Benzophenone imine → 4-[(4-Acetylpiperazin-1-yl)methyl]-2-amino-3-fluoropyridine

HRID 1355532Notes

Reaction equation

HRID 1355532 reaction equation
Cl[C:2]1[C:7]([F:8])=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:84])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C1COCC1>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]>[C:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:84])[C:7]=2[F:8])[CH2:11][CH2:12]1)(=[O:18])[CH3:17]

Participants

8

Reactant 5

HCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 18422008HCl tetrahydrofuranHCID 185069231-[4-(2-Chloro-3-fluoro-pyridin-4-ylmethyl)-piperazin-1-yl]-ethanoneHCID 23676156Sodium t-butoxide

Product 1

HCID 185068144-[(4-Acetylpiperazin-1-yl)methyl]-2-amino-3-fluoropyridine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-[(4-acetylpiperazin-1-yl)methyl]-2-chloro-3-fluoropyridine (14-3, 85 mg, 0.31 mmole) in dry toluene (2 mL) was added NaOtBu (42 mg, 0.44 mmole), racemic BINAP (29 mg, 0.05 mmole), Pd2(dba)3 (14 mg, 0.02 mmole), and benzophenone imine (0.06 mL, 0.38 mmole) then the mixture was heated to 80° C. After 18 hr the mixture was cooled to RT. A solution of 1N HCl:THF (1:1, 10 mL) was added and the mixture stirred for 1 hr. The mixture was washed with EtOAc (2×). The aqueous layer was made basic with saturated NaHCO3 then extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Flash column chromatography (gradient, 0-5% MeOH/CH2Cl2) gave the titled compound as a light yellow solid: 1H-NMR (500 MHz, CDCl3) δ 7.81 (d, 1 H, J=5.12 Hz), 6.71 (t, 1 H, J=4.88 Hz), 4.56 (bs, 2 H), 3.63 (t, 2 H, J=5.13 Hz), 3.56 (s, 2 H), 3.10 (t, 2 H, J=5.13 Hz), 2.46 (m, 2 H), 2.08 (s, 3 H); MS (ES) (M+H)+ 253.

Workup

  1. temperatureAfter 18 hr the mixture was cooled to RT
  2. washThe mixture was washed with EtOAc (2×)
  3. extractionthen extracted with EtOAc (3×)
  4. dry with materialThe combined organic layers were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-b388004f05be4e1b84ef12675ddb6ff9
Source dataset
uspto-grants-2003_07
Patent number
US06586424B2

Reaction notes

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