Hydrochloric Acid → (R)-(3'-(hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetate

HRID 2280682Notes

Reaction equation

HRID 2280682 reaction equation
[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1Br)(=[O:3])[CH3:2].[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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]>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:9]=[C:8]([CH3:18])[C:7]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:21][OH:20])[CH:27]=1)(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2734662[3-(Hydroxymethyl)phenyl]boronic acidHCID 117699365(R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate

Product 1

HCID 89701752(R)-(3'-(hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetateYield 66.8%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
70 °C

Procedure

The crude (R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate 35c (658 mg, 2 mmol) was dissolved in 50 mL of dioxane, followed by addition of 3-hydroxymethyl phenylboronic acid (608 mg, 4 mmol) and 6 mL of aqueous potassium carbonate solution (636 mg, 4 mmol), and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74 mg, 0.10 mmol). The reaction solution was heated to 70° C. and stirred for 4 hours. The resulting solution was cooled, poured into 100 mL 1M aqueous hydrochloric acid solution, and extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-(3′-(hydroxymethyl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)biphenyl-2-yl)methyl acetate 35d (476 mg, yield 66.8%) as a yellow oil.

Workup

  1. temperatureThe resulting solution was cooled
  2. extractionextracted with ethyl acetate (30 mL×3)
  3. washThe combined organic extracts were washed with saturated sodium chloride solution (30 mL)
  4. dry with materialdried with anhydrous magnesium sulphate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography with elution system B

Sources & evidence

ORD record
ord-e8fbf75847da465ba50571bd5e7af61d
Source dataset
uspto-grants-2015_09
Patent number
US09139548B2

Reaction notes

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