=6.5 Hz, 2H), 2.55-2.52 (m, 2H), 1.45 (s, 9H).

Workup

  1. extractionextracted with dichloromethane (3×20 mL)
  2. washThe combined organic layer was washed with brine (30 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue solid was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B

Sources & evidence

ORD record
ord-bbe6aa8fc5094f3fb49039c3a5b92895
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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