CN115417875B - Synthesis method of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine - Google Patents
Synthesis method of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine Download PDFInfo
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- CN115417875B CN115417875B CN202211136529.7A CN202211136529A CN115417875B CN 115417875 B CN115417875 B CN 115417875B CN 202211136529 A CN202211136529 A CN 202211136529A CN 115417875 B CN115417875 B CN 115417875B
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to the technical field of herbicide production, in particular to a synthesis method of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine. The method comprises the steps of adding a solvent, alkali and an amination reagent into 2, 5-dimethoxy-4-hydroxypyrimidine to prepare 3-amino-2, 5-methoxypyrimidine (3H) -4-one, and then adding a cyclization reagent into 3-amino-2, 5-methoxypyrimidine (3H) -4-one to prepare 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine. The invention adopts a brand new two-step synthesis method, has short steps, avoids using extremely toxic chemicals in the synthesis process, and is a safe and controllable synthesis method suitable for amplification.
Description
Technical Field
The invention relates to the technical field of herbicide production, in particular to a synthesis method of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
Background
5, 8-Dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine is an important raw material for the herbicide penoxsulam. Penoxsulam has the characteristics of high efficiency, low toxicity, safety and low volatility, and is particularly suitable for being applied to rice. It is safe to use on rice crops and has high weeding efficiency, and is developed into an extremely important herbicide product nowadays. Currently, there are three main industrial processes for the production of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidin-2-amine.
The method comprises the following steps:
The 2, 5-dimethoxy-4-hydroxy pyrimidine is used as raw material, and the product is obtained through chlorination, hydrazinolysis, ring closing and transposition, and the main problem is that the hydrogen bromide has high toxicity and high price.
The second method is as follows:
2, 4-dihydroxy-5-methoxypyrimidine is taken as a raw material, and the product is obtained through chlorination, hydrazinolysis, ring closure and substitution and transposition. Similar to the first method, hydrogen bromide has high toxicity and high price.
And a third method:
The method takes 2, 4-dihydroxy-5-methoxypyrimidine as a raw material, and the product is obtained through the steps of chlorination, ammoniation, substitution, ring closure and the like, so that hydrogen bromide is avoided, but hydrogen sulfide with extremely toxic malodor is generated in the ring closure step.
The three methods have advantages and disadvantages. The first and second methods need to use highly toxic hydrogen bromide, the third method can generate highly toxic malodorous hydrogen sulfide in the production process, and the production process has great potential safety hazard.
Disclosure of Invention
Aiming at the problems in the prior art, a 5, 8-dimethoxy- [1,2,4] triazolo is provided
A method for synthesizing [1,5-C ] pyrimidine-2-amine. The invention adopts a brand new synthesis method, has short steps, avoids using extremely toxic chemicals, and is a safe and controllable synthesis method suitable for amplification.
The invention provides a method for synthesizing 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine, which comprises the following steps:
adding solvent, alkali and amination reagent into 2.5-dimethoxy-4-hydroxy pyrimidine to prepare 3-amino-2.5-methoxy pyrimidine (3H) -4-ketone, and adding cyclization reagent into 3-amino-2.5-methoxy pyrimidine (3H) -4-ketone to prepare 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
S1, adding 90-110 g of 2.5-dimethoxy-4-hydroxypyrimidine into 1.5-2.5L of anhydrous DMF, adding 270-290 g of anhydrous cesium carbonate, protecting nitrogen, stirring for 1 hour at room temperature, adding 170-190 g of O-2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ and stirring for 5 hours, cooling to 10 ℃, filtering, adding 4-6L of water and 0.5-1.5L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once with 190-210 ml of water, and evaporating a solvent under reduced pressure to obtain light yellow solid, namely 3-amino-2.5-methoxypyrimidine (3H) -4-ketone;
S2, taking a product of the first step, namely 3-amino-2.5-methoxypyrimidine (3H) -4-one, adding the product into 560-650 ml of acetonitrile, adding 20-30 g of urea, 27-29 g of anhydrous sodium acetate and 24-26 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 290-310 g of water, stirring for 30 minutes, filtering, adding 290-310 ml of methanol into the obtained pale yellow solid, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained pale-white solid to obtain 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
Preferably, the synthesis method of the 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine comprises the following steps:
S1, adding 100 g of 2, 5-dimethoxy-4-hydroxypyrimidine into 2L of anhydrous DMF, adding 280 g of anhydrous cesium carbonate, protecting with nitrogen, stirring for 1 hour at room temperature, adding 180 g of O-2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ for 5 hours, cooling to 10 ℃, filtering, adding 5L of water and 1L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once with 200 ml of water, and evaporating solvent under reduced pressure to obtain a light yellow solid;
S2, taking 60 g of the product of the first step, namely 3-amino-2.5-methoxypyrimidine (3H) -4-one, adding into 600 ml of acetonitrile, adding 25 g of urea, 28 g of anhydrous sodium acetate, 25 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 300 g of water, stirring for 30 minutes, filtering, adding 300 ml of the obtained light yellow solid into methanol, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained off-white solid to obtain 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
Compared with the prior art, the invention has the following beneficial technical effects: the invention adopts a brand new two-step synthesis method, has short steps, avoids using extremely toxic chemicals in the synthesis process, and is a safe and controllable synthesis method suitable for amplification.
Detailed Description
Example 1
The invention provides a method for synthesizing 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine, which comprises the following steps:
adding solvent, alkali and amination reagent into 2.5-dimethoxy-4-hydroxy pyrimidine to prepare 3-amino-2.5-methoxy pyrimidine (3H) -4-ketone, and adding cyclization reagent into 3-amino-2.5-methoxy pyrimidine (3H) -4-ketone to prepare 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
Further, the aminating agent may be O-2,4, 6-trimethylbenzenesulfonyl hydroxylamine, hydroxylamine sulfonic acid, phenylphosphonyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, O-2, 4-nitrobenzoyl hydroxylamine, etc. The base may be anhydrous cesium carbonate, potassium carbonate, sodium t-butoxide, potassium t-butoxide, sodium hydrogen, potassium hydroxide, etc. The solvent used may be DMF, DMSO, THF or the like. The cyclization reagent can be urea, O-methyl isourea hydrochloride, O-methyl isourea sulfate, guanidine hydrochloride and the like.
Example two
The invention provides a method for synthesizing 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine, which comprises the following steps of
S1, adding 90-110 g of 2.5-dimethoxy-4-hydroxypyrimidine into 1.5-2.5L of anhydrous DMF, adding 270-290 g of anhydrous cesium carbonate, protecting nitrogen, stirring for 1 hour at room temperature, adding 170-190 g of O-2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ and stirring for 5 hours, cooling to 10 ℃, filtering, adding 4-6L of water and 0.5-1.5L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once with 190-210 ml of water, and evaporating a solvent under reduced pressure to obtain light yellow solid, namely 3-amino-2.5-methoxypyrimidine (3H) -4-ketone;
s2, taking 60 g of 3-amino-2.5-methoxypyrimidine (3H) -4-one which is a product of the first step, adding into 560-650 ml of acetonitrile, adding 20-30 g of urea, 27-29 g of anhydrous sodium acetate, 24-26 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 290-310 g of water, stirring for 30 minutes, filtering, adding 290-310 ml of methanol into the obtained pale yellow solid, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained white-like solid to obtain 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
Example III
The invention provides a method for synthesizing 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine, which comprises the following steps:
S1, adding 100g of 2, 5-dimethoxy-4-hydroxypyrimidine into 2L of anhydrous DMF, adding 280 g of anhydrous cesium carbonate, protecting with nitrogen, stirring for 1 hour at room temperature, adding 180 g of O-2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ for 5 hours, cooling to 10 ℃, filtering, adding 5L of water and 1L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once with 200 ml of water, and evaporating solvent under reduced pressure to obtain 81 g of light yellow solid;
S2, taking 60 g of the product of the first step, namely 3-amino-2.5-methoxypyrimidine (3H) -4-one, adding into 600 ml of acetonitrile, adding 25 g of urea, 28 g of anhydrous sodium acetate, 25 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 300 g of water, stirring for 30 minutes, filtering, adding 300 ml of the obtained light yellow solid into methanol, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained off-white solid to obtain 55 g of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
The invention adopts a brand new two-step synthesis method, has short steps, avoids using extremely toxic chemicals in the synthesis process, and is a safe and controllable synthesis method suitable for amplification.
The embodiments of the present invention have been described in detail, but the present invention is not limited thereto, and various changes may be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (2)
1. A synthesis method of 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine is characterized by comprising the following steps:
The method comprises the following specific steps:
S1, adding 90-110 g of 2, 5-dimethoxy-4-hydroxypyrimidine into 1.5-2.5L of anhydrous DMF, adding 270-290 g of anhydrous cesium carbonate, protecting nitrogen, stirring for 1 hour at room temperature, adding 170-190 g of 2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ and stirring for 5 hours, cooling to 10 ℃, filtering, adding 4-6L of water and 0.5-1.5L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once with 190-210 ml of water, and steaming the solvent under reduced pressure to obtain light yellow solid, namely 3-amino-2, 5-dimethoxy pyrimidine (3H) -4-ketone;
S2, taking the product of the first step, namely 3-amino-2, 5-dimethoxy pyrimidine (3H) -4-ketone, adding the product into 560-650 ml of acetonitrile, adding 20-30 g of urea, 27-29 g of anhydrous sodium acetate and 24-26 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 290-310 g of water, stirring for 30 minutes, filtering, adding 290-310 ml of methanol into the obtained pale yellow solid, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained white solid to obtain 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
2. A method for synthesizing 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidin-2-amine according to claim 1, characterized by the following steps:
s1, adding 100 g of 2, 5-dimethoxy-4-hydroxypyrimidine into 2L of anhydrous DMF, adding 280 g of anhydrous cesium carbonate, protecting by nitrogen, stirring for 1 hour at room temperature, adding 180 g of 2,4, 6-trimethylbenzenesulfonyl hydroxylamine, stirring for 6 hours at room temperature, heating to 50 ℃ and stirring for 5 hours, cooling to 10 ℃, filtering, adding 5L of water and 1L of ethyl acetate, stirring for 30 minutes, separating liquid, washing an ethyl acetate layer once by 200 ml of water, and evaporating the solvent under reduced pressure to obtain a light yellow solid;
S2, taking 60 g of the product of the first step, namely 3-amino-2, 5-dimethoxy pyrimidine (3H) -4-ketone, adding into 600 ml of acetonitrile, adding 25 g of urea, 28 g of anhydrous sodium acetate, 25 g of acetic acid, refluxing for 8 hours, cooling to 10 ℃, filtering, adding the solid into 300 g of water, stirring for 30 minutes, filtering, adding 300 ml of the obtained light yellow solid into methanol, refluxing for 1 hour, cooling to 10 ℃, filtering, and drying the obtained off-white solid to obtain 5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidine-2-amine.
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