Glymes have a number of uses in the industrial world, but in the area of pharmaceutical or specialty chemicals production, it is their use as premier solvents that can enhance yields and reaction rates in a wide variety of reaction types that is of interest. Glymes are amongst the strongest solvents available anywhere. They have properties such as high thermal and chemical stability that recommend them in a variety of pharmaceutical production reactions. They also offer easier and safer handling, a broader range of process conditions in which they are effective, easier recycling and better overall environmental impact.
Glymes are saturated polyethers with no functional groups. As compared to the polyethylene glycols (PEGs), glymes do not contain free hydroxyl groups. Without these, glymes are aprotic solvents, that are inert chemically. These features account for their excellent solvent properties. For example, most glymes are completely miscible with both water and hydrocarbon solvents. Like crown ethers or other oxygen-containing solvents, they tend to solvate cations. This leaves anions active, so that for reactions involving basic reagents, the use of glymes as solvents and reaction media can greatly enhance reaction rates.
Typically, glymes are used when an aprotic, inert, dipolar and active solvent with high performance is required. Using a glyme as a solvent will enhance the yields of many different types of reactions such as organometallic reactions, like Grignards and lithiations, Ullmann couplings, Heck reactions, Pd-catalyzed couplings (e.g. Suzuki), reactions involving alkali metals, oxidations and reductions. They also find use as phase transfer catalysts, with advantages over quaternary ammonium salts (QUATS) or crown ethers. |  |
Today, drugs for treatment of AIDS, hypertension, asthma, depression as well as antihistamines, diuretics and mucolytics are all produced on industrial scale with glyme solvents. Beyond initial synthesis, preparations to increase the transdermal transport of actives and to increase the stability of active ingredients are addressed through the use of glymes. In addition, glymes are useful for extraction of naturally occurring actives from plants.
As mentioned, Glymes are completely miscible with water. However, if butyl groups replace the terminal methyl groups, the resulting “butyl glyme” is no longer miscible with water.
Several metalorganic reactions like Grignards require solvents that are immiscible with water. Butyl diglyme has solubility in water of only 0.3 wt% and is an excellent replacement for THF , diethyl ether or dibutyl ether. Due to its low vapor pressure and high inertness it allows for safe handling and easy work-up of Grignards even on industrial scale.
Clariant offers high quality, extremely pure glymes for use in pharmaceutical synthesis. These are available in a wide range of forms, from fairly liquid, low viscosity monoglyme (monoethylene glycol dimethyl ether, 1.2-dimethoxy ethane) all the way up to compounds such as polyethylene glycol dimethyl ether which is solid and has a melting point of 50º C. |