阅读说明：本技术 一种吡啶溴酸盐合成方法 (Synthesis method of pyridine bromate ) 是由 王治义 刘茂波 张盼 于 2020-12-31 设计创作，主要内容包括：本发明提出了一种吡啶溴酸盐合成方法,所述合成方法包括以下步骤：(1)将48wt％的氢溴酸加入反应釜中,滴加管的出液口插入氢溴酸液面下,通过滴加管向氢溴酸内滴加吡啶进行反应,反应过程中保持温度≤55℃,反应结束后,调节pH为1.5-2.5,得到料液；(2)将步骤(1)中的料液在真空条件-0.0095～-0.085MPa下,进行60～70℃加热蒸发,开始出现结晶后,将料液送至结晶罐,降温结晶,然后离心得到固体析出物和母液；(3)将固体析出物采用纯水或甲醇进行洗涤,烘干得到吡啶溴酸盐,将母液加入活性炭脱色后,返回套用。本发明便于工业大批量合成,质量收率高,纯度高。(The invention provides a synthesis method of pyridine bromate, which comprises the following steps: (1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, keeping the temperature not more than 55 ℃ in the reaction process, and after the reaction is finished, adjusting the pH to be 1.5-2.5 to obtain a feed liquid; (2) heating and evaporating the feed liquid in the step (1) at 60-70 ℃ under the vacuum condition of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to occur, cooling and crystallizing, and then centrifuging to obtain solid precipitates and mother liquid; (3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, decolorizing the mother liquor with activated carbon, and returning for reuse. The invention is convenient for industrial mass synthesis, and has high quality yield and high purity.)

1. A method for synthesizing pyridine bromate is characterized by comprising the following steps:

(1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, keeping the temperature not more than 55 ℃ in the reaction process, and after the reaction is finished, adjusting the pH to be 1.5-2.5 to obtain a feed liquid;

(2) heating and evaporating the feed liquid in the step (1) at 60-70 ℃ under the vacuum condition of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to occur, cooling and crystallizing, and then centrifuging to obtain solid precipitates and mother liquid;

(3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, decolorizing the mother liquor with activated carbon, and returning for reuse.

2. The method for synthesizing pyridine bromate according to claim 1, wherein in the step (1), the molar ratio of hydrobromic acid to pyridine is 1: 1.02.

3. The method for synthesizing pyridine bromate according to claim 1, wherein in step (1), after the pyridine is added dropwise, all the mother liquor of the previous batch is added.

4. The method for synthesizing a pyridine bromate according to claim 1, wherein in the step (2), the temperature is reduced to below 20 ℃, and crystallization is performed.

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing pyridine bromate.

Background

Pyridine hydrobromide is a cephalosporin antibacterial drug such as ceftazidime, cefapirin and ceftazidime, namely a cephalosporin series drug, and is a strong acid weak base salt. The literature (wei army et al, research on synthesis of pyridine hydrobromide, Shandong chemical engineering, vol 46, 15, 2017, pp 35-36 and 38) discloses a research on synthesis of pyridine hydrobromide, which uses n (pyridine): n (hydrobromic acid) ═ 1.01: 1, the reaction temperature is less than 50 ℃, the end point pH value range is 3.0-3.5, the reaction is evaporated to 154 ℃ under normal pressure, the mixture is stirred, cooled and filtered, and then is stirred, washed and filtered by dichloromethane. The method has the advantages that the evaporation temperature of the filtrate under normal pressure is high, the evaporation time is long, the reaction of pyridine and hydrobromic acid is incomplete, the reaction speed is slow, and the production efficiency is reduced.

The 124 th page of the literature (Zhanying et al, research on pyridine hydrobromide, coal and chemical industry, 42 th 9 th of 2019, 42 nd page 125-156) indicates that the preparation process is only on a laboratory scale and has no practical production significance, and the literature also indicates that the pyridine hydrobromide is an important organic chemical intermediate and is widely applied to the field of pharmaceutical and chemical industry, but the research on the industrial synthesis process is rarely reported in the literature, and the related process research needs to be further carried out.

Disclosure of Invention

The invention provides a method for synthesizing pyridine bromate, which is convenient for industrial mass synthesis and has high quality yield and high purity.

The technical scheme of the invention is realized as follows: a method for synthesizing pyridine bromate comprises the following steps:

(1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, keeping the temperature not more than 55 ℃ in the reaction process, and after the reaction is finished, adjusting the pH to be 1.5-2.5 to obtain a feed liquid;

(2) heating and evaporating the feed liquid in the step (1) at 60-70 ℃ under the vacuum condition of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to occur, cooling and crystallizing, and then centrifuging to obtain solid precipitates and mother liquid;

(3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, decolorizing the mother liquor with activated carbon, and returning for reuse.

Further, in the step (1), the molar ratio of hydrobromic acid to pyridine is 1: 1.02.

Further, in the step (1), after the pyridine is completely added, the mother liquor of the previous batch is completely added.

Further, in the step (2), the temperature is reduced to 20 ℃ or lower, and crystallization is carried out.

The invention has the beneficial effects that:

according to the invention, pyridine is directly dripped in hydrobromic acid, so that the volatilization and waste of pyridine are reduced, the reaction time is shortened, the reaction temperature is reduced, the reaction temperature is kept to be less than or equal to 55 ℃, the volatilization and waste of pyridine caused by overhigh temperature are avoided, and the influence on quality and the reduction of production efficiency caused by overhigh temperature, overlow reaction speed are avoided.

The pH value is adjusted to be 1.5-2.5, the reaction is carried out more completely, and the excess of pyridine or hydrobromic acid is avoided; the feed liquid is heated and evaporated under the vacuum condition, the boiling point of water is reduced, and the evaporation time is shortened; the mother liquor is returned after decolorization, so that all materials can be recovered, the discharge of COD is reduced, and basically no loss is caused; purified water or methanol is adopted for washing, so that the purity is improved, and the color of the product is white.

The synthesis method of the invention is convenient for industrial mass synthesis, has high product yield, the quality yield reaches 200 percent, and pyridine is taken as a main material; the content of the pyridine bromate is more than or equal to 99 percent, the purity is high, the appearance is white crystal, and the quality is stable.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.

Example one

A method for synthesizing pyridine bromate comprises the following steps:

(1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, wherein the molar ratio of the hydrobromic acid to the pyridine is 1:1.02, keeping the temperature at 55 ℃ in the reaction process, and adjusting the pH to 1.5 after the reaction is finished to obtain a feed liquid;

(2) heating and evaporating the feed liquid in the step (1) at 60 ℃ under the vacuum condition of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to occur, cooling to below 20 ℃, crystallizing and separating out, and then centrifuging to obtain solid precipitate and mother liquid;

(3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, adding activated carbon into the mother liquor for decolorization, and returning the mother liquor to the reaction kettle for use in the preparation of the next batch of pyridine bromate.

The prepared pyridine bromate is white crystal, takes pyridine as a main material, and has the following mass yield: 200 percent and the product content is more than or equal to 99 percent.

Example two

A method for synthesizing pyridine bromate comprises the following steps:

(1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, wherein the molar ratio of the hydrobromic acid to the pyridine is 1:1.02, keeping the temperature at 53 ℃ in the reaction process, and after the reaction is finished, adjusting the pH to 2 to obtain a feed liquid;

(2) heating and evaporating the feed liquid in the step (1) at 65 ℃ under the vacuum condition and the pressure of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to appear, cooling to below 20 ℃, crystallizing and separating out, and then centrifuging to obtain solid precipitate and mother liquid;

(3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, adding activated carbon into the mother liquor for decolorization, and returning the mother liquor to the reaction kettle for use in the preparation of the next batch of pyridine bromate.

The prepared pyridine bromate is white crystal, takes pyridine as a main material, and has the following mass yield: 200 percent and the product content is more than or equal to 99 percent.

EXAMPLE III

A method for synthesizing pyridine bromate comprises the following steps:

(1) adding 48 wt% of hydrobromic acid into a reaction kettle, inserting a liquid outlet of a dropping pipe below the liquid level of the hydrobromic acid, dropping pyridine into the hydrobromic acid through the dropping pipe for reaction, wherein the molar ratio of the hydrobromic acid to the pyridine is 1:1.02, keeping the temperature at 50 ℃ in the reaction process, and adjusting the pH to 2.5 after the reaction is finished to obtain a feed liquid;

(2) heating and evaporating the feed liquid in the step (1) at 70 ℃ under the vacuum condition of-0.0095-0.085 MPa, sending the feed liquid to a crystallizing tank after crystallization begins to occur, cooling to below 20 ℃, crystallizing and separating out, and then centrifuging to obtain solid precipitate and mother liquid;

(3) washing the solid precipitate with pure water or methanol, drying to obtain pyridine bromate, adding activated carbon into the mother liquor for decolorization, and returning the mother liquor to the reaction kettle for use in the preparation of the next batch of pyridine bromate.

The prepared pyridine bromate is white crystal, takes pyridine as a main material, and has the following mass yield: 200 percent and the product content is more than or equal to 99 percent.

In the step (1), pyridine is dripped below the liquid level of hydrobromic acid, the reaction temperature is kept at 50-55 ℃, compared with the method that pyridine is dripped above the liquid level of hydrobromic acid and the reaction temperature is lower than 50 ℃, the required reaction time is shortened from 8 hours to 2 hours, the method is more favorable for industrial batch production, the pyridine is dripped below the liquid level, the stirring is more favorable for stirring materials more uniformly, the reaction time is more favorable for shortening, the volatilization of pyridine is reduced, and the reaction is more complete and more sufficient.

In the step (2), heating evaporation is carried out under the vacuum condition of-0.0095 to-0.085 MPa, the heating evaporation time is shortened to 3-4 h from 7-8h compared with the heating evaporation time under normal pressure, and the heating temperature is reduced.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.