Synthesis method of cyazofamid

Abstract

The invention provides a cyazofamid synthesis method, and belongs to the field of chemical synthesis. According to the method, p-methylacetophenone is taken as a raw material, and the cyazofamid is efficiently prepared through five-step reaction of oxidation, cyclization, cyanation, chlorination and sulfonylation. The technical core of the method is that a cyano group introduction path is innovatively constructed, and a key intermediate is optimized, specifically, a low-toxicity cyanation reagent is selected to finish specific introduction of a cyano group functional group, and the use of highly toxic cyanide is abandoned; and by adjusting the reaction path, the generation of nitrogen oxides which easily cause the risk of burning explosion in the traditional process is avoided, and the process safety is remarkably improved. Compared with the prior art, the method has the advantages of simple process, economical efficiency and environmental friendliness, is particularly suitable for industrial large-scale production, and provides an innovative solution for safe production of cyazofamid.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of traditional Chinese medicine intermediates in organic chemistry, and particularly relates to an improved synthesis method of cyazofamid. Background Art

[0002] Cyazofamid, full name 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide, has the molecular formula C 13 H 13 ClN4O2S, molecular weight 324.786, English name Cyazofamid, CAS registration number 120116-88-3, is a light yellow odorless powdery solid. Cyazofamid is a sulfonimidazole fungicide mainly used in agricultural production. It can specifically inhibit the electron transport chain of the mitochondrial cytochrome bc1 complex of pathogens, block the energy metabolism process of pathogens, and has significant inhibitory activity against oomycete pathogenic microorganisms and Plasmodiophora brassicae in the class Plasmodiophoromycetes. It can prevent and control various plant diseases such as downy mildew, late blight, and Phytophthora blight, and has advantages such as good control effect, low toxicity, long-lasting effect, and resistance to rain erosion. It has a wide range of uses and is safe and convenient to use. Currently, cyazofamid is widely used at home and abroad and has broad market prospects.

[0003] Existing synthesis methods of cyazofamid are as follows: (1) Patents CN116425681A / CN107501191A use p-methylacetophenone as the starting material. After oxidation to generate 2-oxo-2-(p-tolyl)acetaldehyde, it undergoes a cyclization reaction with glyoxal or glyoxylic acid to construct a 2-aldehyde imidazole skeleton, and then is prepared into cyazofamid through multiple steps of transformation such as oxidation, esterification, cyanation, chlorination, and sulfonamidation. Although the reaction conditions of this process are mild, there are problems such as redundant reaction steps and complex process routes, resulting in limited industrial production efficiency; (2) Patents CN107382871A / CN103936678A use p-methylacetophenone as the raw material. First, the α-carbon of acetophenone is activated by oxidation or halogenation, and then it reacts with glyoxal and hydroxylamine to obtain the intermediate 1-hydroxy-4-(p-tolyl)-2-methyloxime imidazole-3-oxide, and finally cyazofamid is synthesized through dehydration, chlorination, and sulfonamidation reactions. The main disadvantage of this route is the physicochemical properties of the oxime intermediate - high flammability and explosiveness, posing a potential safety hazard in the process; (3) Patent CN108912052A uses 5-(p-tolyl)-1H-imidazole as the raw material. First, it reacts with N,N-dimethylaminosulfonyl chloride to obtain an N-substituted imidazole, and then successively reacts with potassium cyanide and N-chlorosuccinimide to synthesize cyazofamid. Although this method simplifies the synthesis steps, it involves the use of highly toxic cyanides, significantly increasing the safety risk and waste treatment cost. Summary of the Invention

[0004] In the existing technology, the synthesis route of cyazofamid is generally long in steps and low in industrialization efficiency. Some involve high-risk and explosive intermediates and highly toxic reagents, resulting in high safety risks and production costs. To solve the above problems, the present invention provides a new synthesis method of cyazofamid that combines process simplicity, economy, and environmental protection and is suitable for industrial production.

[0005] The present invention first provides a synthesis method of cyazofamid, and the core technology lies in: using 2-oxo-2-(p-tolyl)acetaldehyde as a raw material, performing a ring-closing reaction with acetaldehyde and trimethylsilylamine, and then reacting with sodium nitrite in the presence of an acyl chloride to obtain 2-cyano-5-(p-tolyl)-1H-imidazole.

[0006] For the overall technical solution of the synthesis method of cyazofamid described in the present invention, using p-methylacetophenone as a raw material, cyazofamid is synthesized through five steps: oxidation, cyclization, cyanation, chlorination, and sulfonylation; specifically including the following steps:

[0007] The first step: React p-methylacetophenone with a selenium dioxide oxidant to synthesize 2-oxo-2-(p-tolyl)acetaldehyde;

[0008] The second step: Perform a cyclization reaction on 2-oxo-2-(p-tolyl)acetaldehyde, an ammoniating reagent, and acetaldehyde to obtain 2-methyl-5-(p-tolyl)-1H-imidazole;

[0009] The third step: Perform a cyanation reaction in the presence of an acyl chloride and sodium nitrite to obtain 2-cyano-5-(p-tolyl)-1H-imidazole;

[0010] The fourth step: In the presence of a chlorinating reagent, perform a substitution reaction to obtain 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile;

[0011] The fifth step: In the presence of N,N-dimethylsulfonyl chloride, perform a substitution reaction to obtain 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide.

[0012] A representative scheme of the technical solution of the present invention is represented by a chemical reaction formula:

[0013]

[0014] Further, in the above technical solution, the solvent selected for the first step is dioxane and water, and the volume ratio of the two is 15 - 10:1.

[0015] Further, in the above technical solution, the reaction temperature of the first step is 70 - 80 °C.

[0016] Further, in the above technical solution, the molar ratio of p-tolylglyoxal to acetaldehyde in the second step is 1:1 - 3.

[0017] Further, in the above technical solution, the ammoniating reagent in the second step is selected from ammonia methanol or trimethylsilylamine; preferably trimethylsilylamine.

[0018] Further, in the above technical solution, the second step reaction is carried out under anhydrous conditions.

[0019] Further, in the above technical solution, the solvent in the third step is selected as 1,4-dioxane.

[0020] Further, in the above technical solution, the cyanating reagent in the third step is acyl chloride and sodium nitrite.

[0021] Further, in the above technical solution, the acyl chloride in the third step is selected from acetyl chloride or trifluoroacetyl chloride or trifluoromethanesulfonyl chloride.

[0022] Further, in the above technical solution, the reaction temperature in the third step is 95 - 140 °C.

[0023] Further, in the above technical solution, the third step reaction is carried out under a nitrogen atmosphere.

[0024] Further, in the above technical solution, the molar ratio of 2-methyl-5-(p-tolyl)-1H-imidazole, acyl chloride, and sodium nitrite in the third step is 1:1.5 - 2:2 - 3.

[0025] Further, in the above technical solution, the chlorinating reagent in the fourth step is selected from N-chlorosuccinimide or thionyl chloride.

[0026] Further, in the above technical solution, the molar ratio of 5-(p-tolyl)-1H-imidazole-2-carbonitrile to the chlorinating reagent in the fourth step is 1:1.5 - 2.

[0027] Further, in the above technical solution, the reaction temperature in the fourth step is 30 - 50 °C; the reaction time is 2 - 8 hours.

[0028] Further, in the above technical solution, the molar ratio of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile, anhydrous potassium carbonate, and N,N-dimethylsulfamoyl chloride in the fifth step is 1:1.5 - 3:1.5 - 2.

[0029] Further, in the above technical solution, the reaction time in the fifth step is 4 - 10 hours.

[0030] Further, in the above technical solution, after the fifth step reaction is completed, the crude product is recrystallized with ethyl acetate. Description of the Drawings

[0031] Figure 1 HNMR spectrum of 2-methyl-5-(p-tolyl)-1H-imidazole obtained in Example 1 1 HNMR spectrum;

[0032] Figure 2 For the 13 13 C NMR spectrum of 2-methyl-5-(p-tolyl)-1H-imidazole obtained in Example 1;

[0033] Figure 3 For the LC-MS spectrum of 2-methyl-5-(p-tolyl)-1H-imidazole obtained in Example 1;

[0034] Figure 4 For the 1 HNMR spectrum of 2-cyano-5-(p-tolyl)-1H-imidazole obtained in Example 1;

[0035] Figure 5 For the 13 C NMR spectrum of 2-cyano-5-(p-tolyl)-1H-imidazole obtained in Example 1;

[0036] Figure 6 For the LC-MS spectrum of 2-cyano-5-(p-tolyl)-1H-imidazole obtained in Example 1. Specific examples

[0037] The present invention will be further described in detail below with reference to specific examples.

[0038] Example 1

[0039] First step, synthesis of p-tolylglyoxal: Add 27.7 g of selenium dioxide, 240 mL of dioxane and 20 mL of water to a round-bottom flask, heat to 70 °C, stir until the solid is completely dissolved, then add 26.8 g of p-methylacetophenone, and continue heating until the raw materials react completely. The reaction solution is cooled to room temperature, the catalyst is removed by filtration, the filtrate is concentrated, and recrystallized with water to obtain 27.41 g of a gray solid product, with a product yield of 92.5% and a purity of 98.2%.

[0040] Second step, synthesis of 2-methyl-5-(p-tolyl)-1H-imidazole: Add 39.4 g of trimethylsilylamine and 50 mL of methanol to a round-bottom flask, stir and dropwise add 44.1 g of 40% acetaldehyde-methanol solution at 10 °C, keep the temperature below 20 °C, dissolve 37.0 g of p-tolylglyoxal in 150 mL of methanol, stir and dropwise add this solution, react at 25 °C for 1 hour, after the reaction is completed, filter off the solid, concentrate the filtrate under reduced pressure, stir and crystallize the concentrate with hot water, filter at room temperature to obtain 42.4 g of a yellow solid crystal, which is identified as 2-methyl-5-(p-tolyl)-1H-imidazole, with a yield of 98.4% and a purity of 97.6%. The nuclear magnetic resonance and mass spectrometry results of this intermediate are as follows: 11H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.60 (d, J = 4.8 Hz, 2H), 7.45–7.22 (m, 1H), 7.14 (d, J = 7.6 Hz, 2H), 2.31 (s, 3H), 2.30 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 144.6, 139.9, 135.2, 132.8, 129.5, 124.4, 111.9, 21.2, 14.4. HRMS Calcd (ESI) m / z for [C 11 H 13 N2] + [M + H] + : 173.1073, found: 173.1089.

[0041] Step 3, Synthesis of 2-cyano-5-(p-tolyl)-1H-imidazole: Add 34.4 g of 2-methyl-5-(p-tolyl)-1H-imidazole and 500 mL of dioxane solvent to an autoclave. After dissolving clearly, add 40.0 g of trifluoroacetyl chloride and 27.6 g of sodium nitrite. After introducing nitrogen, stir and react at 140 °C for 10 hours. After the reaction is completed, concentrate and distill off the solvent, then extract with water and ethyl acetate. After concentrating the organic phase, 30.3 g of crude 2-cyano-5-(p-tolyl)-1H-imidazole is obtained, with a yield of 82.7% and a purity of 86.1%. The nuclear magnetic resonance and mass spectrometry results of this intermediate are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 2.31 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 137.1, 129.4, 124.8, 121.5, 118.7, 112.8, 20.8. HRMS Calcd (ESI) m / z for [C 11 H 10 N3] + [M + H] + : 184.0869, found: 184.0893.

[0042] Step 4, Synthesis of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile: Add 32.3 g of the crude product of 2-cyano-5-(p-tolyl)-1H-imidazole, 20 mL of DMAC, and 20 mL of acetonitrile into a round-bottom flask. After stirring evenly, add 40.5 g of sulfonyl chloride dropwise while controlling the temperature below 25 °C. After the addition, react at 20 °C for 0.5 h. After the reaction is completed, remove acetonitrile by rotary evaporation, add 10% sodium hydroxide solution to neutralize to neutrality, continue to stir for 2 h, filter by suction, and dry the filter cake to obtain 30.1 g of the product, with a yield of 92.1% and a purity of 93.76%.

[0043] Step 5, Synthesis of cyazofamid: Add 43.5 g of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile, 150 mL of ethyl acetate, 25 mL of cyclohexane, 30.0 g of anhydrous potassium carbonate, and 0.5 g of DMAP into a round-bottom flask. After heating to 45 °C and stirring evenly, add 43.1 g of dimethylaminosulfonyl chloride, and heat to reflux for 8 h. After the reaction is completed, add 50 mL of ethyl acetate and 100 mL of water, stir well and then cool to crystallize, filter. The crude product is recrystallized with ethyl acetate to obtain 56.8 g of the final product 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide, with a yield of 87.5% and a purity of 96.3%.

[0044] Example 2

[0045] Step 1, Synthesis of p-tolylglyoxal: Add 33.3 g of selenium dioxide, 240 mL of dioxane, and 20 mL of water into a round-bottom flask. Heat to 70 °C and stir until the solid dissolves, then add 26.8 g of p-methylacetophenone and continue to heat until the raw materials react completely. Cool the reaction solution to room temperature, filter off the catalyst by suction, concentrate the filtrate, and recrystallize with water to obtain 27.7 g of a gray solid product, with a product yield of 93.5% and a purity of 98.4%.

[0046] Step 2, Synthesis of 2-methyl-5-(p-tolyl)-1H-imidazole: Add 52.6 g of trimethylsilylamine and 50 mL of methanol into a round-bottom flask, stir and add 33.0 g of 40% acetaldehyde methanol solution dropwise at 10 °C, keep the temperature below 20 °C, dissolve 37.0 g of p-tolylglyoxal in 150 mL of methanol, stir and add this solution dropwise, and react at 25 °C for 1 h. After the reaction is completed, filter off the solid by suction, concentrate the filtrate under reduced pressure, stir the concentrate with hot water to crystallize, cool to room temperature and filter by suction to obtain 41.2 g of a yellow solid crystal, which is identified as 2-methyl-5-(p-tolyl)-1H-imidazole, with a yield of 95.7% and a purity of 97.2%.

[0047] Step 3. Synthesis of 2-cyano-5-(p-tolyl)-1H-imidazole: Add 25.8 g of 2-methyl-5-(p-tolyl)-1H-imidazole and 400 mL of dioxane solvent into an autoclave. After dissolution, add 60.0 g of trifluoromethanesulfonyl chloride and 31.5 g of sodium nitrite. After introducing nitrogen, stir and react at 140 °C for 10 hours. After the reaction is completed, concentrate and distill off the solvent, then extract with water and ethyl acetate. After concentrating the organic phase, 23.5 g of crude 2-cyano-5-(p-tolyl)-1H-imidazole is obtained, with a yield of 85.6% and a purity of 85%.

[0048] Step 4. Synthesis of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile: Add 32.3 g of the crude 2-cyano-5-(p-tolyl)-1H-imidazole, 20 mL of DMAC, and 20 mL of acetonitrile into a round-bottom flask. After stirring evenly, control the temperature below 25 °C and dropwise add 40.5 g of sulfonyl chloride. After the addition is completed, react at 25 °C for 0.5 hour. After the reaction is completed, rotary evaporate to remove acetonitrile, dropwise add 10% sodium hydroxide solution to neutralize to neutral, continue to stir for 2 hours, filter by suction, and dry the filter cake to obtain 30.8 g of the product, with a yield of 94.2% and a purity of 97.7%.

[0049] Step 5. Synthesis of cyazofamid: Add 54.4 g of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile, 150 mL of ethyl acetate, 25 mL of cyclohexane, 69.1 g of anhydrous potassium carbonate, and 0.5 g of DMAP into a round-bottom flask. Heat to 45 °C and stir evenly, then add 71.8 g of dimethylaminosulfonyl chloride, and heat to reflux for 8 hours. After the reaction is completed, add 50 mL of ethyl acetate and 100 mL of water, stir well, cool down to crystallize, filter, and recrystallize the crude product with ethyl acetate to obtain 71.9 g of the final product 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide, with a yield of 88.6% and a purity of 98.5%.

[0050] Example 3

[0051] Step 1. Synthesis of p-tolylglyoxal: Add 27.7 g of selenium dioxide, 215 mL of dioxane, and 15 mL of water into a round-bottom flask. Heat to 80 °C and stir until the solid is completely dissolved, then add 26.8 g of p-methylacetophenone and continue to heat until the raw materials react completely. Cool the reaction solution to room temperature, filter off the catalyst by suction, concentrate the filtrate, and recrystallize with water to obtain 27.74 g of a gray solid product, with a product yield of 93.6% and a purity of 96.2%.

[0052] Step 2, Synthesis of 2-methyl-5-(p-tolyl)-1H-imidazole: Add 39.4 g of trimethylsilylamine and 50 mL of methanol to a round-bottom flask. Stir and dropwise add 55.06 g of 40% acetaldehyde-methanol solution at 10 °C, keeping the temperature below 20 °C. Dissolve 37.0 g of p-tolylglyoxal in 150 mL of methanol, stir and dropwise add this solution, and react at 25 °C for 1 hour. After the reaction is completed, filter off the solid by suction, concentrate the filtrate under reduced pressure, stir the concentrate with hot water for crystallization, cool to room temperature and filter by suction to obtain 40.3 g of yellow solid crystals, which are identified as 2-methyl-5-(p-tolyl)-1H-imidazole, with a yield of 97.6% and a purity of 95.6%.

[0053] Step 3, Synthesis of 2-cyano-5-(p-tolyl)-1H-imidazole: Add 25.8 g of 2-methyl-5-(p-tolyl)-1H-imidazole and 400 mL of dioxane solvent to an autoclave. After dissolving clearly, add 40.0 g of trifluoroacetyl chloride and 31.5 g of sodium nitrite, introduce nitrogen, and stir and react at 140 °C for 12 hours. After the reaction is completed, concentrate and distill off the solvent, then extract with water and ethyl acetate. After concentrating the organic phase, 24.0 g of crude 2-cyano-5-(p-tolyl)-1H-imidazole is obtained, with a yield of 87.5% and a purity of 86.3%.

[0054] Step 4, Synthesis of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile: Add 33 g of the crude product of 2-cyano-5-(p-tolyl)-1H-imidazole, 20 mL of DMAC, and 20 mL of acetonitrile to a round-bottom flask. After stirring evenly, control the temperature below 25 °C and dropwise add 30.4 g of sulfonyl chloride. After the addition is completed, react at 20 °C for 0.5 hour. After the reaction is completed, remove acetonitrile by rotary evaporation, dropwise add 10% sodium hydroxide solution to neutralize to neutral, continue to stir for 2 hours, filter by suction, and dry the filter cake to obtain 30.6 g of the product, with a yield of 93.7% and a purity of 95.2%.

[0055] Step 5, Synthesis of cyazofamid: Add 43.5 g of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile, 150 mL of ethyl acetate, 25 mL of cyclohexane, 30.0 g of anhydrous potassium carbonate, and 0.5 g of DMAP to a round-bottom flask. After heating to 45 °C and stirring evenly, add 43.1 g of dimethylaminosulfonyl chloride, heat to reflux, and react for 10 hours. After the reaction is completed, add 50 mL of ethyl acetate and 100 mL of water, stir well, cool down to crystallize, filter, and recrystallize the crude product with ethyl acetate to obtain 55.5 g of the final product 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide, with a yield of 85.5% and a purity of 97.0%.

[0056] 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 by the above embodiments. The content described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing cyazofamid, characterized in that: The steps include: The first step: reacting p-methylacetophenone with selenium dioxide oxidant to synthesize 2-carbonyl-2-(p-tolyl)acetaldehyde; Step 2: Cyclization reaction of 2-carbonyl-2-(p-tolyl)acetaldehyde, an aminating agent and acetaldehyde to obtain 2-methyl-5-(p-tolyl)-1H-imidazole; The third step: cyanation reaction in the presence of acyl chloride and sodium nitrite to obtain 2-cyano-5-(p-tolyl)-1H-imidazole; Step 4: In the presence of a chlorinating agent, a substitution reaction is performed to obtain 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile; Step 5: In the presence of N,N-dimethylsulfonyl chloride, a substitution reaction is carried out to obtain 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide.

2. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the first step, a mixed solvent of dioxane and water is used, and the volume ratio of the two is 15-10:1; the reaction temperature is 70-80°C.

3. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the second step, the molar ratio of p-tolyl glyoxal to acetaldehyde is 1:1-3.

4. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the second step, the aminating agent is ammonia methanol or trimethylsilane; the reaction is carried out under anhydrous conditions.

5. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the third step, 1,4-dioxane is used as solvent; the acyl chloride is selected from acetyl chloride, trifluoroacetyl chloride or trifluoromethanesulfonyl chloride.

6. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the third step, the reaction temperature is 95-140°C; the reaction is carried out under a nitrogen atmosphere.

7. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the third step, the molar ratio of 2-methyl-5-(p-tolyl)-1H-imidazole, acyl chloride and sodium nitrite is 1:1.5-2:2-3.

8. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the fourth step, the chlorination agent is selected from N-chlorosuccinimide or sulfone chloride.

9. The method for synthesizing cyazofamid according to claim 1, characterized in that: The molar ratio of 5-(p-tolyl)-1H-imidazole-2-carbonitrile to the chlorination reagent is 1:1.5-2; the reaction temperature is 30-50° C., and the reaction time is 2-8 hours.

10. The method for synthesizing cyazofamid according to claim 1, characterized in that: In the fifth step, the molar ratio of 4-chloro-5-(p-tolyl)-1H-imidazole-2-carbonitrile, anhydrous potassium carbonate and N,N-dimethylsulfonyl chloride is 1:1.5-3:1.5-2.

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