Methods for preparing semi-synthetic paclitaxel and intermediate thereof

Abstract

The invention relates to methods for preparing semi-synthetic paclitaxel and an intermediate thereof. The method for preparing the semi-synthetic paclitaxel comprises the following steps: dissolving 10-DABIII (10-deacetylbaccatinIII) into pyridine, protecting hydroxyl on position-7 carbon on the 10-DABIII with triethyl silicyl to obtain an intermediate I, acetylating hydroxyl on position-10 carbon of the intermediate I to obtain an intermediate II, reacting the intermediate II, a side-chain radical compound and 4-dimethylaminopyridine in an organic solvent to prepare an intermediate III, and reacting the intermediate III with trifluoroacetic acid under an acidic condition to obtain a crude paclitaxel product. The preparation methods are simple and easy for industrialization; the active hydroxyl of the raw material 10-DABIII is effectively protected, so that fewer byproducts are finally generated, and a prepared paclitaxel product has high molar yield of 70 to 81 percent and high paclitaxel purity of 99.5 to 99.9 percent; the residual rate of the raw material in the steps of synthesizing the intermediate II and synthesizing the paclitaxel is low, side reactions are reduced, and the raw material is high in reaction selectivity and utilization rate; the product can be directly used as a raw material for the medical field of treatment of ovarian cancer, breast cancer and the like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of semi-synthetic paclitaxel and its intermediate. Background technique [0002] Paclitaxel (trade name: Taxol) is a taxane diterpenoid isolated from the genus Taxus. Its novel structure, unique anti-cancer mechanism, remarkable anti-cancer effect and broad anti-cancer spectrum are considered to be one of the best anti-cancer drugs discovered so far. The total chemical synthesis of paclitaxel has been successful, but the synthetic route is complicated and the cost is too high, which is only of research significance and has no commercial value. Compared with the total synthesis of paclitaxel, the semi-synthesis of paclitaxel is a preparation method with practical value. The semi-synthesis of paclitaxel generally uses 10-deacetylbaccatin III (10-DAB III), which is similar in structure to the macrocycle of paclitaxel, as a raw materi...

AI Technical Summary

Problems solved by technology

In the prior art, in addition to using solvents, various catalysts are used in the method of semi-synthesizing paclitaxel to increase the reaction yield, such as the use of imidazole and other catalysts in patent CN200580011712.2, and the use of Jones when protecting the C7 hydroxyl group in patent US193263 Reagents, and need to react at -23°C when protecting the C10 hydroxyl group, the requirements for the reaction reagents are relatively high, the system components are complex and impurities are produced, so that the content of paclitaxel in the final purified product is not high

[0003] In a word, the common problem in the existing patented technology is: with 10-DABⅢ as raw material, the yield of finally obtained paclitaxel is low, the main reasons are: (1) in the process of acetylating the 10-position hydroxyl group of 10-DABⅢ, in When the reaction is close to the end, it is easy to produce side reactions to generate other impurities; (2) it is easy to cause over-reaction to generate other impurities during the final ring-opening deprotection reaction process

[0004] Because a large amount of raw materials are converted into impurities, the yield is low; in the purification and separation process of paclitaxel, column chromatography and recrystallization are used for purification, so part of the paclitaxel product is lost and the purity of paclitaxel is not improved much.

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