Process for Preparing Isocoumarins

Bauta etal, US Patent 6,664,401 (December 16, 2003) Assignee ILEX Products, Inc. 

Utility High Yielding Method for Preparing Isocoumarin Derivatives 

Sodium hydride (0.8 g) was added to 50 ml THE and diethylmalonate added over 5 minutes. l-Bromo-2,4-dimethoxybenzene (1.08 g) was then added in one portion and the reaction flask cooled to — 20°C. A few crystals of 1,10-phenanthroline were added as an indicator and the flask further cooled to —60°C. A few drops of n-BuLi were added until the brown color of the indicator persisted. Thereafter n-BuLi (3.05 mmol) and 0.91ml diisopropylamine was added to form lithium diisopropyl-amide. In order to observe a product conversion of 97%, a total of 2.5 ml EDA added drop wise via cannula in 24 minutes at —20°C to —24°C. The solution was acidified using 1.0 M HCl and the organic portion isolated, washed with brine and isolated in 93.2% purity as a yellow oil. H-NMR data supplied. 

The product from Step 3 (2.56 g) was dissolved in 100 ml ethyl alcohol and 10 ml 10% NaOH added. The mixture was stirred at ambient temperature 105 minutes and an in-process control indicated that 87.5 conversion to the mono acid had formed. After the mixture was heated to reflux 4 hours only 28.6% of the diacid was observed. The hydrolysis was achieved in 94.8% yield when solid NaOH (3g) was added and stirred 5 hours. The product was extracted with EtOAc, dried, washed and isolated in 88.3% purity. H-NMR data supplied. 

The product from Step 4 (3.97 g) was dissolved in 40ml toluene, 1.72 ml acetic anhydride was added, and the mixture heated to 110°C 3 hours. Crystallization of 6,8-dimethoxyisochroman-l,3-dione occurred as the solution cooled and the product (3.05 g) isolated as a solid. H-NMR data supplied. 

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