1,4-Dioxaspiro(4.5)decan-8-ol → 4-(1,4-Dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acid

HRID 1849802Notes

Reaction equation

HRID 1849802 reaction equation
[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:20]3[C:19]([Cl:18])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:28])[CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 5673521,4-Dioxaspiro(4.5)decan-8-olHCID 148764175-Chloro-2,4-difluorobenzoic acidHCID 23665647Potassium tert-butoxide

Product 1

HCID 867036854-(1,4-Dioxaspiro[4.5]decan-8-yloxy)-5-chloro-2-fluorobenzoic acidYield 21%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (12.90 g, 81.50 mmol) in dimethylsulfoxide (800 mL) was added potassium tert-butoxide (21.00 g, 187.00 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes under nitrogen. To this mixture was added 5-chloro-2,4-difluorobenzoic acid (15.70 g, 81.70 mmol). The mixture was stirred at ambient temperature for 3 days, after which it was split into two equal portions. Each portion was diluted with ethyl acetate (700 mL), washed with 1 M hydrochloric acid (700 mL), a 1:1 mixture of 1 M hydrochloric acid and brine (700 mL), and brine (700 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50%, to afford the title compound as a light yellow solid (5.66 g, 21%): 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 6.69 (d, J=12.4 Hz, 1H), 4.54-4.51 (m, 1H), 3.97-3.95 (m, 4H), 2.06-1.93 (m, 4H), 1.81-1.74 (m, 1H), 1.70-1.51 (m, 3H); MS (ES−) m/z 329.1, 331.1 (M−1).

Workup

  1. stirringThe mixture was stirred at ambient temperature for 3 days
  2. customafter which it was split into two equal portions
  3. additionEach portion was diluted with ethyl acetate (700 mL)
  4. washwashed with 1 M hydrochloric acid (700 mL)
  5. additiona 1:1 mixture of 1 M hydrochloric acid and brine (700 mL), and brine (700 mL)
  6. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo to dryness
  9. customThe residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50%

Sources & evidence

ORD record
ord-e555770ff82947b288060cf1e767c993
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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