Preparation method of 1-substituted aryl-3-pyrazole alcohol compound
By using sodium nitrite as an oxidant in an acidic reaction system, the safety hazards and the problems of high impurities caused by the high activity of the oxidant in the prior art are solved, and the preparation of 1-(4-chlorophenyl)-3-pyrazole alcohol with high purity and high yield is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202410350626.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-26
- Publication Date
- 2025-09-26
AI Technical Summary
The existing synthesis method of 1-(4-chlorophenyl)-3-pyrazolol has the problems of safety hazards caused by the high activity of the oxidant, a large number of impurities, low yield and high industrial processing cost.
Sodium nitrite is used as an oxidant to carry out the oxidation reaction of 1-substituted aryl-3-pyrazolol compounds in an acidic reaction system. Combined with the inorganic acid and base neutralization steps, the reaction conditions are optimized to improve safety and purity.
The preparation of 1-(4-chlorophenyl)-3-pyrazolol with high purity (≥99%) and high yield (≥98%) was achieved, which reduced the production cost and the difficulty of wastewater treatment and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pesticide synthesis, and particularly relates to a method for preparing 1-substituted aryl-3-pyrazolol compounds. Background Art
[0002] 1-(4-chlorophenyl)-3-pyrazolol (CAS No. 76205-19-1), also known as pyrazolol, is a key intermediate in the synthesis of pyraclostrobin. Its synthesis and production have always restricted the production of pyraclostrobin in my country. Pyraclostrobin is a broad-spectrum fungicide based on methoxyacrylates with a pyrazole structure, discovered by BASF in Germany in 1993. It can be used to control plant diseases caused by almost all types of fungal pathogens, including Ascomycetes, Basidiomycetes, Deuteromycetes, and Oomycetes. This variety is not only low in toxicity and safe for non-target organisms, but also safe and friendly to users and the environment. Therefore, the development of 1-(4-chlorophenyl)-3-pyrazolol production technology is key to unleashing domestic pyraclostrobin production capacity. Its chemical structure is as follows:
[0003]
[0004] At present, the main synthesis methods are as follows:
[0005] BASF patent CN1240433A describes a method for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole using Fe(III) as a catalyst and air as an oxidant. 1-(4-chlorophenyl)pyrazolidin-3-one is dissolved in dimethylformamide, and a catalytic amount of ferric chloride is added. Air is introduced, and the reaction mixture is heated to 80°C until oxidation is complete. The reaction mixture is poured into water, and the precipitate is precipitated. After cooling, it is filtered, washed, and dried, resulting in a yield of 92%. This method, using ferric chloride as a catalyst and air as an oxidant for the oxidation reaction, suffers from poor gas-liquid mixing, long oxidation time, high reaction temperature, and high impurities, resulting in low yields. Furthermore, post-processing produces a large amount of dimethylformamide-containing wastewater, which is industrially expensive to process.
[0006] BASF patent CN1240433A describes a method for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole using pure oxygen without catalysis. 1-(4-chlorophenyl)pyrazolidin-3-one is added to a KOH solution, then oxygen is introduced at 50°C and 15 bar for oxidation. After the reaction is complete, the mixture is cooled and acetic acid is added. A paste-like solid precipitates, which is filtered and dried to yield the desired product. This method uses oxygen for the oxidation reaction, and the pressurized reaction creates an oxygen-rich environment, which is quite hazardous. Furthermore, the alkaline system and the addition of acetic acid during post-treatment generate large amounts of organic wastewater, making it difficult to treat industrially.
[0007] Domestic literature, Synthesis of 1-(4-chlorophenyl)-3-pyrazolol, an intermediate of pyraclostrobin (Zhang Qingwei et al., Fine Chemical Intermediates, 2018, 48(1): 28-30), discloses a method for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole using hydrogen peroxide as an oxidant. 1-(4-chlorophenyl)-3-pyrazolidinone is dissolved in a NaOH aqueous solution and oxidized by adding hydrogen peroxide dropwise at 75-80°C. The yield is the highest at 1.5 eq of hydrogen peroxide, reaching 88.4%. This method has a high oxidation temperature and many impurities, which affect the yield. In addition, hydrogen peroxide is easily decomposed and is highly dangerous. Storage and use in production workshops are both potentially dangerous and not suitable for large-scale production.
[0008] Based on the defects in the above-mentioned existing methods, it is very necessary to develop a method for preparing 1-(4-chlorophenyl)-3-hydroxypyrazole that is suitable for industrial application, has high safety, high yield and content, and good appearance. Summary of the Invention
[0009] The present invention provides a method for preparing 1-substituted aryl-3-pyrazolol compounds. By changing the oxidant in the oxidation reaction of the 1-substituted aryl-3-pyrazolol compounds in an acidic reaction system, the technical problems of safety accidents caused by the high activity of the oxidant and high impurity content caused by the acidic reaction system are solved, thereby effectively improving production safety and increasing the content of the finished product, thereby facilitating industrial large-scale production.
[0010] The technical solutions adopted to achieve the above-mentioned invention objects are:
[0011] A method for preparing a 1-substituted aryl-3-pyrazolol compound comprises the following steps: in the presence of an inorganic acid, using sodium nitrite as an oxidant, subjecting a 1-substituted aryl-3-pyrazolone compound of the following formula (I) to an oxidation reaction;
[0012]
[0013] Obtain the following formula (II) 1-substituted aryl-3-pyrazole alcohol compound
[0014]
[0015] The above oxidation reaction formula is as follows:
[0016]
[0017] Wherein, R is C1-C6 alkyl, halogen or C1-C6 alkoxy.
[0018] Preferably, R is halogen;
[0019] Preferably, R is chlorine.
[0020] Wherein, the molar ratio of the compound of formula (I), sodium nitrite and inorganic acid is 1:2-2.5:2.1-3.
[0021] Wherein, the inorganic acid is hydrochloric acid or dilute sulfuric acid, and the concentration of the inorganic acid is 15%-20%.
[0022] Wherein, the concentration of the inorganic acid is 10%-30%.
[0023] Wherein, the oxidation reaction temperature is 0°C-50°C;
[0024] Preferably, the oxidation reaction temperature is 0°C-25°C.
[0025] Wherein, the oxidation reaction time is 0.5h-5h.
[0026] Preferably, the oxidation reaction time is 1 h-3 h.
[0027] The preparation method further comprises the steps of adding alkali to neutralize the oxidation product 1-substituted aryl-3-pyrazolol compound and performing solid-liquid separation.
[0028] Wherein, the pH value of the neutralization by adding alkali is 5-6.
[0029] The technical solution of the present invention has at least the following beneficial technical effects:
[0030] 1. The oxidizing agent used is safer, essentially avoiding safety accidents caused by the high activity of the oxidizing agent;
[0031] 2. Because the system is acidic, which is significantly different from the existing alkaline system, the product produced has fewer impurities and higher content, and can achieve a 1-(4-chlorophenyl)-3-pyrazolol HPLC content of ≥99% and a yield of ≥98%.
[0032] 3. The oxidant is weakly active and solid, making it easy to transport, store, and use;
[0033] 4. The raw materials used are relatively low in price, the wastewater COD is low, and it is easy to treat, which saves production costs and is conducive to industrial-scale production. DETAILED DESCRIPTION
[0034] The present invention will be further described below with reference to specific examples. It should be understood that the following examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.
[0035] In the examples of the present invention, the content of 1-(4-chlorophenyl)-3-hydroxypyrazole was determined by high performance liquid chromatography.
[0036] In the examples of the present invention, the 1-(4-chlorophenyl)pyrazolidin-3-one used was prepared by itself according to the existing technology, and its content was 99%. The sodium nitrite used was a commercial product, and its content was 99%.
[0037] Example 1
[0038] 79.4 g (99% content, 0.4 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 182.5 g of hydrochloric acid (20% content, 1 mol) were added to a four-necked flask, and 182.3 g (0.88 mol, 33.3%) of sodium nitrite aqueous solution was slowly added. The mixture was kept at 20° C. for 2 h, and sampled for HPLC detection. After the reaction was completed, the temperature was lowered to 10° C., liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, rinsed with water, and dried to obtain 76.74 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 99.7% and a yield of 98.3%.
[0039] Example 2
[0040] 39.7 g (99% content, 0.2 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 76.65 g of hydrochloric acid (20% content, 0.42 mol) were added to a four-necked flask, and 82.88 g (0.4 mol, 33.3% content) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 2 h, and sampled for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, rinsed with water, and dried to obtain 38.58 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 98.6% and a yield of 97.8%.
[0041] Example 3
[0042] 119.1 g (99% content, 0.6 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 328.5 g of hydrochloric acid (20% content, 1.8 mol) were added to a four-necked flask, and 310.8 g (1.5 mol, 33.3%) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 2 h, and sampled for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, water was added to make a pulp, and the mixture was filtered again. After drying, 115.6 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product was obtained with a content of 99.6% and a yield of 98.7%.
[0043] Example 4
[0044] 99.2 g (99% content, 0.5 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 228.1 g of hydrochloric acid (20% content, 1.25 mol) were added to a four-necked flask, and 227.93 g (1.1 mol, 33.3%) of sodium nitrite aqueous solution was slowly added. The mixture was kept at 20° C. for 2 h, and sampled for HPLC detection. After the reaction was completed, the temperature was lowered to 10° C., liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, rinsed with water, and dried to obtain 96.46 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 99.2% and a yield of 98.4%.
[0045] Example 5
[0046] 40 g (99% content, 0.2 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 205.8 g of dilute sulfuric acid (20% content, 0.42 mol) were added to a four-necked flask, and 82.88 g (0.4 mol, 33.3% content) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 50° C. for 1 h, and samples were taken for HPLC detection. After the reaction was completed, the temperature was lowered to 10° C., liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, rinsed with water, and dried to obtain 38.58 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 94.8% and a yield of 95.8%.
[0047] Example 6
[0048] 198.5 g (99% content, 1 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 328.5 g of hydrochloric acid (20% content, 1.5 mol) were added to a four-necked flask, and 248.6 g (1.2 mol, 33.3%) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 0°C for 5 h, and sampled for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, water was added to make a pulp, and the mixture was filtered again. After drying, 194.3 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product was obtained with a content of 98.3% and a yield of 98.2%.
[0049] Example 7
[0050] 39.7 g (99% content, 0.2 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 205.8 g of dilute sulfuric acid (20% content, 0.42 mol) were added to a four-necked flask, and 82.88 g (0.4 mol, 33.3% content) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20°C for 0.5 h, cooled to 10°C, and liquid caustic soda was slowly added. The pH was checked at 5, filtered, rinsed with water, and dried to obtain 40.81 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 85.6% and a yield of 89.8%.
[0051] Example 8
[0052] 59.5 g (99% content, 0.3 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 136.9 g of hydrochloric acid (20% content, 0.75 mol) were added to a four-necked flask, and 136.7 g (0.66 mol, 33.3%) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 1 h, and liquid caustic soda was slowly added. The pH was checked at 5, filtered, water was added to make a pulp, filtered again, and dried to obtain 57.5 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 98.6% and a yield of 97.2%.
[0053] Example 9
[0054] 99.2 g (99% content, 0.5 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 228.1 g of hydrochloric acid (20% content, 1.25 mol) were added to a four-necked flask, and 227.93 g (1.1 mol, 33.3%) of sodium nitrite aqueous solution was slowly added. The mixture was kept at 20° C. for 3 h, and a sample was taken for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, rinsed with water, and dried to obtain 96.76 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 99.1% and a yield of 98.6%.
[0055] Example 10
[0056] 198.5 g (99% content, 1 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 328.5 g of hydrochloric acid (20% content, 1.5 mol) were added to a four-necked flask, and 248.6 g (1.2 mol, 33.3%) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 0°C for 5 h, and sampled for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, water was added to make a pulp, and the mixture was filtered again. After drying, 192.5 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product was obtained with a content of 98.7% and a yield of 97.7%.
[0057] Example 11
[0058] 297.7 g (99% content, 1.5 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 684.4 g of hydrochloric acid (20% content, 3.75 mol) were added to a four-necked flask, and 683.8 g (3.3 mol, 33.3%) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 2 h, and sampled for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 5. The mixture was filtered, water was added to make a pulp, and the mixture was filtered again. After drying, 289.1 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product was obtained with a content of 99.2% and a yield of 98.3%.
[0059] Example 12
[0060] 79.4 g (99% content, 0.4 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 182.5 g of hydrochloric acid (20% content, 1 mol) were added to a four-necked flask, and 182.3 g (0.88 mol, 33.3%) of sodium nitrite aqueous solution was slowly added. The mixture was kept at 20° C. for 2 h, and a sample was taken for HPLC detection. After the reaction was completed, liquid caustic soda was slowly added, and the pH was detected to be 6. The mixture was filtered, rinsed with water, and dried to obtain 76.78 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 98.9% and a yield of 97.6%.
[0061] Comparative Example 1
[0062] A solution of 9.75 g (0.05 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one in 150 g of water was added to a 300 ml autoclave, and then 15 bar of oxygen was pressurized into the autoclave. The valve was closed and stirring was started. The mixture was heated to 50° C. and maintained at this temperature for 6 hours. The mixture was cooled, and the pH was adjusted to pH 6 by adding acetic acid. The precipitated solid was filtered, extracted in water at 60° C. for 30 minutes, filtered again, and dried to obtain 9.4 g of a powdered product with a content of 95.4% and a yield of 92.9%.
[0063] Comparative Example 2
[0064] 29.5 g (0.15 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one was dissolved in 100 ml of N,N-dimethylformamide and mixed with 2.4 g (0.015 mol) of FeCl3. The mixture was heated to 80°C, air was introduced, and maintained at this temperature for 1 hour. The mixture was then further stirred for 12 hours without heating. The reaction mixture was poured into 1 liter of water, and the resulting precipitate was filtered, washed with water, and dried under reduced pressure to obtain 27.0 g of a solid with a content of 99.4% and a yield of 92%.
[0065] Comparative Example 3
[0066] 19.85 g (99% content, 0.1 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 61.2 g of acetic acid (98% content, 1 mol) were added to a four-necked flask, and 45.58 g (0.22 mol, 33.3% content) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 3 h, and liquid caustic soda was slowly added. The pH was tested to be 6, filtered, slurried with water, filtered again, and dried to obtain 18.96 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 84.4% and a yield of 82.3%.
[0067] Comparative Example 4
[0068] 39.7 g (99% content, 0.2 mol) of 1-(4-chlorophenyl)pyrazolidin-3-one and 115.2 g of methanesulfonic acid (50% content, 0.6 mol) were added to a four-necked flask, and 82.88 g (0.4 mol, 33.3% content) of sodium nitrite aqueous solution was added dropwise. The mixture was kept at 20° C. for 3 h, then cooled to 10° C. and liquid caustic soda was slowly added. The pH was checked at 6, filtered, rinsed with water, and dried to obtain 39.16 g of 1-(4-chlorophenyl)-3-hydroxypyrazole dry product with a content of 89.7% and a yield of 90.3%.
Claims
1. A method for preparing a 1-substituted aryl-3-pyrazolol compound, comprising the following steps: In the presence of an inorganic acid, sodium nitrite is used as an oxidant to carry out an oxidation reaction on a 1-substituted aryl-3-pyrazolone compound of the following formula (I): The following 1-substituted aryl-3-pyrazolol compound is obtained: Wherein, R is C1-C6 alkyl, halogen or C1-C6 alkoxy.
2. The preparation method according to claim 1, wherein R is a halogen; Preferably, R is chlorine.
3. The preparation method according to claim 1, wherein the molar ratio of the compound of formula (I), sodium nitrite and inorganic acid is 1:2-2.5:2.1-3.
4. The preparation method according to claim 1, wherein the inorganic acid is hydrochloric acid or dilute sulfuric acid, and the concentration of the inorganic acid is 15%-20%. The preparation method according to claim 1 , wherein the concentration of the inorganic acid is 10%-30%.
6. The preparation method according to claim 1, wherein the oxidation reaction temperature is 0°C-50°C; Preferably, the oxidation reaction temperature is 0°C-25°C. The preparation method according to claim 1 , wherein the oxidation reaction time is 0.5 h to 5 h. The preparation method according to claim 1 , wherein the oxidation reaction time is 1 h to 3 h.
9. The preparation method according to claim 1, further comprising the steps of neutralizing the oxidation product 1-substituted aryl-3-pyrazolol compound with a base and performing solid-liquid separation.
10. The preparation method according to claim 9, wherein the neutralization pH is 5-6.