Pyridine → 3-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester

HRID 1431030Notes

Reaction equation

HRID 1431030 reaction equation
[CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51]O>C(Cl)Cl>[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=[C:16]([O:15][C:14]2[CH:29]=[CH:30][C:11]([P:5]([O:7][CH:8]([CH3:10])[CH3:9])([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])=[CH:12][CH:13]=2)[CH:17]=1

Participants

7

Reactant 5

HCID 1049PyridineHCID 6228DimethylformamideHCID 180132-(Trimethylsilyl)ethanolHCID 65578Oxalyl chlorideHCID 585289143-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid

Product 1

HCID 585289823-[4-(Diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl esterYield 41%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (Example 3, route 3, step E) (10 g, 22.9 mmol) in DCM (115 mL) was added DMF (0.09 mL, 1.15 mmol) and oxalyl chloride (4.0 mL, 45.8 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was concentrated. The resulting residue was azeotroped with 50 mL anhydrous toluene and then re-dissolved in DCM (40 mL), cooled to 0° C. A solution of pyridine (3.1 mL, 36.6 mmol) in DCM (10 mL) was added slowly to the reaction flask followed by 2-trimethylsilanylethanol (3.6 mL, 25.2 mmol). The resulting mixture was stirred at rt overnight. On second day solvents were removed and the residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient to afford 5.0 g (41%) of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester. 1H NMR (500 MHz, DMSO-dc): δ 7.72 (dd, 13, 9 Hz, 2H), 7.26 (dd, J=3, 2 Hz, 1H), 7.16 (dd, J=9, 3 Hz, 2H), 7.06 (dd, J=3, 2 Hz, 1H), 6.99 (t, J=3 Hz, 1H), 4.69 (m, 1H). 4.54 (m, 2H), 3.48 (t, 2H), 1.28 (dd, J=8, 3 Hz, 12H), 1.18 (d, J=6 Hz, 6H), 1.04 (t, 2H), −0.16 (s, 9H).

Workup

  1. concentrationThe mixture was concentrated
  2. customThe resulting residue was azeotroped with 50 mL anhydrous toluene
  3. dissolutionre-dissolved in DCM (40 mL)
  4. temperaturecooled to 0° C
  5. stirringThe resulting mixture was stirred at rt overnight
  6. customOn second day solvents were removed
  7. customthe residue was partitioned between EtOAc and saturated sodium bicarbonate
  8. customThe organic layer was separated
  9. washwashed with brine (1×)
  10. dry with materialdried with anhydrous MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient

Sources & evidence

ORD record
ord-3454e368912b4a40aa636526e00d920d
Source dataset
uspto-grants-2015_01
Patent number
US08940927B2

Reaction notes

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