Research On Preparative Process And Quality Control Of Olanzapine

Olanzapine (OLN) is a new atypical antipsychotic drug, which is developed by Lilly and can block both 5-HT and DA receptors. Compared to the classic antipsychotic drugs, OLN processes fewer side effects and well tolerated by patients, widely used for clinical treatment of many mental diseases. OLN came into United States market in 1996, the patent of which expired in April of 2011. Zeprexa sales of Lilly in 2009 were up to 5 billion dollors.Adopting malononitrile route, OLN was synthesized by four steps including thiophene ring formation, nucleophilic substitution, reduction cyclization and addition-elimination. Total yield was 30.3% with per step's average yield 75.0%,83.2%,68.8% and 70.5%. The study focused on optimization of the key step in terms of solvents, proportion of reactants, recovery scheme,aftertreatment and refinement. A synthetic technology of OLN was developed with advantages of time-saving, recyclable process and high yield. The average recovery of N-methyl piperazine was 71.0% and average yield of OLN was 99.7% by many experiments. The products were purifed by recrystallizing from ethanol with average yield 70.5% and purity 99.7%(HPLC).From the crude samples of OLN crystallization mother liquid, two new related impurity were isolated by preparative chromatography and structrally confirmed by X-single crystal diffraction as 1-(5-methyl-thionphen-2-yl)-1H-benzimidazol-2(3H)-one and 1-(2-(5-methyl-thionphen-3-yl)-1H-benzimidazol)-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [ 1,5]-benzodiazepine. Four commonly related impurities of OLN were prepared and characterized by MS and 1H NMR.An efficient and reliable RP-HPLC method was developed for determinining eight OLN's related impurities. The optimum separation was carried out on Agilent TC-C18 using methanol and 0.3% triethylamine in water with pH adjusted to 3.73 by acetic acid as mobile phase in gradient mode. The flow rate was 1.0ml/min in gradient mode at 30℃. The UV detection was at 254nm and injection volume was 20μl. OLN demonstrated good linearity (r2=0.9998) in the range of 50～320μg/ml with RSD of precision 0.91%, LOQ 1.1ng/ml, average recovery 101.11%. For eight related impurities, good linearity was demonstrated when each impurity was in the range of 0.1～6.4p.g/ml, r2) 0.9975, RSD of precision (2.0%, LOD≤0.1μg/ml, average recovery 94.06%～103.55%.