A method for the synthesis of 2,2-difluoroethylamine

Abstract

The application discloses a synthesis method of 2,2-difluoroethylamine, which comprises the following steps: mixing a solvent, a copper-based catalyst and an ammonia source in a sealed container, wherein the ammonia source is gaseous, liquid or supercritical ammonia; heating the mixed system to 80-120 DEG C; adding 2,2-difluoro-1-chloroethane; keeping the reaction for a certain time; filtering the reaction liquid; and distilling the filtrate to obtain 2,2-difluoroethylamine. The reaction selectivity and reaction yield of the method are obviously improved compared with the prior art. The insoluble copper salt and organic ligand are adopted in the form of the catalyst, so that the catalyst recovery is simple and convenient, the ammonia excess ratio can be reduced in the reaction process, the energy consumption for ammonia recovery is greatly saved, the reaction yield is high, the amount of three wastes is small, and large-scale industrial production can be easily realized.

Description

Technical Field

[0001] This invention belongs to the field of 2,2-difluoroethylamine synthesis technology, specifically relating to a method for synthesizing 2,2-difluoroethylamine. Background Technology

[0002] The NH₂: group in 2,2-difluoroethylamine is highly reactive, allowing it to react readily with other substrates, thus making it widely used in pesticides and pharmaceuticals. With the increasing demand for fine chemicals, the market for fluorinated organic compounds is also expanding, and 2,2-difluoroethylamine, as an important intermediate, has gained increasing attention.

[0003] The existing methods for preparing 2,2-difluoroethylamine mainly include the following: hydrogenation reduction of difluoroacetamide, synthesis using boron trifluoride diethyl ether complex, and synthesis using 1-halo-2,2-difluoroethane. Among these, the method of synthesizing 2,2-difluoroethylamine from a solution of 1-halo-2,2-difluoroethane and ammonia is the main route due to its economic efficiency.

[0004] CN 112209839 A utilizes the high-boiling fraction of R142b (i.e., 1-chloro-2,2-difluoroethane) as a raw material and reacts it with ammonia in the presence of inorganic ammonium salt and a phase transfer catalyst at 60°C, achieving a yield of 87%. However, because the product can undergo further substitution reactions with the raw material, numerous side reactions occur, which is detrimental to cost control. CN 103370290 A proposes a solvent-free method to directly obtain 2,2-difluoroethylamine using 1-chloro-2,2-difluoroethane and supercritical ammonia in a reaction vessel at 80°C to 200°C. This method achieves a yield of approximately 60% within a 9-hour reaction time through in-situ catalyst generation. However, because this reaction is carried out under high temperature and pressure and has a long reaction time, it is not conducive to industrial production. CN 102471229 A describes the reaction of 1-chloro-2,2-difluoroethane and supercritical ammonia in a solvent with a maximum water content of 15% by volume to obtain 2,2-difluoroethylamine in the presence of potassium iodide catalyst. The reaction yield can reach 88%. However, due to the high solubility of potassium iodide, catalyst recovery is quite difficult, which is not conducive to large-scale production.

[0005] Furthermore, due to the properties of 2,2-difluoroethylamine, its nucleophilicity is significantly higher than that of ammonia. Therefore, the longer the reaction time, the greater the impact of the disubstituted byproduct di(2,2-difluoroethyl)amine on the low reaction yield. The control of byproduct formation greatly affects the reaction yield. The above-mentioned methods for preparing 2,2-difluoroethylamine do not reveal any methods for controlling the activity of side reactions, and generally suffer from low yields, stringent condition control, and high safety risks, making them unsuitable for large-scale continuous production. Summary of the Invention

[0006] To address the problems of long reaction time, poor selectivity, and large ammonia excess ratio in the preparation of 2,2-difluoroethylamine in existing technologies, this invention provides a method for synthesizing 2,2-difluoroethylamine that has fewer byproducts, higher reaction yield, shorter reaction time, is safer, and has less raw material loss.

[0007] This invention is achieved through the following technical solution: A method for synthesizing 2,2-difluoroethylamine includes the following steps: (1) Mix the solvent, copper-based catalyst and ammonia source in a sealed container, wherein the ammonia source is gaseous, liquid or supercritical ammonia; (2) Heat the mixture in step (1) to 80~120℃, add 2,2-difluoro-1-chloroethane, and keep it at the temperature for a certain time; (3) The reaction solution in step (2) is filtered, and the filtrate is distilled to obtain 2,2-difluoroethylamine.

[0008] Further, the copper-based catalyst in step (1) is composed of an inorganic copper salt and an organic ligand; the inorganic copper salt is one of CuI, CuO, Cu2O, CuCl, and CuSO4; the organic ligand is one of D-glucose, D-glucosamine, ethylenediamine, ethylene glycol, xanthodextrin, and disodium EDTA.

[0009] Furthermore, the molar ratio of the inorganic copper salt, organic ligand, ammonia, and 2,2-difluoroethylamine is 0.05~0.2:0.05~0.2:2.0~10.0:1.0.

[0010] Furthermore, the inorganic copper salt is CuI.

[0011] Furthermore, the molar ratio of the inorganic copper salt to the organic ligand is 1:1.

[0012] Further, the solvent in step (1) is one or more of the following: water, acetone, methanol, cyclohexane, n-hexane, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, isopropyl ether, acetonitrile, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol methyl ethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol methyl ethyl ether, dimethyl carbonate, diethyl carbonate, N-methylpyrrolidone, N,N-dimethylformamide, and dimethyl sulfoxide.

[0013] Furthermore, in step (2), the 2,2-difluoro-1-chloroethane is introduced for 20-50 min, and the reaction time after the introduction is completed is 3-5 h.

[0014] The present invention utilizes inorganic copper salts and organic ligands to significantly improve reactivity and shorten reaction time, thereby reducing disubstituted byproducts.

[0015] This invention, through studying the pKa values ​​of 2,2-difluoroethylamine and ammonia in different solvents, found that in water, the pKa of ammonia is 9.24, while the corresponding pKa of 2,2-difluoroethylamine is 10.71. The nucleophilicity of 2,2-difluoroethylamine is significantly higher than that of ammonia; therefore, the reaction in water usually requires a large excess of ammonia to reduce the formation of byproducts. In methanol, however, the pKa of ammonia is 10.78, while the corresponding pKa of 2,2-difluoroethylamine is 11.00, showing a smaller difference compared to water. Therefore, in the presence of a copper-based catalyst, finding a suitable solvent to reduce the nucleophilicity difference between 2,2-difluoroethylamine and ammonia can significantly improve the selectivity of the reaction.

[0016] The beneficial effects achieved by this invention are as follows: (1) The reaction selectivity and reaction yield of the method of the present invention are significantly improved compared with the existing process.

[0017] (2) The present invention uses insoluble copper salt and organic ligands, which makes catalyst recovery simple and convenient.

[0018] (3) The excess ratio of ammonia during the reaction process of the present invention can be reduced, which greatly saves the energy consumption of ammonia recovery.

[0019] (4) The preparation method is simple to control, has a high reaction yield, and produces little waste, making it easy to achieve large-scale industrial production. Detailed Implementation

[0020] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the present invention.

[0021] Example 1 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucose were added to a reactor containing a 1:1 acetone:water solution. 3.4 g (0.2 mol) liquid ammonia was introduced into the high-pressure reactor and the temperature was raised to 90 °C. 14.5 g (0.1 mol) 2,2-difluoro-1-chloroethane was introduced into the high-pressure reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2. The introduction time was 30 minutes. After the introduction was completed, the reactor was kept at the high temperature for 3 hours. After the reaction was completed, the reactor was cooled, filtered, and excess ammonia was purged with nitrogen. Then, the product was distilled to obtain 4.6 g (99% purity) of 2,2-difluoroethylamine. The reaction yield was 57%.

[0022] Example 2 3.8 g (0.02 mol) CuI and 3.6 g (0.02 mol) D-glucose were added to a reactor containing a 1:1 acetone:water solution. 3.4 g (0.2 mol) liquid ammonia was introduced into the high-pressure reactor and the temperature was raised to 90 °C. 14.5 g (0.1 mol) 2,2-difluoro-1-chloroethane was introduced into the high-pressure reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2. The introduction time was 30 minutes. After the introduction was completed, the reactor was kept at the high temperature for 3 hours. After the reaction was completed, the reactor was cooled, filtered, and excess ammonia was purged with nitrogen. Then, the product was distilled to obtain 2.9 g (99% purity) of 2,2-difluoroethylamine. The reaction yield was 36%.

[0023] Example 3 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine were added to a reactor containing a 1:1 acetone:water solution. 3.4 g (0.2 mol) liquid ammonia was introduced into the high-pressure reactor and the temperature was raised to 90 °C. 14.5 g (0.1 mol) 2,2-difluoro-1-chloroethane was introduced into the high-pressure reactor at a molar ratio of 1:2 to liquid ammonia for 30 minutes. After the introduction was completed, the reactor was kept at the same temperature for 3 hours. After the reaction was completed, the reactor was cooled, filtered, and excess ammonia was purged with nitrogen. Then, the product was distilled to obtain 5.3 g (99% purity) of 2,2-difluoroethylamine, with a reaction yield of 65%.

[0024] Example 4 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine were added to a reactor containing a 1:1 acetone:water solution. 4.3 g (0.25 mol) liquid ammonia was introduced into the high-pressure reactor and the temperature was raised to 90 °C. 14.5 g (0.1 mol) 2,2-difluoro-1-chloroethane was then introduced into the high-pressure reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2.5, and the introduction time was 30 minutes. After the introduction was completed, the reactor was kept at the same temperature for 3 hours. After the reaction was completed, the reactor was cooled, filtered, and excess ammonia was purged with nitrogen. Then, the product was distilled to obtain 6.3 g (99% purity) of 2,2-difluoroethylamine, with a reaction yield of 78%.

[0025] Example 5 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine were added to a reaction vessel containing methanol. 4.3 g (0.25 mol) liquid ammonia was introduced into a high-pressure reaction vessel and the temperature was raised to 90 °C. 14.5 g (0.1 mol) 2,2-difluoro-1-chloroethane was introduced into the high-pressure reaction vessel. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2.5, and the introduction time was 30 minutes. After the introduction was completed, the mixture was kept at the high temperature for 3 hours. After the reaction was completed, the mixture was cooled, filtered, and excess ammonia was purged with nitrogen. Then, it was distilled to obtain 6.6 g (99% purity) of 2,2-difluoroethylamine product, with a reaction yield of 81%.

[0026] Example 6 Add 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine to a solution containing... N,N In a reaction vessel containing dimethylformamide, 4.3 g (0.25 mol) of liquid ammonia was introduced into a high-pressure reactor, and the temperature was raised to 90°C. Then, 14.5 g (0.1 mol) of 2,2-difluoro-1-chloroethane was introduced into the high-pressure reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2.5, and the introduction time was 30 minutes. After the introduction was completed, the mixture was kept at the high-pressure reactor for 3 hours. After the reaction was completed, the mixture was cooled, filtered, and excess ammonia was purged with nitrogen. The resulting product was then distilled to obtain 6.6 g (99% purity) of 2,2-difluoroethylamine, with a reaction yield of 82%.

[0027] Example 7 Add 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine to a solution containing... NIn a reaction vessel containing methylpyrrolidone, 4.3 g (0.25 mol) of liquid ammonia was introduced into a high-pressure reactor and the temperature was raised to 90°C. Then, 14.5 g (0.1 mol) of 2,2-difluoro-1-chloroethane was added to the high-pressure reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2.5. The introduction time was 30 minutes. After the introduction was completed, the mixture was kept at the high temperature for 3 hours. After the reaction was completed, the mixture was cooled, filtered, and excess ammonia was purged with nitrogen. Then, the mixture was distilled to obtain 6.3 g (99% purity) of 2,2-difluoroethylamine product, with a reaction yield of 78%.

[0028] Example 8 Add 1.9 g (0.01 mol) CuI and 1.8 g (0.01 mol) D-glucosamine to a solution containing... N,N In a reaction vessel containing dimethylformamide, 4.3 g (0.25 mol) of liquid ammonia was introduced into a high-pressure reactor, and the temperature was raised to 100°C. Then, 14.5 g (0.1 mol) of 2,2-difluoro-1-chloroethane was introduced into the reactor. The molar ratio of 2,2-difluoro-1-chloroethane to liquid ammonia was 1:2.5, and the introduction time was 30 minutes. After the introduction was completed, the mixture was kept at the high-pressure reactor for 3 hours. After the reaction was completed, the mixture was cooled, filtered, and excess ammonia was purged with nitrogen. The resulting product was then distilled to obtain 6.9 g (99% purity) of 2,2-difluoroethylamine, with a reaction yield of 85%.

[0029] The technical features of the embodiments described above can be combined arbitrarily. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as the combinations of these technical features do not contradict each other, they should be considered within the scope of this specification.

Claims

1. A method for synthesizing 2,2-difluoroethylamine, characterized in that, Includes the following steps: (1) The solvent, copper-based catalyst and ammonia source are mixed in a sealed container, wherein the ammonia source is gaseous, liquid or supercritical ammonia; the copper-based catalyst is composed of inorganic copper salt and organic ligand; (2) Heat the mixture in step (1) to 80~120℃, add 2,2-difluoro-1-chloroethane, and the 2,2-difluoro-1-chloroethane is introduced for 20-50 min. After the introduction is completed, keep the reaction at the temperature for 3 h. (3) The reaction solution in step (2) was filtered, and the filtrate was distilled to obtain 2,2-difluoroethylamine; The solvent is methanol or N,N-dimethylformamide; The molar ratio of the inorganic copper salt, organic ligand, ammonia, and 2,2-difluoroethylamine is 0.05~0.2: 0.05~0.2: 2.0~10.0:1.0, and the molar ratio of the inorganic copper salt to the organic ligand is 1:1; the inorganic copper salt is CuI, and the organic ligand is D-glucose or D-glucosamine.