阅读说明：本技术 一种利福布汀中间体的制备方法 (Preparation method of rifabutin intermediate ) 是由 王羽 房忠雪 陈运 付禅 于 2020-12-04 设计创作，主要内容包括：本发明涉及中间体制备技术领域,尤其涉及一种利福布汀中间体的制备方法,由以下质量份的原料制成：溴酸钾10～15份、溴化钾10～15份、95％乙醇8～12份、利福霉素S 9～13份、吡啶/乙醇溶液10～15份、二氯甲烷9～15份、氯化钠5～12份和水45～60份；上述原料制备中间体的过程包括以下步骤：S1、将溴酸钾和溴化钾加入水中,搅拌令其完全溶解,得溴液；S2、将利福霉素S溶解于95％乙醇中,加入吡啶/乙醇溶液,搅拌混匀；S3、向S2的溶液中加入溴液,反应1～2小时后得反应液。本发明不仅能够方便地获取制备原料,无腐蚀性,易保存,而且还能有效地缓解二氯甲烷在萃取时过度乳化的现象。(The invention relates to the technical field of intermediate preparation, in particular to a preparation method of a rifabutin intermediate, which is prepared from the following raw materials in parts by mass: 10-15 parts of potassium bromate, 10-15 parts of potassium bromide, 8-12 parts of 95% ethanol, 9-13 parts of rifamycin S, 10-15 parts of pyridine/ethanol solution, 9-15 parts of dichloromethane, 5-12 parts of sodium chloride and 45-60 parts of water; the process for preparing the intermediate by the raw materials comprises the following steps: s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid; s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly; and S3, adding bromine liquid into the solution of S2, and reacting for 1-2 hours to obtain a reaction liquid. The method can conveniently obtain the preparation raw materials, has no corrosivity, is easy to store, and can effectively relieve the phenomenon of excessive emulsification of the dichloromethane during extraction.)

1. The preparation method of the rifabutin intermediate is characterized by comprising the following raw materials in parts by mass: 10-15 parts of potassium bromate, 10-15 parts of potassium bromide, 8-12 parts of 95% ethanol, 9-13 parts of rifamycin S, 10-15 parts of pyridine/ethanol solution, 9-15 parts of dichloromethane, 5-12 parts of sodium chloride and 45-60 parts of water;

the process for preparing the intermediate by the raw materials comprises the following steps:

s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid;

s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly;

s3, adding bromine liquid into the solution of S2, and reacting for 1-2 hours to obtain a reaction liquid;

and S4, adding dichloromethane and sodium chloride into the reaction solution for extraction, washing the extract with water, cooling for crystallization, and drying to obtain the intermediate.

Wherein the intermediate is 3-bromorifamycin S.

2. The method of claim 1, wherein the molar ratio of potassium bromate to potassium bromide is 1: 8.

3. The method for preparing a rifabutin intermediate as claimed in claim 1, wherein the reaction temperature of the reaction solution in the S3 is-10 ℃ to 0 ℃.

4. The preparation method of rifabutin intermediate as claimed in claim 1, wherein the mass ratio of dichloromethane to sodium chloride added in S4 is 1: (0.6-0.8).

5. The preparation method of rifabutin intermediate as claimed in claim 1, wherein the temperature for cooling and crystallization in S4 is-5 ℃ to 10 ℃.

6. The preparation method of rifabutin intermediate as claimed in claim 1, wherein the cooling crystallization time in S4 is 2-3 hours.

Technical Field

The invention relates to the technical field of intermediate preparation, in particular to a preparation method of a rifabutin intermediate.

Background

3-bromorifamycin S is an intermediate in the synthesis of rifabutin. Rifabutin, chemical name is 4-N-isobutyl spiropiperidine rifamycin S, is a rifamycin derivative containing spiropiperazinyl, and has broad-spectrum antibacterial activity.

As for the synthesis method of 3-bromorifamycin S, the synthesis process of 3-bromorifamycin S by reacting bromine with rifamycin is mentioned in the "improvement of synthesis process of rifabutin" by Yexiang, Zhongjing, et al, and the reaction process is as follows: dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, adding bromine at the temperature of below 0 ℃ for reaction for 1 hour, extracting the reaction liquid by using dichloromethane, washing with water, drying by using anhydrous sodium sulfate, and concentrating to obtain the rifamycin S, wherein the raw material bromine is a chemical which is easy to produce toxins and explode, belongs to a controlled raw material and is not easy to obtain, and the dichloromethane is easy to have a serious emulsification phenomenon in the extraction process. Therefore, we propose a preparation method of rifabutin intermediate for solving the above problems.

Disclosure of Invention

The invention aims to solve the defects in the prior art and provides a preparation method of a rifabutin intermediate.

A preparation method of a rifabutin intermediate is prepared from the following raw materials in parts by mass: 10-15 parts of potassium bromate, 10-15 parts of potassium bromide, 8-12 parts of 95% ethanol, 9-13 parts of rifamycin S, 10-15 parts of pyridine/ethanol solution, 9-15 parts of dichloromethane, 5-12 parts of sodium chloride and 45-60 parts of water;

the process for preparing the intermediate by the raw materials comprises the following steps:

s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid;

s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly;

s3, adding bromine liquid into the solution of S2, and reacting for 1-2 hours to obtain a reaction liquid;

and S4, adding dichloromethane and sodium chloride into the reaction solution for extraction, washing the extract with water, cooling for crystallization, and drying to obtain the intermediate.

Wherein the intermediate is 3-bromorifamycin S.

Preferably, the molar ratio of the potassium bromate to the potassium bromide is 1: 8.

Preferably, the reaction temperature of the reaction solution in S3 is-10 ℃ to 0 ℃.

Preferably, the mass ratio of the dichloromethane to the sodium chloride added in the S4 is 1: (0.6-0.8).

Preferably, the temperature for cooling and crystallizing in the S4 is-5 ℃ to 10 ℃.

Preferably, the time for cooling and crystallizing in the S4 is 2-3 hours.

The invention has the beneficial effects that:

1. the method selects potassium bromate and potassium bromide as raw materials for preparation, has no corrosivity and is easy to store, compared with bromine, the raw materials of the method are easy to obtain, the difficulty in transportation and storage is avoided, and the preparation of the intermediate 3-bromorifamycin S is facilitated.

2. According to the invention, sodium chloride is additionally added in the extraction process and is matched with dichloromethane for extraction, so that the phenomenon of excessive emulsification of dichloromethane during extraction can be effectively relieved, and the extraction effect is improved.

In conclusion, the method can conveniently obtain the preparation raw materials, has no corrosivity and is easy to store, and can effectively relieve the phenomenon of excessive emulsification of the dichloromethane during extraction.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples.

A preparation method of a rifabutin intermediate is prepared from the following raw materials in parts by mass: 10-15 parts of potassium bromate, 10-15 parts of potassium bromide, 8-12 parts of 95% ethanol, 9-13 parts of rifamycin S, 10-15 parts of pyridine/ethanol solution, 9-15 parts of dichloromethane, 5-12 parts of sodium chloride and 45-60 parts of water;

the process for preparing the intermediate by the raw materials comprises the following steps:

s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid;

s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly;

s3, adding bromine solution into the solution of S2, and reacting at 0 ℃ for 1 hour to obtain a reaction solution;

s4, adding dichloromethane and sodium chloride into the reaction solution for extraction, washing the extract with water, cooling at-5 ℃ for crystallization for 2 hours, and drying to obtain the intermediate.

Wherein the intermediate is 3-bromorifamycin S, and the molar ratio of potassium bromate to potassium bromide is 1: 8; the mass ratio of the dichloromethane to the sodium chloride added in the S4 is 1: 0.6.

example (b):

in each of the first to third examples, the same formulation was used to prepare the intermediate, 3-bromorifamycin S, and the amounts of the formulation used in each example are shown in the following table:

the process for preparing the intermediate 3-bromorifamycin S from the above raw materials is as follows:

s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid;

s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly;

s3, adding bromine solution into the solution of S2, and reacting at 0 ℃ for 1 hour to obtain a reaction solution;

s4, adding dichloromethane and sodium chloride into the reaction solution for extraction, washing the extract with water, cooling at-5 ℃ for crystallization for 2 hours, and drying to obtain the intermediate.

Comparative example (without sodium chloride):

in comparative examples one to three, the same formulation was used to prepare the intermediate, 3-bromorifamycin S, and the amounts of formulation used in each comparative example are shown in the following table:

the process for preparing the intermediate 3-bromorifamycin S from the above raw materials is as follows:

s1, adding potassium bromate and potassium bromide into water, and stirring to completely dissolve the potassium bromate and the potassium bromide to obtain bromine liquid;

s2, dissolving rifamycin S in 95% ethanol, adding pyridine/ethanol solution, and stirring and mixing uniformly;

s3, adding bromine solution into the solution of S2, and reacting at 0 ℃ for 1 hour to obtain a reaction solution;

s4, adding dichloromethane into the reaction liquid for extraction, washing the extract with water, cooling at-5 ℃ for crystallization for 2 hours, and drying to obtain the intermediate.

And (3) testing:

three test groups were designed, and the extraction processes in the examples and comparative examples were observed, respectively, and the emulsification of the upper layer liquid thereof was observed and recorded in the following table:

note: in the above table, "√" indicates that the component is added, and "×" indicates that the component is not added

From the data in the table above, it can be found that no obvious emulsification occurs in the extraction process in the examples, while in the comparative examples, no sodium chloride is added, and no obvious emulsification occurs in the supernatant, so that the sodium chloride is added in the extraction process, which can effectively alleviate the emulsification of the extraction solution.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.