Piperidine derivative, and preparation method and application thereof in preparation of halofuginone

Abstract

The invention discloses a piperidine derivative represented by a formula (VIII), and a preparation method and an application thereof in preparation of halofuginone. Under an alkaline condition and under catalysis of HMPA (hexamethylphosphoramide), cuprous iodide, TMEDA (tetramethylethylenediamine) and the like, a 1,3 dicarbonyl compound which easily generates stable negative ions is adopted to highly selectively undergo a reaction with an epoxy compound to synthesize the compound (VIII) with high yields. Compared with other process routes of synthesis of halofuginone, a process route provided by the invention comprises that the piperidine derivative (VIII) undergoes a one-step reaction to simultaneously complete decarboxylation and removal of a Cbz protecting group, more effectively shortens synthetic steps of the process route, and thereby greatly improving the yield of halofuginone hydrobromide; and moreover, the whole process route is simple and feasible in operation, has mild reaction conditions, has the adopted catalysts which are low in cost and are easy to get, and quite easily realizes the large-scale industrialized production.

Description

(1) Technical field [0001] The present invention relates to a synthesis method or process of the alkaloid hiruzenone hydrobromide, in particular to a preparation method of a piperidine derivative and its application in the preparation of hiruzenone hydrobromide, the method can be used to synthesize hydrogen bromide with a high yield Hemoshenone, and the whole process route is simple and easy to operate, and the reaction conditions are mild; the catalyst used is cheap and easy to obtain; it is very easy to realize large-scale industrial production. (2) Background technology [0002] Hydrogen bromide is a natural alkaloid of quinazolones obtained from a plant Changshan (Dichroa fabrifuga), which is a new type of broad-spectrum anticoccidial drug (Zhang, De-Fu, et al.Parasitology Research, 2012, 111(2), 695-701; Li Anxing, postdoctoral research report of Sun Yat-sen University; Guler Yavas, et al. Medicine, 2009, 91, 73-84.), treatment of chronic graft fibrosis-versus-host dis...

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Problems solved by technology

[0012] In addition, Ogasawara, K et al. (Ogasawara, K Or g Lett, 2000, 2(20), 3193-3195.), Li Shuoliang, Zang Shengli. (Research on the synthesis of hemosanone intermediates [D]. Lanzhou: Lanzhou University. 2003. ), CN1583729A, JP2000007673A and other synthetic methods mostly have low total yields, which affect the final yield and are not easy for industrialization

[0013] In a word, according to the current literature and patents, some special conditions are often required in the preparation process of ruthenone hydrobromide, such as high temperature, high pressure, or anhydrous and oxygen-free conditions, which not only increases equipment cost, energy consumption, but also increases safety hazards, and finally increased the difficulty of industrialization

At the same time, some of the raw and auxiliary materials used in the synthetic route are more expensive, the synthetic route is longer and the cost is higher

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