Cesium carbonate → 2-(2-(1-(3-(Cyclobutylmethoxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetic acid

HRID 1855080Notes

Reaction equation

HRID 1855080 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:13][CH2:12][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:14][CH2:15]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 2734658(Bromomethyl)cyclobutaneHCID 90408312tert-Butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate

Product 1

HCID 904098992-(2-(1-(3-(Cyclobutylmethoxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetic acidYield 67%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (7F; 15 mg, 0.041 mmol), (bromomethyl)cyclobutane (9.25 mg, 0.062 mmol) and Cs2CO3 (41 mg, 0.124 mmol) in MeCN (1.0 mL) was heated to ˜60° C. for 10 h. The reaction was then cooled to rt, filtered and the filtrates were concentrated in vacuo. The crude alkylated phenol ester product was dissolved in THF/MeOH (1 mL of a 1:1 mixture) and aq. NaOH (90 μL of a 1 N solution, 0.090 mmol) and the mixture was stirred at rt for 3 h, then was concentrated in vacuo. The residue was dissolved in EtOAc (3 mL) and washed with 1 N aq. HCl, water, brine, then dried (MgSO4), and concentrated in vacuo. The crude product was purified by preparative HPLC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% HCO2H; Mobile Phase B: 95:5 MeCN:water with 0.1% HCO2H; Gradient: 45-85% B over 20 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (7.7 mg, 67% yield; 99% purity by LC/MS) as a light yellow oil. LCMS [M−H]−=373; 1H NMR (500 MHz, DMSO-d6) δ 7.18 (t, J=8.3 Hz, 1H), 6.97-6.86 (m, 2H), 6.75 (dd, J=8.1, 1.2 Hz, 1H), 3.95 (s, 2H), 3.92 (d, J=6.6 Hz, 2H), 3.77 (s, 2H), 3.53-3.48 (m, 2H), 2.74-2.65 (m, 1H), 2.14-1.98 (m, 4H), 1.97-1.74 (m, 6H), 1.72-1.58 (m, 4H), 1.41 (t, J=6.6 Hz, 2H).

Workup

  1. temperatureThe reaction was then cooled to rt
  2. filtrationfiltered
  3. concentrationthe filtrates were concentrated in vacuo
  4. dissolutionThe crude alkylated phenol ester product was dissolved in THF/MeOH (1 mL of a 1:1 mixture) and aq. NaOH (90 μL of a 1 N solution, 0.090 mmol) and the mixture
  5. concentrationwas concentrated in vacuo
  6. dissolutionThe residue was dissolved in EtOAc (3 mL)
  7. washwashed with 1 N aq. HCl, water, brine
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by preparative HPLC/MS (Column
  11. waitGradient: 45-85% B over 20 min
  12. customa 5-min hold

Sources & evidence

ORD record
ord-5ae8514669ce4022afd02874f209813d
Source dataset
uspto-grants-2015_02
Patent number
US08962660B2

Reaction notes

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