1,1,1-Trimethoxy-n-octane

Synthesis of Mucus-Penetrating Particles from 1,1,1-Trimethoxyoctane for Ophthalmic Application

Winston Zapanta ONG, et al. WO-2019055028-A1, 2017.

Pharmaceutical compositions containing mucus-penetrating particles are particularly important for ophthalmic applications where they need to have the ability to easily penetrate the mucus layer to avoid mucus adhesion and rapid mucus clearance. Compound 108 as shown in the figure is one of the 4-pregenen-1 i p-17-21-triol-3,20-dione derivatives, which can be synthesized from 1,1,1-trimethoxyoctane.
Synthesis process from 1,1,1-trimethoxyoctane
· Dissolve 1,1,1-trimethoxyoctane (25.0g, 122.5mmol), hydrocortisone (12.5g, 34.5mmol) and pyridinium p-toluenesulfonate (2.6g, 10.3mmol) in tetrahydrofuran (150mL )middle. The solution was heated at 70°C for 3 hours to evaporate the solvent.
· Dichloromethane (200 mL) was added followed by hydrochloric acid (1.0 M, 100 mL). The mixture was stirred vigorously for 1 hour. The organic phase was separated, washed with water (3×200 mL) and dried over anhydrous magnesium sulfate.
· Evaporation of the solvent leaves an oily residue consisting mainly of the two isomers. The mixture was dissolved in dichloromethane (50 mL) and applied to a silica column (220 g).
· The isomers were separated by flash chromatography using hexane to hexane:ethyl acetate 1:1. The more polar fractions were evaporated to dryness to obtain the product (11,21-Dihydroxy-17-[(1-oxooctyl)oxy)]-(1^)-pregn-4-ene-3,20 as a white solid -dione).