Pyridine → (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate

HRID 2390760Notes

Reaction equation

HRID 2390760 reaction equation
[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](Cl)=[O:23])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22]([O:8][C@@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:23])[CH:16]=[CH:17][C:18]=1[F:19]

Participants

5

Reactant 3

HCID 1049PyridineHCID 16666(-)-MentholHCID 9920680(2E)-3-(3,4-Difluorophenyl)-2-propenoyl chloride

Product 1

HCID 10268077(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
65 °C

Procedure

A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Step 2) and pyridine (0.18 kg, 2.28 mol) stirring at 65° C. The reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25° C. and stirred for a 14 hours. The solution was diluted with toluene (16 kg), washed with 5% aqueous sodium chloride (6.4 kg), then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide.

Workup

  1. stirringThe reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes
  2. additionafter the addition
  3. temperaturecooled to 25° C.
  4. stirringstirred for a 14 hours
  5. washwashed with 5% aqueous sodium chloride (6.4 kg)
  6. dry with materialThe solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure
  7. additionDimethyl sulfoxide (33.9 kg) was added
  8. distillationthe remaining toluene was distilled off under reduced pressure

Sources & evidence

ORD record
ord-7b753677f3e54a529c9041ba87607fc2
Source dataset
uspto-grants-2012_09
Patent number
US08273879B2

Reaction notes

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