Research On New Synthetic Process And Quality Control Of Erlotinib

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It was developed by Roche Pharm and initially approved by USFDA in November 2004, indicated for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Further, erlotinib in combination with gemcitabine can be used for the treatment of advanced pancreatic cancer.The key intermediate 3-aminophenylacetylene was synthesized by a four-step procedure using acetophenone as the starting material through nitrification, chlorination, elimination and nitro-selective reduction in about 48% overall yield. By optimizing the process conditions, erlotinib hydrochloride was synthesized from ethyl 3,4-dihydroxybenzoate by O-alkylation, nitrification, reduction, cyclization, chlorination to give 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline, which was subjected to nucleophilic substitution with 3-aminophenylacetylene and salt formation with an overall yield of about 67%.The erlotinib we prepared were subjected to LC-MS analysis, the impurities were separated, characterized and synthesized. The structure of four related impurities were determined, including two new impurities.A simple RP-HPLC method was developed and validated for the simultaneous separation and determination of erlotinib and seven related impurities. The separation was carried out on a C8 column. The mobile phase consisted of a mixture of potassium phosphate monobasic water solution (0.05 M, pH was adjusted to 7.0 by potassium hydroxide) and acetonitrile in the ratio of 58:42. The flow rate was 1.0 ml/min. The effluents were detected at 247 nm with the injection volume being 10 μl. The column temperature was 30℃. The method was validated with respect to system suitability, precision, linearity, accuracy, robustness, LOD and LOQ. Regression analysis showed good linearity for erlotinib and seven related impurities (r2≥0.9996). The resolutions were greater than 4.0 and the recoveries ranged from 96.18% to 104.24%. The RSD for precision was found to be less than 1.0%. The proposed method was suitable for routine analysis and quality control of erlotinib bulk drugs.