Acetonitrile → 3-(6-tert-Butyl-8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)-5-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydro-pyridin-3-yl]pyridine-4-carbaldehyde

HRID 1185045Notes

Reaction equation

HRID 1185045 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[N:19]=[CH:18][C:17]3[C:12](=[C:13]([F:24])[CH:14]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)[C:11]2=[O:25])[C:7]=1[CH:8]=[O:9].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][C@@H:50]3[CH3:59])=[CH:45][N:44]=2)[C:28]1=[O:60].CC([O-])=O.[K+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([F:24])[CH:14]=1)[C:11](=[O:25])[N:10]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:54][CH2:53][N:52]([CH:55]6[CH2:56][O:57][CH2:58]6)[CH2:51][C@@H:50]5[CH3:59])=[CH:45][N:44]=4)[C:28](=[O:60])[N:27]([CH3:26])[CH:32]=3)[C:7]=1[CH:8]=[O:9])[N:19]=[CH:18]2)([CH3:23])([CH3:22])[CH3:21]

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 517044Potassium AcetateHCID 866837011-methyl-3-((5-((2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneHCID 866839253-Bromo-5-(6-tert-butyl-8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)pyridine-4-carbaldehyde

Product 1

HCID 866839263-(6-tert-Butyl-8-fluoro-1-oxo-1,2-dihydrophthalazin-2-yl)-5-[1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo-1,6-dihydro-pyridin-3-yl]pyridine-4-carbaldehydeYield 48.3%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A 25 mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 109a (118 mg, 0.29 mmol), 1-methyl-3-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one 105f (140 mg, 0.29 mmol), Pd(dppf)Cl2 (24.8 mg, 0.03 mmol), KOAc (58.9 mg, 0.60 mmol), K3PO4.3H2O (159.8 mg, 0.60 mmol), acetonitrile (6 mL) and water (3 d). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. The reaction mixture was then cooled to room temperature, filtered and the filtrate was evaporated in vacuo. The residue was purified by prep-TLC developing with dichloromethane/methanol (20:1, UV) to afford 109b (95 mg, 36%) as a red solid. MS: [M+H]+ 679

Workup

  1. customA 25 mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customAfter three cycles of vacuum/argon flush
  4. temperatureThe reaction mixture was then cooled to room temperature
  5. filtrationfiltered
  6. customthe filtrate was evaporated in vacuo
  7. customThe residue was purified

Sources & evidence

ORD record
ord-36ee18da09c6479c8df306ef1946c325
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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