Method for preparing 1, 3-dihydroxyacetone from acetone

Abstract

The invention relates to the field of fine chemical materials, and realizes a low-cost and high-efficiency preparation method of 1, 3-dihydroxyacetone by taking acetone as a raw material through two steps of halogenation reaction and alkali substitution reaction for the first time. The whole process is simple to operate, green and environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of fine chemical materials, in particular to a new method for preparing 1,3-dihydroxyacetone by halogenation reaction and base substitution reaction from acetone as raw material. BACKGROUND

[0002] 1,3-dihydroxyacetone (DHA) is a naturally occurring ketose, which has biodegradability and plays a regulatory role in the process of sugar and fat metabolism in humans and animals. It is widely used in the pharmaceutical chemical industry, food industry, feed industry, cosmetics industry and other industries. For example, in the pharmaceutical chemical industry, it can be used as a key raw material for treating cardiovascular diseases (hypoglycemic drug Voglibose); due to its reaction with amino acids in skin keratin to form brown polymers, it can be used for the treatment of "vitiligo". In the food industry, due to its role in sugar and fat metabolism, it has a weight loss effect and can be used as a functional food raw material. In the cosmetics industry, it has the effects of moisturizing and preventing ultraviolet radiation; it can make the skin appear bronze and is used as a "tanning" functional ingredient in cosmetics in European and American countries.

[0003] Currently, the industrial production of DHA mostly adopts biological fermentation method, the key of which is the cultivation of strains; for example, Gluconacetobacter diazotrophicus uses glycerol as raw material to generate DHA under certain conditions. Other strains such as Escherichia coli and genetically engineered bacteria have been studied. In addition, carbon fixation enzyme catalytic synthesis is also frequently reported. However, the biological fermentation method has problems such as low yield, difficulty in product separation and purification, difficulty in screening and preservation of active strains, and easy inactivation. Chemical methods such as metal-catalyzed oxidation of glycerol, photoelectric catalytic oxidation of glycerol, and formaldehyde condensation also have related research, but they mostly face problems such as low yield and high cost, which makes it difficult to realize industrial production.

[0004] In our previous application, we have disclosed a route that forms a glyoxal monoacetal intermediate through glyoxal mono-protection reaction, then generates 1,3-propanediol derivatives through hydroxy aldehyde condensation and Cannizzaro reaction, and finally generates 1,3-dihydroxyacetone through deprotection.

[0005] In this application, we accidentally found that acetone as raw material can be halogenated to generate 1,3-dihydroxyacetone through halogenation reaction and hydrolysis reaction under the catalysis of base. This route is simple and has high total yield and low cost, which can match the existing large industrial production equipment and has great industrialization potential. To our knowledge, this synthesis route has not been reported before. SUMMARY

[0006]

[0007] The present application finds that, as shown in the reaction formula (I), halogenation reaction occurs under the action of reaction condition 1 to generate intermediate A, and then base substitution reaction occurs under the action of reaction condition 2 to efficiently prepare 1,3-dihydroxyacetone.

[0008] X and Y are both halogen Cl, Br or I.

[0009] The reaction condition 1 and the reaction condition 2 are independent of each other in at least one of the reactants, the solvent, the temperature and the additive.

[0010] In the reaction condition 1, the reactant is chlorine, liquid bromine, or iodine, or any combination of the three.

[0011] In the reaction condition 2, the reactant is lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, tetrabutylammonium hydroxide, strong base type anion exchange resin, or an aqueous solution thereof, or an alcohol solution thereof. Preferably, the reactant is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.

[0012] The solvent is selected from at least one of substituted or non-substituted aromatic hydrocarbons containing 1-24 carbons, linear or branched aliphatic hydrocarbons, (sub) sulfones, amides, ethers, esters, alcohols, ketones, nitriles, carboxylic acids, water, amines, carbonates, ionic liquids, and supercritical carbon dioxide. Preferably, in the reaction condition 1, acetone is both the reactant and the solvent, or the solvent is dichloromethane, 1,2-dichloroethane or carbon tetrachloride. Preferably, in the reaction condition 2, the solvent is DMF, THF, t-butanol, ethylene glycol, ethanol, acetonitrile or a mixed solvent with water.

[0013] The temperature is 0-200℃. Preferably, the reaction temperature is 25-130℃.

[0014] The additive refers to a reaction promoter, a synergist, a catalyst, a polymerization inhibitor, an oxidizing agent, a reducing agent and / or a functional auxiliary agent. Preferably, in condition 1, the reaction promoter or catalyst is one or more of diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, benzoyl peroxide, lauryl peroxide, t-butyl peroxybenzoate, t-butyl peroxy-t- valerate, di-t-butyl peroxide, dicumyl peroxide, azobis-isobutyronitrile, azobis-isoheptyl nitrile; the amount of the reaction promoter or catalyst used is 0.005 to 0.05 equivalent based on the molar amount of the reaction raw material. Preferably, in condition 1, the side reaction inhibitor is one or more of triethanolamine, aniline, N,N-dimethylaniline, N,N-diethylaniline, N,N-dihydroxyethylaniline, 2-chloro-4,6-dinitrophenol, 4-chloro-N,N-dimethylaniline; the amount of the reaction promoter or catalyst used is 0.005 to 0.05 equivalent based on the molar amount of the reaction raw material.

[0015] The gist of the present application will be further explained in connection with specific examples. DETAILED DESCRIPTION

[0016] Example 1:

[0017]

[0018] As shown in Reaction Formula (II), 260 g of acetone (4.48 mol) and 0.26 g of triethanolamine were added into a 1 L dry round-bottom flask, 1.30 g of benzoyl peroxide (BPO) was added, a condenser tube was installed, the temperature was first raised to 50°C, the chlorine cylinder was connected and the valve was opened, the chlorine flow rate was controlled at about 0.2 L / min, and the reaction was started. The tail gas was absorbed with a lye. During the reaction, samples were taken at regular intervals, and the progress of the reaction was monitored by gas chromatography. After the complete conversion of acetone, the temperature was raised to 80°C, and the reaction was continued for 3 hours. The content of 1,3-dichloropropanone reached a maximum of 71.5% (the main by-products were 1,1-dichloropropanone and 1,1,3-trichloropropanone). Purification and refinement by vacuum distillation obtained 420 g of 1,3-dichloropropanone with a purity of 92.1% (the main impurity was 1,1-dichloropropanone), and the actual yield was 68.0%.

[0019] In a 2L round-bottom flask, the purified 1,3-dichloroacetone was added, followed by 1000g of ethanol, and stirred to dissolve. In a beaker, 265g of solid NaOH (6.62mol) and 360mL of water were added to prepare an alkaline solution. The alkaline solution was added dropwise while stirring the reaction solution. After the addition was complete, a condenser was attached, the temperature was raised to 80℃, and stirring was continued for 6 hours. After the reaction was complete, the solution was cooled to room temperature, and the pH was adjusted to approximately 3 with hydrochloric acid. Most of the solvent, water, and other volatile impurities were removed by rotary evaporation. Then, THF was added, and the mixture was stirred thoroughly before filtration to desalt the product. The filtrate was concentrated to obtain the crude product. The crude product was recrystallized in a mixed solvent of ethanol and THF to obtain 243g (2.70mol) of pure 1,3-dihydroxyacetone, with an overall yield of 60.3% for both steps.

[0020] Example 2:

[0021]

[0022] As shown in reaction (III), 120 g of acetone (2.07 mol) and 0.12 g of N,N-dihydroxyethyl aniline were added to a 500 mL dry round-bottom flask, along with 0.6 g of diisopropyl peroxide. A condenser was attached, and the temperature was raised to 50 °C. A chlorine cylinder was connected, and the valve was opened, controlling the chlorine flow rate at approximately 0.1 L / min to initiate the reaction. The tail gas was absorbed with alkaline solution. During the reaction, samples were taken periodically, and the reaction progress was monitored using gas chromatography. After 2 hours of reaction, when the acetone was completely converted, the temperature was raised to 80 °C, and the reaction continued for another 3 hours, reaching a maximum content of 82.6% for 1,3-dichloroacetone (the main byproducts were 1,1-dichloroacetone and 1,1,3-trichloroacetone). 212 g of 1,3-dichloroacetone with a purity of 95.2% (the main impurity was 1,1-dichloroacetone) was obtained by vacuum distillation, with an actual yield of 76.8%.

[0023] In a 2L round-bottom flask, the purified 1,3-dichloroacetone was added, followed by 600g of tert-butanol, and stirred until dissolved. In a beaker, 231g of solid K₂CO₃ (1.67mol) and 320mL of water were added to prepare an alkaline solution. The alkaline solution was added dropwise while stirring the reaction solution. After the addition was complete, a condenser was attached, the temperature was raised to 100℃, and stirring was continued for 6 hours. After the reaction was complete, the solution was cooled to room temperature, and the pH was adjusted to approximately 3 with hydrochloric acid. Most of the solvent, water, and other volatile impurities were removed by rotary evaporation. Then, THF was added, and the mixture was stirred thoroughly before filtration to desalt the product. The filtrate was concentrated to obtain the crude product. The crude product was recrystallized in a mixed solvent of ethanol and THF to obtain 132g (1.47mol) of pure 1,3-dihydroxyacetone, with an overall yield of 70.8% for both steps.

[0024] Example 3:

[0025]

[0026] As shown in reaction (IV), 60.0 g of acetone (1.03 mol) and 60 mg of triethanolamine were added to a 1 L dry round-bottom flask. 300 mL of 1,2-dichloroethane was added and stirred to dilute the solution. Liquid bromine (336 g, 2.10 mol) was added dropwise using a constant-pressure dropping funnel while stirring at room temperature. After the addition was complete, a condenser was attached, the temperature was raised to 50 °C, and the mixture was stirred for 2 hours. Then, the temperature was raised to 80 °C, and stirring was continued for another 2 hours. After the reaction was complete, the mixture was cooled to room temperature, washed twice with water, and separated. The organic phase was dried through an anhydrous magnesium sulfate filter cake, and the solvent was removed by rotary evaporation. The resulting crude 1,3-dibromoacetone was directly added to the next reaction step.

[0027] In a 2L round-bottom flask, add the above-mentioned 1,3-dibromoacetone, followed by 500g of ethanol, and stir to dissolve. In a beaker, add 121g of solid KOH (2.16mol) and 150mL of water to prepare an alkaline solution. Add the alkaline solution dropwise while stirring the reaction solution. After the addition is complete, attach a condenser, heat to 60℃, and continue stirring for 3 hours. After the reaction is complete, cool to room temperature and adjust the pH to approximately 3 with hydrochloric acid. Remove most of the solvent, water, and other volatile impurities by rotary evaporation. Then add THF, stir thoroughly, and filter to desalt. Concentrate the filtrate to obtain the crude product. Recrystallize the crude product in a mixed solvent of ethanol and THF to obtain 76.6g (0.85mol) of pure 1,3-dihydroxyacetone, with an overall yield of 82.5% for both steps.

[0028] Example 4:

[0029]

[0030] As shown in reaction (V), 30.0 g of acetone (0.52 mol) and 30 mg of triethanolamine were added to a 500 mL dry round-bottom flask. 150 mL of 1,2-dichloroethane was added and stirred to dilute the solution. 263 g of iodine (1.04 mol) was added in portions. A condenser was then attached, and the mixture was slowly heated to 50 °C and stirred for 2 hours. The temperature was then increased to 80 °C and stirred for another 2 hours. After the reaction was complete, the mixture was cooled to room temperature, washed twice with water, and separated. The organic phase was dried through an anhydrous magnesium sulfate filter cake, and the solvent was removed by rotary evaporation. The resulting crude 1,3-diiodoacetone was directly added to the next reaction step.

[0031] In a 1L round-bottom flask, add the above-mentioned 1,3-diiodoacetone, then add 300g of ethanol and stir to dissolve. In a beaker, add 55g of solid Na₂CO₃ (0.52mol) and 150mL of water to prepare an alkaline solution. Add the alkaline solution dropwise while stirring the reaction solution. After the addition is complete, attach a condenser, heat to 80℃, and continue stirring for 3 hours. After the reaction is complete, cool to room temperature and adjust the pH to approximately 3 with hydrochloric acid. Remove most of the solvent, water, and other volatile impurities by rotary evaporation. Then add THF, stir thoroughly, and filter to desalt. Concentrate the filtrate to obtain the crude product. Recrystallize the crude product in a mixed solvent of ethanol and THF to obtain 35.9g (0.40mol) of pure 1,3-dihydroxyacetone, with an overall yield of 76.6% for both steps.

[0032] It should be emphasized that the above embodiments are merely exemplary and not limiting. Based on the disclosure of this application, any adjustments or changes to the reaction conditions or parameters that a person skilled in the art might normally adopt will not deviate from the spirit of the invention. The scope of protection of this patent shall be determined by the relevant claims.

Claims

1. A method for preparing 1,3-dihydroxyacetone from acetone, as shown in reaction formula (I), wherein acetone is used as a starting material, halogenation reaction occurs under the action of reaction condition 1 to generate intermediate A, and then base substitution reaction occurs under the action of reaction condition 2 to efficiently prepare 1,3-dihydroxyacetone. wherein X and Y are both halogen Cl, Br or I. The reaction condition 1 and the reaction condition 2 are independently at least one of the following: reactants, solvents, temperature and additives.

2. According to claim 1, in the reaction condition 1, the reactants are chlorine, liquid bromine, or iodine, or any combination of the three. In the reaction condition 2, the reactants are lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, tetrabutylammonium hydroxide, strong base type anion exchange resin, or an aqueous solution, an alcohol solution thereof. The solvent is selected from at least one of the following: substituted or non-substituted aromatic hydrocarbons containing 1-24 carbons, linear or branched aliphatic hydrocarbons, (sub) sulfones, amides, ethers, esters, alcohols, ketones, nitriles, carboxylic acids, water, amines, carbonates, ionic liquids, and supercritical carbon dioxide. The temperature is 0-200℃. The additives refer to reaction promoters, synergists, catalysts, polymerization inhibitors, oxidizing agents, reducing agents and / or functional auxiliaries.

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