Structural Studies of an Impurity Obtained During the Synthesis of Telithromycin Derivatives

In an effort to synthesize a key intermediate, for synthesis of a variety of telithromycin derivatives a new by-product has been formed at the third stage of the synthetic scheme. The starting material, Clarithromycin, on treatment with hydrochloric acid and on benzoylation resulted in the formation of (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy- 3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecan-6-yl 3,4,6-trideoxy- 3-(dimethylamino)-2-O-(phenylcarbonyl)-β-D-xylo-hexopyranoside (2). Oxidation of this gave (3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy- 7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecan-6-yl 3,4,6-trideoxy-3-(dimethylamino)-2-O-(phenylcarbonyl)-β-D-xylo-hexopyranoside (3), and also an unexpected by-product 4 in equivalent amounts. The O21–H hydroxyl group in 3 was mesylated with dimethyl sulphoxide (DMSO) in pyridine leading to the precursor (3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl- 12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-12-(methylsulfinyl)- 2,4,10-trioxooxacyclotetradecan-6-yl 3,4,6-trideoxy-3-(dimethylamino)-2-O- (phenylcarbonyl)-β-D-xylo-hexopyranoside (5), which on further treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone and methylene chloride resulted in the formation of intermediate 6. The by-product 4 and the intermediate 6 were isolated and characterized as (1S,2R,5R,7R,8R,9R)-2- ethyl-9-methoxy-1,5,7,9,11,13-hexamethyl-4,6-dioxo-3,15-dioxabicyclo[10.2.1]- pentadeca-11,13-dien-8-yl 3,4,6-trideoxy-3-(dimethylamino)-2-O-(phenylcarbonyl)- β-D-xylo-hexopyranoside (4) and (3R,5R,6R,7R,9R,11E,13S,14R)-14- ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradec- 11-en-6-yl 3,4,6-trideoxy-3-(dimethylamino)-2-O-(phenylcarbonyl)-β-Dxylo- hexopyranoside (6) respectively by 2D NMR and single crystal X-ray diffraction.