阅读说明：本技术 一种磷酸奥司他韦中间体杂质化合物及其制备方法和用途 (Oseltamivir phosphate intermediate impurity compound and preparation method and application thereof ) 是由 杨其龙 杨寿海 陈嘉伟 王刚 于 2021-09-30 设计创作，主要内容包括：本发明公开了一种磷酸奥司他韦中间体杂质化合物及其制备方法和用途,该化合物为(3R,4R,5S)-4-(叔丁基氨基)-5-羟基-3-(戊烷-3-基氧基)环己-1-烯-1-羧酸乙酯,结构如式I。本发明提供的制备方法反应条件温和,后处理简单,可以规模化制备出纯度符合要求的式Ⅰ化合物,以作为磷酸奥司他韦的中间体质量研究的杂质对照品。在磷酸奥司他韦中间体的杂质研究中应控制化合物I含量不高于2％,这对磷酸奥司他韦的中间体工业化生产具有重要的质量监控意义。(The invention discloses an oseltamivir phosphate intermediate impurity compound and a preparation method and application thereof, wherein the compound is (3R, 4R, 5S) -4- (tert-butylamino) -5-hydroxy-3- (pentane-3-yloxy) cyclohex-1-ene-1-carboxylic acid ethyl ester, and the structure of the compound is shown as a formula I. The preparation method provided by the invention has mild reaction conditions and simple post-treatment, and can be used for preparing the compound of the formula I with purity meeting the requirement in a large scale, and the compound can be used as an impurity reference substance for quality research of an oseltamivir phosphate intermediate. In the research on impurities of the oseltamivir phosphate intermediate, the content of the compound I is controlled to be not higher than 2%, which has important quality monitoring significance for the industrial production of the oseltamivir phosphate intermediate.)

1. An oseltamivir phosphate intermediate impurity compound is characterized in that the structure is shown as formula I:

2. the preparation method of the oseltamivir phosphate intermediate impurity compound as claimed in claim 1, which is characterized by comprising the following steps:

the specific operation steps are as follows:

and reacting the compound II in an organic solvent under the catalysis of acid to obtain an oseltamivir phosphate intermediate impurity compound I.

3. The method for preparing the oseltamivir phosphate intermediate impurity compound according to claim 2, wherein the acid is benzenesulfonic acid or zinc chloride.

4. The method for preparing the oseltamivir phosphate intermediate impurity compound according to claim 2, wherein the organic solvent is dichloromethane or toluene.

5. The use of the oseltamivir phosphate intermediate impurity compound of claim 1 as an oseltamivir phosphate intermediate impurity standard or reference.

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an oseltamivir phosphate intermediate impurity and a preparation method and application thereof.

Background

Oseltamivir phosphate (trade name: tamiflu), which is a neuraminidase inhibitor, competitively binds to the active site of influenza virus neuraminidase, reduces the spread of influenza a and b by interfering with the release of the virus from infected host cells, and is widely used for the prevention and treatment of influenza a and b.

The compound III is an important intermediate for preparing oseltamivir phosphate, and has the following structure:

original Research documents Organic Process Research & Development 1999,3,266274 and Organic Process Research & Development 2004,8,86-91 report processes for preparing compound iii from shikimic acid as starting material and oseltamivir phosphate from compound iii, but in the preparation of compound iii, impurity i with a structure similar to that shown below is generated:

so far, no report is made on identification and removal of the impurity, and since the compound III is a key intermediate in the preparation process of oseltamivir phosphate and is important to carry out quality research and impurity control, the intermediate impurity compound I needs to be researched for structure confirmation, separation, purification and the like, and the content of the compound I is further controlled.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide an oseltamivir phosphate intermediate impurity, and a preparation method and application thereof.

The technical scheme is as follows: the oseltamivir phosphate intermediate impurity compound has a structure shown in a formula I:

further, the preparation method of the oseltamivir phosphate intermediate impurity compound comprises the following preparation route:

the specific operation steps are as follows:

and reacting the compound II in an organic solvent under the catalysis of acid to obtain an oseltamivir phosphate intermediate impurity compound I.

Further, the acid is benzenesulfonic acid or zinc chloride, preferably zinc chloride.

Further, the organic solvent is dichloromethane or toluene, preferably toluene.

Further, the application of the oseltamivir phosphate intermediate impurity compound as an oseltamivir phosphate intermediate impurity standard substance or a reference substance.

Has the advantages that: compared with the prior art, the invention researches the oseltamivir phosphate key intermediate impurity, and the impurity prepared by the method is used as an impurity reference substance in the oseltamivir phosphate key intermediate quality research; the content of the impurities in the oseltamivir phosphate key intermediate III is controlled to be not higher than 2%, and the method has important quality monitoring significance for industrial production of the oseltamivir phosphate intermediate.

Drawings

FIG. 1 is an HPLC chromatogram of compound I, with a retention time of 11.6min for compound I;

FIG. 2 is an MS spectrum of compound I;

FIG. 3 is a carbon spectrum of Compound I: (¹³C NMR)；

FIG. 4 shows the hydrogen spectrum of Compound I: (¹H NMR)；

FIG. 5 is an HPLC chromatogram of compound I in compound III, with retention time 10.08 for compound III and retention time 11.6min for compound I.

Detailed Description

The invention is further described with reference to the following drawings and specific embodiments; in the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application, but the present application may be practiced in many ways different from those described herein, and similar modifications may be made by those skilled in the art without departing from the spirit of the present application, and the present application is therefore not limited to the specific implementations disclosed below.

The oseltamivir phosphate intermediate impurity compound has a structure shown in a formula I:

further, an oseltamivir phosphate intermediate impurity compound is prepared by the following route:

the specific operation steps are as follows:

and reacting the compound II in an organic solvent under the catalysis of acid to obtain an oseltamivir phosphate intermediate impurity compound I.

Further, the acid is benzenesulfonic acid or zinc chloride, preferably zinc chloride.

Further, the organic solvent is dichloromethane or toluene, preferably toluene.

Further, the application of the oseltamivir phosphate intermediate impurity compound as an oseltamivir phosphate intermediate impurity standard substance or a reference substance.

Example 1

50g of compound II, 22g of zinc chloride, 200ml of toluene and 14g of water are added into a reaction bottle, the temperature is increased to 90 ℃ for reaction for 3 hours, TLC monitors that no raw material is left, the temperature is reduced to room temperature, the solid is removed by filtration, the water phase of mother liquor is separated, the organic phase is concentrated to obtain 51g of crude compound I, and the yield is 96%.

20g of compound I was purified by 30% ethyl acetate/n-heptane column chromatography to give 13g of pure compound I in 65% yield and 99.19% purity.

The HPLC spectrum of the compound of formula I is shown in figure 1; the MS spectrum of the compound of the formula I is shown in figure 2; the carbon spectrum of the compound of formula I is shown in figure 3; the hydrogen spectrum of the compound of formula I is shown in FIG. 4.

Example 2

Adding 20g of compound II, 10.2g of benzenesulfonic acid, 80ml of toluene and 5.6g of water into a reaction bottle, carrying out reflux reaction for 3 hours, monitoring no residual raw material by TLC, cooling to room temperature, adding 10% NaOH aqueous solution to adjust the pH to 8-9, separating out an aqueous phase, and carrying out spin drying on an organic phase to obtain 17g of crude compound I, wherein the yield is 85%;

dissolving 5g of crude compound I in 5ml of methanol, refining and separating by using a prepared liquid phase, wherein a mobile phase is acetonitrile-water, gradient elution is carried out by 10-100%, product fractions are collected, and 3.71g of pure compound I is obtained by decompression and concentration, the yield is 74%, and the purity is 98.13%.

Example 3

Adding 5g of compound II, 2.2g of zinc chloride, 20ml of dichloromethane and 1.5g of water into a reaction bottle, heating to 40 ℃ for reaction for 3 hours, monitoring by TLC (thin layer chromatography), wherein no raw material remains, cooling to room temperature, filtering to remove solids, leaching a filter cake by using 20ml of dichloromethane, separating a mother solution to obtain an aqueous phase, and concentrating an organic phase to obtain 4.7g of a crude product of the compound I, wherein the yield is 88%;

4.7g of crude compound I were purified by 30% ethyl acetate/n-heptane column chromatography to give 2.4g of pure compound I in 52% yield and 92.16% purity.

The above description of the embodiments is only intended to facilitate the understanding of the core ideas of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.