7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one → [4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester

HRID 32947

Reaction equation

HRID 32947 reaction equation
[OH:1][C:2]1[C:3]([CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])=[C:4]([O:13][CH3:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.Br[CH2:22][P:23](=[O:32])([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:29]([O:28][P:23]([CH2:22][O:19][CH2:18][C:17]([CH3:20])=[CH:16][CH2:15][C:3]1[C:2]([OH:1])=[C:10]2[C:6](=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])[CH2:7][O:8][C:9]2=[O:11])(=[O:32])[O:24][CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:30]

Participants

5

Reactant 3

HCID 30062907-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-oneHCID 4366885Diisopropyl bromomethylphosphonateHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)

Product 1

HCID 76541024[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl esterYield 32%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate, and concentrated. The residue was purified by chromatography on silica gel, affording [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester 1B (25 mg, 32%); 1H NMR (300 MHz, CDCl3) δ1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.

Workup

  1. customThe reaction was quenched with 1N HCl
  2. additionThe mixture was poured into 5% aqueous lithium chloride
  3. extractionextracted with ethyl acetate
  4. concentrationconcentrated
  5. customThe residue was purified by chromatography on silica gel

Sources & evidence

ORD record
ord-36fd017814b44c18bc6c7ec52b746007
Source dataset
uspto-grants-2008_09
Patent number
US07427636B2

Linked notes

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