Phenol → [4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester

HRID 2378789Notes

Reaction equation

HRID 2378789 reaction equation
[OH:1][C:2]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:21])[CH2:14][O:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:26]1([O:20][P:17]([CH2:16][O:15][CH2:14][C:13]([CH3:21])=[CH:12][CH2:11][C:10]2[C:2]([OH:1])=[C:3]3[C:7](=[C:8]([CH3:24])[C:9]=2[O:22][CH3:23])[CH2:6][O:5][C:4]3=[O:25])(=[O:19])[OH:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

Participants

6

Reactant 3

HCID 996PhenolHCID 10868DicyclohexylcarbodiimideHCID 67010219[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid

Product 1

HCID 76541028[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl esterYield 31.7%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent2×

Procedure

To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg, 0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed to warm to room temperature and heated to 140° C. for 10 hours. After cooling to room temperature the mixture was filtered and extracted with aqueous 1N NaOH solution. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by RP HPLC to provide 18.5 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester, as a pale yellow solid and 4.1 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diphenyl ester (minor product) also as a pale yellow solid. Major product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d, 2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s, 2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm; 31P (121.4 MHz, CD3OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]+, 471.2 [M+Na]+. Minor product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H), 5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; 31P (121.4 MHz, CD3OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]+, 547.2 [M+Na]+.

Workup

  1. customslowly at 0° C
  2. temperatureheated to 140° C. for 10 hours
  3. temperatureAfter cooling to room temperature the mixture
  4. filtrationwas filtered
  5. extractionextracted with aqueous 1N NaOH solution
  6. extractionextracted with EtOAc
  7. dry with materialThe organic layer was dried over Na2SO4
  8. concentrationconcentrated to dryness
  9. customThe residue was purified by RP HPLC

Sources & evidence

ORD record
ord-5ef3fd74650e4f64b914216febec3506
Source dataset
uspto-grants-2008_12
Patent number
US07470724B2

Reaction notes

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