Carvacrol → 6-Chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine

HRID 251647

Reaction equation

HRID 251647 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:11](=O)[C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][C:15]([Cl:22])=[N:14][C:13]=1[CH3:23])(C)C.O=S(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH:35]1[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[C:38]([CH3:39])[C:36]=1[OH:37]>C1COCC1.C(Cl)Cl.O>[Cl:22][C:15]1[N:14]=[C:13]([CH3:23])[C:12]([CH2:11][O:37][C:36]2[CH:35]=[C:42]([CH:43]([CH3:45])[CH3:44])[CH:41]=[CH:40][C:38]=2[CH3:39])=[C:17]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=1

Participants

9

Reactant 5

HCID 10364CarvacrolHCID 10796Cesium carbonateHCID 24386Thionyl ChlorideHCID 21226445Aluminium lithium hydrideHCID 865939896-Chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester

Product 1

HCID 865939916-Chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

LiAlH4 (14 mL of 1 M solution in THF, 14 mmol) is added to a solution of 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester (2.0 g, 7.4 mmol) in THF (10 mL) at 0° C. The mixture is stirred for 3 hours at ambient temperature. After quenching with water, the mixture is extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated to give the crude alcohol as a colorless oil which is dissolved in CH2Cl2 (10 mL) and treated with SOCl2 (2.7 mL, 37 mmol). The mixture is stirred for 1 hour at room temperature and concentrated in vacuo. The residue is dissolved in DMF (15 mL). To this is added Cs2CO3 (7.2 g, 11 mmol) and carvacrol (1.6 g, 11 mmol). The mixture is stirred for 16 hours at room temperature, poured into water, and extracted with Et2O. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 6:1) to yield 6-chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine. 1H NMR (CDCl3) 7.05 (d, 1H), 6.82 (s, 1H), 6.79 (d, 1H), 6.724 (s, 1H), 5.02 (s, 2H), 4.60 (m, 1H), 2.88 (m, 1H), 2.59 (s, 3H), 2.12 (s, 3H), 1.37 (d, 6H), 1.24 (d, 6H).

Workup

  1. customAfter quenching with water
  2. extractionthe mixture is extracted with EtOAc
  3. washThe combined extracts are washed with saturated brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customto give the crude alcohol as a colorless oil which
  7. stirringThe mixture is stirred for 1 hour at room temperature
  8. concentrationconcentrated in vacuo
  9. dissolutionThe residue is dissolved in DMF (15 mL)
  10. stirringThe mixture is stirred for 16 hours at room temperature
  11. extractionextracted with Et2O
  12. washThe combined extracts are washed with saturated brine
  13. dry with materialdried (Na2SO4)
  14. concentrationconcentrated in vacuo
  15. customThe residue is purified by flash chromatography (elution with Hex/EtOAc 6:1)

Sources & evidence

ORD record
ord-f2eaa5e6db2c4375b85bf303909c4c20
Source dataset
uspto-grants-2011_01
Patent number
US07863454B2

Linked notes

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