Benzophenone imine → 4-[({(1R,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}methoxy)methyl]aniline

HRID 1468846Notes

Reaction equation

HRID 1468846 reaction equation
Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[Na+].C(=[NH:68])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([NH2:68])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]

Participants

9

Reactant 6

HCID 136809Benzophenone imineHCID 443297Hydroxyamine hydrochlorideHCID 517045Sodium AcetateHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 23676156Sodium t-butoxideHCID 711352722-[4-((1R,2R)-2-{[(4-bromobenzyl)oxy]methyl}cyclopropyl)piperidin-1-yl]-5-ethyl pyrimidine

Product 1

HCID 867177934-[({(1R,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}methoxy)methyl]aniline

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

The product of example 54 (step A) (100 mg, 0.2 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), (2-biphenyl)di-tert-butylphosphine (14 mg, 0.046 mmol), NaOtBu (48 mg, 0.5 mmol), and benzophenone imine (50 mg, 0.28 mmol) were dissolved in toluene (1.5 mL), and the solution was heated under N2 at 60° C. for 6 hours. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in MeOH (3 mL), and sodium acetate (38 mg, 0.46 mmol) and hydroxylamine hydrochloride (32 mg, 0.46 mmol) were added. The solution was stirred at RT for 1 h. The solution was partitioned between sat. NaHCO3 (aq.) and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) which provided the title compound.

Workup

  1. filtrationThe mixture was filtered
  2. concentrationthe filtrate concentrated in vacuo
  3. dissolutionThe residue was dissolved in MeOH (3 mL)
  4. customThe solution was partitioned between sat. NaHCO3 (aq.) and EtOAc
  5. extractionThe aqueous layer was extracted with EtOAc
  6. dry with materialThe combined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) which

Sources & evidence

ORD record
ord-1b7800c13f67428dbf72f5ab2f0dc8d4
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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