Potassium Phosphate, Tribasic → HCID 68291887, compound

HRID 1507992Notes

Reaction equation

HRID 1507992 reaction equation
[CH2:1]([O:8][C@H:9]([CH3:27])[C@H:10]([NH:13][C:14]1[C:15]2[N:16]([CH:23]=[C:24](Br)[CH:25]=2)[N:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C@H:9]([CH3:27])[C@H:10]([NH:13][C:14]1[C:15]2[N:16]([CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=2)[N:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 68291774HCID 68291774, compound

Product 1

HCID 68291887HCID 68291887, compoundYield 73.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-(((2R,3R)-3-(benzyloxy)-1-hydroxybutan-2-yl)amino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (2.98 g, 6.88 mmol), phenylboronic acid (1.677 g, 13.75 mmol), palladium (II) acetate (0.309 g, 1.375 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (1.311 g, 2.75 mmol) and potassium phosphate, tribasic, 2M (20.63 mL, 41.3 mmol) in dioxane (50 mL) was heated to 100° C. for 1 hr. After cooling to rt, the reaction mixture was filtered through a celite and the filtrate was partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was washed with brine (150 ml), dried (MgSO4) and concentrated to afford a brown solid that was triturated with ether. Filtration and drying afforded 4-(((2R,3R)-3-(benzyloxy)-1-hydroxybutan-2-yl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (2.17 g, 5.04 mmol, 73.3% yield) as a tan solid. 1H NMR (400 MHz, CD3OD) δ 8.16-8.11 (m, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.73-7.67 (m, 2H), 7.45-7.21 (m, 9H), 4.76 (d, J=11.9 Hz, 1H), 4.56 (d, J=11.9 Hz, 1H), 4.44-4.33 (m, 1H), 4.09 (qd, J=6.3, 2.8 Hz, 1H), 3.96-3.83 (m, 2H), 1.31 (d, J=6.4 Hz, 3H). MS (ES+) m/z: 431.1 (M+H); LC retention time: 2.858 min (analytical HPLC Method B).

Workup

  1. temperatureAfter cooling to rt
  2. filtrationthe reaction mixture was filtered through a celite
  3. customthe filtrate was partitioned between EtOAc (200 ml) and water (200 ml)
  4. washThe organic layer was washed with brine (150 ml)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customto afford a brown solid that
  8. customwas triturated with ether
  9. filtrationFiltration
  10. customdrying

Sources & evidence

ORD record
ord-4217c1a4aee940e4892fd82cd7f87a5a
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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