Methyl iodide → 2-Chloro-4-(methoxymethyl)-6-(trifluoromethyl)pyridine
Reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.Cl[C:15]1C(CO)=CC=C(C(F)(F)F)N=1.C(=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:15])[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 2
Procedure
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (0.84 g, 4.0 mmol) and [2-chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (0.84 g, 4.0 mmol) (as a mixture of regioisomers from Step A) in N,N-dimethylformamide (8.6 mL) was added potassium carbonate (3.3 g, 24 mmol), followed by methyl iodide (0.99 mL, 16 mmol). The reaction was stirred overnight. Additional DMF (10 mL), methyl iodide (2.0 mL, 32 mmol) and potassium carbonate (3.3 g, 24 mmol) were added and the reaction was stirred for 72 hours. Water was added into the reaction and the product was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes allowed for isolation of desired isomer, contaminated with a small amount of the undesired isomer. Desired isomer: 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (s, 1H), 4.53 (dd, 2H), 3.48 (s, 3H).
Workup
- stirringthe reaction was stirred for 72 hours
- extractionthe product was extracted with three portions of ethyl acetate
- dry with materialThe combined organic extracts were dried over sodium sulfate
- filtrationfiltered
- concentrationconcentrated
- washFlash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes
Sources & evidence
- ORD record
- ord-437cc3103d29404daefc99fd45208bcd
- Source dataset
- uspto-grants-2015_01
- Patent number
- US08933085B2
Reaction notes
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