Process for the preparation of 4,5-dicyanoimidazole

Abstract

This invention belongs to the field of chemical synthesis technology, specifically providing a method for preparing 4,5-dicyanimidazole. The method for preparing 4,5-dicyanimidazole according to an embodiment of the present invention includes the following steps: Step S1, diaminomaleonitrile undergoes a condensation reaction with triethyl orthoformate under the action of a first catalyst to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester; Step S2, the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester undergoes a cyclization reaction under the action of a second catalyst to generate 4,5-dicyanimidazole. The preparation method according to this embodiment of the present invention adopts a stepwise synthesis, with the condensation reaction and cyclization reaction carried out separately under the action of catalysts. 4,5-dicyanimidazole can be synthesized under low-temperature conditions, avoiding the generation of highly polar impurities and tar that are difficult to remove in high-temperature reactions, effectively reducing the occurrence of side reactions and the difficulty of purification, and also effectively reducing energy consumption.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for preparing 4,5-dicyanimidazole. Background Technology

[0002] 4,5-Dicyanimidazole is an important nitrogen-containing heterocyclic fine chemical intermediate. It is mainly used as a highly efficient activator in the solid-phase synthesis of DNA and RNA oligonucleotides, exhibiting higher coupling efficiency and fewer side reactions compared to traditional tetrazolium reagents, effectively reducing the risk of depurination. Simultaneously, it can also be used in peptide synthesis and nucleoside drug preparation, and is a key synthetic building block in optoelectronic materials, energetic materials, and organocatalysis, demonstrating significant application value in the biopharmaceutical field.

[0003] Currently, the main methods for synthesizing 4,5-dicyanimidazole are as follows: Firstly, 4,5-dicyanimidazole is obtained by reacting diaminomaleitrile and triethyl orthoformate in xylene under high temperature conditions via a one-step reaction (see Org. Lett. 2006, 8, 5, pp. 923-926).

[0004] The specific route is as follows:

[0005] However, the yield of this synthetic route is only 80%; moreover, the reaction under high temperature conditions will produce highly polar impurities that are difficult to purify and tar, making it difficult to achieve industrial production.

[0006] Secondly, the production of 4,5-dicyanimidazolium from potassium cyanide, ammonium formate, and formamide at high temperatures has a low yield and requires the use of cyanide (which is highly toxic), making it difficult to scale up production (see Nature Chemistry volume 12, pp. 1023-1028). Summary of the Invention

[0007] In view of this, the purpose of this invention is to provide a method for preparing 4,5-dicyanimidazolium that is safe, easy to operate, has a mild reaction, few byproducts, high yield, generates little waste, and has strong route feasibility.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: The preparation method of 4,5-dicyanimidazole according to an embodiment of the present invention includes the following steps: In step S1, diaminomaleonitrile and triethyl orthoformate undergo a condensation reaction under the action of the first catalyst to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester. In step S2, the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester undergoes a cyclization reaction under the action of a second catalyst to generate 4,5-dicyanoimidazole.

[0009] According to some embodiments of the present invention, in step S1, the first catalyst is selected from one or more of p-toluenesulfonic acid monohydrate, acetic acid, sulfuric acid, and methanesulfonic acid.

[0010] Further, step S1 includes: Diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate are added to acetonitrile to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

[0011] Further, in step S1, the molar ratio of diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate is 1.0 : (1.0~1.5) : (0.01~0.1), the reaction temperature of the condensation reaction is 20~30℃, and the reaction time is 3~5 hours.

[0012] Further, in step S1, after the reaction is complete, the solvent is concentrated and removed, dichloromethane is added and the mixture is slurried, filtered, and dried to obtain the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

[0013] According to some embodiments of the present invention, in step S2, the second catalyst is selected from one or more of ammonia, ammonium chloride, DBU, sodium ethoxide, and sodium acetate.

[0014] Furthermore, in step S2, the second catalyst is a combination of ammonia and ammonium chloride.

[0015] Furthermore, step S2 includes: (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester and ammonium chloride were added to methanol, and ammonia gas was introduced to carry out the cyclization reaction to generate 4,5-dicyanimidazole.

[0016] Further, the molar ratio of ammonia to (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester and ammonium chloride is (2.0~3.0):1.0:(0.1~0.5), the temperature of ammonia gas is 5~10℃, the reaction time is 4~6 hours, and the reaction temperature is 25~30℃.

[0017] Further, in step S2, after the reaction is complete, the mixture is concentrated, slurried with water, filtered, and dried to obtain the 4,5-dicyanimidazolium.

[0018] The above-described technical solution of the present invention has at least one of the following beneficial effects: The preparation method according to the embodiments of the present invention is highly safe, easy to operate, has a mild reaction, few by-products, high yield, generates little waste, and has strong route feasibility. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0020] The preparation method of 4,5-dicyanimidazolium according to an embodiment of the present invention is described in detail below.

[0021] The preparation method of 4,5-dicyanimidazole according to an embodiment of the present invention includes the following steps: In step S1, diaminomaleonitrile and triethyl orthoformate undergo a condensation reaction under the action of the first catalyst to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester. In step S2, the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester undergoes a cyclization reaction under the action of a second catalyst to generate 4,5-dicyanoimidazole.

[0022] Specifically, the synthesis route is shown in the following equation:

[0023] In other words, according to the preparation method of this invention, diaminomaleonitrile is used as the starting material. It is first condensed with triethyl orthoformate under the action of a first catalyst to generate an intermediate. Subsequently, this intermediate undergoes a cyclization reaction under the action of a second catalyst to generate the target compound, 4,5-dicyanimidazole. This stepwise synthesis, with the condensation and cyclization reactions carried out separately under catalysts, allows for the synthesis of 4,5-dicyanimidazole at low temperatures. This avoids the generation of highly polar impurities and tar that are difficult to remove during high-temperature reactions, effectively reducing the occurrence of side reactions and the difficulty of purification. It also effectively reduces the reaction temperature and energy consumption, making the reaction conditions more moderate.

[0024] The following section will explain each step in detail.

[0025] (a) Condensation reaction That is: in step S1, diaminomaleonitrile and triethyl orthoformate undergo a condensation reaction under the action of the first catalyst to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

[0026] Existing technologies involve the condensation and cyclization reaction of diaminomaleitrile with triethyl orthoformate under high temperature conditions. However, this synthetic route is characterized by slow reaction, numerous side reactions, low yield, and difficulty in purification.

[0027] To address this issue, this application employs a stepwise synthesis method and selects a suitable first catalyst in the condensation reaction, which can significantly reduce the reaction temperature of the condensation reaction, while reducing the occurrence of side reactions, avoiding the generation of difficult-to-remove impurities and by-products, and improving the purity and yield of the intermediate.

[0028] According to some embodiments of the present invention, in step S1, the first catalyst is selected from one or more of p-toluenesulfonic acid monohydrate, acetic acid, sulfuric acid, and methanesulfonic acid.

[0029] These catalysts can efficiently activate the departure of alkoxy groups from triethyl orthoformate, promoting the efficient condensation reaction while avoiding side reactions caused by high temperatures. Among them, p-toluenesulfonic acid monohydrate has moderate catalytic activity, few side reactions, and is inexpensive, making it suitable for industrial production and therefore preferred.

[0030] Further, step S1 includes: Diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate are added to acetonitrile to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

[0031] Acetonitrile has moderate polarity, good solubility in raw materials and intermediates, and low toxicity, making it suitable as a reaction solvent for condensation reactions. It can also stabilize the reaction system and reduce the occurrence of side reactions.

[0032] Specifically, the reaction formula in step S1 is as follows:

[0033] Further, in step S1, the molar ratio of diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate is 1.0 : (1.0~1.5) : (0.01~0.1), preferably 1.0 : 1.05 : 0.03. Using a slight excess of triethyl orthoformate is beneficial for complete reaction, and the excess triethyl orthoformate is easily removed during post-processing.

[0034] The condensation reaction can be carried out at a temperature of 20-30°C for 3-5 hours. In other words, the condensation reaction can be completed at room temperature without the need for additional heating and temperature control. The reaction is highly efficient, produces few byproducts, and has a yield of over 98%.

[0035] Furthermore, in step S1, after the reaction is complete, the solvent is concentrated and removed, dichloromethane is added and the mixture is slurried, filtered, and dried to obtain the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester, with a liquid phase purity of over 99.5% by HPLC.

[0036] In other words, this application can be easily processed and proceeded directly to the next step; that is, it is simple to operate and produces very little waste.

[0037] (ii) Ring-closing reaction That is, in step S2, the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester undergoes a ring-closing reaction under the action of a second catalyst to generate 4,5-dicyanimidazole.

[0038] In other words, by further selecting a suitable second catalyst, the ring-closing reaction can also avoid high-temperature reactions, thereby avoiding the generation of highly polar impurities and tar that are difficult to remove.

[0039] Specifically, the second catalyst is selected from one or more of ammonia, ammonium chloride, DBU, sodium ethoxide, and sodium acetate. These catalysts can promote the cyclization process and improve the reaction selectivity. Among them, the combination of ammonia and ammonium chloride has the best effect, and the two can have a synergistic effect, thereby further improving the selectivity of the cyclization reaction.

[0040] Specifically, the reaction formula in step S2 is as follows:

[0041] Furthermore, step S2 includes: Ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimide and ammonium chloride were added to methanol, and ammonia gas was introduced to carry out the ring-closure reaction, producing 4,5-dicyanimidazole. Methanol, as a reaction solvent for the ring-closure reaction, has good solubility and low toxicity.

[0042] Further, the molar ratio of ammonia to ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimide and ammonium chloride is (2.0~3.0):1.0:(0.1~0.5). Using excess ammonia is beneficial for increasing the reaction rate and yield. Preferably, the molar ratio of ammonia to ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimide and ammonium chloride is 3.0:1.0:0.03.

[0043] Furthermore, the temperature at which ammonia gas is introduced is 5-10°C, the reaction time is 4-6 hours, and the reaction temperature is 25-30°C. In other words, by using a combination of ammonia and ammonium chloride, the reaction temperature can be controlled within the normal temperature range, avoiding high-temperature side reactions and reducing reaction costs.

[0044] Furthermore, in step S2, after the reaction is complete, the mixture is concentrated, slurried with water, filtered, and dried to obtain the 4,5-dicyanimidazole. With simple processing, the purity can reach over 99.5%, meeting the requirements for subsequent applications.

[0045] To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to embodiments.

[0046] Experimental Example 1: Preparation of Compound 4,5-Dicyanoimidazole Step 1: Take a 500ml three-necked flask and add acetonitrile (200ml, 4w / w), diaminomaleonitrile (50g, 0.462mol, 1.0eq), and triethyl orthoformate (71.9g, 0.485mol, 1.05eq). Add p-toluenesulfonic acid monohydrate (2.64g, 0.013mol, 0.03eq) all at room temperature. React at 20-30℃ for 4h, monitored by TLC. After the reaction is complete, concentrate the system to dryness with acetonitrile, add 100g of dichloromethane and stir for 0.5h, filter, and dry to obtain 74.6g of (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester, yield 98.3%, HPLC: 99.9%.

[0047] Step 2: Take a 500ml three-necked flask and add methanol (240ml, 4w / w), (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester (60g, 0.365mol, 1.0eq), and ammonium chloride (0.58g, 0.01mol, 0.03eq). Control the temperature at 5-10℃ and pass ammonia gas (18.68g, 1.097mol, 3eq). After passing the ammonia gas, raise the temperature to 25-30℃ and react for 4 hours. After the reaction is complete, concentrate the solution, add 100g of water to make a slurry, filter, and dry to obtain 41.8g of the 4,5-dicyanoimidazolium, with a yield of 97% and an HPLC yield of 99.9%.

[0048] The structure of the obtained product was confirmed by nuclear magnetic resonance (NMR) experiments, and the data are as follows: 1¹H NMR (400 MHz, DMSO-d6) δ 13.80–12.50 (s, 1H), 8.50–8.00 (s, 1H). The results are consistent with the structure of the target product, 4,5-dicyanimidazolium.

[0049] Experimental Example 2: Preparation of 4,5-dicyanimidazole Step 1: Take a 2L three-necked flask and add acetonitrile (800ml, 4w / w), diaminomaleonitrile (200g, 1.85mol, 1.0eq), and triethyl orthoformate (287.9g, 1.94mol, 1.05eq). Add p-toluenesulfonic acid monohydrate (10.55g, 0.055mol, 0.03eq) all at room temperature. React at 20-30℃ for 4h, monitored by TLC. After the reaction is complete, concentrate the system to dryness with acetonitrile, add 400g of dichloromethane and stir for 0.5h, filter, and dry to obtain 300g of (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester, yield 98.8%, HPLC: 99.9%.

[0050] Step 2: Take a 2L three-necked flask and add methanol (960ml, 4w / w), (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester (240g, 1.462mol, 1.0eq), and ammonium chloride (2.34g, 0.043mol, 0.03eq). Control the temperature at 5-10℃ and pass ammonia gas (74.68g, 4.38mol, 3eq). After passing the ammonia gas, raise the temperature to 25-30℃ and react for 4 hours. After the reaction is complete, concentrate the solution, add 400g of water to make a slurry, filter, and dry to obtain 169.2g of the 4,5-dicyanoimidazolium, with a yield of 98% and an HPLC accuracy of 99.9%.

[0051] The structure of the obtained product was confirmed by nuclear magnetic resonance (NMR) experiments, and the data are as follows: 1 ¹H NMR (400 MHz, DMSO-d6) δ 13.80–12.50 (s, 1H), 8.50–8.00 (s, 1H). The results are consistent with the structure of the target product, 4,5-dicyanimidazolium.

[0052] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing 4,5-dicyanimidazole, characterized in that, Includes the following steps: In step S1, diaminomaleonitrile and triethyl orthoformate undergo a condensation reaction under the action of the first catalyst to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester. In step S2, the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester undergoes a cyclization reaction under the action of a second catalyst to generate 4,5-dicyanoimidazole.

2. The preparation method according to claim 1, characterized in that, In step S1, the first catalyst is selected from one or more of p-toluenesulfonic acid monohydrate, acetic acid, sulfuric acid, and methanesulfonic acid.

3. The preparation method according to claim 2, characterized in that, Step S1 includes: Diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate are added to acetonitrile to generate (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

4. The preparation method according to claim 3, characterized in that, In step S1, the molar ratio of diaminomaleitrile, triethyl orthoformate, and p-toluenesulfonic acid monohydrate is 1.0 : (1.0~1.5) : (0.01~0.1), the reaction temperature of the condensation reaction is 20~30℃, and the reaction time is 3~5 hours.

5. The preparation method according to claim 3, characterized in that, In step S1, after the reaction is complete, the solvent is removed by concentration, dichloromethane is added and the mixture is slurried, filtered, and dried to obtain the (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester.

6. The preparation method according to claim 1, characterized in that, In step S2, the second catalyst is selected from one or more of ammonia, ammonium chloride, DBU, sodium ethoxide, and sodium acetate.

7. The preparation method according to claim 6, characterized in that, In step S2, the second catalyst is a combination of ammonia and ammonium chloride.

8. The preparation method according to claim 7, characterized in that, Step S2 includes: (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester and ammonium chloride were added to methanol, and ammonia gas was introduced to carry out the cyclization reaction to generate 4,5-dicyanimidazole.

9. The preparation method according to claim 8, characterized in that, The molar ratio of ammonia to (Z)-N-(2-amino-1,2-dicyanovinyl)formimide ethyl ester and ammonium chloride is (2.0~3.0):1.0:(0.1~0.5), the temperature of the ammonia gas is 5~10℃, the reaction time is 4~6 hours, and the reaction temperature is 25~30℃.

10. The preparation method according to claim 1, characterized in that, In step S2, after the reaction is complete, the mixture is concentrated, slurried with water, filtered, and dried to obtain the 4,5-dicyanimidazolium.

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