Sodium Hydroxide → 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenyl)-2H-phthalazin-1-one

HRID 402928Notes

Reaction equation

HRID 402928 reaction equation
C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:13]=[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])=[CH:24][N:23]=3)[C:15]3[N:16]([N:18]=[CH:19][N:20]=3)[CH:17]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[O:29])=[CH:24][N:23]=4)[C:15]4[N:16]([N:18]=[CH:19][N:20]=4)[CH:17]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:49])([CH3:47])[CH3:48]

Participants

6

Reactant 2

HCID 14798Sodium HydroxideHCID 866868282-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(8-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl acetate

Product 1

HCID 866868306-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenyl)-2H-phthalazin-1-oneYield 23%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(8-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzyl acetate (289 mg, 418 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (1.0 N, 5.0 ml, 5.00 mmol, Eq: 12.0). The solution was heated to 60° C. for 18 h. The reaction was cooled to room temperature. The reaction was diluted with sat NaHCO3 (aq) and DCM. The layers were separated. The aqueous layer was extracted three times with DCM, and then dried over MgSO4. The solid was removed by filtration. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM gradient) to give a residue. The residue was triturated with Et2O to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenyl)-2H-phthalazin-1-one (61 mg, 23%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.36-1.49 (m, 9H) 3.51-3.95 (m, 8H) 4.40 (s, 2H) 7.20 (dd, J=18.13, 7.18 Hz, 1H) 7.41-7.67 (m, 6H) 7.76 (dd, J=8.31, 2.27 Hz, 1H) 8.31 (d, J=2.64 Hz, 1H) 8.36-8.48 (m, 2H) 8.66 (s, 1H) 8.95 (s, 1H) LC/MS-ESI observed [M+H]+ 649.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. customThe layers were separated
  3. extractionThe aqueous layer was extracted three times with DCM
  4. dry with materialdried over MgSO4
  5. customThe solid was removed by filtration
  6. concentrationThe filtrate was concentrated in vacuo
  7. customThe crude material was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM gradient)
  8. customto give a residue
  9. customThe residue was triturated with Et2O

Sources & evidence

ORD record
ord-940a1ed9f93c45739ba4b7afba7ad196
Source dataset
uspto-grants-2014_06
Patent number
US08742098B2

Reaction notes

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