Acetoacetic Acid → (1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl]-methyl acetate

HRID 1482782Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:13][OH:14])[CH2:10][C@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:15](OC=C)(=[O:17])[CH3:16].CC(CC(O)=O)=O>CCOC(C)=O.CCCCCCC>[C:15]([O:12][CH2:11][C@@H:9]1[CH2:10][C@:8]1([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:13][OH:14])(=[O:17])[CH3:16]

Participants

Conditions

Temperature: 22.5 °C

Procedure

((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol (5, 7.89 g, 0.040 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (23.68 mL), under nitrogen. Lipase acrylic resin (Candida Antarctica Lipase B, Sigma-Aldrich, Saint Louis, Mo.) (417.5 mg, 5.0 wt %) was added. Vinyl acetate (5.56 mL, 0.060 mol, 1.5 equiv.) was added, and the reaction mixture was stirred at 20-25° C. while monitoring the ratio of mono-acetate and diacetate (8-9 h) by HPLC and TLC (EtOAc/Heptane=1/1). Upon reaction completion, the lipase was removed by filtration and rinsed with 2-methyl-THF (71.04 mL). The filtrate and the rinse were combined and washed with 15% NaCl aq. solution (27.63 mL) followed by sat. aqueous NaCl solution (23.68 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl acetate, 6 (9.59 g).

Workup

customUpon reaction completion
customthe lipase was removed by filtration
washrinsed with 2-methyl-THF (71.04 mL)
washwashed with 15% NaCl aq. solution (27.63 mL)
customThe solvent was removed under reduced pressure
customthen azeotroped with 2-methyl-THF until KF

Sources & evidence

ORD record: ord-5466fcf3eea341f3abad10f14d428ed5
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09416109B2

Reaction notes

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