Preparation method of vinorelbine

Abstract

The invention belongs to the field of pharmaceutical synthesis, and provides a novel method used for synthesizing vinorelbine tartrate. According to the novel method, catharanthine tartrate and vindoline are taken as initial raw materials, vinorelbine crude products are obtained via a two-step one-pot procedure reaction instead of an original four-step reaction, synthesis steps are simplified, and yield is increased. The vinorelbine crude products are subjected to normal phase silica gel column purification and reverse phase silica gel column purification, so that purity of obtained vinorelbine purified products is increased substantially; and at the same time, increasing of vinorelbine purity possesses significant influences on salifying effects of vinorelbine with tartaric acid, so that after recrystallization, purity of the obtained vinorelbine tartrate is higher than 99.5%, and accords with requirements of United States Pharmacopeia; competitive advantage is more excellent; all of the operation processes are normal operation processes; and it is more beneficial for industrialized production.

Description

Technical field: [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of an antitumor compound vinorelbine tartrate. Background technique: [0002] Vinorelbine tartrate is a vinca alkaloid drug developed by PierreFabre in France, which was first launched in France in 1989. This product has broad-spectrum anti-tumor activity, less adverse reactions, blocks the activity in the metaphase of cell mitosis, binds to tubulin monomer, inhibits the formation of microtubules, causes cell division, and finally leads to cell apoptosis. Clinically, it is mainly used for the treatment of non-small cell carcinoma, breast cancer, ovarian cancer, soft tissue and visceral metastatic cancer and lymphoma. [0003] The relevant literature reports about vinorelbine tartrate mainly include Chen Yongjiang and other Chinese Journals of Pharmaceutical Industry, 1999,30(1),6-8, Yan Jiafu and other Chinese Journals of Traditional Chinese Medicine...

AI Technical Summary

Problems solved by technology

[0015] The five synthetic methods are basically the same, but there are differences due to the sequence of the introduced substituents and the modification methods of the substituents.

The first synthetic method has fewer steps, mild reaction conditions, and fewer side reactions, but the synthetic starting material dehydrated vinblastine is expensive, resulting in higher costs; the second method has more similarities with the third method, and the side reactions There are many reactions, so it needs to be reacted at ultra-low temperature, which is difficult to control in industrial production; the fourth method is compared with other synthetic methods, and the difference is that it uses vinblastine sulfate as the starting material, and dehydrates with DMF to form anhydrovinblastine For the first step, the other steps are basically the same as the second method

Although the reaction conditions of the fifth synthetic method are mild, there are many reaction steps and side reactions, and the resulting intermediate is unstable; in addition, ring-opening rearrangement reactions occur due to the lack of treatment with halogenated hydrocarbons and silver tetrafluoroborate Difficulties, so that the yield of the final product is low, the purity is not high, although the cost of raw materials is low, but the overall production cost is high, which is not conducive to industrialization

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