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Short Paper | Special issue | Vol 86, No. 2, 2012, pp. 1637 - 1646
Published online: 30th October, 2012
DOI: 10.3987/COM-12-S(N)115
■ SYNTHESIS AND STABILITY OF 3-HYDROXYANAGRELIDE, A BIOLOGICALLY POTENT METABOLITE OF ANAGRELIDE

Richard B. Scott, Kristin M. Downey, Keith P. Healy, Alistair P. Henderson, Claire L. Robinson, William Clegg, Ross W. Harrington, Richard Franklin, and Bernard T. Golding*

*School of Chemistry, Newcastle University, Bedson Building, NE1 7RU, U.K.

Abstract

Human metabolism of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2-one (anagrelide), a drug used for the treatment of essential thrombocythemia, gives 6,7-dichloro-3-hydroxy-1,5-dihydroimidazo[2,1-b]quinazolin-2-one (3-hydroxyanagrelide) and 2-amino-5,6-dichloro-3,4-dihydroquinazoline. To enable the chemical and biological properties of 3-hydroxyanagrelide to be fully evaluated, a synthetic route to the racemic compound has been developed. In an aqueous buffer (pH 7.4, 37 ºC) 3-hydroxyanagrelide readily equilibrates with an isomer, 6,7-dichloro-1-hydroxy-3,5-dihydro-imidazo[1,2-a]quinazolin-2-one, and is also hydrolyzed to 2-amino-5,6-dichloro-3,4-dihydroquinazoline. 3-Hydroxyanagrelide (half-life 40 hours) was the dominant species at equilibrium and it was concluded that the equilibration and decomposition are sufficiently slow that published assays of 3-hydroxyanagrelide are reliable.

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