A method for synthesizing 1-methylhydantoin

Abstract

This invention discloses a green synthesis method for 1-methylhydantoin, belonging to the field of pharmaceutical intermediates technology. The method uses industrial-grade sodium sarcosinate aqueous solution and urea as raw materials, heating to 120-160℃ under acidic conditions for simultaneous dehydration and cyclization. High-purity 1-methylhydantoin is obtained through steps such as anhydrous ethanol extraction, activated carbon decolorization, and low-temperature crystallization. This invention solves the problems of existing technologies relying on highly toxic sodium cyanate, high production costs, and difficult waste treatment. It enables the synthesis of 1-methylhydantoin using urea instead of sodium cyanate, significantly reducing raw material costs and avoiding the generation of cyanide-containing wastewater. The reaction is completed in a single reactor, the process is simple, safe to operate, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a chemical synthesis method for 1-methylhydantoin, belonging to the field of pharmaceutical intermediate synthesis. Background Technology

[0002] 1-Methylhydantoin (CAS No.: 616-04-6), also known as methylhydantoin, has the molecular formula C4H6N2O2 and a relative molecular mass of 114.10. It is a colorless crystal, readily soluble in water and chloroform, soluble in methanol and ethanol, but insoluble in ether and petroleum ether. Current research indicates that it possesses a wide range of pharmacological activities, including anti-inflammatory, antitussive, antiasthmatic, expectorant, hypoglycemic, lipid-lowering, antioxidant, and reactive oxygen species and free radical scavenging effects. It can be used for conditions such as hypoalbuminemia and is considered a promising candidate drug.

[0003] Currently, there are two main types of methods for synthesizing 1-methylhydantoin: ① Taking JP2001365436A as an example, this method uses hydroxyacetonitrile as a raw material to first obtain sarcosine, which is then reacted with sodium cyanate to obtain 1-methylhydantoin. This route relies on highly toxic hydroxyacetonitrile and sodium cyanate, making waste treatment difficult. ② Taking CN101054366A as an example, this method uses methylamine and sodium chloroacetate as raw materials, and obtains 1-methylhydantoin through a four-step reaction. Although this avoids the use of highly toxic chemicals, the reaction steps are lengthy, the raw material price is high, and the yield is only about 60%. Summary of the Invention

[0004] The present invention discloses a method for synthesizing 1-methylhydantoin, which innovatively uses sarcosine and urea as raw materials. By strictly controlling the reaction conditions, 1-methylhydantoin can be efficiently obtained in a single step. The chemical reaction formula is as follows:

[0005] The method for synthesizing 1-methylhydantoin according to the present invention includes the following steps: 1) Raw material mixing and pH adjustment: Mix sodium sarcosinate, urea and catalyst, and add inorganic acid to adjust the pH of the system to 1-3; 2) Dehydration cyclization reaction: The mixture is heated to 120-160℃ and dehydrated simultaneously with stirring until the water in the system is evaporated to dryness, resulting in a salt-containing solid mixture; 3) Post-processing purification: The salt-containing solid mixture was successively extracted with organic solvents, concentrated, decolorized, crystallized and dried to obtain 1-methylhydantoin.

[0006] Furthermore, in the above technical solution, the molar ratio of urea to sodium sarcosinate is 1.0-1.5:1, preferably 1.1-1.3:1.

[0007] Furthermore, in the above technical solution, the catalyst is zirconium oxychloride octahydrate, zirconium sulfate, zirconium oxynitrate, or supported zirconium oxychloride octahydrate, and the amount of catalyst used is 2-8 mol relative to sodium sarcosinate.

[0008] Furthermore, in the above technical solution, the sodium sarcosinate is added in the form of an industrial-grade aqueous solution with a mass fraction of 30-40%.

[0009] Furthermore, in the above technical solution, the inorganic acid is selected from any one of concentrated hydrochloric acid, concentrated sulfuric acid, and phosphoric acid, preferably concentrated hydrochloric acid.

[0010] Furthermore, in the above technical solution, the heating reaction temperature is 130-150℃, preferably 140℃.

[0011] Furthermore, in the above technical solution, the dehydration treatment is vacuum dehydration with reduced pressure, and the vacuum degree is controlled between -0.08MPa and -0.1MPa.

[0012] Furthermore, in the above technical solution, the organic solvent extraction specifically involves: adding anhydrous ethanol to the salt-containing solid mixture, heating and refluxing for 10-20 minutes to fully dissolve the organic matter, filtering while hot, washing the filter cake with hot ethanol 1-2 times, and combining the filtrates.

[0013] Furthermore, in the above technical solution, the crystallization specifically involves: placing the decolorized filtrate in an environment of 0-5℃ and stirring to crystallize for 1-3 hours, filtering it, washing the crystals with ice water 1-2 times, and vacuum drying them at 60-80℃ to constant weight.

[0014] The advantages of this invention are: the raw materials used in this synthesis method are inexpensive and readily available, the reaction process is simple to operate, the synthesis route is short, which greatly reduces the cost of the entire production process, the yield of 1-methylhydantoin is high and the purity is good, the entire reaction process is non-toxic and pollution-free, reducing environmental pollution and enabling environmentally friendly production. Detailed Implementation

[0015] The present invention will be further described in detail below with reference to specific embodiments. Example 1

[0016] 50.7 g of 35% sodium sarcosinate aqueous solution (0.16 mol) and 10.6 g of urea (0.176 mol, 1.1 eq) were added to a 250 mL three-necked flask and stirred. 2.6 g of zirconium oxychloride octahydrate (5 mol%) was added, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was gradually heated to 140 °C with stirring, and then vacuum-sealed. After drying, a salt-containing solid mixture was obtained. After cooling to room temperature, 30 mL of deionized water and 30 mL of ethyl acetate were added to the solid, and extraction was performed after thorough stirring. The organic phase was collected. The organic phase was concentrated by adding 30 mL of anhydrous ethanol to the concentrate and heating under reflux for 15 minutes to fully dissolve the organic matter. The mixture was filtered while hot, and the filter cake was washed with a small amount of hot ethanol. The filtrate was collected and concentrated under reduced pressure to obtain a pale yellow crude product. The crude product was dissolved in a small amount of hot water, decolorized with a small amount of activated carbon, and filtered. The filtrate was placed in a 0°C cold trap and stirred for 2 h to crystallize. After filtration, the crystals were washed with a small amount of ice water and dried thoroughly to obtain 15.5 g of 1-methylhydantoin, with a yield of 85.2%. Example 2

[0017] 50.7 g of 35% sodium sarcosinate aqueous solution (0.16 mol) and 14.4 g of urea (0.176 mol, 1.5 eq) were added to a 250 mL three-necked flask and stirred. 2.6 g of zirconium oxychloride octahydrate (5 mol%) was added, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was gradually heated to 140 °C with stirring, and then vacuum-sealed. After drying, a salt-containing solid mixture was obtained. After cooling to room temperature, 30 mL of deionized water and 30 mL of ethyl acetate were added to the solid, and extraction was performed after thorough stirring. The organic phase was collected. The organic phase was concentrated by adding 30 mL of anhydrous ethanol to the concentrate and heating under reflux for 15 minutes to fully dissolve the organic matter. The mixture was filtered while hot, and the filter cake was washed with a small amount of hot ethanol. The filtrate was collected and concentrated under reduced pressure to obtain a pale yellow crude product. The crude product was dissolved in a small amount of hot water, decolorized with a small amount of activated carbon, and filtered. The filtrate was placed in a 0°C cold trap and stirred for 2 h to crystallize. After filtration, the crystals were washed with a small amount of ice water and dried thoroughly to obtain 16.1 g of 1-methylhydantoin, with a yield of 88.4%. Example 3

[0018] 50.7 g of 35% sodium sarcosinate aqueous solution (0.16 mol) and 14.4 g of urea (0.176 mol, 1.5 eq) were added to a 250 mL three-necked flask and stirred. 2.3 g of zirconium sulfate (5 mol%) was added, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was gradually heated to 140 °C with stirring, and then vacuum-sealed to remove excess water, yielding a salt-containing solid mixture. After cooling to room temperature, 30 mL of deionized water and 30 mL of ethyl acetate were added to the solid, and the mixture was extracted after thorough stirring. The organic phase was collected. The organic phase was concentrated by adding 30 mL of anhydrous ethanol to the concentrate and heating under reflux for 15 minutes to fully dissolve the organic matter. The mixture was filtered while hot, and the filter cake was washed with a small amount of hot ethanol. The filtrate was collected and concentrated under reduced pressure to obtain a pale yellow crude product. The crude product was dissolved in a small amount of hot water, decolorized with a small amount of activated carbon, and filtered. The filtrate was placed in a 0°C cold trap and stirred for 2 h to crystallize. After filtration, the crystals were washed with a small amount of ice water and dried thoroughly to obtain 15.1 g of 1-methylhydantoin, with a yield of 82.8%. Comparative Example 1

[0019] 50.7 g of a 35% sodium sarcosinate aqueous solution (0.16 mol) and 14.4 g of urea (0.176 mol, 1.5 eq) were added to a 250 mL three-necked flask, mixed and stirred. Concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was gradually heated to 140°C while stirring, and then vacuum-sealed. After drying, a salt-containing solid mixture was obtained. The post-processing was the same as in Example 3. 9.2 g of 1-methylhydantoin was obtained, with a yield of 50.4%. Comparative Example 2

[0020] 50.7 g of a 35% sodium sarcosinate aqueous solution (0.16 mol) and 14.4 g of urea (0.176 mol, 1.5 eq) were added to a 250 mL three-necked flask and mixed. Then, 10.9 g of zinc chloride (0.08 mol, 0.5 eq) was added, and concentrated hydrochloric acid was added to adjust the pH to 2. The mixture was gradually heated to 140 °C with stirring, and then vacuumed. After drying, a salt-containing solid mixture was obtained. The post-processing was the same as in Example 3. 10.2 g of 1-methylhydantoin was obtained, with a yield of 55.7%.

[0021] As can be seen from Comparative Examples 1 and 2, the yield is significantly reduced when zirconium catalyst is not used, indicating that the selection of catalyst in this invention plays a key role in improving the yield.

[0022] 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 synthesizing 1-methylhydantoin, characterized in that, The process includes the following steps: 1) Raw material mixing and pH adjustment: Sodium sarcosinate, urea and catalyst are mixed and inorganic acid is added to adjust the pH of the system to 1-3; 2) Dehydration and cyclization reaction: The mixture is heated to 120-160℃ and dehydrated simultaneously with stirring until the water in the system is evaporated to obtain a salt-containing solid mixture; 3) Post-treatment purification: The salt-containing solid mixture is sequentially extracted with organic solvents, concentrated, decolorized, crystallized and dried to obtain 1-methylhydantoin.

2. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 1), the molar ratio of urea to sodium sarcosinate is 1.0-1.5:

1.

3. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 1), the catalyst is zirconium oxychloride octahydrate, zirconium sulfate, zirconium oxynitrate, or supported zirconium oxychloride octahydrate, and the amount of catalyst used is 2-8 mol relative to sodium sarcosinate.

4. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 1), the sodium sarcosinate is added in the form of an industrial-grade aqueous solution with a mass fraction of 30-40%.

5. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 1), the inorganic acid is selected from concentrated hydrochloric acid, concentrated sulfuric acid, or phosphoric acid.

6. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 2), the heating reaction temperature is 130-150℃.

7. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 2), the dehydration process is vacuum dehydration with reduced pressure, and the vacuum degree is controlled between -0.08MPa and -0.1MPa.

8. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 3), the organic solvent extraction specifically involves: adding anhydrous ethanol to the salt-containing solid mixture, heating and refluxing for 10-20 minutes to fully dissolve the organic matter, filtering while hot, washing the filter cake with hot ethanol 1-2 times, and combining the filtrates.

9. The method for synthesizing 1-methylhydantoin according to claim 1, characterized in that: In step 3), the crystallization specifically involves: placing the decolorized filtrate in an environment of 0-5℃ and stirring to crystallize for 1-3 hours, filtering, washing the crystals with ice water 1-2 times, and drying them under vacuum at 60-80℃ to constant weight.

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