2-Bromopyridine → N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amine

HRID 869150Notes

Reaction equation

HRID 869150 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(OB(OC(C)C)OC(C)C)(C)C.[Li]CCCC.Cl[C:27]1[N:32]=[N:31][C:30]([NH:33][CH2:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)([CH3:37])[CH3:36])=[CH:29][CH:28]=1.P(C(C)(C)C)(C(C)(C)C)(C(C)(C)C)=O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1.C1COCC1>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]([CH3:37])([CH3:36])[CH2:34][NH:33][C:30]2[N:31]=[N:32][C:27]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:28][CH:29]=2)=[CH:43][CH:42]=1

Participants

10

Reactant 6

HCID 79732-BromopyridineHCID 21531Triisopropyl borateHCID 522689Potassium FluorideHCID 10927323Tri-tert-butylphosphine oxideHCID 866861256-Chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amineHCID 178418339Butyllithium

Product 1

HCID 67452706N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amineYield 6.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolventHCID 22635083Tetrahydrofuran tolueneSolvent

Conditions

Temperature
-78 °C

Procedure

To a 25 mL round bottom flask was added 2-bromopyridine (500 mg, 3.2 mmol, 1.0 equiv), triisopropylborate (654 mg, 3.5 mmol, 1.1 equiv), and an 80% toluene/THF mixture (16 mL). The mixture was cooled to −78° C. After stirring for 10 min, n-BuLi (1.7 mL, 3.48 mmol, 1.1 equiv of a 2.0 M/hexanes solution) was slowly added over an hour. After the addition was complete, the reaction mixture was stirred for 30 min and allowed to warm to rt and stirred overnight. The reaction was then concentrated at 100° C. and dried in vacuo for 2 h. To 100 mg of this crude solid in a microwave vial was added 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (70 mg, 0.25 mmol), Pd2 dba3 (10 mg, 0.011 mmol), PO(tBu)3 (5 mg, 0.030 mmol), potassium fluoride (43 mg, 0.75 mmol), and dioxane (0.75 mL). The reaction was degassed with nitrogen for 5 minutes and then heated in a microwave reactor at 160° C. for 15 min. The reaction was then concentrated, dissolved in EtOAc (25 mL), washed with water, dried over Na2SO4, filtered, concentrated, and purified by reverse phase column chromatography to give 5 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amine as a white solid. m/z=323.1 [M+H]+.

Workup

  1. additionAfter the addition
  2. stirringthe reaction mixture was stirred for 30 min
  3. temperatureto warm to rt
  4. stirringstirred overnight
  5. concentrationThe reaction was then concentrated at 100° C.
  6. customdried in vacuo for 2 h
  7. customThe reaction was degassed with nitrogen for 5 minutes
  8. temperatureheated in a microwave reactor at 160° C. for 15 min
  9. concentrationThe reaction was then concentrated
  10. dissolutiondissolved in EtOAc (25 mL)
  11. washwashed with water
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. custompurified by reverse phase column chromatography

Sources & evidence

ORD record
ord-5c629727c3974d0fa6dfc41b950ce42a
Source dataset
uspto-grants-2015_03
Patent number
US08969346B2

Reaction notes

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