阅读说明：本技术 一种氧代乙胺化合物的纯化方法 (Method for purifying oxoethylamine compound ) 是由 曾洁滨 寇景平 王仲清 陈永好 周自洪 巫锡伟 王二龙 黄芳芳 罗忠华 袁希 丘 于 2020-02-12 设计创作，主要内容包括：本发明提供了一种氧代乙胺化合物的纯化方法,属于医药化工领域；本发明所述方法通过将氧代乙胺化合物,经过成盐、萃取、游离、再萃取得到高纯度的该化合物。该方法生产得到的产物纯度高,收率高,成本低,操作简单,工艺稳定的特点。(The invention provides a method for purifying an oxoethylamine compound, belonging to the field of pharmaceutical chemicals; the method of the invention obtains the compound with high purity by salifying, extracting, dissociating and re-extracting the oxoethylamine compound. The method has the advantages of high product purity, high yield, low cost, simple operation, and stable process.)

1. A method for purifying compound C, comprising the steps of:

(1) mixing the dichloromethane solution of the compound C with acid, and stirring;

(2) adding seed crystals into the step (1), stirring at controlled temperature, separating out solids, and filtering to obtain a filter cake;

(3) dissolving the filter cake obtained in the step (2) with water, mixing with an alkali water solution, and stirring at room temperature;

(4) adding dichloromethane into the step (3), extracting, combining organic phases, and removing the solvent to obtain a compound C; the structural formula of compound C is shown below:

2. the method of claim 1, wherein the temperature controlled stirring in step (2) is at a temperature of-20 ℃ to 20 ℃.

3. The method of claim 1, wherein the acid in step (1) is at least one of acetic acid, formic acid, propionic acid, benzoic acid, oxalic acid, phosphoric acid, citric acid, or tartaric acid.

4. The method of claim 1, wherein the seed crystals in step (2) are seed crystals of a salt of compound C with an acid.

5. The method according to claim 1, wherein the mass ratio of the seed crystal to the compound C in the step (2) is 0.5% to 5.0%.

6. The method of claim 1, wherein the base in step (3) is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide, or sodium methoxide.

7. A process for the preparation of a solution of compound C in dichloromethane according to the process of any one of claims 1 to 6, characterized in that it comprises the following steps:

a) mixing an alkaline reagent and ethanolamine, and heating;

b) adding 2-chloroacetaldehyde dimethyl acetal into the step a), and continuously stirring for reaction;

c) after the reaction, water was added and extracted with dichloromethane to obtain a dichloromethane solution of compound C.

8. The process of claim 7, wherein the basic agent in step a) is potassium hydroxide, or at least one of sodium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, lithium hydroxide or sodium hydride.

9. The method of claim 7, wherein the elevated temperature in step a) is from 80 ℃ to 150 ℃.

10. The method of any one of claims 1 to 6, comprising the steps of:

mixing potassium hydroxide and ethanolamine, heating to 80-150 ℃, adding 2-chloroacetaldehyde dimethyl acetal, and continuing stirring for reaction; after the reaction is finished, adding water, and extracting with dichloromethane to obtain a dichloromethane solution of a compound C; mixing the obtained dichloromethane solution of the compound C with acid, and stirring; adding crystal seeds of salt formed by the compound C and acid, stirring at controlled temperature, separating out solid, and filtering to obtain a filter cake; dissolving the obtained filter cake in water, mixing with an alkali water solution, and stirring at room temperature; adding dichloromethane, extracting, combining organic phases, and removing the solvent to obtain a compound C; wherein, the acid is at least one of acetic acid, propionic acid, citric acid, oxalic acid and phosphoric acid, and the alkali is at least one of sodium hydroxide and sodium ethoxide.

Technical Field

The invention relates to the field of pharmaceutical chemicals, and in particular relates to a method for purifying an oxoethylamine compound.

Background

Xofluza (BaloxavirMarvoxil) is an innovative Cap-dependent endonuclease inhibitor, is a small number of new drugs which can inhibit the proliferation of influenza virus in the world, is developed by Nippon salt wild pharmaceutical Co., Ltd, is subjected to accelerated approval, and is marketed in Japan. Xofluza can inhibit the CAP structure at the 5' end of host mRNA obtained from host cells aiming at the key link of influenza virus replication, thereby inhibiting the transcription of the self mRNA of the influenza virus. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell. In 2015, baloxavirmrvoxil was identified in japan as a pioneer (Sakigake) drug for preventing influenza a and b.

BaloxavirMarvoxil was first described in PCT patent WO2016175224 and has the following structural formula:

patent WO2017221869 discloses a preparation method of a fused cyclic compound, which is as follows:

intermediate compound C is present in this route, as shown in the formula:

the compound C is an essential intermediate for synthesizing a target product, and the purity of the compound C is greatly related to the subsequent reaction result; the method disclosed in the above prior art has the following disadvantages:

1. the compound C has good water solubility, water is added for treatment, the obtained tetrahydrofuran solution of the compound C is obtained, and a pure product cannot be separated;

2. compound D has a low purity due to the inability to isolate compound C;

3. since compound C could not be separated, compound E had a low conversion and was in a black mud state, resulting in difficulty in crystallization.

Therefore, in order to prepare and obtain the compound C with higher purity more efficiently and reduce the production cost, the invention provides a purification method of the compound C, and the method has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a method for purifying the compound C, which has the advantages of high product purity, high yield, low cost, simple operation and mild conditions.

According to one aspect of the present invention, there is provided a process for the preparation of compound C comprising the steps of:

a) mixing an alkaline reagent and ethanolamine, and heating;

b) adding 2-chloroacetaldehyde dimethyl acetal into the step a), and continuously stirring for reaction;

c) after the reaction, water was added and extracted with dichloromethane to obtain a dichloromethane solution of compound C.

According to some embodiments of the invention, the base reagent in step a) of the method for preparing intermediate compound C is at least one of potassium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, lithium hydroxide or sodium hydride.

According to some embodiments of the invention, the temperature of the intermediate compound C in step a) is between 80 ℃ and 150 ℃.

According to some embodiments of the invention, the reaction equation of the method for preparing intermediate compound C is as follows:

according to another aspect of the present invention, there is provided a method for purifying compound C, comprising the steps of:

(1) mixing the dichloromethane solution of the compound C with acid, and stirring;

(2) adding seed crystals into the step (1), stirring at controlled temperature, separating out solids, and filtering to obtain a filter cake;

(3) dissolving the filter cake obtained in the step (2) with water, mixing with an alkali water solution, and stirring at room temperature;

(4) adding dichloromethane into the step (3), extracting, combining organic phases, and removing the solvent to obtain a compound C.

According to some embodiments of the invention, in the method for purifying compound C, the acid in step (1) is at least one of acetic acid, formic acid, propionic acid, benzoic acid, oxalic acid, phosphoric acid, citric acid, or tartaric acid.

According to some embodiments of the present invention, in the method for purifying compound C, the seed crystal in step (2) is a seed crystal of a salt of compound C with the acid in step (1).

According to some embodiments of the present invention, in the method for purifying compound C, the temperature of the temperature-controlled stirring in step (2) is-20 ℃ to 20 ℃.

According to some embodiments of the present invention, in the method for purifying compound C, the mass ratio of the seed crystal to compound C in step (2) is 0.5% to 5.0%.

According to some embodiments of the present invention, in the method for purifying compound C, the base in step (3) is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide, or sodium methoxide.

In some embodiments, a method of purifying compound C as described above, comprises: mixing an alkaline reagent and ethanolamine, and heating; then adding 2-chloroacetaldehyde dimethyl acetal, and stirring for reaction; after the reaction is finished, adding water, and extracting with dichloromethane to obtain a dichloromethane solution of a compound C; mixing the obtained dichloromethane solution of the compound C with acid, and stirring; adding crystal seeds of salt formed by the compound C and acid, stirring at controlled temperature, separating out solid, and filtering to obtain a filter cake; dissolving the obtained filter cake in water, mixing with an alkali water solution, and stirring at room temperature; adding dichloromethane, extracting, combining organic phases, and removing the solvent to obtain a compound C; wherein the alkali reagent is at least one of potassium hydroxide, or sodium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-amylate, lithium hydroxide or sodium hydride; the alkali is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide or sodium methoxide, and the acid is at least one of acetic acid, formic acid, propionic acid, benzoic acid, oxalic acid, phosphoric acid, citric acid or tartaric acid.

In some embodiments, a method of purifying compound C as described above, comprises: mixing potassium hydroxide and ethanolamine, and heating to 80-150 deg.c; then adding 2-chloroacetaldehyde dimethyl acetal, and continuing stirring for reaction; after the reaction is finished, adding water, and extracting with dichloromethane to obtain a dichloromethane solution of a compound C; mixing the obtained dichloromethane solution of the compound C with acid, and stirring; adding crystal seeds of salt formed by the compound C and acid, stirring at controlled temperature, separating out solid, and filtering to obtain a filter cake; dissolving the obtained filter cake in water, mixing with an alkali water solution, and stirring at room temperature; adding dichloromethane, extracting, combining organic phases, and removing the solvent to obtain a compound C; wherein, the acid is at least one of acetic acid, propionic acid, citric acid, oxalic acid and phosphoric acid, and the alkali is at least one of sodium hydroxide and sodium ethoxide.

In some embodiments, a method of purifying compound C as described above, comprises: mixing potassium hydroxide and ethanolamine, and heating to 80-150 deg.c; then adding 2-chloroacetaldehyde dimethyl acetal, and continuing stirring for reaction; after the reaction is finished, adding water, and extracting with dichloromethane to obtain a dichloromethane solution of a compound C; mixing the obtained dichloromethane solution of the compound C with acetic acid, and stirring; adding crystal seeds of salt formed by the compound C and acetic acid, stirring at controlled temperature, separating out solid, and filtering to obtain a filter cake; dissolving the obtained filter cake with water, mixing with the aqueous solution of sodium hydroxide, and stirring at room temperature; dichloromethane was added, extraction was performed, organic phases were combined, and the solvent was removed to obtain compound C.

In some embodiments, a method of purifying compound C as described above, comprises: mixing potassium hydroxide and ethanolamine, and heating to 100 ℃; then adding 2-chloroacetaldehyde dimethyl acetal, and continuing stirring for reaction; after the reaction is finished, adding water, and extracting with dichloromethane to obtain a dichloromethane solution of a compound C; mixing the obtained dichloromethane solution of the compound C with acetic acid, and stirring; adding crystal seeds of salt formed by the compound C and acetic acid, stirring at controlled temperature, separating out solid, and filtering to obtain a filter cake; dissolving the obtained filter cake with water, mixing with the aqueous solution of sodium hydroxide, and stirring at room temperature; dichloromethane was added, extraction was performed, organic phases were combined, and the solvent was removed to obtain compound C.

Definition of terms

In this specification, "g" means g.

In the present specification, "room temperature" means 10 ℃ to 35 ℃.

Detailed Description

The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The conditions for measuring Mass Spectrometry (MS) data were: electrospray ionization (ESI).

Measurement conditions of H spectrum: 400MHz, deuterated DMSO.