| Tumor is a malignant disease in the body that is associated with changes at the genetic level.It will promote abnormal reproduction of normal cells in the body.It is a local mass formed by normal cells in the human body under the long-term effects of certain adverse factors,the excessive proliferation or abnormal differentiation of the cell population.The current tumor treatment methods mainly include drug therapy,surgery and radiation therapy.Tyrosine kinase inhibitors(TKI)are a new class of high-efficiency,low-toxicity,and specificity-targeted New anti-cancer drugs targeted by small molecules from the early 21st century.Epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that belongs to the family of receptor tyrosine kinase growth factor receptors.EGFR inhibitors control the occurrence and metastasis of tumors by acting on key links in the EGFR signal transduction pathway,and continue to divide,thereby destroying tumor cells.Erlotinib hydrochloride,approved by the US FDA in 2004,a small molecule EGFR tyrosine kinase inhibitor(Tarceva,trade name:Tarceva),is used to treat locally advanced or metastatic non-small patients after at least one chemotherapy regimen failure The patents for compounds and crystalline forms of innovative drugs for cell lung cancer will also expire in November 2020.At present,there are literatures related to the synthesis process of erlotinib hydrochloride at home and abroad.The synthesis process is long,the work is cumbersome and complicated,and the cost is high,which is not suitable for industrial production.In this dissertation,the preparation process of erlotinib hydrochloride is designed and developed:Using 2-amino-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester hydrochloride(SM1)as the starting material,a cyclization reaction with formamidine acetate was first obtained to obtain 6,7-Bis(2-methoxyethoxy)quinazolin-4-one(Ⅰ);Chlorination with thionyl chloride gives 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline(Ⅱ);followed by a nucleophilic substitution reaction with 3-aminophenylacetylenehydrochloride After purification,erlotinib(Ⅲ)is obtained;finally,the crude product(Ⅳ)is obtained by forming a salt with hydrochloric acid.After purification,high-purity erlotinib hydrochloride finished product(API)is obtained.The total yield is 55.6%,and the product purity is ≥99.8%.This paper has completed the optimization of the operating parameters of the preparation process.The four impurities of the key intermediate Ⅱ were discussed,and the acceptable limits of the impurities were established.Three batches of small trial yields are stable,the product quality is controllable,and a kilogram-scale scale-up trial production is carried out.This route preparation process comprising:modest market raw materials,reaction conditions,less by-products,the process operation is simple,stable and controllable product quality,higher yields entire route,without the use of a class of agents on the environment and the operator and to produce.In this study,homemade erlotinib hydrochloride refined products were used,and then samples were analyzed by high-performance liquid chromatography,elemental analyzer,infrared absorption spectrum,ultraviolet-visible absorption spectrum,nuclear magnetic resonance spectrum,liquid chromatography-mass spectrometer,and X-ray powder diffraction.The structure is verified.Analysis of the experimental data confirmed that the structure of sample is identical to erlotinib hydrochloride.The method for the analysis of the four solvents in the preparation process of erlotinib hydrochloride was verified in detail.The verification of the stability and solution stability proves that the indicators of the analysis method are good and feasible.Through preliminary analysis of four batches of homemade samples,the samples produced by this preparation process have stable quality,good uniformity and strong controllability. |
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