阅读说明：本技术 一种三氟乙脒的制备方法 (Preparation method of trifluoroacetamidine ) 是由 娄凯 陆电云 于 2020-12-28 设计创作，主要内容包括：本发明公开了一种三氟乙脒的制备方法,属于有机合成技术领域。以三氟乙酰胺为原料,在催化剂作用下回流分水收集气态三氟乙腈,随后三氟乙腈通入DBU/液氨中反应,加入阻聚剂蒸馏得到三氟乙脒。该方法反应步骤连贯,操作简便,收率高,减少三废,在脱水过程中的催化剂可重复利用高达10次以上,得到产品的含量大于99％,具备潜在的工业化放大前景。(The invention discloses a preparation method of trifluoroacetamidine, belonging to the technical field of organic synthesis. Taking trifluoroacetamide as a raw material, refluxing and water-dividing under the action of a catalyst to collect gaseous trifluoroacetonitrile, introducing the trifluoroacetonitrile into DBU/liquid ammonia for reaction, adding a polymerization inhibitor, and distilling to obtain trifluoroacetamidine. The method has the advantages of continuous reaction steps, simple and convenient operation, high yield, reduction of three wastes, reutilization of the catalyst in the dehydration process for more than 10 times, product content of more than 99 percent, and potential industrial amplification prospect.)

1. A preparation method of trifluoroacetamidine is characterized by comprising the following steps:

mixing trifluoroacetamide and a catalyst in an organic solvent, refluxing and dividing water under normal pressure to obtain dry trifluoroacetonitrile; and then introducing the trifluoroacetonitrile into a DBU/liquid ammonia solution, adding a polymerization inhibitor, and distilling at normal pressure to obtain trifluoroacetamidine.

2. The process for preparing trifluoroacetamidine according to claim 1, wherein: the organic solvent is selected from toluene, n-heptane or cyclohexane.

3. The process for preparing trifluoroacetamidine according to claim 1, wherein: the catalyst is selected from tris (pentafluorophenyl) borane.

4. The process for preparing trifluoroacetamidine according to claim 1, wherein: the molar ratio of the raw material trifluoroacetamide to the catalyst is 1: 0.1-0.05.

5. The process for preparing trifluoroacetamidine according to claim 1, wherein: and in the first step, the reaction process is subjected to rapid reflux and water diversion, and gaseous trifluoroacetonitrile is directly introduced into a liquid ammonia solution dissolved in DBU after passing through a drying device.

6. The process for preparing trifluoroacetamidine according to claim 1, wherein: the polymerization inhibitor is selected from hydroquinone or 2, 6-di-tert-butyl-4-methylphenol.

7. The process for preparing trifluoroacetamidine according to claim 1, wherein: the distillation temperature is selected from 56.2-60.5 ℃.

Technical Field

The invention relates to a preparation method of trifluoroacetamidine, belonging to the technical field of organic synthesis.

Background

Trifluoroacetamidine, CAS 354-37-0, British name 2,2, 2-trifluoethanamide, trifluoroacetamidine are important medical intermediates, because of having fluorine atoms with higher biological activity, the trifluoroacetamidine can be used for pyrimidine, pyridine and triazine compounds containing trifluoromethyl, and is one of important raw materials of many medicines, and the synthesized heterocyclic compounds have good biological activity and are very widely applied to the aspects of medicines, pesticides and the like.

In the prior published patent or literature, the compound is mainly synthesized by using trifluoroacetonitrile as a raw material, such as CN108727224A and [ Journal of American Chemical Society,1981,103,6164-6169], but trifluoroacetonitrile as a raw material has strong toxicity and low melting point and is not easy to be used as a raw material. Patent CN106187911A/2016 adopts more stable trifluoroacetamide as raw material, and synthesizes trifluoroacetonitrile through phosphorus pentoxide dehydration to further synthesize trifluoroacetamidine, however, the phosphorus pentoxide is used in an excessive amount, a large amount of waste water is generated in the treatment of phosphorus pentoxide, further trifluoroacetonitrile has more loss in the liquid ammonia, the post-treatment distillation yield is low, and the like.

Therefore, the synthesis process of the trifluoroacetamidine needs to be deeply improved, and a process route which is better, easily available in raw materials, safe and stable, less in three wastes and high in yield is provided, so as to meet the increasing market demand.

Disclosure of Invention

In order to overcome the technical defects, according to the invention, trifluoroacetamide is used as a raw material, refluxing and water dividing are carried out under the action of a catalyst to collect gaseous trifluoroacetonitrile, then the trifluoroacetonitrile is introduced into liquid ammonia for reaction, and trifluoroacetamidine is obtained by adding a polymerization inhibitor and distilling. The method has the advantages of continuous reaction steps, simple and convenient operation, high yield, reduction of three wastes, reutilization of the catalyst in the dehydration process for more than 10 times, product content of more than 99 percent, and potential industrial amplification prospect.

The invention relates to a preparation method of trifluoroacetamidine, which comprises the following steps:

mixing trifluoroacetamide and a catalyst in an organic solvent, refluxing and dividing water at normal pressure, and obtaining dry trifluoroacetonitrile at a gas phase port; and then introducing gaseous trifluoroacetonitrile into the DBU/liquid ammonia solution, adding a polymerization inhibitor, and rectifying at normal pressure to obtain trifluoroacetamidine.

Further, in the above technical solution, in the first step, the organic solvent is selected from toluene, n-heptane or cyclohexane.

Further, in the above technical solution, in the first step, the catalyst is selected from tris (pentafluorophenyl) borane.

Further, in the above technical scheme, in the first step, the reaction process is rapidly refluxed and water-separated, and gaseous trifluoroacetonitrile is directly introduced into a liquid ammonia solution dissolved in DBU after passing through a drying device.

Further, in the technical scheme, in the first step, the molar ratio of the raw material trifluoroacetamide to the catalyst is 1: 0.1-0.05.

Further, in the above technical solution, in the second step, the polymerization inhibitor is selected from hydroquinone or 2, 6-di-tert-butyl-4-methylphenol.

Further, in the above technical scheme, in the second step, the rectification temperature is selected from 56.2-60.5 ℃.

Advantageous effects of the invention

1) The raw materials are easy to obtain, the used catalyst greatly reduces the generation of three wastes and can be repeatedly applied, thereby greatly facilitating the industrial scale-up production and saving the cost.

2) The invention adopts a coherent operation mode, DBU and liquid ammonia are mixed, the operation can be carried out at ordinary low temperature, and DBU can also be used as a bottom distillation solvent.

3) And adding a polymerization inhibitor during distillation of the product to prevent deterioration polymerization in the distillation process, so that the content of the obtained trifluoroacetamidine is up to more than 99%.

Drawings

FIG. 1 shows the preparation of trifluoroacetamidine in example 1¹HNMR spectrogram;

FIG. 2 shows the preparation of trifluoroacetamidine in example 1¹⁹FNMR spectrogram.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.

Example 1

60g (0.531mol) of trifluoroacetamide, 13.6g (0.027mol) of tris (pentafluorophenyl) borane and 300mL of toluene were put into a reaction flask (a) equipped with a reflux condenser and a drier, and the mixture was slowly warmedHeating to reflux, generating trifluoroacetonitrile at a gas phase port in the heating reflux water diversion process, and introducing the generated trifluoroacetonitrile into a DBU (85 g)/liquid ammonia (17g) mixed solution reaction bottle (b) which is pre-frozen to about-10 ℃. And (3) carrying out reflux dehydration reaction for 2 hours, and stopping reaction for reuse after the reaction of the sampled raw materials is finished and no gas is generated. And (b) keeping the temperature of-10 ℃ to 0 ℃ in a reaction bottle (b) for reacting for 2 hours (the system is connected to a gas outlet by a double-layer balloon and sealed, the same is applied below), sampling raw materials for completely reacting, adding 2, 6-di-tert-butyl-4-methylphenol (1.2g), slowly heating while recovering ammonia gas, starting normal-pressure distillation after the temperature is raised to room temperature, controlling the reflux ratio, distilling and collecting 56.3-59.2 ℃ fractions to obtain 53.7g of trifluoroacetamidine, wherein the yield is 90.3%, and the GC content is 99.3%.¹HNMR(400MHz,CDCl₃):6.35(br s)；¹⁹FNMR(376MHz,CDCl₃):-74.7,-75.4.

Example 2

60g (0.531mol) of trifluoroacetamide, 13.6g (0.027mol) of tris (pentafluorophenyl) borane and 600mL of n-heptane are put into a reaction flask (a) provided with a reflux condenser and a drying device and mixed, the temperature is slowly increased to reflux, during the heating reflux water separation process, trifluoroacetonitrile is generated at a gas phase port, and the generated trifluoroacetonitrile is introduced into a reaction flask (b) of a DBU (90 g)/liquid ammonia (18.5g) mixed solution which is pre-frozen to about-10 ℃. And (3) carrying out reflux dehydration reaction for 3 hours, and stopping reaction for reuse after the reaction of the sampled raw materials is finished and no gas is generated. And (2) keeping the temperature of the reaction bottle (b) at-10 ℃ to 0 ℃ for 2 hours, taking samples, completely reacting the raw materials, adding hydroquinone (0.8g), slowly heating while recovering ammonia gas, starting normal-pressure distillation after the temperature is raised to the room temperature, controlling the reflux ratio, distilling and collecting fractions at 56.3-59.2 ℃ to obtain 52.0g of trifluoroacetamidine, the yield is 87.5%, and GC: 99.1 percent.

Example 3

60g (0.531mol) of trifluoroacetamide, 13.6g (0.027mol) of tris (pentafluorophenyl) borane and 600mL of cyclohexane are put into a reaction bottle (a) provided with a reflux condenser and a drying device to be mixed, the temperature is slowly increased to reflux, during the heating reflux and water diversion process, trifluoroacetonitrile is generated at a gas phase port, and the generated trifluoroacetonitrile is introduced into a reaction bottle (b) of a DBU (90 g)/liquid ammonia (17.5g) mixed solution which is pre-frozen to about-10 ℃. And (3) carrying out reflux dehydration reaction for 3 hours, and stopping reaction for reuse after the reaction of the sampled raw materials is finished and no gas is generated. Keeping the temperature of-10 ℃ to 0 ℃ for reacting for 2 hours, sampling raw materials, completely reacting, adding hydroquinone (0.9g), slowly heating while recovering ammonia, starting normal-pressure distillation after the temperature is raised to the room temperature, controlling the reflux ratio, distilling and collecting fractions at 56.3-59.2 ℃ to obtain 50.6g of trifluoroacetamidine, wherein the yield is 85.1%, and GC: 99.0 percent.

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 able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.