Automated flash chromatography

Purification by automated flash chromatography, preparative HPLC... 

Preparation of the monobrominated bisquinolone. A mixture of 109 mg (0.25mmol) of 4,4 -bis(6,7-dimethoxy-l-methylquinolin-2(l/7)-one), 111.2mg (0.625mmol, 2.5 equiv) of A-bromosuccinimide (NBS), and 0.6 mL of DMF in a vial equipped with a magnetic stir bar was stirred for 35 min at room temperature. The reaction was quenched by addition of ice water and was filtered. The resulting crude product mixture was purified by automated flash chromatography using EtOAc/CHjCN as eluent to give 80 mg (62%) of the monobrominated material as a yellow solid. 

The differentiating feature of an open versus closed system is the ability to interact with and maximize the use of individual components. The closed system, on the other hand, represents a turnkey approach which enables full automation of the entire process. However, this instrument does not allow the user to interact with the individual system components dining processing. An example of a closed system is an HPLC instrument while flash chromatography represents an open system. 

It has already been mentioned that the scope of reactions that lend themselves to solution-phase combinatorial chemistry is dependent on the possibility of purifying the products. A number of techniques have been used for this purpose, though their significance often depends on the size of the library and on how easily they can be automated. This applies particularly to most chromatographic methods. One of these that can be easily run in parallel fashion is flash chromatography, and this has therefore also been applied in library synthesis (e.g. [47, 111]) even of mixtures (e.g. [6]). Also simply shaking with sorbents (e.g., alumina/silica gel [115]) may be sufficient to purify the products Extraction procedures have been followed widely in solution-phase combinatorial chemistry, and these and some other techniques will now be reviewed briefly. 

The purification of chemical hbraries has also been performed with the use of flash chromatography systems. Current instmmentation allows the simultaneous semiautomated purification of several compounds. An example system is the Quad3 (Biotage, Inc.), which allows simultaneous purification on up to 12 columns prepacked with sorbent for normal or reverse-phase separation. This system was successfully used for peptide hbrary purification, as well as for low-weight molecule hbraries. A natural product library including several hundred compounds was effectively purified with the use of an updated FlashMaster II, capable of 10 fully automated independent separations in one run (Figure 3.25). 

Liquid chromatography cleanup on a LiChrosorb Diol column has been further proposed for the offline purification of chloramphenicol residues from bovine muscle and eggs (32). An online approach based on reversed-phase principles has also been described for isolation of chloramphenicol residues from swine kidney by an automated column switching system (63). Use of a protein exclusion column (Hisep) has been also suggested in an online trace-enrichment method for the determination of chloramphenicol in animal tissues (52). By employing a column-switching system, all chloramphenicol that eluted from the protein exclusion column was trapped at the entry of a 5 m Supelcosil LC-18 preconcentration column, to be subsequently back-flashed into the analytical column. 

---