A method for synthesizing 1,4-dioxane-2-one

Abstract

The application discloses a synthesis method of 1,4-dioxane-2-ketone, which comprises the following steps: step a: diethylene glycol is selectively reacted under the action of a solvent A and phosphorus tribromide to generate 2-(2-bromoethoxy) ethanol; step b: 2-(2-bromoethoxy) ethanol is subjected to the action of a solvent B, an oxidant, a catalyst and a buffer salt to generate 2-(2-bromoethoxy) acetic acid; step c: 2-(2-bromoethoxy) acetic acid is subjected to acid-base neutralization reaction under the action of a solvent methanol and sodium hydroxide to generate 2-(2-bromoethoxy) sodium acetate; and step d: 2-(2-bromoethoxy) sodium acetate is subjected to ring closure reaction under the action of a solvent C and a phase transfer catalyst to generate 1,4-dioxane-2-ketone. The application has the characteristics of simple operation, high total yield, less waste, small corrosion to equipment, no need of high-temperature and high-pressure equipment and the like, and is more beneficial to industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing 1,4-dioxane-2-one. Background Technology

[0002] Various lactones (such as e-caprolactone or d-valerolactone) and cyclic diesters (such as diethylene glycol esters or L,L-dilactone lactone) can be polymerized via ring-opening polymerization, using catalysts including coordination catalysis or transesterification catalysis. Besides their use in synthesizing high-molecular-weight aliphatic polyesters, their end-capped oligomers can also be used to prepare high-molecular-weight polymers through chain-lengthening reactions such as polycondensation or addition. Furthermore, end-capped oligomers are also used to prepare network structure materials. Typically, end-capped materials need to possess well-defined molecular weight and functional group characteristics to meet the requirements of subsequent reactions. 1,4-Dioxane-2-one, as a homopolymer, is a recognized high-quality material in the biomedical field, particularly suitable for biodegradable surgical sutures. .

[0003] There are existing literature reports on the synthesis of 1,4-dioxane-2-one, with three main synthetic routes: Route 1: Using 2,3-dichloro-1,4-dioxane as a starting material, the target product is obtained by removing hydrogen chloride through heating in an alcohol solvent. This route generates hydrogen chloride during the reaction, which not only leads to ring-opening and cleavage of 1,4-dioxane-2-one, resulting in lower reaction yield and selectivity, but also causes the generated hydrogen chloride gas to corrode equipment. Therefore, this route has no potential for industrial production. .

[0004] Route 2: Using diethylene glycol as a raw material, the target product is generated through catalytic oxidative dehydrogenation cyclization. This route requires a precious metal catalyst, which is not only expensive but also generates waste that is difficult to treat. The reaction temperature needs to reach 200-300℃, and there are many side reactions, poor selectivity, and the product is difficult to separate and purify, resulting in low industrial feasibility. .

[0005] Route 3: Using ethylene glycol as a raw material, carbon monoxide gas is reacted with a carbonyl group under the action of a catalyst to obtain the target product. This reaction requires toxic carbon monoxide to synthesize carbonyl groups, posing safety hazards during production. Furthermore, the reaction requires very high temperatures and produces large amounts of salt, making it unsuitable for large-scale industrial production. . Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing 1,4-dioxane-2-one, which has the advantages of simple operation, no need for precious metal catalysts, high overall yield, low waste generation, low corrosiveness to equipment, and no need for high temperature and high pressure equipment, making it more conducive to industrial production.

[0007] The technical solution adopted by this invention to solve its technical problem is: A method for synthesizing 1,4-dioxane-2-one. Includes the following steps: Step a: Diethylene glycol reacts selectively with solvent A and phosphorus tribromide to produce 2-(2-bromoethoxy)ethanol; Step b: 2-(2-bromoethoxy)ethanol is reacted with solvent B, an oxidant, a catalyst, and a buffer salt to yield 2-(2-bromoethoxy)acetic acid; Step c: 2-(2-bromoethoxy)acetic acid undergoes an acid-base neutralization reaction in the solvents methanol and sodium hydroxide to produce sodium 2-(2-bromoethoxy)acetate; Step d: Sodium 2-(2-bromoethoxy)acetate undergoes a ring-closing reaction in solvent C and a phase transfer catalyst to generate 1,4-dioxane-2-one (PDO).

[0008] In step a, solvent A is selected from any one or more of dichloromethane, toluene, and n-heptane. Dichloromethane is preferred, as it not only dissolves the reagents better but also offers simple post-processing, high safety, and the ability to be recycled after processing.

[0009] In step a, the molar ratio of diethylene glycol to phosphorus tribromide is 2.7-3.3:1.0, the reaction temperature is 0-10℃, and the reaction time is 8-12 h. Excess diethylene glycol can improve reaction selectivity, reduce byproducts from the top two bromine atoms, and increase the reaction yield. Preferably, the molar ratio of diethylene glycol to phosphorus tribromide is 3.0:1.0. The preferred reaction temperature is 0-5℃, and the preferred reaction time is 10 h; conducting the reaction at low temperatures helps to improve reaction selectivity.

[0010] In step b, solvent B is selected from any one or more of acetonitrile, ethyl acetate, acetone, and water; the oxidant is a combination of sodium hypochlorite and sodium chlorite; the catalyst is a combination of TEMPO and potassium bromide; and the buffer salt is sodium dihydrogen phosphate dihydrate. Preferably, solvent B is a combination of acetonitrile and water. Acetonitrile dissolves TEMPO, and water not only dissolves inorganic salts but is also miscible with acetonitrile, ensuring a homogeneous reaction and preventing the formation of byproducts.

[0011] In step b, the molar ratio of 2-(2-bromoethoxy)ethanol:sodium hypochlorite:sodium dihydrogen phosphate dihydrate:TEMPO:potassium bromide:sodium chlorite is 1.0:0.1-0.3:2.0-2.4:0.01-0.03:0.1-0.3:1.0-1.2; the reaction temperature is 20-40℃, and the reaction time is 3-5 hours. The preferred reaction temperature is 20-25℃. Conducting the reaction at a lower temperature helps avoid side reactions during oxidation.

[0012] In step c, the molar ratio of 2-(2-bromoethoxy)acetic acid to sodium hydroxide is 1.0:1.0-1.2; the reaction temperature is 10-40℃, and the reaction time is 1-3 h. Preferably, the reaction temperature is 30-35℃, and the reaction time is 2 h, indicating mild and easily controllable reaction conditions.

[0013] In step d, the phase transfer catalyst is one of 18-crown 6, 15-crown 5, and tetrabutylammonium bromide; the solvent C is any one or more of methanol, ethanol, acetonitrile, and water. Solvent C is preferably acetonitrile, as acetonitrile is a polar aprotic solvent with good solubility for the phase transfer catalyst, thus accelerating the forward reaction. The phase transfer catalyst can increase the solubility of inorganic substances in organic solvents, which is beneficial for promoting the above reaction. Among these, 15-crown 5 is preferred, as it not only has good catalytic effect but also improves the solubility of sodium salts in organic solvents.

[0014] In step d, the molar ratio of sodium 2-(2-bromoethoxy)acetate to the phase transfer catalyst is 1.0:0.1-0.3, the reaction temperature is 50-80℃, and the reaction time is 8-12 h. A slight excess of the phase transfer catalyst can promote the reaction rate and shorten the reaction time. Preferably, the molar ratio of sodium 2-(2-bromoethoxy)acetate to the phase transfer catalyst is 1.0:0.2. The preferred reaction temperature is 60-70℃, and the preferred reaction time is 10 h, which improves both the conversion rate and the reaction rate.

[0015] The beneficial effects of this invention are: The reaction process requires only inexpensive non-metallic catalysts, avoiding the use of expensive metal catalysts and preventing the introduction of metal contaminants in subsequent operations. This not only reduces production costs but also simplifies post-processing operations. In this application, the reaction temperature is below 100℃, which can be achieved with ordinary reaction equipment, avoiding the use of high temperature and high pressure equipment, improving production safety, and further reducing production costs; The method of this invention is simple to operate, has mild reaction conditions, high yield, generates little waste, has strong feasibility, and is suitable for industrial production. Detailed Implementation

[0016] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0017] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.

[0018] Example 1 (I) Preparation of 2-(2-bromoethoxy)ethanol (II) In a 1 L round-bottom flask, under nitrogen protection, 105 g (2.8 eq.) of diethylene glycol (I) and 600 mL of toluene were added. The temperature was controlled at 4 °C, and 96 g (1.0 eq.) of phosphorus tribromide was added dropwise. The mixture was stirred at 10 °C for 9 h. 100 mL of 40% sodium hydroxide aqueous solution was added and stirred for 20 min. The mixture was allowed to stand and separated. The organic phase was washed with 200 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to column chromatography (PE:EA = 1:1). After evaporation of the solvent, 42 g of the product 2-(2-bromoethoxy)ethanol (II) was obtained, with a yield of 70%.

[0019] 1 H-NMR(300 MHz, CDCl3)δ(ppm):2.63 (s, 1H), 3.42 (t, J = 6.0 Hz, 2H), 3.54−3.57(m, 2H), 3.67−3.70 (m, 2H), 3.75 (t, J = 5.7 Hz, 2H).

[0020] (II) Preparation of 2-(2-bromoethoxy)acetic acid(III) In a 1 L round-bottom flask, 32 g (1.0 eq.) 2-(2-bromoethoxy)ethanol (II), 55 mL water, and 10 mL acetone were added. Then, 62 g (2.1 eq.) sodium dihydrogen phosphate dihydrate, 0.3 g (0.01 eq.) Tempo, 2.3 g (0.1 eq.) potassium bromide, and 14 g (0.1 eq.) sodium hypochlorite (10%) were added sequentially. The temperature was maintained at 20 °C, and 55 g (1.0 eq.) sodium chlorite (31%) was added dropwise. The mixture was stirred at 30 °C for 3 h. 21 g sodium bisulfite was added and stirred for 20 min, followed by 100 mL ethyl acetate and stirring for another 20 min. The mixture was allowed to stand and separated. The organic phase was washed once with 50 mL water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 28.7 g of 2-(2-bromoethoxy)acetic acid (III), with a yield of 83%.

[0021] 1H-NMR (400 MHz, CDCl3) δ(ppm):10.01 (s, 1H), 4.24-4.25 (m, 2H), 3.94-3.91 (m, 2H), 3.54-3.51 (m, 2H).

[0022] (III) Preparation of sodium 2-(2-bromoethoxy)acetate (IV) In a 1 L round-bottom flask, under nitrogen protection, 50 g (1.0 eq.) of 2-(2-bromoethoxy)acetic acid (III) and 600 mL of methanol were added. The temperature was controlled at 10 °C, and 11 g (1.0 eq.) of sodium hydroxide was added. The mixture was stirred for 1 h. The solvent was evaporated to dryness, and the mixture was stirred in 200 mL of acetonitrile for 20 min. The mixture was then filtered, and the filter cake was dried to obtain 55 g of sodium 2-(2-bromoethoxy)acetic acid (IV), with a yield of 99%.

[0023] 1 H-NMR (400 MHz, D2O) δ(ppm):4.24-4.25 (m, 2H), 3.94-3.91 (m, 2H),3.54-3.51 (m, 2H).

[0024] (iv) Preparation of 1,4-dioxane-2-one (PDO) In a 1 L round-bottom flask, under nitrogen protection, 50 g (1.0 eq.) sodium 2-(2-bromoethoxy)acetate (IV), 500 mL methanol, and 12.8 g (0.2 eq.) 18-crown-6 were added. The mixture was heated to 60 °C and stirred for 9 h. After cooling, the mixture was filtered, the solvent in the filtrate was evaporated to dryness, dissolved in dichloromethane, washed with 20 mL of 20% sodium chloride aqueous solution, the solvent was evaporated to dryness, 200 mL of ethyl acetate / n-heptane (1:10) was added, and the mixture was stirred at 10 °C for 20 min. After cooling, the mixture was filtered, the solvent in the filter cake was evaporated to dryness, and the product was distilled under reduced pressure to obtain 15 g of 1,4-dioxane-2-one (PDO), with a yield of 60%.

[0025] 1 ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 4.66 – 4.43 (m, 2H), 4.37 (d, J = 0.7Hz, 2H), 3.88 (dd, J = 5.0, 4.4 Hz, 2H), consistent with the structure of 1,4-dioxane-2-one.

[0026] Example 2 (I) Preparation of 2-(2-bromoethoxy)ethanol (II) In a 1 L round-bottom flask, under nitrogen protection, 113 g (3.0 eq.) of diethylene glycol (I) and 490 mL of dichloromethane were added. The temperature was controlled at 2 °C, and 96 g (1.0 eq.) of phosphorus tribromide was added dropwise. The mixture was stirred at 10 °C for 10 h. 100 mL of 40% sodium hydroxide aqueous solution was added and stirred for 20 min. The mixture was allowed to stand and separated. The organic phase was washed with 200 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to rapid column chromatography (PE:EA = 1:1). After evaporating the solvent, 46 g of the product 2-(2-bromoethoxy)ethanol (II) was obtained, with a yield of 77%.

[0027] (II) Preparation of 2-(2-bromoethoxy)acetic acid(III) In a 1 L round-bottom flask, 32 g (1.0 eq.) 2-(2-bromoethoxy)ethanol (II), 55 mL of water, and 10 mL of acetonitrile were added. Then, 65 g (2.2 eq.) sodium dihydrogen phosphate dihydrate, 0.6 g (0.02 eq.) Tempo, 4.6 g (0.2 eq.) potassium bromide, and 28 g (0.2 eq.) sodium hypochlorite (10%) were added sequentially. The temperature was maintained at 20 °C, and 60 g (1.1 eq.) sodium chlorite (31%) was added dropwise. The mixture was stirred at 25 °C for 4 h. 21 g of sodium bisulfite was added and stirred for 20 min. Then, 100 mL of ethyl acetate was added and stirred for 20 min. The mixture was allowed to stand and separated. The organic phase was washed once with 50 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 30.4 g of the product 2-(2-bromoethoxy)acetic acid (III), with a yield of 88%.

[0028] (III) Preparation of sodium 2-(2-bromoethoxy)acetate (IV) This step involves performing the corresponding experimental operations according to the method in Example 1.

[0029] (iv) Preparation of 1,4-dioxane-2-one (PDO) In a 1 L round-bottom flask, under nitrogen protection, 50 g (1.0 eq.) sodium 2-(2-bromoethoxy)acetate (IV), 500 mL acetonitrile, and 10.7 g (0.2 eq.) 15-crown ether-5 were added. The mixture was heated to 70 °C and stirred for 10 h. After cooling, the mixture was filtered, the solvent in the filtrate was evaporated to dryness, dissolved in dichloromethane, washed with 20 mL of 20% sodium chloride aqueous solution, the solvent was evaporated to dryness, 200 mL of ethyl acetate / n-heptane (1:10) was added, and the mixture was stirred at 10 °C for 20 min. After cooling, the mixture was filtered, the solvent in the filter cake was evaporated to dryness, and the product was distilled under reduced pressure to obtain 17 g of 1,4-dioxane-2-one (PDO), with a yield of 67%.

[0030] 1¹H-NMR (400 MHz, CDCl₃) δ(ppm): 4.66 – 4.43 (m, 2H), 4.37 (d, J = 0.7Hz, 2H), 3.88 (dd, J = 5.0, 4.4 Hz, 2H), consistent with the structure of 1,4-dioxane-2-one.

[0031] Example 3 (I) Preparation of 2-(2-bromoethoxy)ethanol (II) In a 1 L round-bottom flask, under nitrogen protection, 120 g (3.2 eq.) of diethylene glycol (I) and 490 mL of n-heptane were added. The temperature was controlled to 0 °C, and 96 g (1.0 eq.) of phosphorus tribromide was added dropwise. The mixture was stirred at 10 °C for 12 h. 100 mL of 40% sodium hydroxide aqueous solution was added and stirred for 20 min. The mixture was allowed to stand and separated. The organic phase was washed with 200 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then subjected to rapid column chromatography (PE:EA = 1:1). After evaporating the solvent, 44 g of the product 2-(2-bromoethoxy)ethanol (II) was obtained, with a yield of 73.3%.

[0032] (II) Preparation of 2-(2-bromoethoxy)acetic acid(III) In a 1 L round-bottom flask, 32 g (1.0 eq.) 2-(2-bromoethoxy)ethanol (II), 55 mL of water, and 10 mL of ethyl acetate were added. Then, 70 g (2.4 eq.) sodium dihydrogen phosphate dihydrate, 0.9 g (0.03 eq.) Tempo, 4.6 g (0.2 eq.) potassium bromide, and 42 g (0.3 eq.) sodium hypochlorite (10%) were added sequentially. The temperature was maintained at 20 °C, and 66 g (1.2 eq.) sodium chlorite (31%) was added dropwise. The mixture was stirred at 20 °C for 5 h. 21 g of sodium bisulfite was added and stirred for 20 min, followed by 100 mL of ethyl acetate and stirring for another 20 min. The mixture was allowed to stand and separated. The organic phase was washed once with 50 mL of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 27.4 g of 2-(2-bromoethoxy)acetic acid (III), with a yield of 80%.

[0033] (III) Preparation of sodium 2-(2-bromoethoxy)acetate (IV) This step involved performing the corresponding experimental operations according to the method in Example 1, and similar experimental results were obtained.

[0034] (iv) Preparation of 1,4-dioxane-2-one (PDO) In a 1 L round-bottom flask, under nitrogen protection, 50 g (1.0 eq.) sodium 2-(2-bromoethoxy)acetate (IV), 50 mL water, 450 mL ethanol, and 23.5 g (0.3 eq.) TBAB were added. The temperature was controlled at 80 °C, and the mixture was stirred for 12 h. The solvent in the filtrate was evaporated to dryness, dissolved in dichloromethane, cooled, and filtered. The filtrate was washed with 20 mL of 20% sodium chloride aqueous solution, the solvent was evaporated to dryness, and 200 mL of ethyl acetate / n-heptane (1:10) was added. The mixture was stirred at 10 °C for 20 min, cooled, filtered, and the solvent in the filter cake was evaporated to dryness. The product, 1,4-dioxane-2-one (PDO), was obtained by vacuum distillation, yielding 16 g of product, with a yield of 64%.

[0035] 1 ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 4.66 – 4.43 (m, 2H), 4.37 (d, J = 0.7Hz, 2H), 3.88 (dd, J = 5.0, 4.4 Hz, 2H), consistent with the structure of 1,4-dioxane-2-one.

[0036] Example 4 The difference between this embodiment and Embodiment 1 is that: The molar ratio of diethylene glycol to phosphorus tribromide was 2.7:1.0, the reaction temperature was 0℃, and the reaction time was 12h.

[0037] Example 5 The difference between this embodiment and Embodiment 1 is that: The molar ratio of diethylene glycol to phosphorus tribromide was 3.3:1.0, the reaction temperature was 10℃, and the reaction time was 8h.

[0038] Example 6 The difference between this embodiment and Embodiment 1 is that: The molar ratio of 2-(2-bromoethoxy)ethanol:sodium hypochlorite:sodium dihydrogen phosphate dihydrate:TEMPO:potassium bromide:sodium chlorite was 1.0:0.1:2.0:0.01:0.1:1.0; the reaction temperature was 20℃ and the reaction time was 5h.

[0039] Example 7 The difference between this embodiment and Embodiment 1 is that: The molar ratio of 2-(2-bromoethoxy)ethanol:sodium hypochlorite:sodium dihydrogen phosphate dihydrate:TEMPO:potassium bromide:sodium chlorite was 1.0:0.3:2.4:0.03:0.3:1.2; the reaction temperature was 40℃ and the reaction time was 3h.

[0040] Example 8 The difference between this embodiment and Embodiment 1 is that: The molar ratio of 2-(2-bromoethoxy)acetic acid to sodium hydroxide is 1.0:1.0; the reaction temperature is 10℃ and the reaction time is 3h.

[0041] The molar ratio of sodium 2-(2-bromoethoxy)acetate to phase transfer catalyst was 1.0:0.1, the reaction temperature was 50℃, and the reaction time was 12h.

[0042] Example 9 The difference between this embodiment and Embodiment 1 is that: The molar ratio of 2-(2-bromoethoxy)acetic acid to sodium hydroxide is 1.0:1.2; the reaction temperature is 40℃ and the reaction time is 1h.

[0043] The molar ratio of sodium 2-(2-bromoethoxy)acetate to phase transfer catalyst was 1.0:0.3, the reaction temperature was 80℃, and the reaction time was 8h.

[0044] In summary, the method for preparing 1,4-dioxane-2-one (PDO) of the present invention has the advantages of mild reaction conditions, simple operation, low cost, and high yield. In the final cyclization reaction, the synthesis method of combining phase transfer catalyst and organic solvent is preferred, which not only improves the conversion rate and yield, but also reduces the reaction temperature, effectively avoids side reactions, facilitates post-processing purification, and is more conducive to large-scale industrial production.

[0045] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for synthesizing 1,4-dioxane-2-one, characterized in that, Includes the following steps: Step a: Diethylene glycol reacts selectively with solvent A and phosphorus tribromide to produce 2-(2-bromoethoxy)ethanol; Step b: 2-(2-bromoethoxy)ethanol is reacted with solvent B, an oxidant, a catalyst, and a buffer salt to yield 2-(2-bromoethoxy)acetic acid; Step c: 2-(2-bromoethoxy)acetic acid undergoes an acid-base neutralization reaction in the solvents methanol and sodium hydroxide to produce sodium 2-(2-bromoethoxy)acetate; Step d: Sodium 2-(2-bromoethoxy)acetate undergoes a ring-closure reaction in solvent C and a phase transfer catalyst to generate 1,4-dioxane-2-one.

2. The synthesis method according to claim 1, characterized in that, In step a, solvent A is selected from any one or more of dichloromethane, toluene, and n-heptane.

3. The synthesis method according to claim 1, characterized in that, In step a, the molar ratio of diethylene glycol to phosphorus tribromide is 2.7-3.3:1.0, the reaction temperature is 0-10℃, and the reaction time is 8-12h.

4. The synthesis method according to claim 1, characterized in that, In step b, solvent B is selected from any one or more of acetonitrile, ethyl acetate, acetone, and water; the oxidant is a combination of sodium hypochlorite and sodium chlorite; the catalyst is a combination of TEMPO and potassium bromide; and the buffer salt is sodium dihydrogen phosphate dihydrate.

5. The synthesis method according to claim 4, characterized in that, In step b, the molar ratio of 2-(2-bromoethoxy)ethanol:sodium hypochlorite:sodium dihydrogen phosphate dihydrate:TEMPO:potassium bromide:sodium chlorite is 1.0:0.1-0.3:2.0-2.4:0.01-0.03:0.1-0.3:1.0-1.2; the reaction temperature is 20-40℃, and the reaction time is 3-5h.

6. The synthesis method according to claim 1, characterized in that, In step c, the molar ratio of 2-(2-bromoethoxy)acetic acid to sodium hydroxide is 1.0:1.0-1.2; the reaction temperature is 10-40℃, and the reaction time is 1-3h.

7. The synthesis method according to claim 1, characterized in that, In step d, the phase transfer catalyst is one of 18-crown 6, 15-crown 5, and tetrabutylammonium bromide; the solvent C is any one or more of methanol, ethanol, acetonitrile, and water.

8. The synthesis method according to claim 1, characterized in that, In step d, the molar ratio of sodium 2-(2-bromoethoxy)acetate to phase transfer catalyst is 1.0:0.1-0.3, the reaction temperature is 50-80℃, and the reaction time is 8-12h.

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