Citric Acid → 1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone

HRID 2357089Notes

Reaction equation

HRID 2357089 reaction equation
[CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(C1C=CC=CC=1)(=O)C>C1COCC1.CCCCCCC>[CH2:1]([O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 9571-OctanolHCID 7410AcetophenoneHCID 6056784'-Fluoro-3'-(trifluoromethyl)acetophenoneHCID 23665647Potassium tert-butoxide

Product 1

HCID 593844461-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanoneYield 325.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent4×HCID 8900HeptaneSolvent

Conditions

Temperature
65 °C

Procedure

A solution of n-octanol (13.3 g, 0.102 mol), in THF (224 mL) was treated with 1.0 M potassium t-butoxide in THF (112 mL, 1.1 equiv) at room temperature and heated to 65° C. After 15 minutes, a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21 g, 1.0 equiv) in THF (224 mL) was charged slowly over 30 minutes. Vigorous gas evolution was noted during the addition. The reaction was monitored by HPLC and deemed complete after 1.5 h. The reaction mixture was cooled to ambient temperature, treated with 10% aqueous citric acid (250 mL), extracted with MTBE (2×500 mL), dried, and concentrated to afford the product (31.99 g, 99.3%, 88.1% AUC by HPLC). This reaction was repeated with slight modification as described above (reducing the amount of THF used to dissolve the acetophenone to 3 mL/g from 10.7 mL/g with improved control of gas evolution) on a 100 g scale to give 137.1 g, >100% yield). The two lots were combined and purified by column chromatography using silica-gel (1 kg), eluted with 10% ethyl acetate: 90% heptane to afford the title product (105 g, 75% yield) as a pale yellow color oil. Impure fractions were collected and provided 22.8 g (16.3% yield) of the product.

Workup

  1. additionVigorous gas evolution was noted during the addition
  2. waitdeemed complete after 1.5 h
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. extractionextracted with MTBE (2×500 mL)
  5. customdried
  6. concentrationconcentrated
  7. customto afford the product (31.99 g, 99.3%, 88.1% AUC by HPLC)
  8. customto give 137.1 g, >100% yield)
  9. custompurified by column chromatography
  10. washeluted with 10% ethyl acetate

Sources & evidence

ORD record
ord-50c87d479557450d822f645de4cfc634
Source dataset
uspto-grants-2010_07
Patent number
US07759370B2

Reaction notes

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