Glaucoma Serotonergic 5-HT2 Receptor Agonists

Title 6-Hydroxy-indazole Derivatives for Treating Glaucoma 

Invention Significance The early detection and prompt treatment of 

A solution of 2-fluoro-4-methoxyacetophenone (11.3 mmol) dissolved in 20 ml ethyl alcohol was treated with 1.4 ml hydrazine hydrate and then refluxed 6 hours. This mixture was concentrated and the residue treated with 10 ml ethylene glycol. This mixture was heated 18 hours at 150°C, then cooled, and diluted with 50 ml water. It was then extracted three times with 60 ml CH2C12, washed with 10 ml brine, dried with MgS04, and concentrated. The residue was recrystallized from EtOAc and the product isolated in 59% yield. 

The Step 1 product (6.7 mmol) dissolved in 10 ml DMF was treated with sodium hydride (10.2 mmol), then stirred 30 minutes at ambient temperature. The mixture was then treated with 0.79 ml chloroacetone and heated 6 hours at 60°C. After cooling, it was diluted with 10 ml saturated NH4C1 solution and extracted three times with 65 ml EtOAc. The combined extracts were washed with 10 ml brine, dried, and concentrated. The residue was purified by chromatography using 20-30% EtOAc/hexane and the product isolated in 88% yield as an oil. 

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