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Sci. Pharm. 2009, 77(4), 775-790; doi:10.3797/scipharm.0907-01

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

1
Department of Analytical Research, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500049, India
2
Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, 500 072, India
3
Department of Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500049, India
*
Author to whom correspondence should be addressed.
Received: 3 July 2009 / Accepted: 27 August 2009 / Published: 28 August 2009
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Abstract

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.
Keywords: Ketolide synthesis; By-product isolation; Characterization; 2D NMR; Single crystal Xray structures Ketolide synthesis; By-product isolation; Characterization; 2D NMR; Single crystal Xray structures
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

MUNIGELA, N.; J., M.B.; YERRAMILLI, A.; SINGH, G.; REDDY, B.; TAKHI, M.; TATINI, L.K.; R., S.B.; VISHWESHWAR, P. Structural Studies of an Impurity Obtained During the Synthesis of Telithromycin Derivatives. Sci. Pharm. 2009, 77, 775-790.

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