阅读说明：本技术 一种2-氰基吩噻嗪的制备方法 (Preparation method of 2-cyanophenothiazine ) 是由 张力 邹远林 李畅达 华阳 黄友元 史丹丹 刘郝敏 吴晓东 于 2021-09-01 设计创作，主要内容包括：本发明属于有机化学合成技术领域,具体涉及一种2-氰基吩噻嗪的制备方法,所述制备方法包括以下步骤：在有机溶剂中加入3,4-二氟苯腈、2-氨基苯硫醇和缚酸剂进行回流反应,回流反应完成后降温,对反应物进行淬灭后处理,过滤得到粗品,经有机溶剂重结晶制得2-氰基吩噻嗪；本发明采用全新的合成路线,不同于市面上主流的以2-氯吩噻嗪和氢化亚铜或氰化钠为原料合成2-氰基吩噻嗪,原料价格便宜,原料成本大大降低,避免了复杂的后处理操作,完全避免了铜离子,污染小,“三废”少,同时反应溶剂和后处理重结晶溶剂均可回收,进一步降低了生产成本,本发明制备的产品纯度十分高,可达到99.5％以上,酰胺体杂质小于0.05％,远高于市面上主流产品的质量。(The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 2-cyanophenothiazine, which comprises the following steps: adding 3, 4-difluorobenzonitrile, 2-aminobenzenethiol and an acid-binding agent into an organic solvent to carry out reflux reaction, cooling after the reflux reaction is finished, carrying out quenching post-treatment on a reactant, filtering to obtain a crude product, and recrystallizing by using the organic solvent to obtain 2-cyanophenothiazine; the invention adopts a brand new synthesis route, is different from the synthesis of 2-cyanophenothiazine by taking 2-chlorophenothiazine and cuprous hydride or sodium cyanide as raw materials which are the mainstream in the market, has the advantages of low raw material price, greatly reduced raw material cost, avoidance of complex post-treatment operation, complete avoidance of copper ions, little pollution, less three wastes, recovery of reaction solvent and post-treatment recrystallization solvent, and further reduction of production cost, and the prepared product has high purity which can reach more than 99.5 percent, and amide impurities which are less than 0.05 percent and are far higher than the quality of the mainstream products in the market.)

1. A preparation method of 2-cyanophenothiazine is characterized by comprising the following steps: the preparation method comprises the following steps: adding 3, 4-difluorobenzonitrile, 2-aminobenzenethiol and an acid-binding agent into an organic solvent for reflux reaction, cooling after the reflux reaction is finished, quenching the reactant, filtering to obtain a crude product, and recrystallizing by using the organic solvent to obtain the 2-cyanophenothiazine.

2. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the organic solvent is N-methyl pyrrolidone or DMF.

3. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the acid-binding agent is one of potassium carbonate, sodium hydroxide, potassium hydroxide and sodium acetate.

4. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the molar ratio of the 3, 4-difluorobenzonitrile, the 2-aminobenzenethiol, the organic solvent and the organic base acid-binding agent is 1.0: 1.1: 2.0: 2.0.

5. a process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the reflux temperature of the reflux reaction is 170-190 ℃, and the reaction is carried out for 15 hours.

6. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the quenching method comprises the following steps: after the reflux reaction is finished, the temperature is reduced to 30-50 ℃, and water is added into the reaction system for quenching.

7. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the addition amount of the water is 1-4 times of the mass of the reactant.

8. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the filtration temperature is 15-25 ℃.

9. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the solvent used for recrystallization is 0.5 to 5 times of the mass of the reaction mass.

10. A process for the preparation of 2-cyanophenothiazine according to claim 1, wherein: the solvent used for recrystallization is a mixed solvent of methanol and toluene, and the volume ratio of the mixed solvent to the solvent is 1.0: (0.5-1.5), heating the recrystallization to 40-60 ℃, stirring for 1h, cooling to 20 ℃, and filtering to obtain the 2-cyanophenothiazine.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 2-cyanophenothiazine.

Background

The 2-cyanophenothiazine is an important medical intermediate, and the medicine prepared from the 2-cyanophenothiazine has various medicinal effects, especially has important effects in lowering blood pressure, tranquilizing mind, relieving pain and resisting cancer. The demand of the international market for the drug intermediate is large at present. The structural formula of the 2-cyanophenothiazine is as follows:

the synthesis of the compound generally adopts 2-chlorophenothiazine and cuprous cyanide as raw materials, and prepares the 2-cyanophenothiazine by reflux reaction in organic solvents with high boiling points such as N-methylpyrrolidone or quinoline and the like under the condition of taking iodine or sodium iodide and potassium iodide as catalysts. The reaction formula is as follows:

the above-mentioned reactions were reported in both Japanese patent No. 53-92788 (Japanese patent laid-open No. 53-92788) and Japanese patent No. 1-216982 (Japanese patent laid-open No. 1-216982) in 1978, but the yields were not high and some of the starting materials were not reacted. The invention patent of China (application number: 200410012337.0) with the publication number of CN1255390C discloses a method for preparing 2-cyanophenothiazine, which adopts phosphorus oxychloride as a dehydrator, obviously reduces the content of amide impurities after reaction, and avoids the generation of high-toxicity hydrocyanic acid gas. However, the separation and refinement process of the crude 2-cyanophenothiazine obtained by the reaction is complicated, the recrystallization times are large, the yield of the reaction is low, the product is easy to decompose, and the operation is difficult, so that the production cost of the 2-cyanophenothiazine is high, the production efficiency is low, and the industrialization is difficult to realize. In 2020, Nature Communications reports that 2-chlorophenol thiazine and carbon dioxide are used as raw materials to synthesize 2-cyanophenol thiazine at high temperature, the method avoids the trouble of copper ions in post-treatment, but the reaction is difficult, the yield is very low, and the method is not suitable for industrial production. In 1998, Journal of Heterocyclic Chemistry reports that tris (tetra) fluorobenzonitrile and 2-aminothiophenol are used as raw materials, DMF is used as a reaction solvent, sodium hydrogen is used as alkali, ferric citrate is added as a catalyst, and 2-cyanophenol thiazine is prepared by reflux reaction.

Therefore, the 2-cyanophenol thiazine obtained by the method obviously has inconvenient defects in preparation and use, and needs to be further improved. In view of the above problems, it is necessary to provide a general synthetic route for 2-cyanophenol thiazine compounds. In order to solve the problems of the 2-cyanophenol thiazine in the preparation method, the relevant manufacturers have tried to solve the problems without diligent thought, but it has not been found that a suitable design is developed and completed for a long time, and the general method can not solve the problems, which is obviously a problem to be solved urgently by the relevant manufacturers.

In view of the above-mentioned drawbacks of the existing 2-cyanophenol thiazine in the preparation method, the present inventors have actively studied and innovated based on practical experience and professional knowledge that is abundant over many years in the design and manufacture of such products, and in cooperation with the application of the theory, in order to create a new preparation method of 2-cyanophenol thiazine, which can improve the existing preparation method of 2-cyanophenol thiazine and make it more applicable. After continuous research and design, trial operation and improvement, the invention with practical value is finally created.

Disclosure of Invention

The invention aims to: overcomes the defects in the prior art, and provides a preparation method of 2-cyanophenothiazine, which has low preparation cost, high yield and purity and can effectively avoid the difficulty in product decomposition and post-treatment operation.

In order to achieve the purpose, the invention provides the following technical scheme:

a method of preparing 2-cyanophenothiazine, comprising the steps of: adding 3, 4-difluorobenzonitrile, 2-aminobenzenethiol and an acid-binding agent into an organic solvent for reflux reaction, cooling after the reflux reaction is finished, quenching the reactant, filtering to obtain a crude product, and recrystallizing by using the organic solvent to obtain the 2-cyanophenothiazine.

Further, the organic solvent is N-methyl pyrrolidone or DMF.

Further, the acid-binding agent is one of potassium carbonate, sodium hydroxide, potassium hydroxide and sodium acetate.

Further, the molar ratio of the 3, 4-difluorobenzonitrile, the 2-aminobenzenethiol, the organic solvent and the organic base acid-binding agent is 1.0: 1.1: 2.0: 2.0.

further, the reflux temperature of the reflux reaction is 170-190 ℃, and the reaction is carried out for 15 hours.

Further, the quenching method comprises the following steps: after the reflux reaction is finished, the temperature is reduced to 30-50 ℃, and water is added into the reaction system for quenching.

Furthermore, the adding amount of the water is 1-4 times of the mass of the reaction substance.

Further, the filtration temperature is 15-25 ℃.

Further, the solvent used for recrystallization is 0.5 to 5 times the mass of the reaction product.

Further, the solvent used for recrystallization is a mixed solvent of methanol and toluene, and the volume ratio of the mixed solvent to the solvent is 1.0: (0.5-1.5), heating the recrystallization to 40-60 ℃, stirring for 1h, cooling to 20 ℃, and filtering to obtain the 2-cyanophenothiazine.

The technical scheme adopted by the invention has the beneficial effects that:

the invention adopts a brand new synthesis route, is different from the synthesis of 2-cyanophenothiazine by taking 2-chlorophenothiazine and cuprous hydride or sodium cyanide as raw materials which are the mainstream in the market, has the advantages of low raw material price, greatly reduced raw material cost, avoidance of complex post-treatment operation, complete avoidance of copper ions, little pollution, less three wastes, recovery of reaction solvent and post-treatment recrystallization solvent, and further reduction of production cost, and the prepared product has high purity which can reach more than 99.5 percent, and amide impurities which are less than 0.05 percent and are far higher than the quality of the mainstream products in the market.

Drawings

FIG. 1 is an HPLC chromatogram of 2-cyanophenothiazine in example 1;

FIG. 2 is an HPLC chromatogram of 2-cyanophenothiazine in example 2;

FIG. 3 is an HPLC chromatogram of 2-cyanophenothiazine in example 3;

Detailed Description

The following will clearly and completely describe the technical solutions in the embodiments of the present invention, 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 derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

It should be noted that: the reactants written in the patent all refer to pure 3, 4-difluorobenzonitrile.

Example 1

(1) Preparation of crude 2-cyanophenothiazine: 3, 4-difluorobenzonitrile, 2-aminobenzenethiol, potassium carbonate and N-methylpyrrolidone are mixed according to a molar ratio of 1.0: 1.0: 2.0: 2.0, adding the mixture into a reaction kettle, heating to 170 ℃, and reacting for 15 hours;

(2) separation of crude 2-cyanophenothiazine: reducing the temperature of the reaction kettle to 30 ℃, adding 2 times of water into the reaction kettle to separate out solids, continuously reducing the temperature to 35 ℃, and filtering to obtain a crude product of 2-cyanophenothiazine;

(3) purification of 2-cyanophenothiazine: putting the crude product of the 2-cyanophenothiazine into a mixed solvent of methanol and toluene, wherein the volume ratio of the methanol to the toluene in the mixed solvent is as follows: 1.0: 0.5, raising the temperature to 40 ℃, stirring for 1 hour, reducing the temperature to 20 ℃, and filtering to obtain the 2-cyanophenothiazine.

(4) Through detection, the yield of the 2-cyanophenothiazine prepared by the embodiment is 86.3%, as shown in fig. 1, the product purity is 99.71%, and the content of amide impurities is 0.05%.

Example 2

(1) Preparation of crude 2-cyanophenothiazine: 3, 4-difluorobenzonitrile, 2-aminobenzenethiol, potassium carbonate and N-methylpyrrolidone are mixed according to a molar ratio of 1.0: 1.1: 2.0: 3.0, adding the mixture into a reaction kettle, heating to 180 ℃, and reacting for 15 hours;

(2) separation of crude 2-cyanophenothiazine: reducing the temperature of the reaction kettle to 40 ℃, adding 3 times of water into the reaction kettle to separate out solids, continuously reducing the temperature to 30 ℃, and filtering to obtain a crude product of 2-cyanophenothiazine;

(3) purification of 2-cyanophenothiazine: putting the crude product of the 2-cyanophenothiazine into a mixed solvent of methanol and toluene, wherein the volume ratio of the methanol to the toluene in the mixed solvent is as follows: 1.0: 1.0, raising the temperature to 50 ℃, stirring for 1 hour, reducing the temperature to 20 ℃, and filtering to obtain the 2-cyanophenothiazine.

(4) Through detection, the yield of the 2-cyanophenothiazine prepared by the embodiment is 88.6%, as shown in fig. 2, the product purity is 99.63%, and the content of amide impurities is 0.05%.

Example 3

(1) Preparation of crude 2-cyanophenothiazine: 3, 4-difluorobenzonitrile, 2-aminobenzenethiol, potassium carbonate and N-methylpyrrolidone are mixed according to a molar ratio of 1.0: 1.2: 2.0: 4.0, adding the mixture into a reaction kettle, heating to 190 ℃, and reacting for 15 hours;

(2) separation of crude 2-cyanophenothiazine: reducing the temperature of the reaction kettle to 50 ℃, adding 4 times of water into the reaction kettle to separate out solid, continuously reducing the temperature to 20 ℃, and filtering to obtain a crude product of 2-cyanophenothiazine;

(3) purification of 2-cyanophenothiazine: putting the crude product of the 2-cyanophenothiazine into a mixed solvent of methanol and toluene, wherein the volume ratio of the methanol to the toluene in the mixed solvent is as follows: 1.0: 1.5, raising the temperature to 60 ℃, stirring for 1 hour, reducing the temperature to 20 ℃, and filtering to obtain the 2-cyanophenothiazine.

(4) Through detection, the yield of the 2-cyanophenothiazine prepared by the embodiment is 90.2%, as shown in fig. 3, the product purity is 99.60%, and the content of amide impurities is 0.02%.

Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.