Methyl 2-chloropyridine-4-carboxylate → HCID 66731874, compound

HRID 1963266Notes

Reaction equation

HRID 1963266 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Zn+])=[CH:16][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1

Participants

5

Reactant 2

HCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178505764HCID 178505764, compound

Product 1

HCID 66731874HCID 66731874, compoundYield 88.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved under nitrogen in THF (100 mL) and (4-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 19 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and water. The organic layer was evaporated, dissolved in DCM and washed with NH4Cl (aq) and then dried by passage through a phase separator. The solvent was evaporated to yield a brown oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(4-fluorobenzyl)isonicotinate 7.08 g (88%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.92 (s, 3H), 4.18 (s, 2H), 6.94-7.02 (m, 2H), 7.19-7.27 (m, 2H), 7.65-7.69 (m, 2H), 8.68-8.71 (m, 1H). MS m/z 246 (M+H)+

Workup

  1. customThe reaction was quenched by addition of methanol (50.0 mL)
  2. additionThe solution was diluted with EtOAc
  3. washwashed with NH4Cl (aq) and water
  4. customThe organic layer was evaporated
  5. dissolutiondissolved in DCM
  6. washwashed with NH4Cl (aq)
  7. customdried by passage through a phase separator
  8. customThe solvent was evaporated
  9. customto yield a brown oil
  10. customThe compound was purified in 2

Sources & evidence

ORD record
ord-ce75e3d1a6ac4950bab418bf23f9174f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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