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Potassium Phosphate, Tribasic → (2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-methyl-6-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate

HRID 407767
Notes
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Reaction equation

HRID 407767 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:57]=[C:50]3[CH2:51][N:52]([CH3:56])[C:53](=[O:55])[CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.[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:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:57]=[C:50]3[CH2:51][N:52]([CH3:56])[C:53](=[O:55])[CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1)(=[O:3])[CH3:2]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86683972(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 866840332-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-5-methyl-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one

Product 1

HCID 86684034
(2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-methyl-6-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-3-yl)methyl Acetate
Yield 45%

Reagents, catalysts & solvents 2

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
100 °C

Procedure

A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyri-din-4-ylboronic acid 116c (165 mg, 0.40 mmol), 146e (141 mg, 0.40 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), Pd(dppf)Cl2 (15 mg, 0.020 mmol), and acetonitrile/water (8/0.2 mL). The mixture was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 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 (30 mL) and water (30 mL). The organic layer was separated and the water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 146f (115 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 641.4

Workup

  1. customA 25-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (30 mL) and water (30 mL)
  6. customThe organic layer was separated
  7. extractionthe water layer was extracted with dichloromethane (2×30 mL)
  8. extractionThe combined organic extract
  9. dry with materialwas dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe dark residue was purified by silica-gel column chromatography
  13. washeluting with dichloromethane/methanol (80/1 to 30/1)

Sources & evidence

ORD record
ord-59d9ae8098ad4cea89ae3ad54cae3710
Source dataset
uspto-grants-2014_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08754077B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes