Potassium Phosphate, Tribasic → 4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1507913Notes

Reaction equation

HRID 1507913 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:17]([NH:18][C@H:19]([CH3:24])[C:20]([F:23])([CH3:22])[CH3:21])=[C:16]([C:25]([NH2:27])=[O:26])[CH:15]=[N:14][N:13]2[CH:28]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:20]([CH3:22])([CH3:21])[C@H:19]([NH:18][C:17]1[C:12]2[N:13]([CH:28]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:11]=2)[N:14]=[CH:15][C:16]=1[C:25]([NH2:27])=[O:26])[CH3:24]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 683495236-bromo-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide2×

Product 1

HCID 665471494-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamideYield 51.2%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

Potassium phosphate (2M aqueous solution, 0.22 mL, 0.44 mmol) was added in one portion to a stirred solution of 6-bromo-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 3, 20 mg, 0.058 mmol), phenyl boronic acid (11 mg, 0.087 mmol), X-Phos ligand (2.8 mg, 0.0058 mmol) and palladium acetate (0.7 mg, 0.0029 mmol) in anhydrous 1,4-dioxane (0.25 mL). The resulting biphasic mixture was then heated in the CEM microwave at 120° C. for 10 min. The reaction was allowed to cool to rt and the phases separated. The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to afford 10.1 mg (45%) of the title compound as a white solid. HPLC (condition B): retention time=3.84 min. LCMS (condition B): MH+m/z 341.2. 1H NMR (400 MHz, MeOD) δ ppm 8.38 (1 H, d, J=3.52 Hz), 8.15 (1 H, d, J=1.76 Hz), 7.76-8.03 (3 H, m), 7.61-7.76 (1 H, m), 7.53 (1 H, br. s.), 7.38 (1 H, br. s.), 4.87 (1 H, buried s.), 1.60-2.06 (9 H, m).

Workup

  1. temperatureto cool to rt
  2. customthe phases separated
  3. extractionThe aqueous phase was extracted with ethyl acetate (2×5 mL)
  4. dry with materialThe combined organics were then dried (MgSO4)
  5. customevaporated in vacuo
  6. custombefore purifying by reverse-phase Prep HPLC (condition A)
  7. additionThe fraction containing the major product
  8. concentrationwas concentrated on the rotovap

Sources & evidence

ORD record
ord-4fb1672c481a42c2bc45a74a8007e1b7
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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