Study On Triarylmethane And Its Application In The Synthesis Of Pazopanil Trimer Impurities

This thesis consists of two parts: the synthesis of poly-substituted triarylmethane and the synthesis of impurity intermediates of pazopanib trimer.Part 1: Triarylmethane is widely used in group protection,organic dyes,optical materials and other fields because of its unique structure and properties.Triarylmethane and its derivatives are also components of many bioactive compounds,which are important intermediates for the synthesis of many anti-tumor,anti-oxidation,anti-inflammatory,anti-tuberculosis,anti-fungus and anti-virus drugs.In work,triarylmethanol was prepared by reacting diarylketone derivatives with aryllithium reagents,and triarylmethane with multiple substituents on the benzene ring was synthesized by dehydroxylation.Part 2: Pazopanil(PZPN)is a new oral targeting drug,which is mainly used in the treatment of advanced renal cell carcinoma(RCC)and advanced soft tissue sarcoma(STS).A number of studies have shown that pazopanil can inhibit thyroid cancer,non-small cell lung cancer(NSCLC),breast cancer and ovarian cancer.In the industrial production process of pazopanib,related impurities will be generated,among which the trimer impurity is a more important impurity with a molecular weight of 1240.Firstly,the impurity molecule has the characteristics of strong hydrophobicity,large molecular weight and high symmetry,which is not conducive to separation and analysis,and brings a huge challenge to the quality control of pazopanil;secondly,the impurity molecule contains a triarylmethane core with steric hindrance,which brings a huge difficulty to the synthesis of trimer impurities.In this paper,5-chloro-2-methylbenzaldehyde was synthesized from 2-bromo-4-chlorotoluene,which was combined with 2-bromo-4-chlorotoluene to form bis(5-chloro-2-methylphenyl)methanol,In this paper,5-chloro-2-methylbenzaldehyde was synthesized from 2-bromo-4-chlorotoluene,which was combined with 2-bromo-4-chlorotoluene to form bis(5-chloro-2-methylphenyl)methanol.After oxidation,bis(5-chloro-2-methylphenyl)ketone was combined with p-bromoanisole to form bis(5-chloro-2-methylphenyl)(4-methoxyphenyl)methanol,and then reacted with reducing agent to produce 2,2 ’((4-methoxyphenyl)methylene)bis(4-chloro-1-methylbenzene).The raw material of the method is cheap and easy to obtain,and the operation is simple.At last,the pyrimidine side chain of pazopanil trimer impurity was modified to provide reference for the synthesis of pazopanil trimer impurity.