Cesium carbonate → 2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) acetic acid

HRID 1050001Notes

Reaction equation

HRID 1050001 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[CH2:13]([O:15][C:16]1[C:17]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:18][CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1)[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:19]=[N:18][C:17]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:14]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 140537922-(4-Bromo-2-fluorophenyl)acetic acidHCID 904167753-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Product 1

HCID 904166242-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) acetic acidYield 60.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
110 °C

Procedure

A suspension of 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol) in 1,4-dioxane (3 mL) and H2O (1.000 mL) was added to a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (496 mg, 1.287 mmol) in 1,4-dioxane (3 mL) and H2O (1.000 mL). PdCl2(dppf) (94 mg, 0.129 mmol) and Cs2CO3 (1049 mg, 3.22 mmol) were added and the mixture was stirred at 110° C. for 30 min under microwave irradiation. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1:1, Rf=0.5) to yield a light yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (320 mg, 0.778 mmol, 60.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.93 (d, J=1.8 Hz, 1H), 7.18-7.50 (m, 6H), 6.78-7.00 (m, 2H), 5.28-5.54 (m, 2H), 4.04-4.21 (m, 2H), 3.74-3.84 (m, 3H), 3.30-3.38 (m, 2H), 1.32-1.52 (m, 3H); ES-LCMS m/z 412.0 (M+H).

Workup

  1. temperatureThe mixture was cooled to rt
  2. concentrationthe solution was concentrated
  3. extractionThe combined organic extract
  4. washwas washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by preparative TLC (PE/EA=1:1, Rf=0.5)

Sources & evidence

ORD record
ord-a5dd498f7ce9407daa11ba82f0233376
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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