A green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one

Abstract

This invention provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, comprising the following steps: (a) adding an organic solvent, 3,5-diamino-1,2,4-triazole and methyl dimethoxypropionate to a reaction vessel, heating to 50-115°C, adding sodium methoxide, and continuing to heat to reflux to carry out a cyclization reaction to obtain a reaction mixture; (b) subjecting the reaction mixture to negative pressure distillation to distill off the fraction, concentrating until no liquid distills off; (c) adding water to the product of step (b) to form a solution, and adjusting the pH of the solution to 5-6 with acid; cooling and filtration or centrifugation to obtain a filtrate and a filter residue, and drying and packaging the filter residue; (d) allowing the filtrate to stand and separate into upper and lower layers, using the upper layer and the fraction in step (a), and using the lower layer in step (c). The reaction solvent can be recycled throughout the entire process, and the mother liquor can also be reused. There is no high-nitrogen wastewater discharge, making it green and environmentally friendly, and significantly reducing production costs.

Description

Technical Field

[0001] This invention belongs to the field of agricultural intermediate technology and relates to a production method of a paraquat emetic triazole pyrimidinone intermediate, specifically a green production method of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one. Background Technology

[0002] Triazole pyrimidinone is an important intermediate in organic synthesis and pharmaceuticals, used to synthesize many derivatives. It is also an important active emetic ingredient in both medical and veterinary medicine, and is used in medicine for the prevention of bronchospasm and in weight-loss drugs. Triazole pyrimidinone can be used as a special functional adjuvant in the fast-contact herbicides 1-dimethyl-4,4'-bipyridinium salt dichloride and 1,2-ethylene-2,2-bispyridinium salt bipyridine herbicides. 2-Amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one is an intermediate in the synthesis of triazole pyrimidinone.

[0003] Chinese invention patent CN106749271B discloses a class of [1,2,4]-triazolo[1,5-a]pyrimidinone heterocyclic compounds, their preparation method, and uses. The compounds are prepared by reacting acyl chlorides (or acids, esters) as starting materials in the presence of a catalyst (p-toluenesulfonic acid). The yield of the reaction product in this application is only 50-75%, which does not meet the requirements for industrial-scale mass production. Summary of the Invention

[0004] In order to solve the above-mentioned technical problems, the purpose of this invention is to provide a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one.

[0005] To address the aforementioned technical problems, this invention provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, comprising the following steps:

[0006] (a) Add organic solvent, 3,5-diamino-1,2,4-triazole and methyl dimethoxypropionate to the reaction vessel, heat to 50~115°C, add sodium methoxide, and continue to heat to reflux to carry out the cyclization reaction to obtain the reaction mixture;

[0007] (b) The reaction mixture is subjected to negative pressure distillation to distill off the fractions and concentrated until no liquid distillate is distilled off;

[0008] (c) Add water to the product of step (b) to form a solution, and adjust the pH of the solution to 5-6 with acid; cool and filter or centrifuge to obtain filtrate and filter residue, and dry and package the filter residue;

[0009] (d) The filtrate is allowed to stand and separate into upper and lower layers. The upper layer and the fraction are used in step (a), and the lower layer is used in step (c).

[0010] Ideally, the organic solvent is an alcohol or ether solvent that interacts with the water layer.

[0011] Furthermore, the organic solvent is n-butanol.

[0012] Ideally, in step (a), the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxypropionate and sodium methoxide is 1:0.8~1.4:1~3.

[0013] Furthermore, the cyclization reaction takes 2 to 18 hours.

[0014] Ideally, in step (c), the amount of water added to the product of step (b) is equal to the mass of the organic solvent described in step (a).

[0015] Further, in step (c), the temperature is lowered to 10~25℃ for filtration or centrifugation.

[0016] The present invention provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one. By precisely controlling the type of organic solvent, the ratio of reaction raw materials, and other conditions, and by recycling the upper layer, lower layer, and distillate, a product with a yield of ≥90% can be obtained. Moreover, the reaction solvent can be recycled and the mother liquor can be reused throughout the entire process, with no high-nitrogen wastewater discharged. This method is green and environmentally friendly, and significantly reduces production costs. Attached Figure Description

[0017] Figure 1 This is a process flow diagram of the green production method of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one of the present invention. Detailed Implementation

[0018] The present invention provides a green production method for 2-amino-6-methyl-1,2,4-triazol[1,5-a]pyrimidin-5(1H)-one, such as... Figure 1As shown, the process includes the following steps: (a) adding an organic solvent, 3,5-diamino-1,2,4-triazole and methyl dimethoxypropionate to a reaction vessel, heating to 50-115°C, adding sodium methoxide, and continuing to heat to reflux to carry out a cyclization reaction to obtain a reaction mixture; (b) subjecting the reaction mixture to negative pressure distillation to distill off the fraction, and concentrating until no liquid distills off; (c) adding water to the product of step (b) to form a solution, and adjusting the pH of the solution to 5-6 with acid; cooling and filtration or centrifugation to obtain a filtrate and a filter residue, and drying and packaging the filter residue; (d) allowing the filtrate to stand and separate into layers to obtain an upper layer and a lower layer, using the upper layer and the fraction in step (a), and using the lower layer in step (c). By precisely controlling the type of organic solvent, the ratio of reaction raw materials, and other conditions, and by recycling the upper liquid, lower liquid, and distillate, a product with a yield of ≥90% can be obtained. Moreover, the reaction solvent can be recycled and the mother liquor can be reused throughout the entire process, with no high-nitrogen wastewater discharged, making it green and environmentally friendly, and significantly reducing production costs.

[0019] The organic solvent is an alcohol or ether solvent that separates from the water layer, preferably n-butanol. In step (a), the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxypropionate, and sodium methoxide is 1:0.8~1.4:1~3. The cyclization reaction takes 2~18 h. In step (c), the amount of water added to the product of step (b) is equal to the mass of the organic solvent in step (a). In step (c), the product is cooled to 10~25°C and filtered or centrifuged.

[0020] The present invention will be further described below with reference to the embodiments shown in the accompanying drawings. Example 1

[0021] This embodiment provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, comprising the following steps:

[0022] (a) Add 400g n-butanol, 60g 3,5-diamino-1,2,4-triazole and 120g methyl dimethoxypropionate to the reaction vessel, heat to 50°C, add 40g sodium methoxide, and continue to heat to reflux to carry out the cyclization reaction (reaction for 4 hours) to obtain the reaction mixture.

[0023] (b) Distill the reaction mixture under negative pressure (vacuum of approximately -0.09 MPa) to distill off the fraction (i.e., the n-butanol mentioned above) until no liquid distills off;

[0024] (c) Add 400g of water to the product of step (b) to form a solution, add hydrochloric acid (commercially available hydrochloric acid solution, 32%) to adjust the pH of the solution to 5.5, cool to 20°C and filter to obtain filtrate and filter residue; dry and package the solid (i.e. filter residue) to obtain 91.51g of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, with a yield of 91.5% and a liquid phase purity ≥99% (i.e., purity measured by liquid chromatography). Example 2

[0025] This embodiment provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, which is basically the same as that in Example 1, except that it also includes:

[0026] (d) Allow the filtrate to stand and separate into upper and lower layers. Use the upper layer and fraction in step (a) and the lower layer in step (c).

[0027] After reprocessing, 95.2 g of the product 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one was obtained, with a yield of 95.2% and a liquid phase purity of ≥99%. Example 3

[0028] This embodiment provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of n-butanol, 60g of 3,5-diamino-1,2,4-triazole and 78.6g of methyl dimethoxypropionate are added to the reaction vessel, the temperature is raised to 50°C, and 36.2g of sodium methoxide is added (at this time, the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxypropionate and sodium methoxide is 1:0.8:1).

[0029] 72.8 g of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one was obtained with a yield of 90.9% and a liquid phase purity of ≥99%. Example 4

[0030] This embodiment provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of n-butanol, 60g of 3,5-diamino-1,2,4-triazole and 139.0g of methyl dimethoxypropionate are added to the reaction vessel, the temperature is raised to 50°C, and 108.5g of sodium methoxide is added (at this time, the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxypropionate and sodium methoxide is 1:1.4:3).

[0031] We also obtained 95.2 g of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one product with a yield of 95.2% and a liquid phase purity of ≥99%, but the concentration cost and raw material cost of step (b) both increased.

[0032] Comparative Example 1

[0033] This example provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of diethyl ether is added and no reaction occurs.

[0034] Comparative Example 2

[0035] This example provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of acetone is added. Sodium methoxide reacts with acetone in a condensation reaction, and the desired product is not obtained.

[0036] Comparative Example 3

[0037] This example provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of ethyl acetate is added. Sodium methoxide reacts with ethyl acetate to produce sodium acetate, which does not yield the desired product.

[0038] Comparative Example 4

[0039] This example provides a green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidine-5(1H)-one, which is basically the same as that in Example 2, except that in step (a), 400g of n-butanol, 60g of 3,5-diamino-1,2,4-triazole and 49.1g of methyl dimethoxypropionate are added to the reaction vessel, the temperature is raised to 50°C, and 36.2g of sodium methoxide is added (at this time, the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxypropionate and sodium methoxide is 1:0.5:1).

[0040] 46.1 g of the product 2-amino-6-methyl-1,2,4-triazol[1,5-a]pyrimidine-5(1H)-one was obtained, with a yield of 47%.

[0041] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A green production method for 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one, characterized in that, Includes the following steps: (a) Add an organic solvent, 3,5-diamino-1,2,4-triazole and methyl dimethoxy-2-methylpropionate to a reaction vessel, heat to 50~115°C, add sodium methoxide, and continue heating to reflux to carry out a cyclization reaction to obtain a reaction mixture; the organic solvent is n-butanol, and the reaction time of the cyclization reaction is 4h; (b) The reaction mixture is subjected to negative pressure distillation to distill off the fractions and concentrated until no liquid distillate is distilled off; (c) Add water to the product of step (b) to form a solution, and adjust the pH of the solution to 5-6 with acid; cool and filter or centrifuge to obtain filtrate and filter residue, and dry and package the filter residue; (d) The filtrate is allowed to stand and separate into upper and lower layers. The upper layer and the fraction are used in step (a), and the lower layer is used in step (c).

2. The green production method of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one according to claim 1, characterized in that: In step (a), the molar ratio of 3,5-diamino-1,2,4-triazole, methyl dimethoxy-2-methylpropionate and sodium methoxide is 1:0.8~1.4:1~3.

3. The green production method of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one according to claim 1, characterized in that: In step (c), the amount of water added to the product of step (b) is equal to the mass of the organic solvent described in step (a).

4. The green production method of 2-amino-6-methyl-1,2,4-triazole[1,5-a]pyrimidin-5(1H)-one according to claim 1, characterized in that: In step (c), the temperature is lowered to 10~25℃ for filtration or centrifugation.

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