Methyl 2-chloropyridine-4-carboxylate → HCID 66731807, compound

HRID 1963288Notes

Reaction equation

HRID 1963288 reaction equation
[Br-].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Zn+].Cl[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1>[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=1)[C:18]([O:20][CH3:21])=[O:19]

Participants

4

Reactant 2

HCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178506138HCID 178506138, compound

Product 1

HCID 66731807HCID 66731807, compoundYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

Freshly made (2-(trifluoromethyl)benzyl)zinc(II) bromide (8.91 g, 29.28 mmol) in tetrahydrofuran (50 mL) was added to a solution of methyl 2-chloroisonicotinate (3.35 g, 19.52 mmol) and bis(tri-tert-butylphosphine)Pd(0) (0.399 g, 0.78 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask. The resulting red mixture was heated to 60° C. overnight (16 h). After cooling to room temperature, the reaction was quenched by the addition of 10% aq NH4Cl and diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was dissolved in 100 mL MTBE. Insolubles were filtered off and the filtrate was evaporated. Purification via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 1 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(2-(trifluoromethyl)benzyl)isonicotinate (4.61 g, 80%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.91 (s, 3H), 4.43 (s, 2H), 7.28-7.40 (m, 2H), 7.47 (t, 1H), 7.54-7.65 (m, 1H), 7.65-7.72 (m, 2H), 8.71 (d, 1H). MS m/z 296 (M+H)+

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe reaction was quenched by the addition of 10% aq NH4Cl
  3. additiondiluted with ethyl acetate
  4. customAfter phase separation
  5. washthe organic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. customevaporated
  8. dissolutionThe residue was dissolved in 100 mL MTBE
  9. filtrationInsolubles were filtered off
  10. customthe filtrate was evaporated
  11. customPurification via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 1 CV

Sources & evidence

ORD record
ord-045d7104e73740eaa2319b5d29b51271
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…