Dimethylformamide → 2-Chloro-4-(chloromethyl)-3-methylpyridine

HRID 1355459Notes

Reaction equation

HRID 1355459 reaction equation
[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 24813Phosphorus oxychlorideHCID 22504279(2-Chloro-3-methylpyridin-4-yl)methanol

Product 1

HCID 185068432-Chloro-4-(chloromethyl)-3-methylpyridine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).

Workup

  1. customThe reaction was quenched with sat NaHCO3 (aq)
  2. extractionextracted 3× with DCM
  3. dry with materialThe organic phases were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-bba2777b87084f7da3b6a3e2d44a5bf0
Source dataset
uspto-grants-2003_07
Patent number
US06586423B2

Reaction notes

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