Preparation method of piroctone and piroctone olamine salt

Abstract

The invention provides a preparation method of piroctone and piroctone olamine salt, and belongs to the technical field of antibacterial agent synthesis. The preparation method of the piroctone comprises the following steps: adding 4-methyl-6-(2, 4, 4-trimethylpentyl)-2H-pyran-2-one, hydroxylamine salt and an alkaline compound into an organic solvent to carry out hydroxylamine reaction, and then carrying out post-treatment to obtain the piroctone, the organic solvent is a mixed solvent of methylbenzene and absolute ethyl alcohol. Compared with the prior art, the preparation method of piroctone provided by the invention has the advantages that the reaction time is saved, and the reaction efficiency is improved. According to the preparation method of piroctone, the total yield is increased to about 70% or above, and the production cost is reduced; the materials in each step of the route are simple and easy to obtain, high pollution to the environment is avoided, and the three-waste treatment cost is reduced.

Description

Technical Field

[0001] The invention relates to the field of antimicrobial agent synthesis, and in particular to a method for preparing piroctone and piroctone ethanolamine salt. Background Art

[0002] Piroctone ethanolamine (Octopirox, OCT) is a novel anti-dandruff and antipruritic agent, and has a broad-spectrum killing and inhibiting effect on fungi and molds, and also has good therapeutic effects on foot and tinea manuum. It can be used as a preservative in cosmetics and as a bactericide in soaps. Its anti-dandruff mechanism is to kill and inhibit the abnormal reproduction of Malassezia furfur that causes excessive dandruff and scalp itching, and has an antioxidant effect and the ability to decompose oxides, thereby fundamentally blocking the external factors that dandruff produces, thereby achieving the purpose of radically curing dandruff, and effectively relieving itching. Under the same amount or less addition conditions, its anti-dandruff and antipruritic effect is significantly better than other anti-dandruff and antipruritic agents.

[0003] In addition, pyridone ethanolamine salt has excellent solubility and compounding properties, and will not precipitate or delaminate when mixed with other cosmetic raw materials; it has extremely low irritation and will not cause hair loss, hair breakage and other problems, and its safety is better than similar anti-dandruff and anti-itching products. Therefore, pyridone ethanolamine salt is a multifunctional anti-dandruff and anti-itching bactericidal agent, which has been widely used in shampoo, hair care products, bath lotion, cosmetics, and detergents.

[0004] At present, patent US4916228A discloses a method for preparing piroctone, which uses pyrone and hydroxylamine sulfate or hydroxylamine hydrochloride as raw materials, uses alkali metal carbonate or alkali metal bicarbonate equivalent to hydroxylamine as catalyst and acidifying agent, and adds a small amount of water to catalyze the preparation of piroctone; the reaction temperature is 95°C, hydroxylamine sulfate is added in three batches, and the reaction is kept warm for 20 hours, with a yield of 50-60%. The catalyst is cheap and easy to obtain, the cost is low, and the process feasibility is high. However, this method of preparing piroctone has the problems of complex process and long reaction time, low yield, and more waste salt. Summary of the invention

[0005] In view of this, the present invention aims to provide a method for preparing piroctone and piroctone olamine salt. The method for preparing piroctone and piroctone olamine salt provided by the present invention greatly shortens the reaction time, improves the reaction efficiency, and improves the product purity.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing piroctone, which comprises the following steps:

[0008] 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one, hydroxylamine salt and alkaline compound are added into an organic solvent to carry out hydroxylation reaction, and then post-processed to obtain piroctone; the organic solvent is a mixed solvent of toluene and anhydrous ethanol.

[0009] Preferably, the step of performing the hydroxylation reaction comprises:

[0010] Add hydroxylamine salt to the organic solvent, and add 8 to 12 g of the alkaline compound to the organic solvent every 3 to 8 minutes until the alkaline compound is added;

[0011] Stir and heat to 45-60°C, add 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the organic solvent, and maintain the temperature for 20-45 minutes after the materials are added;

[0012] The reaction solution was heated to 85-110°C and the hydroxylation reaction was carried out for 0.5-2h.

[0013] Preferably, after the hydroxylamine salt and the alkaline compound are added to the organic solvent, the water content in the organic solvent is detected; when the water content in the organic solvent is less than a preset value, 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one is added to the organic solvent.

[0014] Preferably, the post-processing step comprises:

[0015] Filtration: The reaction liquid after the hydroxylamine reaction is cooled and filtered, and the filter cake is washed with toluene to obtain a filtrate;

[0016] First water washing: add tap water to the filtrate, keep warm at 20-30°C, stir for 20-40 minutes, let stand and separate to obtain the first water-washed oil phase;

[0017] Acid adjustment: add tap water to the first water-washed oil phase, keep warm at 20-30°C, drop dilute hydrochloric acid to pH 5-6, stir and wash for 20-40 minutes, stand and separate to obtain an acid-adjusted oil phase;

[0018] Second water washing: add tap water to the acid-adjusting oil phase, keep warm at 20-30°C, stir and wash for 20-40 minutes, stand and separate, and obtain the second water-washed oil phase;

[0019] Distillation: distill the second water-washed oil phase at atmospheric pressure to obtain piroctone.

[0020] Preferably, the molar ratio of the anhydrous ethanol to the toluene is 1:5-20;

[0021] The molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the hydroxylamine salt is 1:1.5-6;

[0022] The molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the basic compound is 1:0.8-3.

[0023] Preferably, the hydroxylamine salt is selected from hydroxylammonium sulfate, hydroxylammonium chloride, hydroxylammonium acetate, hydroxylammonium phosphate, hydroxylammonium nitrate, hydroxylammonium perchlorate, hydroxylammonium oxalate, hydroxylammonium hydrogen sulfate, 4-methylbenzenesulfonate, hydroxylammonium bromide, and mixtures thereof.

[0024] Preferably, the alkaline compound is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium carbonate, magnesium carbonate, barium carbonate, nickel carbonate, zirconium carbonate, calcium hydroxide, magnesium hydroxide, barium hydroxide, nickel hydroxide, zirconium hydroxide and mixtures thereof.

[0025] The present invention also provides a method for preparing piroctone ethanolamine salt, comprising the steps of the piroctone preparation method, and further comprising, after obtaining the piroctone, salifying the obtained piroctone with ethanolamine to obtain the piroctone ethanolamine salt.

[0026] Preferably, the step of salifying piroctone with ethanolamine to obtain piroctone ethanolamine salt may include:

[0027] Add piroctone to ethyl acetate, heat to 50-70°C and then drop ethanolamine;

[0028] After the addition of ethanolamine is completed, keep the temperature at 55-65°C for 1-2 hours, then slowly cool down to 0-5°C;

[0029] The cooled solution is filtered, and the filter cake is washed with ethyl acetate to obtain piroctone olamine salt.

[0030] Optionally, the molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the ethanolamine is 1:0.7-3.

[0031] The invention provides a method for preparing piroctone, comprising the following steps: adding 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one, hydroxylamine salt and alkaline compound into an organic solvent for hydroxylation reaction, and then performing post-treatment to obtain piroctone; the organic solvent is a mixed solvent of toluene and anhydrous ethanol. The invention uses ethanol and toluene as ethanol in the mixed organic solvent to absorb water generated by the hydroxylation reaction, and controls the water dissolved in the piroctone reaction system to be less than 1%, so that the hydroxylation reaction is completed quickly. Compared with the prior art, the method for preparing piroctone and piroctone ethanolamine salt provided by the invention saves reaction time and improves the efficiency of hydroxylation reaction. The total yield of the method for preparing piroctone of the invention is increased to more than about 70%, thereby reducing the production cost; the materials in each step of the route of the invention are simple and easy to obtain, there is no high pollution to the environment, and the cost of three waste treatment is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The figure is the HPLC spectrum of the piroctone olamine salt of the present invention. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0034] The present invention provides a method for preparing piroctone, comprising the following steps:

[0035] 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one, hydroxylamine salt and alkaline compound are added into an organic solvent to carry out hydroxylation reaction, and then post-processed to obtain piroctone; the organic solvent is a mixed solvent of toluene and anhydrous ethanol.

[0036] Unless otherwise specified, the present invention has no special requirements on the sources of the raw materials used in the preparation, and commercially available products known to those skilled in the art can be used.

[0037] In the present invention, the hydroxylamine salt is selected from hydroxylamine sulfate, hydroxylamine chloride, hydroxylamine acetate, hydroxylamine phosphate, hydroxylamine nitrate, hydroxylamine perchlorate, hydroxylamine oxalate, hydroxylamine hydrogen sulfate, 4-methylbenzenesulfonic acid hydroxylamine, hydroxylamine bromide, and mixtures thereof. Among them, the hydroxylamine salt is preferably hydroxylamine hydrochloride. In the present invention, the molar ratio of 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the hydroxylamine salt is 1:1.5-6, preferably 1:2-4.

[0038] In the present invention, the basic compound is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium carbonate, magnesium carbonate, barium carbonate, nickel carbonate, zirconium carbonate, calcium hydroxide, magnesium hydroxide, barium hydroxide, nickel hydroxide, zirconium hydroxide and mixtures thereof. The basic compound is preferably sodium carbonate and / or sodium hydroxide. In the present invention, the molar ratio of 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the basic compound is 1:0.8-3, preferably 1:1.4-2.

[0039] In the present invention, the molar ratio of anhydrous ethanol to the toluene is 1:5-20.

[0040] In the present invention, the step of carrying out the hydroxylation reaction comprises:

[0041] Add hydroxylamine salt to the organic solvent, and add 8 to 12 g of the alkaline compound to the organic solvent every 3 to 8 minutes until the alkaline compound is added;

[0042] Stir and heat to 45-60°C, add 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the organic solvent, and maintain the temperature for 20-45 minutes after the materials are added;

[0043] The reaction solution was heated to 85-110°C and the hydroxylation reaction was carried out for 0.5-2h.

[0044] In the present invention, after the hydroxylamine salt and the alkaline compound are added to the organic solvent, the water content in the organic solvent is detected; when the water content in the organic solvent is less than a preset value, 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one is added to the organic solvent. The preset value may be 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, or 0.4%.

[0045] In the present invention, the specific method for post-treatment after the hydroxylation reaction is as follows:

[0046] Filtration: The reaction liquid after the hydroxylamine reaction is cooled and filtered, and the filter cake is washed with toluene to obtain a filtrate;

[0047] First water washing: add tap water to the filtrate and keep it warm at 20-30℃, stir for 20-40min, let it stand and separate to obtain the first water-washed oil phase;

[0048] Acid adjustment: add tap water to the first water-washed oil phase, keep warm at 20-30°C, drop dilute hydrochloric acid to pH 5-6, stir and wash for 20-40 minutes, stand and separate to obtain an acid-adjusted oil phase;

[0049] Second water washing: add tap water to the acid-adjusting oil phase, keep warm at 20-30°C, stir and wash for 20-40 minutes, stand and separate, and obtain the second water-washed oil phase;

[0050] Distillation: distill the second water-washed oil phase at atmospheric pressure to obtain piroctone.

[0051] The present invention also provides a method for preparing piroctone ethanolamine salt, including a method for preparing piroctone, and further comprising, after obtaining piroctone, salifying the obtained piroctone with ethanolamine to obtain the piroctone ethanolamine salt.

[0052] In the present invention, the step of salifying piroctone with ethanolamine to obtain piroctone ethanolamine salt comprises:

[0053] Add the distilled piroctone to ethyl acetate, raise the temperature to 50-70°C and add ethanolamine dropwise;

[0054] After the addition of ethanolamine is completed, keep the temperature at 55-65°C for 1-2 hours, then slowly cool down to 0-5°C;

[0055] The cooled solution is filtered, and the filter cake is washed with ethyl acetate to obtain piroctone olamine salt.

[0056] In the present invention, 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one is subjected to hydroxylation to obtain piroctone according to the following reaction equation:

[0057]

[0058] In the present invention, the equation for obtaining the piroctone ethanolamine salt by salifying piroctone with ethanolamine is as follows:

[0059]

[0060] The present invention can make the hydroxylation reaction quickly completed within 30 minutes by controlling the amount of ethanol added, the water content added to the ethanol, and the ethanol absorbing the water generated by the hydroxylation reaction. Among them, the water content of the piroctone reaction system is controlled between 0.1 and 1% by ethanol, so that a rapid reaction can be achieved. The present invention uses ethanol and toluene as ethanol in the mixed organic solvent to absorb the water generated by the hydroxylation reaction, and controls the water dissolved in the piroctone reaction system to be less than 1%, so that the hydroxylation reaction is quickly completed. Compared with the prior art, the preparation method of piroctone and piroctone ethanolamine salt provided by the present invention saves reaction time and improves the efficiency of the hydroxylation reaction.

[0061] The total yield of the piroctone preparation method of the present invention is increased to more than about 70%, thereby reducing the production cost; the materials in each step of the route of the present invention are simple and easy to obtain, there is no high pollution to the environment, and the cost of three waste treatment is reduced.

[0062] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0063] Example 1

[0064] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 104.2g of hydroxylamine hydrochloride to a clean, anhydrous three-necked flask; slowly add 60g of sodium hydroxide and stir at room temperature for 1h, and take the liquid to detect the moisture; when the moisture is ≤1.0%, add 111.2g of pyrone, start stirring, and raise the internal temperature to 50°C; after the addition is completed, keep 50°C for 30min, raise the temperature to 95°C, react for 0.5h, and terminate the reaction after TLC monitoring shows that there is no residual raw material.

[0065] Filtration: After the internal temperature drops to 40°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0066] First water wash: add 100g water to the filtrate, keep warm at 20℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water wash oil phase enters the next process.

[0067] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 30℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition process, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 30℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0068] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 20℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0069] Distillation: Add the organic layer after the second water washing into a single-necked flask, use a rotary evaporator to perform reduced pressure distillation, and distill until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 72.4% and the purity is 93.0%.

[0070] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 60°C, add 30 g of ethanolamine dropwise, keep warm at 60°C for 1 h after the addition is complete, slowly cool to 2°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt was 70.7% and the purity was 99.9%.

[0071] Experimental Example 2

[0072] This embodiment is the same as embodiment 1;

[0073] After testing, the yield of piroctone was 73.4% and the purity was 93.2%.

[0074] After testing, the yield of piroctone olamine salt was 71.1% and the purity was 99.9%.

[0075] Example 3

[0076] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 104.2g of hydroxylamine hydrochloride to a clean anhydrous three-necked flask, slowly add 60g of sodium hydroxide and stir at room temperature for 1h, take the liquid to detect the moisture; when the moisture is ≤1.0%, filter it, add 111.2g of pyrone, start stirring, raise the internal temperature to 60℃, maintain 60℃ for 30min, raise the temperature to 90℃, react for 2h, and terminate the reaction after TLC monitoring shows no residual raw materials.

[0077] Filtration: After the internal temperature drops to 40°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0078] First water wash: add 100g water to the filtrate, keep warm at 25℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0079] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 20℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 20℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0080] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 20℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0081] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 73.1% and the purity is 92.7%.

[0082] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 55°C, add 30 g of ethanolamine dropwise, keep warm at 55°C for 1.5 h after the addition is complete, slowly cool to 5°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt is 68.4% and the purity is 99.8%.

[0083] Example 4

[0084] Reaction: Add 11.1g of anhydrous ethanol, 333.6g of toluene, and 164.1g of hydroxylamine sulfate to a clean, anhydrous three-necked flask, add 126g of sodium carbonate in batches and stir at room temperature for 1h, take the liquid to test the water content, filter it after the water content is ≤1.0%, and put the filtrate into a clean, anhydrous three-necked flask; add 111.2g of pyrone to the filtrate, and raise the internal temperature to 55°C; after the addition is completed, keep 50°C for 30min, raise the temperature to 90-95°C, react for 1h, and terminate the reaction after TLC monitoring shows that there is no residual raw material.

[0085] Filtration: After the internal temperature drops to 40°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0086] First water washing: add 100g water to the filtrate, keep warm at 20-30℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water washing oil phase enters the next process.

[0087] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 20-30℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 20-30℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0088] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 20-30℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0089] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 71.9% and the purity is 89.7%.

[0090] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 60°C, add 30 g of ethanolamine dropwise, keep warm at 60°C for 2 h after the addition is complete, slowly cool to 1°C, filter with suction, rinse the filter cake with 50 g of ethyl acetate, and obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt is 68.8% and the purity is 99.9%.

[0091] Example 5

[0092] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 131.1g of hydroxylamine phosphate to a clean, anhydrous three-necked flask, add 56.1g of potassium hydroxide in batches and stir at room temperature for 1h, take the liquid to detect the moisture; when the moisture is ≤1.0%, add 111.2g of pyrone, raise the internal temperature to 55°C, maintain 55°C for 30min after the addition, raise the temperature to 100°C, react for 1.5h, and terminate the reaction after TLC monitoring shows no residual raw materials.

[0093] Filtration: After the internal temperature drops to 40°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0094] First water wash: add 100g water to the filtrate, keep warm at 28℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper first water wash oil phase enters the next process.

[0095] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 24℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 24℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0096] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 26℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0097] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 71.3% and the purity is 92.6%.

[0098] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 57°C, add 30 g of ethanolamine dropwise, keep warm at 57°C for 1 h after the addition is complete, slowly cool to 3°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt is 70.3% and the purity is 99.9%.

[0099] Example 6

[0100] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 104.2g of hydroxylamine hydrochloride to a clean, anhydrous three-necked flask, add 60g of sodium hydroxide in batches, stir at room temperature for 1.5h, and take the liquid to detect the moisture; when the moisture is ≤1.0%, add 111.2g of pyrone, start stirring, and raise the internal temperature to 60°C. After the addition, keep 60°C for 30min, raise the temperature to 105°C, react for 1h, and terminate the reaction after TLC monitoring to see if there is any residual raw material.

[0101] Filtration: After the internal temperature drops to 35°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0102] First water wash: add 100g water to the filtrate, keep warm at 23℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0103] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 27℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 27℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0104] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 22℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0105] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 71.8% and the purity is 92.3%.

[0106] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 58°C, add 30 g of ethanolamine dropwise, keep warm at 58°C for 2 h after the addition is complete, slowly cool to 1°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt is 69.6% and the purity is 99.8%.

[0107] Example 7

[0108] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 104.2g of hydroxylamine hydrochloride to a clean anhydrous three-necked flask, add 50.5g of triethylamine and 63g of sodium carbonate in batches, mix the two alkalis and add them, stir at room temperature for 1h, take the liquid to detect the moisture; when the moisture is ≤1.0%, filter, add 111.2g of pyrone, start stirring, raise the internal temperature to 58°C, maintain 58°C for 30min after addition, raise the temperature to 105°C, react for 1.5h, and terminate the reaction after TLC monitoring to see that there is no residual raw material.

[0109] Filtration: After the internal temperature drops to 35°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0110] First water wash: add 100g water to the filtrate, keep warm at 29℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0111] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 24℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 24℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0112] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 21°C, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0113] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 72.7% and the purity is 91.9%.

[0114] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 57°C, add 30 g of ethanolamine dropwise, keep warm at 57°C for 1 h after the addition is complete, slowly cool to 0-5°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone olamine salt; after testing, the yield of piroctone olamine salt is 70.8% and the purity is 99.9%.

[0115] Example 8

[0116] Reaction: Add 11.1g of anhydrous ethanol, 222.4g of toluene, and 131g of hydroxylamine phosphate to a clean, anhydrous three-necked flask, add 23g of potassium carbonate and 63g of sodium carbonate in batches, mix the two alkalis and add them, stir at room temperature for 1.5h, take the liquid to detect the moisture; when the moisture is ≤1.0%, filter, add 111.2g of pyrone, start stirring, raise the internal temperature to 47°C, maintain 47°C for 45min after addition, raise the temperature to 92°C, react for 2h, and terminate the reaction after TLC monitoring shows that there is no residual raw material.

[0117] Filtration: After the internal temperature drops to 30°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0118] First water wash: add 100g water to the filtrate, keep warm at 27℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0119] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 26℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 26℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0120] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 27℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0121] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 71.6% and the purity is 92.5%.

[0122] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 55-60°C, add 30 g of ethanolamine dropwise, keep at 55-60°C for 2 h after the addition is complete, slowly cool to 0-5°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone ethanolamine salt; after testing, the yield of piroctone ethanolamine salt is 72.3% and the purity is 99.8%.

[0123] Example 9

[0124] Reaction: Add 22.2g of anhydrous ethanol, 222.4g of toluene, 104.2g of hydroxylamine hydrochloride to a clean, anhydrous three-necked flask, add 46g of potassium carbonate and 40g of sodium hydroxide in batches, mix the two alkalis and add them, stir at room temperature for 1h, take the liquid to test the moisture; when the moisture is ≤1.0%, add 111.2g of pyrone, keep at 45℃ for 20min after addition, raise the temperature to 95℃, react for 1.5h, and terminate the reaction after TLC monitoring shows no residual raw materials.

[0125] Filtration: After the internal temperature drops to 35°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0126] First water wash: add 100g water to the filtrate, keep warm at 30℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0127] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 30℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 30℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0128] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 20℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0129] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 72.1% and the purity is 92.8%.

[0130] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 55°C, add 30 g of ethanolamine dropwise, keep warm at 55°C for 2 h after the addition is complete, slowly cool to 5°C, filter, and rinse the filter cake with 100 g of ethyl acetate to obtain a white solid, which is piroctone ethanolamine salt; after testing, the yield of piroctone ethanolamine salt is 71.6% and the purity is 99.9%.

[0131] Example 10

[0132] Reaction: Add 22.2g of anhydrous ethanol, 444.8g of toluene, and 164.2g of hydroxylamine sulfate to a clean, anhydrous three-necked flask, and start adding 28g of potassium hydroxide and 42g of sodium carbonate in batches. Mix the two alkalis and add them. Stir at room temperature for 1.5h, and take the liquid to test the moisture; when the moisture is ≤1.0%, add 111.2g of pyrone. After the addition, keep at 50℃ for 30min, raise the temperature to 90-95℃, react for 0.5h, and terminate the reaction after TLC monitoring to see if there is no residual raw material.

[0133] Filtration: After the internal temperature drops to 40°C, filter with suction and rinse with 100g of toluene. The filter cake is sent to environmental protection for treatment and the filtrate is used for the next process.

[0134] First water wash: add 100g water to the filtrate, keep warm at 30℃, stir for 30min, let stand for 30min to separate the liquids, the lower water phase is sent to environmental protection treatment, and the upper first water-washed oil phase enters the next process.

[0135] Acid adjustment: add 100g water to the first water-washed oil phase, keep warm at 25℃, slowly add 2M dilute hydrochloric acid, check the pH during the addition, add dilute hydrochloric acid until the pH is 5-6, and stop adding; keep warm at 205℃ and stir for 20min, let stand for 30min to separate the liquids, send the lower aqueous phase to environmental protection treatment, and the upper acid-adjusted oil phase enters the next process.

[0136] Second water washing: add 100g water to the acid-adjusting oil phase, keep warm at 30℃, stir for 30min, let stand for 30min to separate the liquids, send the lower water phase to environmental protection treatment, and the upper second water-washed oil phase enters the next process.

[0137] Distillation: Add the organic layer after the second water washing into a single-necked flask, and use a rotary evaporator to perform reduced pressure distillation until no fraction flows out; the bottom of the distillation is piroctone. After testing, the yield of piroctone is 71.4% and the purity is 92.3%.

[0138] Salt formation: add 222.4 g of ethyl acetate to the bottom of the distillation, raise the temperature to 65°C, add 30 g of ethanolamine dropwise, keep at 65°C for 2 h after the addition is complete, slowly cool to 2°C, filter, and rinse the filter cake with 50 g of ethyl acetate to obtain a white solid, which is piroctone ethanolamine salt; after testing, the yield of piroctone ethanolamine salt was 71.6% and the purity was 99.8%.

[0139] The yield and purity of piroctone in Examples 1 to 10 of the present invention are shown in Table 1 below.

[0140] Table 1

[0141]

[0142]

[0143] The present invention also provides Examples 11 to 38.

[0144] The difference between this embodiment and embodiment 1 is only that the solvent and reaction time for hydroxylation of piroctone are different, and the rest are the same as embodiment 1.

[0145] After testing, the yield and purity of piroctone are shown in Table 2 below.

[0146] The present invention can be concluded from Examples 1 to 38 that the hydroxylation reaction can be quickly completed within 30 minutes by using anhydrous ethanol and toluene as the toluene in the mixed solvent to dissolve pyrone, and ethanol absorbing the original moisture of the reaction and reaction system, while other organic solvents (including single organic solvents and mixed organic solvents) cannot achieve the rapid completion of the hydroxylation reaction.

[0147] Table 2

[0148]

[0149]

[0150] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention rather than all the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing piroctone, characterized in that: The following steps are involved: 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one, hydroxylamine salt and alkaline compound are added into an organic solvent to carry out hydroxylation reaction, and then post-processed to obtain piroctone; the organic solvent is a mixed solvent of toluene and anhydrous ethanol.

2. The method for preparing piroctone according to claim 1, wherein The step of carrying out the hydroxylation reaction comprises: Add hydroxylamine salt to the organic solvent, and add 8 to 12 g of the alkaline compound to the organic solvent every 3 to 8 minutes until the alkaline compound is added; Stir and heat to 45-60°C, add 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the organic solvent, and maintain the temperature for 20-45 minutes after the materials are added; The reaction solution was heated to 85-110°C and the hydroxylation reaction was carried out for 0.5-2h.

3. The method for preparing piroctone according to claim 2, wherein After the hydroxylamine salt and the alkaline compound are added to the organic solvent, the water content in the organic solvent is detected; when the water content in the organic solvent is less than a preset value, 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one is added to the organic solvent.

4. The method for preparing piroctone according to claim 1, wherein The post-processing steps include: Filtration: The reaction liquid after the hydroxylamine reaction is cooled and filtered, and the filter cake is washed with toluene to obtain a filtrate; First water washing: add tap water to the filtrate, keep warm at 20-30°C, stir for 20-40 minutes, let stand and separate to obtain the first water-washed oil phase; Acid adjustment: add tap water to the first water-washed oil phase, keep warm at 20-30°C, drop dilute hydrochloric acid to pH 5-6, stir and wash for 20-40 minutes, stand and separate to obtain an acid-adjusted oil phase; Second water washing: add tap water to the acid-adjusting oil phase, keep warm at 20-30°C, stir and wash for 20-40 minutes, stand and separate, and obtain the second water-washed oil phase; Distillation: distill the second water-washed oil phase at atmospheric pressure to obtain piroctone.

5. The method for preparing piroctone according to any one of claims 1 to 4, characterized in that: The molar ratio of the anhydrous ethanol to the toluene is 1:5-20; The molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the hydroxylamine salt is 1:1.5-6; The molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the basic compound is 1:0.8-3.

6. The method for preparing piroctone according to any one of claims 1 to 5, characterized in that: The hydroxylamine salt is selected from hydroxylammonium sulfate, hydroxylammonium chloride, hydroxylammonium acetate, hydroxylammonium phosphate, hydroxylammonium nitrate, hydroxylammonium perchlorate, hydroxylammonium oxalate, hydroxylammonium hydrogen sulfate, 4-methylbenzenesulfonate, hydroxylammonium bromide, and mixtures thereof.

7. The method for preparing piroctone according to any one of claims 1 to 5, characterized in that: The alkaline compound is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium carbonate, magnesium carbonate, barium carbonate, nickel carbonate, zirconium carbonate, calcium hydroxide, magnesium hydroxide, barium hydroxide, nickel hydroxide, zirconium hydroxide and mixtures thereof.

8. A method for preparing piroctone olamine salt, comprising the method for preparing piroctone according to any one of claims 1 to 7, further comprising, after obtaining piroctone, salifying the obtained piroctone with ethanolamine to obtain piroctone olamine salt.

9. The method for preparing piroctone olamine salt according to claim 8, wherein The step of salifying piroctone with ethanolamine to obtain piroctone ethanolamine salt comprises: Add piroctone to ethyl acetate, heat to 50-70°C and then drop ethanolamine; After the addition of ethanolamine is completed, keep the temperature at 55-65℃ for 1-2h, then slowly cool down to 0-5℃; The cooled solution is filtered, and the filter cake is washed with ethyl acetate to obtain piroctone olamine salt.

10. The method for preparing the piroctone olamine salt according to claim 8, wherein The molar ratio of the 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one to the ethanolamine is 1:0.7-3.

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