Water → methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate

HRID 890882Notes

Reaction equation

HRID 890882 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1)[O:16][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 256687Methyl 4-(bromomethyl)benzoateHCID 117362763-Fluoro-5-(4-methoxytetrahydro-2H-pyran-4-yl)phenol

Product 1

HCID 22246346methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoateYield 89%

Reagents, catalysts & solvents 2

HCID 2855718-Crown-6CatalystHCID 31374DimethylacetamideSolvent

Procedure

A mixture of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (1.5 g, 6.6 mmol), methyl 4-(bromomethyl)benzoate (1.7 g, 7.4 mmol), K2CO3 (0.6 g, 4.3 mmol), 18-crown-6 (0.05 g) and KI (0.05 g) in dimethylacetamide (5.00 mL) was stirred at room temperature for 16 h, and at 80° C. for 2 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 20% EtOAc in hexane, to furnish 2.2 g (88%) of methyl 4-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl]benzoate as a white solid: m.p. 88–89° C. 1H NMR (CDCl3/300 Hz) δ 8.07 (d, 2H, J=7.8 Hz), 7.5 (d, 2H, J=7.8 Hz), 6.81 (s, 1H), 6.72 (d, 1H, J=9.9 Hz), 6.6 (d, 1H, J=9.9 Hz), 5.12 (s, 2H), 3.93 (s, 3H), 3.82 (m, 4H), 2.97 (s, 3H), 1.92 (m, 4H). FABMS m/z 375 (M+H).

Workup

  1. waitat 80° C. for 2 h
  2. extractionextracted with EtOAc (2×25 mL)
  3. washThe combined organic extracts were washed with water (2×25 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was purified by flash column chromatography on silica gel
  8. washeluting with 20% EtOAc in hexane

Sources & evidence

ORD record
ord-5aad18f34e5445bba163e44a192c03e9
Source dataset
uspto-grants-2006_02
Patent number
US06998415B2

Reaction notes

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