Hydrochloric Acid → 5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-1-enecarboxylic acid methyl ester

HRID 512147

Reaction equation

[F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:14])[CH:12]=[CH2:13].CC([O-:21])(C)C.[K+].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1.Cl>C1COCC1.C(=O)=O.CCO>[CH3:25][O:26][C:27]([C:23]1[CH2:24][C:8]([C:9]#[N:10])([C:5]2[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][C:11]=1[OH:14])=[O:21]

Participants

Conditions

Temperature: -70 °C

Procedure

To a solution of (6-fluoro-pyridin-3-yl)-acetonitrile (15 g, 0.11 mol) and methyl acrylate (19 g, 0.22 mol) in dry THF (150 mL) cooled to −70° C. in dry ice-EtOH bath was added t-BuOK-THF solution (1M, 330 mL, 0.33 mol) in portions. The reaction mixture was stirred at −70° C. for 4 h. After completion (LCMS) 1N HCl (aq) was added slowly at −70° C. (the temperature of reaction mixture don't rise above −50° C.) to adjust the pH to 5-6. The THF layer was separated and the aqueous phase was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the crude title compound (32 g), which was used directly for the next step.

Workup

customthe temperature of reaction mixture don't rise above −50° C.)
customThe THF layer was separated
extractionthe aqueous phase was extracted with EtOAc (2×150 mL)
washThe combined organic layers were washed with brine
dry with materialdried over anhydrous sodium sulphate
filtrationfiltered
concentrationconcentrated under reduced pressure

Sources & evidence

ORD record: ord-d9f87cf64d314f93b46430131ebd9c92
Source dataset: uspto-grants-2015_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09102591B2

Linked notes

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