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Total Synthesis of an Experimental Antitubercular Drug CDRI-830

Abstract The triarylmethane antituberculosis drug CDRI-830 is synthesized. The triarylmethane derivative 4 is prepared from ether 6 by a rearrangement process. The total synthesis of the drug CDRI-830 is achieved in a good overall yield of 35% from a simple thiophene derivative 8. GRAPHICAL ABSTRACT


INTRODUCTION
Tuberculosis (TB), an infectious disease, is caused by Mycobacterium tuberculosis. [1,2] The emergence of multi-drug-resistant (MDR) strains and its synergy with human immunodeficiency virus (HIV) [3] is a major concern of the World Health Organization. The CDRI (Central Drug Research Institute, Lucknow, India) identified compound CDRI-830 in their anti-TB program. CDRI-830 is triarylmethane (TRAM) derivative. [4]

RESULTS AND DISCUSSION
A novel method of building CDRI-830 was envisaged via an ether rearrangement method. Retrosynthetic analysis of CDRI-830 leads to phenol 4, which can be synthesized from ether 6 via a known rearrangement method. Ether 6 can be made from diary methanol 3, which can be synthesized from readily available anisole 1 and thiophene-2-carbonyl chloride 8, as shown in Scheme 1.
In conclusion, we report a practical synthesis of CDRI-830, an experimental anti-TB compound.

EXPERIMENTAL
Most of the reagents used in this work were obtained from commercial suppliers and were of laboratory reagent or analytical reagent grade. Solvents were purified before use by standard procedures. Melting points were determined using open capillary tubes on a Polmon melting-point apparatus (model 96) and are uncorrected. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded using a Bruker 400 Spectrometer with tetramethylsilane (TMS) as internal standard. Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum 100 FTIR spectrophotometer as KBr pellets or with the neat products. Mass spectra were recorded on an API 2000 LCMS=MS Applied Bio Systems MDS Sciex spectrometer. Microanalysis was performed on a Perkin-Elmer 240CHN elemental analyzer. Analytical thin-layer chromatography (TLC) was conducted on E-Merck 60F254 aluminium-packed plates of silica gel (0.2 mm). Developed plates were visualized by using ultraviolet (UV) light or in an iodine chamber. High-performance liquid chromatography (HPLC) was performed by using a Shimadzu 2010 instrument.
Diisopropyl-(2-f4-[(4-methoxy-phenyl)-thiophen-2-yl-methyl]phenoxyg-ethyl)-amine (CDRI-830) Lithium aluminum hydride (0.86 g, 0.022 mol) was taken in a round-bottomed flask under nitrogen atmosphere, and THF (15 mL) was added slowly for 5 min at rt (little exothermic). To this reaction mass 11 (5.0 g, 0.011 mol, dissolved in 10 mL THF) was added at rt for 5 min. It was exothermic, and the temperature slowly went up to reflux. It was refluxed for 30 min, and after completion of the reaction (monitored by TLC), the reaction mass was cooled to 5-10 C and quenched by adding chilled water (25 mL). The product was extracted with ethyl acetate (2 Â 50 mL), and the organic layer was washed with brine solution (50 mL) and dried over sodium sulfate. It was concentrated under reduced pressure to get product (CDRI-830), a light green viscous liquid. IR (neat, cm À1 ) 2965, 1507, 1247; mass for C 26