Toluene → HCID 86609667, compound

HRID 1591867Notes

Reaction equation

HRID 1591867 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[F:16])[CH2:4][CH2:3]1.[C:17](=[NH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CO.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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:30]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=2[F:16])[CH2:4][CH2:3]1

Participants

8

Reactant 4

HCID 1140TolueneHCID 136809Benzophenone imineHCID 23676156Sodium t-butoxideHCID 43123011HCID 43123011, compound

Product 1

HCID 86609667HCID 86609667, compoundYield 53.3%

Reagents, catalysts & solvents 3

HCID 27342162-(Dicyclohexylphosphino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolvent

Procedure

Combine 1-methyl-4-(3-Chloro-2-fluorophenylamino)piperidine (Preparation 19) (0.439 g, 1.8 mmol), benzophenone imine (0.393 g), Pd2(dba)3 (4.1 mg), 2-(dicyclohexylphosphino)biphenyl (4.7 mg), and sodium t-butoxide (0.242 g) with toluene (5 mL) and heat at reflux overnight. Dissolve the reaction mixture in methanol and filter through a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate the solvent, and further purify on a silica gel column (35 g, using a dichloromethane-2M NH3 in methanol gradient) to give crude 1-methyl-4-(3-benzhydrylideneamino-2-fluorophenylamino)piperidine (0.372 g). Add 1N HCl (2 mL) into a solution of the benzhydrylidenyl intermediate in THF (10 mL) and stir at room temperature for 30 minutes. Basicify with NH4OH, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (10 g), using a gradient of dichloromethane-2M NH3 in methanol to give the title intermediate (0.08 g): mass spectrum (ion spray): m/z=224 (M+1); 1H NMR (CDCl3): 6.75 (ddd, 1H), 6.12 (m, 2H), 3.70 (br d, 1H), 3.62 (br s, 2H), 3.25 (m, 1H), 2.80 (m, 2H), 2.29 (s, 3H), 2.10 (m, 4H), 1.53 (m, 2H).

Workup

  1. temperatureat reflux overnight
  2. filtrationfilter through a SCX column (10 g)
  3. washwash with methanol
  4. washelute the product with 2M NH3 in methanol
  5. customevaporate the solvent
  6. customfurther purify on a silica gel column (35 g

Sources & evidence

ORD record
ord-dc5baab6a1074082b23d93f836ef665c
Source dataset
uspto-grants-2007_11
Patent number
US07291632B2

Reaction notes

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