Methyl 6-chloro-5-methylpyridine-3-carboxylate → Methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate

HRID 715441Notes

Reaction equation

HRID 715441 reaction equation
Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[I-].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17][Zn+]>CN(C=O)C.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>[CH3:12][C:11]1[C:2]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]

Participants

5

Reactant 2

HCID 12404031Methyl 6-chloro-5-methylpyridine-3-carboxylateHCID 178506322HCID 178506322, compound

Product 1

HCID 89874082Methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinateYield 86%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55° C. for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55° C. for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86% yield) of the title compound as an orange solid.

Workup

  1. temperatureAfter cooling to rt
  2. additionthe mixture is poured onto water (100 mL)
  3. extractionthe aqueous layer is extracted with EtOAc (30 mL×2)
  4. dry with materialThe combined organic layer is dried over sodium sulfate
  5. filtrationafter filtration
  6. concentrationthe filtrate is concentrated in vacuo
  7. customThe residue is purified by column chromatography on silica-gel
  8. washeluting with n-hexane/EtOAc (5:1 to EtOAc only)

Sources & evidence

ORD record
ord-b64f0fe030f04b2fbdf2f387838a5b59
Source dataset
uspto-grants-2015_11
Patent number
US09187475B2

Reaction notes

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