阅读说明：本技术 一种索氟布韦中间体杂质的合成方法 (Synthetic method of sofosbuvir intermediate impurity ) 是由 倪润炎 徐剑锋 曾淼 丁亭玉 程晓文 于 2020-08-03 设计创作，主要内容包括：本发明公开了一种索氟布韦中间体杂质的合成方法,它包括以下步骤：(a)使第一化合物的端羟基接上第一保护基团得第一中间体；(b)使第一中间体的环羟基接上苯甲酰基得第二中间体；(c)脱去所述第二中间体上的第一保护基团即得索氟布韦中间体杂质。通过制备特殊结构的第一中间体和第二中间体,进而制备特定结构且高纯度的索氟布韦中间体杂质,可以用于最终索氟布韦杂质的分析以评价药物索氟布韦的纯度。(The invention discloses a method for synthesizing sofosbuvir intermediate impurities, which comprises the following steps: (a) grafting a terminal hydroxyl group of the first compound with a first protective group to obtain a first intermediate; (b) attaching benzoyl to the cyclic hydroxyl of the first intermediate to obtain a second intermediate; (c) and removing the first protective group on the second intermediate to obtain the sofosbuvir intermediate impurity. The first intermediate and the second intermediate with special structures are prepared, so that the sofosbuvir intermediate impurity with a specific structure and high purity is prepared, and the sofosbuvir intermediate impurity can be used for analyzing the final sofosbuvir impurity to evaluate the purity of the medicine sofosbuvir.)

1. A synthetic method of sofosbuvir intermediate impurities is characterized by comprising the following steps:

(a) the terminal hydroxyl of a first compound is grafted with a first protective group to obtain a first intermediate, and the general chemical structure formula of the first compound is

(b) Attaching benzoyl to the cyclic hydroxyl of the first intermediate to obtain a second intermediate;

(c) removing the first protective group on the second intermediate to obtain the sofosbuvir intermediate impurity, wherein the chemical structural general formula of the sofosbuvir intermediate impurity isAnd in the formula, Bz is benzoyl.

2. The method for synthesizing the sofosbuvir intermediate impurity according to claim 1, characterized in that: in the step (a), the first protecting group is tert-butyl dimethyl silicon group.

3. The method for synthesizing the sofosbuvir intermediate impurity according to claim 2, wherein the step (a) comprises the following steps:

(a1) adding the first compound into a mixed solvent of dichloromethane and pyridine, respectively adding imidazole and tert-butyldimethylsilyl chloride under an ice bath condition, naturally heating to room temperature, and reacting overnight to obtain a first mixture;

(a2) and washing the first mixture with HCl, saturated sodium bicarbonate and saturated saline in sequence, drying, concentrating, and performing column chromatography to obtain a white first intermediate.

4. The method for synthesizing the sofosbuvir intermediate impurity according to claim 3, which is characterized in that: in step (a1), the molar ratio of the first compound to pyridine to imidazole to tert-butyldimethylsilyl chloride is 1: 2-3: 1.5-2: 1.5 to 2.

5. The method for synthesizing sofosbuvir intermediate impurities according to claim 3 or 4, characterized in that: in step (a2), the eluent used for column chromatography is petroleum ether and ethyl acetate in a volume ratio of 5: 1.

6. The method for synthesizing the sofosbuvir intermediate impurity according to claim 3, wherein the step (b) comprises the following steps:

(b1) dissolving the first intermediate in dichloromethane, sequentially adding triethylamine and 4-dimethylaminopyridine, dropwise adding benzoyl chloride under an ice bath condition, and moving to room temperature for reaction to obtain a second mixture;

(b2) and adding saturated sodium bicarbonate into the second mixture for quenching, washing with water, drying, concentrating, and performing column chromatography to obtain a white second intermediate.

7. The method for synthesizing the sofosbuvir intermediate impurity according to claim 6, which is characterized in that: in the step (b1), the molar ratio of the first intermediate, triethylamine and benzoyl chloride is 1: 1-1.2: 1.

8. the method for synthesizing sofosbuvir intermediate impurities according to claim 6 or 7, characterized in that: in step (b2), the eluent used for column chromatography is petroleum ether and ethyl acetate in a volume ratio of 50: 1.

9. The method for synthesizing sofosbuvir intermediate impurities as claimed in claim 6, wherein the step (c) comprises the steps of:

(c1) dissolving the second intermediate in tetrahydrofuran, and dropwise adding tetrabutylammonium fluoride trihydrate under an ice bath condition to perform heat preservation reaction for 1.5-2.5 h to obtain a reaction solution; the molar ratio of the second intermediate to tetrabutylammonium fluoride trihydrate is 1: 2;

(c2) pouring the reaction solution into a saturated sodium bicarbonate solution, controlling the temperature within 10 ℃, extracting with dichloromethane, washing an organic phase with water, drying, concentrating, and performing column chromatography; the eluent used for column chromatography is petroleum ether and ethyl acetate with the volume ratio of 2: 1.

10. The method for synthesizing the sofosbuvir intermediate impurity according to claim 9, characterized in that: in the step (c1), the aqueous phase obtained in the step (c2) is further added to the reaction mixture to continue the reaction.

Technical Field

The invention belongs to the field of organic synthesis, relates to a synthetic method of organic drug impurities, and particularly relates to a synthetic method of sofosbuvir intermediate impurities.

Background

The impurities of the medicine refer to substances which have no treatment effect or influence the stability and the curative effect of the medicine and are even harmful to the health of human bodies. In the aspects of research, production, storage, clinical application and the like of the medicine, the purity of the medicine must be maintained, and the impurities of the medicine are reduced, so that the effectiveness and the safety of the medicine can be ensured. The purity of a drug can be generally evaluated by integrating the structure, appearance, physicochemical constants, impurity inspection, content measurement, and the like of the drug into a whole.

Impurities contained in the medicine are main factors influencing the purity of the medicine, and if the medicine contains more than limited amount of impurities, the physicochemical constants can be changed, the appearance character can be changed, and the stability of the medicine can be influenced; the increase of impurities also inevitably causes the content of the medicine to be lower or the activity to be reduced, and the toxic and side effects are obviously increased.

Impurities are not only present in the final drug but may also be present in the respective intermediates in the synthesis of the drug. It is therefore necessary to have a thorough and thorough study of the impurities of the drug, which requires the synthesis of high purity intermediate impurities.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthetic method of a sofosbuvir intermediate impurity.

The invention aims to provide a method for synthesizing sofosbuvir intermediate impurities, which comprises the following steps:

(a) the terminal hydroxyl of a first compound is grafted with a first protective group to obtain a first intermediate, and the general chemical structure formula of the first compound is

(b) Attaching benzoyl to the cyclic hydroxyl of the first intermediate to obtain a second intermediate;

(c) removing the first protective group on the second intermediate to obtain the sofosbuvir intermediate impurity, wherein the chemical structural general formula of the sofosbuvir intermediate impurity isAnd in the formula, Bz is benzoyl.

Preferably, in step (a), the first protecting group is tert-butyldimethylsilyl.

Further, the step (a) includes the steps of:

(a1) adding the first compound into a mixed solvent of dichloromethane and pyridine, respectively adding imidazole and tert-butyldimethylsilyl chloride under an ice bath condition, naturally heating to room temperature, and reacting overnight to obtain a first mixture;

(a2) and washing the first mixture with HCl, saturated sodium bicarbonate and saturated saline in sequence, drying, concentrating, and performing column chromatography to obtain a white first intermediate.

Further, in the step (a1), the molar ratio of the first compound to the pyridine to the imidazole to the tert-butyldimethylsilyl chloride is 1: 2-3: 1.5-2: 1.5 to 2.

Specifically, in the step (a2), the eluent used for column chromatography is petroleum ether and ethyl acetate in a volume ratio of 5: 1.

Further, the step (b) comprises the steps of:

(b1) dissolving the first intermediate in dichloromethane, sequentially adding triethylamine and 4-dimethylaminopyridine, dropwise adding benzoyl chloride under an ice bath condition, and moving to room temperature for reaction to obtain a second mixture;

(b2) and adding saturated sodium bicarbonate into the second mixture for quenching, washing with water, drying, concentrating, and performing column chromatography to obtain a white second intermediate.

Further, in step (b1), the molar ratio of the first intermediate, triethylamine and benzoyl chloride is 1: 1-1.2: 1.

further, in the step (b2), the eluent used for the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 50: 1.

Still further, step (c) comprises the steps of:

(c1) dissolving the second intermediate in tetrahydrofuran, and dropwise adding tetrabutylammonium fluoride trihydrate under an ice bath condition to perform heat preservation reaction for 1.5-2.5 h to obtain a reaction solution; the molar ratio of the second intermediate to tetrabutylammonium fluoride trihydrate is 1: 2;

(c2) pouring the reaction solution into a saturated sodium bicarbonate solution, controlling the temperature within 10 ℃, extracting with dichloromethane, washing an organic phase with water, drying, concentrating, and performing column chromatography; the eluent used for column chromatography is petroleum ether and ethyl acetate with the volume ratio of 2: 1.

Further, in the step (c1), the aqueous phase obtained in the step (c2) is further added to the reaction mixture to continue the reaction.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: according to the synthetic method of the sofosbuvir intermediate impurity, the first intermediate and the second intermediate with special structures are prepared, so that the sofosbuvir intermediate impurity with a specific structure and high purity is prepared, and the method can be used for analyzing the sofosbuvir impurity finally to evaluate the purity of the medicine sofosbuvir.

Drawings

FIG. 1 is a process flow diagram of the synthetic method of the sofosbuvir intermediate impurity of the present invention;

FIG. 2 is a nuclear magnetic spectrum of a first intermediate in the synthetic method of sofosbuvir intermediate impurities of the present invention;

FIG. 3 is a nuclear magnetic spectrum of a second intermediate in the method for synthesizing sofosbuvir intermediate impurities;

fig. 4 is a nuclear magnetic spectrum of the sofosbuvir intermediate impurity in the synthetic method of the sofosbuvir intermediate impurity.

Detailed Description

The invention relates to a synthetic method of sofosbuvir intermediate impurities, which comprises the following steps: (a) the terminal hydroxyl of a first compound is grafted with a first protective group to obtain a first intermediate, and the general chemical structure formula of the first compound is

(b) Attaching benzoyl to the cyclic hydroxyl of the first intermediate to obtain a second intermediate; (c) removing the first protective group on the second intermediate to obtain the sofosbuvir intermediate impurity, wherein the chemical structural general formula of the sofosbuvir intermediate impurity is

And in the formula, Bz is benzoyl. The first intermediate and the second intermediate with special structures are prepared, so that the sofosbuvir intermediate impurity with a specific structure and high purity is prepared, and the sofosbuvir intermediate impurity can be used for analyzing and contrasting the final sofosbuvir intermediate impurity to evaluate the purity of the medicine sofosbuvir.

In the step (a), the first protecting group is tert-butyl dimethyl silicon group. Step (a) preferably comprises the steps of: (a1) adding the first compound into a mixed solvent of dichloromethane and pyridine, respectively adding imidazole and tert-butyldimethylsilyl chloride under an ice bath condition, naturally heating to room temperature, and reacting overnight to obtain a first mixture; (a2) washing the first mixture with HCl, saturated sodium bicarbonate and saturated saline solution in sequence, drying, concentrating, and performing column chromatography to obtain a white first intermediate; in step (a1), the molar ratio of the first compound, pyridine, imidazole, and tert-butyldimethylsilyl chloride is preferably 1: 2-3: 1.5-2: 1.5-2; in the step (a2), the eluent adopted by the column chromatography is preferably petroleum ether and ethyl acetate in a volume ratio of 5: 1; is beneficial to improving the yield and the purity of the first intermediate.

Step (b) preferably comprises the steps of: (b1) dissolving the first intermediate in dichloromethane, sequentially adding triethylamine and 4-dimethylaminopyridine, dropwise adding benzoyl chloride under an ice bath condition, and moving to room temperature for reaction to obtain a second mixture; (b2) adding saturated sodium bicarbonate into the second mixture for quenching, washing with water, drying, concentrating, and performing column chromatography to obtain a white second intermediate; in step (b1), the molar ratio of the first intermediate, triethylamine and benzoyl chloride is preferably 1: 1-1.2: 1; in step (b2), the eluent used for column chromatography is petroleum ether and ethyl acetate with the preferred volume ratio of 50: 1; is beneficial to improving the yield and the purity of the second intermediate.

Step (c) preferably comprises the steps of: (c1) dissolving the second intermediate in tetrahydrofuran, and dropwise adding tetrabutylammonium fluoride trihydrate under an ice bath condition to perform heat preservation reaction for 1.5-2.5 h to obtain a reaction solution; the molar ratio of the second intermediate to tetrabutylammonium fluoride trihydrate is 1: 2; (c2) pouring the reaction solution into a saturated sodium bicarbonate solution, controlling the temperature within 10 ℃, extracting with dichloromethane, washing an organic phase with water, drying, concentrating, and performing column chromatography; the eluent adopted by column chromatography is petroleum ether and ethyl acetate with the volume ratio of 2: 1; in the step (c1), adding the aqueous phase obtained in the step (c2) into the reaction solution to continue the reaction; to improve the yield and purity of the final product

The following provides a detailed description of preferred embodiments of the invention.