2-Bromopyridine → 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile

HRID 1025653Notes

Reaction equation

HRID 1025653 reaction equation
[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[N:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=4)[C:16]3=[O:29])[C:10]=2[CH2:30][OH:31])[N:3]=1.Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CCOC(C)=O.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]>[C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:29])[N:15]([C:11]1[C:10]([CH2:30][OH:31])=[C:9]([N:4]3[CH:5]=[C:6]([C:7]#[N:8])[C:2]([NH:1][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:3]3)[CH:14]=[CH:13][CH:12]=1)[N:24]=[CH:23]2)([CH3:26])([CH3:27])[CH3:28]

Participants

8

Reactant 4

HCID 79732-BromopyridineHCID 10796Cesium carbonateHCID 25112535BrettphosHCID 710081183-amino-1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile

Product 1

HCID 710085451-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrileYield 51%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 5 mL microwave reaction vial were introduced 3-amino-1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile (25 mg, 0.060 mmol), 2-bromopyridine (11 mg, 0.072 mmol), Pd2(dba)3 (3.9 mg, 0.004 mmol), 2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′-4′-6′-TRI-I-PROPYL-1,1′-BIPHENYL (Brett-Phos) (4.5 mg, 0.008 mmol), cesium carbonate (29.5 mg, 0.091 mmol) and suspended in t-butanol (0.609 mL). The reaction vessel was inerted three times by alternating vacuum and an Ar purge, then stirred at room temperature for 5 minutes to give a heterogeneous mixture that turned color from purplish-red to reddish-orange. The reaction was heat to 100° C. (external), during which the color of the reaction mixture changed to orange after ˜2 minutes of heating. After 2 hr, the reaction was judged complete by TLC. The mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth and bound to silica gel. The crude product was purified over silica gel using a 12 g RediSep silica gel cartridge eluting the column with a 30%-100% EtOAc/hexanes gradient to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile (15 mg, 51%) as a white powder.

Workup

  1. customTo a 5 mL microwave reaction
  2. customan Ar purge
  3. customto give a heterogeneous mixture that
  4. temperatureThe reaction was heat to 100° C. (external)
  5. customorange after ˜2 minutes
  6. temperatureof heating
  7. waitAfter 2 hr
  8. filtrationfiltered through a pad of diatomaceous earth
  9. customThe crude product was purified over silica gel using a 12 g RediSep silica gel cartridge
  10. washeluting the column with a 30%-100% EtOAc/hexanes gradient

Sources & evidence

ORD record
ord-3cbcd82870a6481082c495ff2280a87d
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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