Potassium Phosphate, Tribasic → (S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluorobenzaldehyde

HRID 1185052Notes

Reaction equation

HRID 1185052 reaction equation
Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH2:27]([C@H:29]1[CH2:34][N:33]([CH:35]2[CH2:38][O:37][CH2:36]2)[CH2:32][CH2:31][N:30]1[C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]2[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:51]=2)=[N:43][CH:44]=1)[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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(#N)C>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:50]3[CH:51]=[C:46]([NH:45][C:42]4[CH:41]=[CH:40][C:39]([N:30]5[CH2:31][CH2:32][N:33]([CH:35]6[CH2:36][O:37][CH2:38]6)[CH2:34][C@@H:29]5[CH2:27][CH3:28])=[CH:44][N:43]=4)[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:23])([CH3:22])[CH3:24]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86683743(S)-3-(5-(2-Ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 866839112-Bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde

Product 1

HCID 86683930(S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(2-ethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluorobenzaldehydeYield 35.2%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102h (168 mg, 0.40 mmol), 111f (198 mg, 0.40 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), and water (0.8 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 111g as a white solid (100 mg, 35%). MS: [M+H]+ 710.3

Workup

  1. customA 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperaturethe mixture was heated
  4. temperatureat reflux for 2 h
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe resulting residue was purified by silica-gel column chromatography
  8. washeluting with 30:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-06ade0daa26f434282c3f0b897d47dce
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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