The second undesirable reagent, methylamine, was present as an impurity in dimethyl amine and this also reacts with 8 to yield the related compound 13 (Scheme 6). Compound 13 was synthesized by the reaction of DCC-treated 8 with methyl amine (CH3NH2). The mass spectrum of 13 displayed a protonated molecular ion at m/z 294 and a sharp band at 1659 cm-1 was observed in the IR spectrum which was attributed to amide C=O stretching. In the 1H NMR spectrum, two singlet signals at • 4.05 ppm and 6.05 ppm were observed and are characteristic for amide methyl and amide NH, respectively. This spectral data is consistent with the structure of N-methyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetamide (13).
Scheme 6
Conclusions
In conclusion, we have identified, synthesized and characterized five potential process-related impurities (9-13) of zolpidem (1).
Experimental Section
General Procedures. The 1H NMR spectra were recorded on a Gemini 200 MHz FT NMR spectrometer with chemical shifts reported in ppm relative to TMS. The IR spectra were recorded in the solid state as KBr discs using a Perkin Elmer FT-IR spectrophotometer. The mass spectra were recorded on Shimadzu LCMS-QP8000 and AB-4000 Q-trap LC-MS/MS instruments. Elemental analysis for CHN were performed on a Perkin Elmer model 2400 CHNS/O analyzer at Dr. Reddy's Laboratories Ltd., Hyderabad.
(6-Methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-methanol (9). To a mixture of 4 (40.0 g, 0.180 mol) and acetic acid (60.0 mL), 36% formalin (37.5 g, 0.45 mol) was added under stirring. The reaction was stirred at 25-35 °C till completion. The reaction mass was cooled to 0-5 °C and to it a solution of sodium hydroxide (48% w/w, 60.0 mL) in water (160.0 mL) was added and stirred for 2 hours at 25-35 °C. The precipitated compound was filtered, washed with water methanol mixture (50.0 mL 1:1) and dried at 85 °C to yield 9 (35 g, % yield: 77.0, purity by HPLC: 99.2%); IR (cm-1): 3085 (OH); 1H NMR (DMSO-d6, • ppm): 2.45 (s, 6H, CH3), 5.00 (s,
