Improved preparation method of formamidine acetate

Abstract

The invention provides an improved preparation method of formamidine acetate, and belongs to the technical field of fine chemical engineering. According to the preparation method, formamide, acetic acid and ammonia gas are taken as reaction raw materials, and formamidine acetate can be efficiently prepared through one-step reaction in the presence of a dehydrating agent and a catalyst. Different from a traditional process, the technical core of the method is that formamide is innovatively selected as a starting raw material, and the reaction path is remarkably simplified. Compared with the problems of long multi-step reaction process, high safety risk and the like in the prior art, the method disclosed by the invention is mild in reaction condition, simple and convenient to operate and high in product yield, and has good industrial application potential.

Description

Technical Field

[0001] This invention relates to an improved preparation method of formamidine acetate, belonging to the field of fine chemical or pharmaceutical intermediates technology. Background Technology

[0002] Formamidine acetate, CAS: 3473-63-0, molecular formula: C3H8N2O2, relative molecular mass 104.11, chemical structure: Formamidine acetate is an important organic carboxylate compound. Its molecular structure combines the properties of both the formamidine group and the acetate ion, exhibiting unique chemical stability and reactivity, and thus finding wide applications in many fields. In the synthesis of fine chemicals, formamidine acetate can be used as a formamidine reagent, providing H₂C=N₂. + As an H2 reactive intermediate, formamidine acetate is used to construct nitrogen-containing heterocyclic skeletons such as pyrimidines and triazines (e.g., for the synthesis of the antiviral drug ribavirin). It can also serve as a mild basic catalyst, forming a buffer system between acetate and formamidine, suitable for reactions sensitive to strong bases. In the pharmaceutical and biochemical fields, formamidine acetate can be used in drug molecule design, for the synthesis of purine antimetabolites (such as 6-aminopurine), as a modifying group for histone deacetylase inhibitors, and as a carboxyl activating agent in protein sequencing. Furthermore, in the fields of new energy materials and functional materials, formamidine acetate is a key raw material for preparing formamidine-lead-iodine-based perovskite (FAPbI3), a next-generation high-efficiency solar cell absorber layer material.

[0003] Existing methods for synthesizing formamidine acetate include the following: 1) Patent CN 101717351 A uses hydrogen cyanide, ethanol, and dilute hydrochloric acid to produce ethyl iminoformate hydrochloride, which is then reacted with ammonium acetate to produce ethyl iminoformate acetate. Finally, ammonia gas is introduced to obtain pure formamidine acetate. This method involves many steps and is complex to operate; 2) Formamidine acetate is prepared by hydrogenation reduction reaction using cyanamide and acetic acid as raw materials. Zhou Yang et al. (2004) used a Pd-In bimetallic catalyst supported on activated carbon to catalyze the hydrogenation of cyanamide in acetic acid to synthesize formamidine acetate. However, this method requires the reaction to be carried out in a hydrogen atmosphere, which carries a high safety risk in industrial implementation. Martin Klein et al. (2021) adopted an electrochemical synthesis strategy, using porous nickel and graphite as the cathode and anode, respectively, to generate hydrogen gas through in-situ electrolysis of water, thereby realizing the reduction reaction of cyanamide. This method avoids the direct use of hydrogen, but it still has significant drawbacks, such as high equipment investment costs and significant energy consumption, which greatly restricts its large-scale industrial application. Summary of the Invention

[0004] To overcome the aforementioned technical deficiencies, this invention provides an improved method for preparing formamidine acetate. This method uses formamide, acetic acid, and ammonia as reactants, and in the presence of a dehydrating agent and a catalyst, formamidine acetate can be efficiently prepared in a single step. Unlike traditional processes, the core technology of this invention lies in the innovative use of formamide as the starting material, significantly simplifying the reaction pathway. Compared to the lengthy multi-step reaction processes and higher safety risks inherent in existing technologies, the method described in this invention offers mild reaction conditions, simple operation, and high product yield, demonstrating excellent potential for industrial application.

[0005] The present invention discloses a method for preparing formamidine acetate, comprising the following steps: using formamide, acetic acid, and ammonia as reactants, and reacting them in the presence of a dehydrating agent and a catalyst to obtain formamidine acetate.

[0006] The chemical equation is shown below:

[0007]

[0008] Furthermore, in the above technical solution, the steps are as follows: formamide, acetic acid, dehydrating agent and catalyst are added to the reaction vessel, an ammonia generator is connected, and the reaction is carried out under heating conditions. After the reaction is completed, the mixture is cooled and filtered, then cooled to crystallize, washed multiple times with pre-cooled solvent, and dried to obtain formamidine acetate.

[0009] Furthermore, in the above technical solution, the molar ratio of formamide to acetic acid is 1-2:1.

[0010] Furthermore, in the above technical solution, the dehydrating agent is selected from activated alumina and molecular sieve.

[0011] Furthermore, in the above technical solution, the catalyst is selected from one of copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, and scandium trifluoromethanesulfonate.

[0012] Furthermore, in the above technical solution, the ammonia generator contains ammonia water with a mass concentration of 25-30%.

[0013] Furthermore, in the above technical solution, the reaction temperature is 90–110℃; the reaction time is 6–10h.

[0014] Furthermore, in the above technical solution, the washing solvent used during cooling crystallization is one of pre-cooled anhydrous ethanol or anhydrous diethyl ether.

[0015] Compared with the shortcomings of existing technologies, such as the difficulty in storing raw materials, low reaction yield, and difficulty in industrialization, the present invention has a mild reaction, simple operation, high yield, and is easy to industrialize. Specific Implementation

[0016] The present invention will be further described in detail below with reference to specific embodiments. The general reaction equation used in the reaction embodiments is as follows:

[0017]

[0018] Example 1

[0019] Add 22.5 g of formamide, 30.0 g of acetic acid, and 60 g of activated alumina to a dry three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, reflux condenser, and ammonia inlet tube. Start stirring and continuously introduce ammonia gas into the system using an ammonia generator to purge air. Slowly heat to 100°C using a heating device and stir continuously at this temperature for 6 hours. After the reaction is complete, stop heating and allow the reaction mixture to cool naturally to 50°C. Filter the mixture and then place the filtrate in an ice-water bath at 0-4°C and let it stand overnight to allow formamidine acetate crystals to fully precipitate. Collect the white crystals by filtration and wash them several times with a small amount of pre-cooled anhydrous ethanol to remove residual formamide and impurities. Finally, transfer the filter cake to a vacuum drying oven and dry at 50°C for 4 hours to obtain 27.5 g of pure white powdered formamidine acetate, with a yield of 52.8% and a purity of 99.3%.

[0020] Example 2

[0021] Add 22.5 g of formamide, 30.0 g of acetic acid, 60 g of activated alumina, and 12.3 g of scandium trifluoromethanesulfonate to a dry three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, reflux condenser, and ammonia inlet tube. Start stirring and continuously introduce ammonia gas into the system using an ammonia generator to purge air. Slowly heat to 100°C using a heating device and stir continuously at this temperature for 6 hours. After the reaction is complete, stop heating and allow the reaction mixture to cool naturally to 50°C, then filter. Place the filtrate in an ice-water bath at 0-4°C and let it stand overnight to allow formamidine acetate crystals to fully precipitate. Collect the white crystals by filtration and wash them several times with a small amount of pre-cooled anhydrous ethanol to remove residual formamide and byproducts. Finally, transfer the filter cake to a vacuum drying oven and dry at 50°C for 4 hours to obtain 47.0 g of pure white powdered formamidine acetate, with a yield of 90.3% and a purity of 99.4%.

[0022] Example 3

[0023] To a dry three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, reflux condenser, and ammonia inlet tube, add 27.0 g of formamide, 30.0 g of acetic acid, 60 g of activated alumina, and 12.3 g of scandium trifluoromethanesulfonate. Start stirring and continuously introduce ammonia gas into the system using an ammonia generator to purge air. Slowly heat to 110°C using a heating device and continue stirring at this temperature for 7 hours. After the reaction is complete, stop heating and allow the reaction mixture to cool naturally to 50°C, then filter. Place the filtrate in an ice-water bath at 0-4°C and let it stand overnight to allow formamidine acetate crystals to fully precipitate. Collect the white crystals by filtration, and wash the crystals several times with a small amount of pre-cooled anhydrous ether to remove residual formamide and byproducts. Finally, transfer the filter cake to a vacuum drying oven and dry at 50°C for 4 hours to obtain 48.2 g of pure white powdered formamidine acetate, with a yield of 92.6% and a purity of 99.2%.

[0024] Example 4

[0025] 27.0 g of formamide, 30.0 g of acetic acid, 60 g of activated alumina, and 9.0 g of copper trifluoromethanesulfonate were added to a dry three-necked round-bottom flask equipped with a magnetic stirrer, thermometer, reflux condenser, and ammonia inlet tube. Stirring was started, and ammonia gas was continuously introduced into the system through an ammonia generator to purge air. The mixture was slowly heated to 110°C using a heating device, and the reaction was continuously stirred at this temperature for 8 hours. After the reaction was complete, heating was stopped, and the reaction mixture was allowed to cool naturally to 50°C and then filtered. The filtrate was then placed in an ice-water bath at 0-4°C and allowed to stand overnight to allow formamidine acetate crystals to fully precipitate. The white crystals were collected by filtration and washed several times with a small amount of pre-cooled anhydrous ether to remove residual formamide and byproducts. Finally, the filter cake was transferred to a vacuum drying oven and dried at 50°C for 4 hours to obtain 42.4 g of pure white powdered formamidine acetate, with a yield of 81.4% and a purity of 99.7%.

[0026] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing formamidine acetate, characterized in that, Includes the following steps: Formamide acetate was prepared by reacting formamide, acetic acid, and ammonia in the presence of a dehydrating agent and a catalyst.

2. The method for preparing formamidine acetate according to claim 1, characterized in that: Formamide, acetic acid, dehydrating agent and catalyst are added to the reaction vessel, and an ammonia generator is connected. The reaction is carried out under heating conditions. After the reaction is completed, the mixture is cooled and filtered. Then it is cooled to crystallize, washed multiple times with pre-cooled solvent, and dried to obtain formamidine acetate.

3. The method for preparing formamidine acetate according to claim 1 or 2, characterized in that: The molar ratio of formamide to acetic acid is 1-2:

1.

4. The method for preparing formamidine acetate according to claim 1 or 2, characterized in that: The dehydrating agent is selected from activated alumina or molecular sieve.

5. The method for preparing formamidine acetate according to claim 1 or 2, characterized in that: The catalyst is copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, or scandium trifluoromethanesulfonate.

6. The method for preparing formamidine acetate according to claim 1 or 2, characterized in that: The ammonia generator contains ammonia water with a mass concentration of 25-30%.

7. The method for preparing formamidine acetate according to claim 1 or 2, characterized in that: The reaction temperature is 90–110℃; the reaction time is 6–10 h.

8. The method for preparing formamidine acetate according to claim 2, characterized in that: The pre-cooling solvent is selected from anhydrous ethanol or anhydrous diethyl ether.

Images