Rapid preparation of the mitotic kinesin Eg5 inhibitor monastrol using controlled microwave-assisted synthesis.
We present here a protocol for the synthesis of the dihydropyrimidine (DHPM) derivative monastrol, which is known to be a specific mitotic kinesin Eg5 inhibitor. By applying controlled microwave heating under sealed-vessel conditions, the synthesis via the one-pot three-component Biginelli condensation can be performed in a shorter reaction time (30 min) compared with conventional heating methods that normally require several hours of reflux heating. For the purification of the crude target compound, two different methods are presented. The first protocol includes a simple precipitation/filtration step to provide monastrol in 76% isolated yield and high purity so that no recrystallization step is necessary. This can be ascribed to the microwave heating technology in which less side-product formation is typically one of the advantages. In an alternative purification step, column chromatography is performed, which provides the product in a slightly higher yield (86%). Monastrol synthesis can be conducted in approximately 2 h by employing the precipitation/filtration purification method.
Dallinger
Doris
D
Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
Kappe
C Oliver
CO
D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D005374:Filtration; D016547:Kinesins / Q000037:antagonists & inhibitors; D008872:Microwaves; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000302:isolation & purification*; D013871:Thiones / Q000138:chemical synthesis* / Q000302:isolation & purification*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors
C088335:KIF11 protein, Xenopus; D011743:Pyrimidines; D013871:Thiones; D029867:Xenopus Proteins; C400223:monastrol; D016547:Kinesins