A kind of preparation method of voriconazole and its intermediate

Abstract

The invention provides Voriconazole prepared from Voriconazole isomers and a preparation method of an intermediate of the Voriconazole. According to the method, the Voriconazole isomers are used as raw materials, under the condition of an alkaline reaction and 25-100 DEG C, reaction is performed for 1-24 hours, and then a condensation reaction is performed, so that a Voriconazole despinner is prepared; and chiral separation is performed on the Voriconazole despinner, so that the Voriconazole is obtained. According to the method, massive waste Voriconazole isomers generated in an industrialized production process can be recycled, and waste of raw auxiliary materials and resources in the preparation process of the Voriconazole can be avoided. Not only can the production cost be greatly reduced, but also recycling production can also be developed, so that the purposes of saving resources and protecting environment can be achieved.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new preparation method of the second generation triazole antifungal drug voriconazole and its intermediates for treating acute or chronic deep fungal infections. Background technique [0002] Voriconazole is a chiral drug with two chiral centers in its molecule and four isomers. They are (2R, 3S / 2S, 3R) and (2S, 3S / 2R, 3R). The structure-activity relationship study (SAR) confirmed that the antibacterial activity of the (2R, 3S / 2S, 3R) enantiomer is more than 200 times that of the (2S, 3S / 2R, 3R) enantiomer. Further experimental studies on the resolution of a pair of enantiomers with good activity (2R, 3S / 2S, 3R) showed that a single isomer (2R, 3S), namely voriconazole. The inhibitory activity against Aspergillus (fungi) is more than 200 times that of the (2S, 3R) isomer, and compared with (2S, 3R), the isomer (2R, 3S) has a broader antibacterial spectrum. The active ingredient...

AI Technical Summary

Problems solved by technology

Using this strategy to prepare voriconazole has the advantage that (2R, 3S) isomers account for a relatively high proportion (generally greater than 50%), but there are currently the following problems. One is in the process of asymmetric synthesis of voriconazole or its intermediates , it is necessary to use transition metal catalysts that are expensive and difficult to obtain in large quantities (such as bistriphenylphosphine palladium dichloride (II), CuF (PPh3) 2) and chiral ligands ((S)-1-((SP )-2-[2-(diphenylphosphino)phenyl]ferrocenyl)ethylbis[3,5-bis(trifluoromethyl)phenyl]phosphine), at present, this method is still in experimental The small-scale preparation of voriconazole samples in the laboratory cannot meet the requirements of industrial production for cost control

The second is that although voriconazole is prepared by asymmetric synthesis, the content ratio of (2R, 3S) isomers is increased, but due to the selectivity of asymmetric synthesis, the increase range is limited. In the prepared voriconazole, the isomer impurities (2S ,3R) content can still account for (5% to 30%), so if it is necessary to finally obtain a voriconazole product with qualified isomer impurity content, subsequent purification still needs to be resolved

[0005] To sum up, using the above method to prepare the compound of formula I, due to the limitation of theory and large-scale production on cost control, although some parameters can be optimized, in the process of industrial production, it is still impossible to greatly improve the utilization rate of raw materials and auxiliary materials, and then obtain a higher yield. Voriconazole bulk drug with high production cost and lower production cost. For this reason, a new technical solution is urgently needed to provide better process conditions, improve the utilization rate of raw and auxiliary materials, reduce resource waste and protect the environment, and reduce production costs to the greatest extent. It is more conducive to large-scale industrial production

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