A kind of refining method of bortezomib

Abstract

The invention belongs to the field of synthesis of a drug, and relates to a method for refining a drug compound bortezomib. The method comprises the following steps: adding a bortezomib crude product into water to adjust a pH value to alkalinity to dissolve; removing impurities with poor water solubility through washing by an organic solvent; adding a water layer to the organic solvent to acidify; removing water-soluble impurities under an acidic condition; and devitrifying to obtain high-purity bortezomib by adding the organic solvent, a cosolvent and a decolorizing agent after feed liquid at an organic layer is concentrated. The method has the advantages of being simple and convenient to operate and significant in impurity removing effect, the yield is greater than 80%, and the purity is greater than 99.85% by HPLC (high performance liquid chromatography) detection.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for refining the drug compound bortezomib. Background technique [0002] Bortezomib, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl ]amino]butyl]-boronic acid, molecular formula: C 19 h 25 BN 4 o 4 , the structural formula is as follows: [0003] [0004] Bortezomib is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. Bortezomib is a dipeptide borate, which is a reversible proteasome inhibitor, and can selectively bind to threonine in the active site of protease , Inhibit the chymotrypsin and (or) trypsin activity of the 26S subunit of the proteasome. Blocking NF-kB, thereby preventing tumor cell apoptosis and participating in cell drug resistance; acting on the myeloma microenvironment, inhibiting the growth and survival of tumor cells in the microenvironment, etc...

AI Technical Summary

Problems solved by technology

[0011] This synthetic route avoids the use of expensive chiral ligands, and (1s,2s,3R,5s)-(+)-2,3-pinanediol is the starting material, which reduces the cost to a certain extent, but this method The intermediate needs to be separated by column chromatography for many times, and the final crude product is also separated by silica gel column chromatography to obtain a pure product, and the purity of the product is not mentioned

[0012] The method described in CN201110300750.7 uses starting materials of different protecting groups to obtain bortezomib through condensation, debenzylation, condensation, and oxidation deprotection, and mentions that the prior art uses methanol or ethyl acetate and methyl tert-butyl base ether or n-hexane, because bortezomib has a large solubility in methanol, it is not easy to separate out, and impurities and products are precipitated together in ethyl acetate, methyl tert-butyl ether or n-hexane, which is difficult to remove by conventional recrystallization methods. High-purity bortezomib is readily available

And the method for obtaining bortezomib after purification by acetone, toluene and methyl tert-butyl ether is provided, which improves the purity of bortezomib, and the reported purity reaches 99.66%. It is difficult to achieve the above effects by recrystallization by this method

[0013] Because bortezomib uses condensing agent and coupling agent in the condensation and coupling reactions, it is easy to decompose and difficult to remove in the reaction. At the same time, bortezomib is chemically synthesized through multi-step reactions. The difficulty of its synthesis lies in the product chemistry. Unstable in nature, containing easily oxidized groups, prone to side reactions during the reaction process, thereby introducing other impurities; the existence of chiral groups makes the process of product synthesis more difficult, and the existence of isomer impurities makes The optical purity of the product is generally low, especially isomer impurities and oxidized impurities. Since these two types of impurities are closer in nature to bortezomib, it is difficult to achieve a good impurity removal effect according to traditional methods. In view of the toxicity of impurities in bortezomib Stronger, so the purification of raw material impurities is the key to the preparation of bortezomib, which is in urgent need of a good purification method to purify bortezomib

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