Trimethyl phosphite → [2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonic Acid

HRID 33673

Reaction equation

HRID 33673 reaction equation
Br[CH2:2][C:3]([CH2:26][CH3:27])=[CH:4][CH2:5][C:6]1[C:14]([O:15]CC[Si](C)(C)C)=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25].C[Si](Br)(C)C.C[O:34][P:35]([O:38]C)[O:36]C>CC#N>[CH2:26]([C:3](=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25])[CH2:10][O:11][C:12]2=[O:22])[CH2:2][P:35](=[O:34])([OH:38])[OH:36])[CH3:27]

Participants

5

Reactant 3

HCID 8472Trimethyl phosphiteHCID 76113Bromotrimethylsilane2×HCID 670103606-(3-Bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

Product 1

HCID 67011550[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonic AcidYield 63%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A solution of 6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C. After 2 hrs the reaction was complete. The reaction was cooled to room temperature and the excess trimethylphosphite was removed in vacuo. The crude material was used in the next step without further purification. The crude product of the Arbuzov reaction was dissolved in MeCN (0.8 mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and the reaction was stirred at room temperature. After 2 hrs a second batch of trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3 hrs the reaction was quenched with MeOH (2 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 15.7 mg (63%) of the product. 1H NMR (300 MHz, DMSO-d6): δ=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; 31P NMR (121 MHz, DMSO-d6): δ=22.26 ppm; MS=355 [M++1].

Workup

  1. customthe excess trimethylphosphite was removed in vacuo
  2. customThe crude material was used in the next step without further purification
  3. customThe crude product of the Arbuzov reaction
  4. customAfter 3 hrs the reaction was quenched with MeOH (2 mL)
  5. customThe solvents were evaporated in vacuo
  6. customthe crude material was purified by RP-HPLC (eluent: water/MeCN)

Sources & evidence

ORD record
ord-4364c8a30eb847808add45bc99aeb96d
Source dataset
uspto-grants-2008_09
Patent number
US07429565B2

Linked notes

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