Potassium Phosphate, Tribasic → (S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185153Notes

Reaction equation

HRID 1185153 reaction equation
[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])=[O:17])=[CH:12][N:11]=2)=[CH:5][C:4](B(O)O)=[CH:3]1.[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48](Cl)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:30])[CH3:29].[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].C(#N)C.O>[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48]([C:4]3[CH:5]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]5[CH3:24])=[O:17])=[CH:12][N:11]=4)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:29])[CH3:30]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehydeHCID 86684011(S)-1-Methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronic Acid

Product 1

HCID 86684010(S)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 43%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 136c (260 mg, 0.70 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (180 mg, 0.50 mmol), K3PO4 (297 mg, 1.4 mmol), sodium acetate (114 mg, 1.4 mmol), 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) (57 mg, 0.07 mmol), and acetonitrile/water (10/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layers was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 136d (140 mg, 43%) as a yellow solid. MS-ESI: [M+H]+ 652.3

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/N2 flush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (20 mL) and water (10 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with dichloromethane (3×20 mL)
  8. dry with materialThe combined organic layers was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe dark residue was purified by silica-gel column chromatography
  12. washeluting with 60:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-301ac2c83158496ba98eef07b17eb685
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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