Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib

Abstract

The invention relates to a method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino)oxypropyl] cyanophenyl and a process for preparing gefitinib. The method comprises the following steps of (e1) reacting 4-methoxyl-2-nitryl-3-[3-(4-morpholino)oxypropyl]cyanophenyl with a reducer in water, and controlling the reaction temperature to be between 20 and 40 DEG C; (e2) heating the mixture to 50 to 70 DEG C, adding hydrochloric acid to adjust the pH value of the mixture to 1 to 3, and reacting for 1 to 10 hours; (e3) cooling the mixture to 20 to 25 DEG C, and adjusting the pH value to 10 to 12; and (e4) extracting a reaction solution obtained in the step (e3) by using an organic solvent, and concentrating an organic phase obtained by extraction to obtain the finished product. By the method, the gefitinib can be prepared. The method has the advantages that initial raw materials are low in price and readily-available, the reaction conditions are mild, the six-step reaction of which the scales are enlarged to 100 gram-level is adopted, the yield is high, the cost is low, the flow is shortened due to the adoption of Dimroth rearrangement reaction, a highly toxic reagent is not needed, chlorinated pollution is avoided, the product purity is over 99.7 percent, and the method is environment-friendly and suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of an intermediate used for chemically synthesizing antitumor drug Gefitinib and a preparation process of Gefitinib. Background technique [0002] Gefitinib (Gefitinib, ZD1839, trade name: Iressa, Iressa) chemical name is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4 -propoxy)quinazolin-4-amine, which is a highly specific anti-tumor targeted therapy drug developed in recent years, is the first small molecule epidermal growth factor receptor (EGFR) for the treatment of solid tumors. EGFR) protein tyrosine kinase inhibitor. Gefitinib is not only effective for advanced non-small cell lung cancer and can improve disease-related symptoms, but also has anti-tumor activity against other solid tumors, including prostate cancer, breast cancer, gastric cancer, intestinal cancer, etc. Antitumor activity of hormone therapy. At present, phase II / III clinical research on the efficacy of other tumors is still...

AI Technical Summary

Problems solved by technology

[0015] The disadvantage of this method is: the Dimroth rearrangement process needs to be reacted for a long time (96 hours) at a very high temperature. Under this condition, the amidine as a raw material is easily decomposed and causes a decline in yield, and a large amount of formamidine The excess of the target product was not further purified

[0018] However, the main disadvantage of this method is that the reduction of nitro compounds to amines uses Pd-C reduction in one step to obtain a mixed product, which needs to be transformed again to obtain the target product, which is cumbersome to operate and difficult to master.

Images