Synthesis method of 1, 3-dimethyl-5-hydroxypyrazole

Abstract

The invention discloses a synthesis method of 1, 3-dimethyl-5-hydroxypyrazole, which comprises the following steps: taking malonic acid diester as an initial raw material, reacting with acetaldehyde under an alkaline condition to generate a compound 1, reacting the obtained compound 1 with methylhydrazine to generate a compound 2, hydrolyzing the compound 2 under the alkaline condition, decarboxylating, and acidifying the decarboxylated product to obtain the 1, 3-dimethyl-5-hydroxypyrazole. According to the invention, the conventional synthesis method taking ethyl acetoacetate as a starting material is avoided, the yield is improved, one-pot operation can be carried out, the operation is simple, the types of used solvents are few, less three wastes are generated, and the method has higher environmental protection value and economic value.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 1,3-dimethyl-5-hydroxypyrazole, and belongs to the technical field of compound synthesis. Background Art

[0002] 1,3-Dimethyl-5-hydroxypyrazole is an important intermediate for medicines and pesticides. Among them, pyrasulfotole is widely known as a herbicide for controlling dicotyledonous weeds in cereal crop fields in the late seedling stage. Pyrasulfotole was developed by Bayer and launched on the market in 2007. As the first HPPD-inhibiting highly active systemic herbicide in cereal fields, it is mainly used to control dicotyledonous weeds in cereal crop fields in the late seedling stage. 1,3-Dimethyl-5-hydroxypyrazole is an important intermediate for the preparation of pyrasulfotole.

[0003] At present, the synthesis of 1,3-dimethyl-5-hydroxypyrazole is mainly based on ethyl acetoacetate. For example, Journal of Fluorine Chemistry, 48 (1990), 123-131, Tetrahedron, 69 (39), 8429-8438 and patent CN200580028091.9 all use ethyl acetoacetate as the starting material and then react with methylhydrazine. The yields range from 74% to 85%. No other synthesis methods have been reported. Summary of the invention

[0004] In view of the problems of single synthesis method and low yield in the prior art, the present invention provides a synthesis method of 1,3-dimethyl-5-hydroxypyrazole, which provides a new idea for the synthesis of 1,3-dimethyl-5-hydroxypyrazole. The intermediate product does not need to be extracted, and the reaction can be completed in a reaction container. The operation is simple and extensive, and the product yield is high.

[0005] The 1,3-dimethyl-5-hydroxypyrazole of the present invention has the structural formula shown below: The present invention provides a method for synthesizing 1,3-dimethyl-5-hydroxypyrazole, comprising the following steps: (A) under alkaline conditions, the malonic acid diester of formula (a) reacts with acetaldehyde to generate compound 1; (B) Compound 1 reacts with methylhydrazine to generate compound 2; (C) Compound 2 is hydrolyzed and decarboxylated under alkaline conditions, and the decarboxylation product is acidified to obtain 1,3-dimethyl-5-hydroxypyrazole; .

[0006] Furthermore, in the malonic acid diester of formula (a), R 1 , R 2 Each is independently a C1~C3 alkyl group, such as methyl, ethyl, and propyl.

[0007] Furthermore, in step (A), the diester of malonate and acetaldehyde undergo a Novo-Wenge reaction, and the molar ratio of the diester of malonate to acetaldehyde is 1:1.02-1.5, for example, 1:1.02, 1:1.05, 1:1.1, 1:1.15, 1:1.20, 1:1.25, 1:1.30, 1:1.35, 1:1.40, 1:1.45, 1:1.50.

[0008] Furthermore, in step (A), acetaldehyde is added in the form of an aqueous solution, and the mass concentration of the acetaldehyde aqueous solution can be 20%-60%, for example, 20%, 30%, 40%, 50%, 60%.

[0009] Furthermore, in step (A), the alkaline condition is provided by an alkaline substance, and the alkaline substance includes but is not limited to an organic base, which may be one or more of pyridine, piperidine, etc. The molar ratio of the malonic acid diester to the alkaline substance is 1:1.02-2, for example, 1:1.02, 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.

[0010] Furthermore, in step (A), the reaction is carried out in the presence of an organic solvent, which is used as a reaction medium to dissolve the malonic acid diester and the reaction product to ensure that the reaction is carried out in a homogeneous phase. The organic solvent includes, but is not limited to, at least one of 1,4-dioxane, tetrahydrofuran, toluene, xylene, n-heptane and n-octane. The amount of the organic solvent can be adjusted as needed.

[0011] Furthermore, in step (A), the reaction temperature is 80-150° C., for example, 80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., 150° C. Preferably, the reaction is carried out at reflux temperature, which varies depending on the solvent.

[0012] Furthermore, in step (A), the reaction is stopped when the amount of malonic acid diester in the system is less than 0.5%, and the reaction time is generally 3-5 hours.

[0013] Further, in step (B), compound 1 and methylhydrazine undergo Michael addition reaction to obtain a keto product, which is then subjected to resonance to obtain compound 2. The molar ratio of the malonic acid diester in step (A) to the methylhydrazine in step (B) is 1:1.02 to 1.5, for example, 1:1.02, 1:1.05, 1:1.1, 1:1.15, 1:1.20, 1:1.25, 1:1.30, 1:1.35, 1:1.40, 1:1.45, 1:1.50.

[0014] Furthermore, the intermediate product obtained in step (A) is directly used in step (B) without separation. Preferably, methylhydrazine is dripped into the reaction system of step (A). Methylhydrazine exists in the form of an aqueous solution, and its mass concentration is 20%-60%, for example, 20%, 30%, 40%, 50%, 60%.

[0015] Furthermore, in step (B), after adding methylhydrazine, the reaction is continued. The methylhydrazine addition temperature and the reaction temperature are both maintained at -15 to 20°C, for example, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C.

[0016] Furthermore, in step (B), the reaction is carried out until compound 1 is substantially reacted completely. When the concentration of compound 1 in the system is less than 0.5%, the reaction is considered substantially reacted completely. The reaction time is generally 0.5-1 h.

[0017] Furthermore, the intermediate product obtained in step (B) does not need to be separated and can be directly used in step (C). After the reaction in step (B) is completed, an alkaline substance is added to the reaction system in step (B), and the temperature is raised under alkaline conditions to perform hydrolysis and decarboxylation reactions. The alkaline substance includes but is not limited to inorganic bases such as sodium hydroxide and potassium hydroxide, and the alkaline substance can be one, or two or more.

[0018] Furthermore, the molar ratio of the malonic acid diester in step (A) to the alkaline substance in step (C) is 1:2-4, for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4.

[0019] Furthermore, in step (C), when the alkaline substance is an inorganic base, water may be further added to fully dissolve the salt formed during the reaction.

[0020] Furthermore, in step (C), the reaction temperature is 80-150° C., for example, 80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., 150° C. Preferably, the reaction is carried out at reflux temperature, which varies depending on the solvent.

[0021] Furthermore, in step (C), the hydrolysis and decarboxylation reaction is considered to be complete when the concentration of compound 2 in the system is less than 0.5%, and then the reaction solution is separated, and an acid is added to the aqueous phase for acidification to obtain the final product. The acid used for acidification is an inorganic acid or an organic acid, which can be hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, etc.

[0022] Further, in step (C), the pH value of the acidification is 0 to 6, for example, 0, 1, 2, 3, 4, 5, 6. The reaction temperature of the acidification is -5 to 50°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C.

[0023] Furthermore, in step (C), after the acidification reaction, the reaction solution is filtered, and the obtained solid is washed and dried to obtain 1,3-dimethyl-5-hydroxypyrazole.

[0024] The present invention has the following beneficial effects: 1. The present invention develops a new route for the synthesis of 1,3-dimethyl-5-hydroxypyrazole. The method is simple to operate and can complete the reaction in one reaction device, realizing one-pot operation without separating intermediate products, thereby greatly reducing the generation of three wastes.

[0025] 2. The present invention avoids the conventional synthesis method using ethyl acetoacetate as the starting material, uses fewer types of solvents, produces less three wastes, has higher product yield and purity, and has higher economic value and environmental value. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with specific embodiments. The following description is only exemplary and does not limit the scope of protection. Other implementation schemes obtained by those skilled in the art without creative work without departing from the inventive concept of the present invention are also within the scope of protection.

[0027] In the following examples, unless otherwise specified, all raw materials used are commercially available products.

[0028] In the following examples, unless otherwise specified, the concentrations are all mass percentage concentrations.

[0029] In the following examples, yield = actual mass of product × purity / theoretical mass of product.

[0030] Example 1 Take 200g of toluene and put it into the reaction bottle, add 13.48g of dimethyl malonate (content 98%, 0.1mol) and 10.39g of pyridine (0.13mol), heat to 110℃ and reflux, then add 12.11g (0.11mol) of 40% acetaldehyde aqueous solution, react for 4h, GC detection of dimethyl malonate <0.5% (GC area%), compound 1 purity >97% (GC area%). After the reaction is completed, cool to 0℃, add 12.67g (0.11mol) of 40% methylhydrazine aqueous solution, keep at 0℃ for 0.5h, GC detection of compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%). After the reaction of compound 1 was completed, 30 g of water and 12.12 g (0.3 mol) of sodium hydroxide were added, and the temperature was raised to reflux of the reaction solution. After reacting for 2 hours, GC detected compound 2 <0.5% (GC area %). After the reaction of compound 2 was completed, the temperature was lowered to 0°C, the reaction solution was separated to obtain an aqueous layer, hydrochloric acid was added to the aqueous layer to adjust the pH value of the reaction system to 3, the reaction solution was filtered to obtain a solid, and after drying, 10.14 g of a white solid was obtained with a purity (GC) of 97.8%, and a total yield of 88.4% based on dimethyl malonate.

[0031] Example 2 Take 185g of toluene and 15g of tetrahydrofuran and put them into a reaction bottle, add 16.34g of diethyl malonate (content 98%, 0.1mol) and 9.46g of piperidine (0.11mol), heat to reflux and drop 11.56g (0.105mol) of 40% acetaldehyde aqueous solution, react for 5h, GC detection diethyl malonate <0.5% (GC area%), compound 1 purity >98% (GC area%). After the reaction is completed, cool to 10℃, drop 12.09g (0.105mol) of 40% methylhydrazine aqueous solution, keep at 10℃ for 0.5h, HPLC detection compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%). After the reaction of compound 1 was completed, 30 g of water and 19.80 g of potassium hydroxide (content 85%, 0.3 mol) were added, and the temperature was raised to reflux of the reaction solution. After reacting for 2 hours, GC detected compound 2 <0.5% (GC area %). After the reaction of compound 2 was completed, the temperature was lowered to 20°C, the reaction solution was separated to obtain an aqueous layer, hydrochloric acid was added to the aqueous layer to adjust the pH value of the reaction system to 4, the reaction solution was filtered to obtain a solid, and after drying, 10.41 g of a white solid was obtained with a purity (GC) of 98.2%, and a total yield of 91.2% based on diethyl malonate.

[0032] Example 3 Take 180g of xylene and 20g of 1,4-dioxane and put them into a reaction bottle, add 19.21g of dipropyl malonate (content 98%, 0.1mol) and 11.19g of pyridine (0.14mol), heat to reflux and drop 14.32g (0.13mol) of 40% acetaldehyde aqueous solution. After 3.5h of reaction, GC detection of dipropyl malonate <0.5% (GC area%), compound 1 purity >98% (GC area%). After the reaction is completed, cool to -5℃, drop 14.97g (0.13mol) of 40% methylhydrazine aqueous solution, keep at -5℃ for 1h and detect compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%) by HPLC. After the reaction of compound 1 was completed, 30 g of water and 26.40 g of potassium hydroxide (content 85%, 0.4 mol) were added, and the temperature was raised to reflux of the reaction solution. After the reaction for 1 hour, GC detected compound 2 <0.5% (GC area %). After the reaction of compound 2 was completed, the temperature was lowered to 10°C, the reaction solution was separated to obtain an aqueous layer, sulfuric acid was added to the aqueous layer to adjust the pH value of the reaction system to 1, the reaction solution was filtered to obtain a solid, and 10.33 g of a white solid was obtained after drying, with a purity (GC) of 97.5%, and a total yield of 89.8% based on dipropyl malonate.

[0033] Example 4 Take 180g of n-heptane and 10g of tetrahydrofuran and put them into a reaction bottle, add 15.38g of ethyl methyl malonate (content 95%, 0.1mol) and 10.39g of pyridine (0.13mol), heat to reflux and drop 13.22g (0.12mol) of 40% acetaldehyde aqueous solution, react for 4h, GC detection of ethyl methyl malonate <0.5% (GC area%), compound 1 purity >98% (GC area%). After the reaction is completed, cool to 5℃, drop 13.82g (0.12mol) of 40% methyl hydrazine aqueous solution, keep at 5℃ for 1h, HPLC detection of compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%). After the reaction of compound 1 was completed, 30 g of water and 16.50 g of potassium hydroxide (content 85%, 0.25 mol) were added, and the temperature was raised to reflux of the reaction solution. After reacting for 2 hours, GC detected compound 2 <0.5% (GC area %). After the reaction of compound 2 was completed, the temperature was lowered to 30°C, the reaction solution was separated to obtain an aqueous layer, acetic acid was added to the aqueous layer to adjust the pH value of the reaction system to 5, the reaction solution was filtered to obtain a solid, and 10.38 g of a white solid was obtained after drying, with a purity (GC) of 97.5%, and a total yield of 90.3% based on methyl ethyl malonate.

[0034] Example 5 Take 180g of n-octane and 20g of 1,4-dioxane and put them into a reaction bottle, add 13.48g of dimethyl malonate (content 98%, 0.1mol) and 15.48g of piperidine (0.18mol), heat to reflux and drop 15.42g (0.14mol) of 40% acetaldehyde aqueous solution. After 3h of reaction, GC detection of dimethyl malonate <0.5% (GC area%), compound 1 purity >98% (GC area%). After the reaction is completed, cool to -10℃, drop 16.12g (0.14mol) of 40% methylhydrazine aqueous solution, keep at -10℃ for 1h, HPLC detection of compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%). After the reaction of compound 1 was completed, 30 g of water and 12.12 g (0.3 mol) of sodium hydroxide were added, and the temperature was raised to reflux of the reaction solution. After reacting for 2 hours, GC detected compound 2 <0.5% (GC area %). After the reaction of compound 2 was completed, the temperature was lowered to 40°C, the reaction solution was separated to obtain an aqueous layer, phosphoric acid was added to the aqueous layer to adjust the pH value of the reaction system to 4, the reaction solution was filtered to obtain a solid, and after drying, 10.24 g of a white solid was obtained with a purity (GC) of 97.4%, and a total yield of 88.9% based on dimethyl malonate.

[0035] Comparative Example 1 200 g of toluene was put into a reaction flask, and 13.48 g of dimethyl malonate (content 98%, 0.1 mol) was added. After the temperature was raised to reflux, 15.42 g (0.14 mol) of 40% acetaldehyde aqueous solution was added dropwise. After reacting for 24 hours, GC detection of dimethyl malonate>90% (GC area%), and compound 1 was not detected.

[0036] Comparative Example 2 Take 200g of toluene and put it into the reaction bottle, add 13.48g of dimethyl malonate (content 98%, 0.1mol) and 9.59g of pyridine (0.12mol), heat to reflux and add 13.22g (0.12mol) of 40% acetaldehyde aqueous solution, react for 4h, GC detection dimethyl malonate <0.5% (GC area%), compound 1 purity >97% (GC area%). After the reaction is completed, cool to 0℃, add 12.67g (0.11mol) of 40% methylhydrazine aqueous solution, keep at 0℃ for 0.5h, GC detection compound 1 <0.5% (GC area%), compound 2 purity >99% (GC area%). After the reaction of compound 1 is completed, add 30g of water and 16.16g (0.4mol) of sodium hydroxide, continue to keep at 0℃ for reaction, and GC detection compound 2 >80% (GC area%) after 24h of reaction.

Claims

1. A method for synthesizing 1,3-dimethyl-5-hydroxypyrazole, characterized in that: The following steps are involved: (A) under alkaline conditions, the malonic acid diester of formula (a) reacts with acetaldehyde to generate compound 1; (B) Compound 1 reacts with methylhydrazine to generate compound 2; (C) Compound 2 is hydrolyzed and decarboxylated under alkaline conditions, and the decarboxylation product is acidified to obtain 1,3-dimethyl-5-hydroxypyrazole; 。 2. The synthesis method according to claim 1, characterized in that In formula (a), R1 and R2 are each independently a C1-C3 alkyl group.

3. The synthesis method according to claim 1, characterized in that In step (A), the molar ratio of the malonic acid diester to acetaldehyde is 1:1.02-1.

5.

4. The synthesis method according to claim 1, characterized in that In step (A), the alkaline condition is provided by an alkaline substance, and the alkaline substance includes an organic base; preferably, the organic base is at least one of pyridine and piperidine.

5. The synthesis method according to claim 4, characterized in that In step (A), the molar ratio of the malonic acid diester to the alkaline substance is 1:1.02-2.

6. The synthesis method according to claim 1, characterized in that In step (A), the reaction is carried out in the presence of an organic solvent; preferably, the organic solvent comprises at least one of 1,4-dioxane, tetrahydrofuran, toluene, xylene, n-heptane and n-octane.

7. The synthesis method according to claim 1, characterized in that In step (A), the reaction temperature is 80 to 150° C., and the reaction is preferably carried out under reflux.

8. The synthesis method according to claim 1, characterized in that The molar ratio of the malonic acid diester in step (A) to the methylhydrazine in step (B) is 1:1.02-1.5; preferably, in step (B), the reaction temperature is -15-20°C.

9. The synthesis method according to claim 1, characterized in that In step (C), compound 2 is first hydrolyzed and decarboxylated under alkaline conditions, and after the reaction, the aqueous phase is separated and acidified by adding acid to obtain 1,3-dimethyl-5-hydroxypyrazole.

10. The synthesis method according to claim 1, characterized in that In step (C), at least one of the following conditions is included: Condition 1: The alkaline condition is provided by an alkaline substance. Preferably, the alkaline substance comprises at least one of sodium hydroxide and potassium hydroxide. Preferably, the molar ratio of the malonic acid diester in step (A) to the alkaline substance in step (C) is 1:2-4. Condition 2: The reaction temperature is 80-150° C., preferably under reflux; Condition 3: The acid used for acidification is an inorganic acid or an organic acid; Condition 4: Adjust pH to 0-6 during acidification; Condition 5: Acidification temperature is -5 to 50°C.

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