Dichloromethane → 6-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

HRID 449565Notes

Reaction equation

HRID 449565 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]([O:25][C:26]([CH3:32])([CH3:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=3)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=2)[C:36]1=[O:50])(=O)C.[OH-].[Na+].C(Cl)Cl>O1CCOCC1.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([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]([O:25][C:26]([CH3:31])([CH3:32])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:44]=[CH:43]2)([CH3:46])([CH3:47])[CH3:48]

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 14798Sodium HydroxideHCID 667425422-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzyl acetate

Product 1

HCID 566565066-tert-Butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-oneYield 26.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzyl acetate (292 mg, 0.43 mmol) in dioxane (1.5 ml) was added a solution of 2N sodium hydroxide (2.5 ml, 5 mmol). The flask was heated at 50° C. (oil bath) with vigorous stirring under argon atmosphere for 3 hours. The material was cooled to ambient and the contents were taken up in water (25 ml) and methylene chloride (50 ml) and transferred to a reparatory funnel and shaken. The organic phase was collected and washed with a solution of 50% diluted brine (25 ml). The aqueous phases were back extracted with methylene chloride (2×40 ml) and the organic phases combined, dried (magnesium sulfate), filtered and stripped. The remainder was purified by preparative thin layer chromatography (3 plates), eluting with 6% methanol/dichloromethane and then re-developing the plates with first 8% and then 11% methanol/dichloromethane. The product band was collected providing the desired product as a light yellow-white solid (72 mg). MP=136-144° C.; (M+H)+=642 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6H) 1.42 (s, 9H) 2.40 (s, 6H) 2.51 (s, 2H) 3.90 (s, 3H) 4.42 (s, 2H) 6.90 (d, J=9.06 Hz, 1H) 7.33 (dd, J=8.69, 3.02 Hz, 1H) 7.41-7.72 (m, 5H) 8.09 (d, J=3.02 Hz, 1H) 8.20-8.35 (m, 2H) 8.53 (s, 1H).

Workup

  1. temperatureThe material was cooled to ambient and the contents
  2. stirringshaken
  3. customThe organic phase was collected
  4. washwashed with a solution of 50% diluted brine (25 ml)
  5. extractionThe aqueous phases were back extracted with methylene chloride (2×40 ml)
  6. dry with materialdried (magnesium sulfate)
  7. filtrationfiltered
  8. customThe remainder was purified by preparative thin layer chromatography (3 plates)
  9. washeluting with 6% methanol/dichloromethane
  10. customThe product band was collected

Sources & evidence

ORD record
ord-b644a67cfc6947a9bac0b3db443ddabe
Source dataset
uspto-grants-2013_07
Patent number
US08481540B2

Reaction notes

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