Isopropanol → 6-Chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester

HRID 1392680Notes

Reaction equation

HRID 1392680 reaction equation
[CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17](Cl)=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]>C1COCC1.[Cu]I>[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]

Participants

6

Reactant 3

HCID 3776IsopropanolHCID 24758Sodium hydrideHCID 86593990Isopropyl 4,6-dichloro-2-methylnicotinate

Product 1

HCID 865939896-Chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

Anhydrous isopropanol (1.5 mL, 20 mmol) is added to a suspension of NaH (1.5 g of 60% dispersion in mineral oil, 37 mmol) in THF (90 mL) at 0° C. and the mixture is stirred for 30 minutes at ambient temperature. To this is added a solution of 4,6-dichloro-2-methyl-nicotinic acid isopropyl ester (4.6 g, 19 mmol) in THF (10 mL) and CuI (178 mg, 0.94 mmol). The mixture is refluxed for 1 hour, cooled to room temperature, and poured into water-ice mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 6:1) to yield 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester as a pale yellow oil. 1H NMR (CDCl3) 6.65 (s, 1H), 5.24 (m, 1H), 4.60 (m, 1H), 2.41 (s, 3H), 1.28 (d, 12H).

Workup

  1. temperatureThe mixture is refluxed for 1 hour
  2. temperaturecooled to room temperature
  3. customThe layers are separated
  4. extractionthe aqueous layer is extracted with EtOAc
  5. dry with materialThe combined organic layers are dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue is purified by flash chromatography (elution with Hex/EtOAc 6:1)

Sources & evidence

ORD record
ord-3038211b886045b78fb3f0322e3c444c
Source dataset
uspto-grants-2008_03
Patent number
US07342115B2

Reaction notes

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