p-Bromoacetophenone → 3-(4-Acetyl-phenylamino)-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitrile

HRID 1025652Notes

Reaction equation

HRID 1025652 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][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH: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:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N:15]4[N:24]=[CH:23][C:22]5[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])[CH:21]=5)[C:16]4=[O:29])[C:10]=3[CH2:30][OH:31])[N:3]=2)=[CH:34][CH:35]=1)(=[O:41])[CH3:40]

Participants

8

Reactant 4

HCID 7466p-BromoacetophenoneHCID 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 710082213-(4-Acetyl-phenylamino)-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitrileYield 62.1%

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 (50 mg, 0.121 mmol), 1-(4-bromophenyl)ethanone (29 mg, 0.145 mmol), Pd2(dba)3 (7.7 mg, 0.008 mmol), 2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′-4′-6′-TRI-I-PROPYL-1,1′-BIPHENYL (Brett-Phos) (9.1 mg, 0.017 mmol), cesium carbonate (59 mg, 0.181 mmol) and suspended in t-butanol (1.5 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 1.5 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 silica gel cartridge eluting the column with a 30%-100% EtOAc/hexanes gradient to give 3-(4-Acetyl-phenylamino)-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitrile (40 mg, 62%) 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 1.5 hr
  8. filtrationfiltered through a pad of diatomaceous earth
  9. customThe crude product was purified over silica gel using a 12 g silica gel cartridge
  10. washeluting the column with a 30%-100% EtOAc/hexanes gradient

Sources & evidence

ORD record
ord-4bc51649620247deaa4b2be28828c5f1
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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