Isolation of Optically Pure (S)-(+)-Ibuprofen

Isolation of Optically Pure (S)-(+)-Ibuprofen

In this laboratory exercise we will isolate (S)-(+)-Ibuprofen from a racemic mixture of both enantiomers of this compound.

This will be accomplished by treating the racemic mixture of Ibuprofen with (S)-(-)-alpha-Phenethylamine, whose molecules are themselves chiral, to form (S,S) and (R,S) Ibuprofen/Phenethylamine diastereomeric salts. Because the (S,S) salt is much less soluble than the (R,S) salt, the (S,S) salt can be separated from the (R,S) salt by simple filtration. Subsequently the (S,S) Ibuprofen/Phenethylamine salt can be recrystallized to increase its purity and then acidified to recover pure (S)-(+)-Ibuprofen. The (S)-(+)-Ibuprofen can be extracted from the acidic solution and solidified after removal of the extraction solvent.

Our resolution of racemic Ibuprofen will involve adding a Resolving Agent, (S)-(-)-alpha Phenethylamine, to the racemic mixture. This Resolving Agent will undergo an acid-base reaction with Ibuprofen, producing two salts that are diastereomers.

Generation of the Diastereomeric Salts

To a 100 mL round bottom flask, add a stir bar, 3.0g of racemic Ibuprofen and 30 mL of 0.24 M KOH. Clamp the flask into a heating mantle and insert a thermometer. Initiate stirring. Heat the solution to a temperature between 75oC-85oC. Most but not all of the Ibuprofen will dissolve at this temperature. Next, add 0.9 mL of (S)-(-)- Phenethylamine dropwise and slowly to the flask. (Wear gloves when handling this compound as it is irritating to the skin. Recap the bottle immediately after use as the compound reacts with the Carbon Dioxide in the Air.) Precipitate will form within a few minutes. Keep the solution at this temperature for 1 hour. Remove the flask from the sand bath and allow it to cool to Room Temperature. Collect the precipitated slat by vacuum filtration. Wash the solid with a small amount (~2-3 mL) of ice cold Water. Weigh the solid.

Recrystallization of the (S,S) Ibuprofen/Phenethylamine Salt

Place the salt in a 50 mL beaker that contains a boiling stone. Add 2-Propanol (16 mL per gram, dry weight, of salt. If the salt was not dried before weighing use 30 mL of 2-Propanol.). Place a watch glass on top of the beaker and heat the solution to a boil. At this point all the solids should dissolve. (If all the solid does not dissolve, remove from heat and add 1-2 mL 2-Propanol. Bring back to reflux.) Remove the solution from the heat source and allow it to cool to Room Temperature; 1-15 minutes. Filter the resulting crystals. Wash the crystals with 2-3 mL of ice cold Water. Weigh the crystals after they are dry. Set aside enough for a melting point determination.

Recovery of (S)-(+)-Ibuprofen

Place the recrystalized salt into a 50 mL beaker. Add a stir bar and 25 mL of 2M H2SO4. Stir the solution for 5 minutes. The crystals will quickly dissolve and will leave behind thick oily droplets suspended in the solution. Extract the aqueous layer with 15 mL of MTBE three times. Combine the organic layers together and extract them once with 15 mL of Water and the once with 15 mL of sat’d aqueous NaCl. Dry the organic layer over anhydrous Sodium Sulfate. Transfer the MTBE solution to a pre-weighed beaker with a boiling chip. Boil off all the ether on a sand bath set to a temperature of 100oC. The product at first will be a thick, clear oil but it usually solidifies on standing. Weigh the product. If solid, take a melting point. Determine your percentage recovery.