2-Bromopyridine → N-[(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine

HRID 273063Notes

Reaction equation

HRID 273063 reaction equation
[CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.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]>[CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([CH2:23][NH:24][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 4

HCID 79732-BromopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 598374711-(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine

Product 1

HCID 59837495N-[(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amineYield 7.4%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

1-(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine (0.175 g, 0.53 mmol) was dissolved in toluene (5 mL), 2-bromopyridine (0.051 mL, 0.53 mmol), 2,2′-bis(diphenylphosphino)-1,1′binapthyl (0.013 g, 0.02 mmol) and sodium tert-butoxide (0.076 g, 0.79 mmol) were added. The reaction mixture was purged with nitrogen, tris(dibenzylideneacetone)dipalladium(0) (0.011 g, 0.01 mmol) was added. The mixture was heated under nitrogen at 70° C. for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by HPLC eluting with methanol: 10 nM ammonium formate (aq) (1:1), fractions were combined and concentrated in vacuo to leave a clear oil. This was dissolved in DCM (50 mL) and washed with saturated sodium hydrogen carbonate solution in water (10 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound (0.016 g, 7%) as a clear colourless oil. 1H NMR (400 MHz, CDCl3) δ 1.60-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.92 (m, 2H), 1.92-2.0 (m, 2H), 2.18 (m, 2H), 2.90 (m, 1H), 3.10 (t, 2H), 3.15 (m, 1H), 3.40 (t, 2H), 3.50 (d, 2H), 3.60 (m, 2H), 3.80 (m, 2H), 4.0 (m, 1H), 4.10 (d, 2H), 6.22 (d, 1H), 6.50 (d, 1H), 6.90 (d, 2H), 7.28 (d, 2H), 7.32 (t, 1H), 8.0 (d, 1H). HRMS ESI+ m/z 408.2641 [MH]+.

Workup

  1. additionwas added
  2. extractionextracted with DCM (2×30 mL)
  3. dry with materialThe combined organics were dried over sodium sulphate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto provide a yellow oil
  7. customThis was purified by HPLC
  8. washeluting with methanol
  9. concentrationconcentrated in vacuo
  10. customto leave a clear oil
  11. washwashed with saturated sodium hydrogen carbonate solution in water (10 mL)
  12. dry with materialThe organic was dried over sodium sulphate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-260af81e06514f0fa4f7ba44760ec598
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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