Chlorosuccinimide → 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine

HRID 1963809Notes

Reaction equation

HRID 1963809 reaction equation
[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.[OH-].[Na+].C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[CH:4][CH:3]=1.[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16]

Participants

7

Reactant 2

HCID 31398ChlorosuccinimideHCID 58127218HCID 58127218, compound

Product 2

HCID 581272586-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amineHCID 581273416-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine

Reagents, catalysts & solvents 3

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
33 °C

Procedure

A solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (C, 1000 mg, 3.69 mmol) in chloroform (15 mL) was diluted with 1-chloropyrrolidine-2,5-dione (NCS, 492 mg, 3.69 mmol). The mixture then was heated in a sealed tube at about 33° C. for about 16 hr, followed by heating the reaction mixture for about 24 hr at about 37° C., and then for an additional 5 days at about 43° C. The reaction mixture then was cooled to ambient temperature, diluted with 1N aqueous sodium hydroxide solution and DCM. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 80 g, EtOAc/heptane=5/95 2 min, 5/95 to 30/70 2-15 min, to 35/65 15-18 min, then 35%]. Fractions were combined and concentrated in vacuo yielding 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (F, 453 mg), and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (E, ˜500 mg). (F): LCMS (m/z): 305.0[M+H]+; Retention time=1.01 min. (E): LCMS (m/z): 305.0 [M+H]+; Retention time=0.96 min.

Workup

  1. temperatureby heating the reaction mixture for about 24 hr at about 37° C.
  2. temperatureThe reaction mixture then was cooled to ambient temperature
  3. customThe organic layer was separated
  4. washwashed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered off
  7. concentrationconcentrated in vacuo
  8. customThe resulting resulting residue
  9. customwas purified by column chromatography [ISCO, SiO2, 80 g, EtOAc/heptane=5/95 2 min, 5/95 to 30/70 2-15 min
  10. customto 35/65 15-18 min
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-fc858b27abba4954900ff3e38a50d14c
Source dataset
uspto-grants-2013_04
Patent number
US08415381B2

Reaction notes

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