阅读说明：本技术 一种琥布宗的合成方法 (Synthesis method of amber ) 是由 袁拥军 王秀云 顾健波 滕飞 于 2021-09-16 设计创作，主要内容包括：本发明提出的是一种琥布宗的合成方法,将保泰松、多聚甲醛和丁二酸酐各原料分别置于碱性溶液中,在反应釜中升温并进行保温反应,将反应液缓慢降至室温,将反应液酸化,搅拌一定时间,离心后用水淋洗,过滤得粗品；将所得粗品溶于溶剂中,加热至全溶后热过滤除去机械杂质,将滤液降温并保持一定时间,离心后用乙醇淋洗,烘干得琥布宗成品。本发明采用“一锅煮”的操作方式,避免复杂的中间处理过程,在节约时间的同时降低了生产成本及三废的排放量；反应结束后经过酸化过程将杂质溶于母液中,与产品达到有效分离,提高粗品及成品的纯度；所涉及工艺步骤均为常规反应,可操作性强,适合大面积工业化生产和推广使用。(The invention provides a synthesis method of amber, which comprises the steps of respectively placing phenylbutazone, paraformaldehyde and succinic anhydride into alkaline solution, heating in a reaction kettle, carrying out heat preservation reaction, slowly cooling the reaction solution to room temperature, acidifying the reaction solution, stirring for a certain time, centrifuging, leaching with water, and filtering to obtain a crude product; dissolving the obtained crude product in a solvent, heating to completely dissolve, performing hot filtration to remove mechanical impurities, cooling the filtrate, maintaining for a certain time, centrifuging, leaching with ethanol, and drying to obtain the final product of amber. The invention adopts the operation mode of 'one-pot boiling', avoids the complex intermediate treatment process, saves time and reduces the production cost and the discharge amount of three wastes; after the reaction is finished, impurities are dissolved in the mother liquor through an acidification process, and are effectively separated from the product, so that the purity of the crude product and the finished product is improved; the related process steps are conventional reactions, the operability is strong, and the method is suitable for large-area industrial production and popularization and use.)

1. The synthesis method of amber, which is characterized in that the method comprises the following steps:

(1) respectively placing the phenylbutazone, the paraformaldehyde and the succinic anhydride in an alkaline solution, heating in a reaction kettle, and carrying out heat preservation reaction to obtain a reaction solution;

(2) slowly cooling the reaction liquid obtained in the step (1) to room temperature, adding water and dropwise adding acid, acidifying the reaction liquid, stirring for a certain time, centrifuging, leaching with water, and filtering to obtain a crude product;

(3) and (3) dissolving the crude product obtained in the step (2) in a solvent, heating until the crude product is completely dissolved, carrying out hot filtration to remove mechanical impurities, cooling the filtrate, keeping the temperature for a certain time, carrying out centrifugation, carrying out leaching with the same solvent, and drying to obtain the finished product of the amber.

2. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the mass ratio of the phenylbutazone, the paraformaldehyde and the succinic anhydride in the step (1) is 1.0: 1.0-1.5: 1.0-1.5.

3. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the alkali used in the alkaline solution in the step (1) is organic alkali, inorganic alkali or a mixture thereof; wherein the organic base comprises one or more of triethylamine, TEA, DIEA, DBU, sodium alkoxide and butyl lithium, and the inorganic base comprises one or more of metal hydroxide, metal carbonate, metal bicarbonate, metal oxide and metal alkoxide.

4. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the solvent used in the alkaline solution in the step (1) is one or a mixture of amides, alcohols and ketones, wherein the amides comprise DMF or DMA, the alcohols comprise methanol or ethanol, and the ketones comprise one or a mixture of acetone, methyl ethyl ketone and cyclohexanone.

5. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the temperature for the heat preservation reaction in the step (1) is 50-80 ℃.

6. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: in the heat preservation reaction process in the step (1), the content of the raw materials is detected by high performance liquid chromatography, and the reaction is finished when the mass fraction of the raw materials is less than or equal to 0.5%.

7. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the acid used in the step (2) is organic acid, inorganic acid or a mixture thereof, wherein the organic acid comprises formic acid or acetic acid, and the inorganic acid comprises hydrochloric acid or sulfuric acid; acid was added dropwise until the reaction solution pH = 1-2.

8. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the solvent used in the step (3) is alcohol, ketone or a mixture thereof, wherein the alcohol comprises methanol and ethanol, and the ketone comprises one or more of acetone, methyl ethyl ketone and cyclohexanone; the dosage of the solvent is 2-3 times of the mass of the crude product.

9. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the dissolving temperature in the step (3) is 50-80 ℃.

10. The synthesis method of amber as claimed in claim 1, which is characterized by comprising the following steps: the filtrate cooling process in the step (3) is specifically as follows: cooling the filtrate to below 10 deg.C and maintaining for a certain time.

Technical Field

The invention relates to a synthesis method of amber and buperazone, belonging to the technical field of chemical pharmacy.

Background

The suxibuzone (suxibuzone) is an analgesic for joint and muscle pain, is a prodrug of non-steroidal anti-inflammatory drug (NSAID) phenylbutazone (phenylbutazone), is commonly used for treating horses, has higher acidity and is easy to cause gastrointestinal irritation, and has only 1/10 of the phenylbutazone on the stimulation effect of the suxibuzone on the gastrointestinal tract, so that the application prospect is promising. At present, the related documents of the synthesis method of the amber are very few, and no process flow suitable for industrial production is provided, so that the synthesis and production process of the amber which can be applied in industry is urgently needed, and a foundation is laid for further research and development of the amber.

Disclosure of Invention

The invention aims to solve the problem of deficiency of an industrial synthesis method of amber in the prior art, and provides a synthesis method of amber with low cost and strong operability.

The technical solution of the invention is as follows: a synthesis method of amber, buperazone, comprises the following steps:

(1) respectively placing the phenylbutazone, the paraformaldehyde and the succinic anhydride in an alkaline solution, heating in a reaction kettle, and carrying out heat preservation reaction to obtain a reaction solution;

(2) slowly cooling the reaction liquid obtained in the step (1) to room temperature, adding water and dropwise adding acid, acidifying the reaction liquid, stirring for a certain time, centrifuging, leaching with water, and filtering to obtain a crude product;

(3) and (3) dissolving the crude product obtained in the step (2) in a solvent, heating until the crude product is completely dissolved, carrying out hot filtration to remove mechanical impurities, cooling the filtrate, keeping the temperature for a certain time, carrying out centrifugation, carrying out leaching with the same solvent, and drying to obtain the finished product of the amber.

The reaction formula of the synthetic route is as follows:

。

further, the ratio of the amounts of phenylbutazone, paraformaldehyde and succinic anhydride in step (1) is 1.0 (1.0-1.5) to 1.0-1.5, preferably 1.0:1.1: 1.0.

Further, the base used in the basic solution in the step (1) is one or more of organic base (such as triethylamine, TEA, DIEA, DBU, sodium alkoxide, butyl lithium, etc.) or inorganic base (such as metal hydroxide, metal carbonate, metal bicarbonate, metal oxide, metal alkoxide, etc.), preferably organic base, and more preferably pyridine.

Further, the solvent used in the alkaline solution in the step (1) is one or more of amides (such as DMF, DMA, etc.), alcohols (such as methanol, ethanol, etc.), ketones (such as acetone, methyl ethyl ketone, cyclohexanone, etc.), preferably amides, and more preferably DMF (N, N-dimethylformamide).

Further, the temperature for the heat-preserving reaction in the step (1) is 50 to 80 ℃, preferably 65 to 80 ℃.

Further, in the heat preservation reaction process in the step (1), the content of the raw materials is detected by High Performance Liquid Chromatography (HPLC), and the reaction is finished when the mass fraction of the raw materials is less than or equal to 0.5%.

Further, the acid used in the step (2) is one or more of organic acid (such as formic acid, acetic acid and the like) or inorganic acid (such as hydrochloric acid, sulfuric acid and the like), preferably hydrochloric acid; acid was added dropwise until the reaction solution pH = 1-2.

Further, the solvent used in step (3) is one or more mixtures of alcohols (such as methanol, ethanol, etc.), ketones (such as acetone, methyl ethyl ketone, cyclohexanone, etc.), preferably alcohols, and further preferably ethanol; the dosage of the solvent is 2-3 times of the mass of the crude product.

Further, the dissolving temperature in the step (3) is 50-80 ℃, preferably 50-60 ℃.

Further, the cooling process of the filtrate in the step (3) specifically comprises: cooling the filtrate to below 10 deg.C and maintaining for a certain time.

Compared with the prior art, the invention has the advantages that:

1) the raw materials are kept in the same container for reaction by adopting a one-pot operation mode, so that a complex intermediate treatment process is avoided, the operation is simple, the time is saved, and the production cost and the discharge amount of three wastes are reduced;

2) after the reaction is finished, through a simple acidification process, unreacted succinic anhydride and the like can be destroyed into impurities with larger polarity to be dissolved in the mother liquor, the impurities are effectively separated from the product, and the purity of the crude product and the finished product of the amber is improved;

3) the related process steps are conventional reactions, special equipment or special instruments are not needed, the operability is strong, and the method is suitable for large-area industrial production and popularization and use.

Detailed Description

The technical solution of the present invention is further illustrated below according to a number of examples. In the description of the present specification, the contents of each embodiment means that a specific technical feature described in connection with it is included in at least one embodiment of the present invention. In this specification, schematic representations of the embodiments do not necessarily refer to the same embodiment or example. Furthermore, the particular features described may be combined in any suitable manner in any one or more of the embodiments or examples.

Example 1

Putting 50.0kg of phenylbutazone, 5.4kg of paraformaldehyde, 16.2kg of succinic anhydride, 16.0kg of pyridine and 40.0kg of DMF (dimethyl formamide) into a reaction kettle, slowly heating to 70 ℃, keeping the temperature to react until the raw materials are less than or equal to 0.5 percent (HPLC), slowly cooling the system to room temperature, adding 80.0kg of water, slowly dropwise adding hydrochloric acid until the pH is =1-2, stirring for 0.5 hour, centrifuging, and leaching with proper water to obtain a crude product.

Dissolving the obtained crude product in 3 times of ethanol, heating to 50-70 deg.C, dissolving, heat filtering, removing mechanical impurities, cooling the filtrate to 10 deg.C, maintaining for 0.5 hr, centrifuging, rinsing with appropriate ethanol to obtain Succinum Zong product, oven drying to obtain 53.8kg, and total yield of 75.7%.

Example 2

Putting 100.0kg of phenylbutazone, 10.8kg of paraformaldehyde, 32.5kg of succinic anhydride, 32.1kg of pyridine and 80.0kg of DMF (dimethyl formamide) into a reaction kettle, slowly heating to 75 ℃, keeping the temperature to react until the raw materials are less than or equal to 0.5 percent (HPLC), slowly cooling the system to room temperature, adding 160.0kg of water, slowly dropwise adding hydrochloric acid until the pH is =1-2, stirring for 0.5 hour, centrifuging, and leaching with proper water to obtain a crude product.

Dissolving the obtained crude product in 3 times of ethanol, heating to 50-70 deg.C, dissolving, heat filtering, removing mechanical impurities, cooling the filtrate to 10 deg.C, maintaining for 0.5 hr, centrifuging, rinsing with appropriate ethanol to obtain Succinum-buperazone product, oven drying to obtain 108.7kg, and total yield of 76.5%.

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.