Sci Pharm; 2009; 77: 775–789
Structural Studies of an Impurity Obtained During the Synthesis of Telithromycin Derivatives
Nirmala MUNIGELA * 1, Moses BABU J. 1, Anjaneyulu YERRAMILLI 2, Gurpreet SINGH 3, Bhaskar REDDY 3, Mohamed TAKHI 3, Lakshmi Kumar TATINI 1, Sreekanth BUKKAPATTANAM R. 1, Peddy VISHWESHWAR 1
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.
3Department of Chemistry, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500049, India.
* Corresponding author. E-mail: nirmala_m@aurigene.com (N. Munigela)
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-meth-oxy-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). Oxi-dation of this gave (3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydr-oxy-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-hexopyran-oside (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-(phenylcarb-onyl)-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-trioxooxacyclo-tetradec-11-en-6-yl 3,4,6-trideoxy-3-(dimethylamino)-2-O-(phenylcarbonyl)-β-D-xylo-hexopyranoside (6) respectively by 2D NMR and single crystal X-ray diffraction.
Supporting Information
The scanned HR-MS spectrum of 2–4 and 6, the scanned 1H NMR spectrum of 2–4 and 6, the scanned gHMBC spectrum of of 3, 4 and 6, and the scanned gHSQC spectrum of of 4 and 6 are available: Supporting Information (Format: PDF, Seize: ca. 0.3 MB)
Keywords
Ketolide synthesis • By-product isolation • Characterization • 2D NMR • Single crystal X-ray structures
Received July 3rd, 2009 | Accepted August 27th, 2009 | Published Online August 28th, 2009
