Method for preparing p-dioxanone from diethylene glycol

Abstract

The invention discloses a method for preparing p-dioxanone from diethylene glycol, which comprises the following steps: by taking diethylene glycol (DEG) as a raw material, 2, 2, 6, 6-tetramethylpiperidine oxide (TEMPO) as a catalyst and trichloroisocyanuric acid (TCCA) as an oxidant, reacting in a solvent in the presence of an acidic material and inert gas to obtain the p-dioxanone. The invention provides a novel method for preparing p-dioxanone. A target product is obtained through one-step oxidative cyclization of diethylene glycol. Wherein the required raw materials are easy to obtain and low in price, no metal participates in catalysis, the yield is good, the reaction conditions are mild, and the method has industrial prospects.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis, and in particular to a method for preparing p-dioxanone by using diethylene glycol. Background Art

[0002] Paradioxanone (PDO) is an important organic chemical product with a wide range of uses, such as biodegradable material monomers, pharmaceutical intermediates, etc. Polyparadioxanone (PPDO) is obtained by ring-opening polymerization of the monomer PDO. It is a polymer with excellent biodegradability, biocompatibility and bioabsorbability. It can be used in surgical sutures, tissue repair materials and drug carriers.

[0003] In order to obtain high molecular weight PPDO, you must first have a high purity monomer. Then, PDO has not been a general and readily available commercial product for a long time in the past. In the 1970s, the US patent application document with publication number US4052988 disclosed a method of using ethylene glycol, sodium metal and chloroacetic acid through a series of chemical reactions to prepare high-purity PDO, but because this method has many steps and complicated operations, the cost of PDO is increased. In recent years, scholars have conducted a lot of research on the synthesis of PDO. The Chinese patent application document with publication number CN112724122A discloses a method of preparing p-dioxanone by catalyzing diethylene glycol with active metal, but it uses metals such as Ru, Pd, Ir, V, Cr, and Cu to catalyze the reaction on an apatite carrier, and some of the precious metals used greatly increase the reaction cost, and the reaction is carried out under high pressure (0.1-2MPa) and high temperature (150-250°C), and the conditions are relatively harsh. Summary of the invention

[0004] The technical problem to be solved by the present invention is how to prepare p-dioxanone conveniently and under mild conditions.

[0005] The present invention solves the above technical problems through the following technical means:

[0006] A method for preparing p-dioxanone from diethylene glycol comprises the following steps: using diethylene glycol (DEG) as a raw material, 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO) as a catalyst, and trichloroisocyanuric acid (TCCA) as an oxidant, and reacting in a solvent in the presence of an acidic substance and an inert gas to obtain the p-dioxanone.

[0007] Preferably, the acidic substance is a mixture of one or more of nitromethane, nitrobenzene, trifluoroethanol, hexafluoroisopropanol, benzoic acid and citric acid.

[0008] Preferably, the acidic substance is hexafluoroisopropanol or nitromethane, or a mixture of the two.

[0009] Preferably, the solvent is a mixture of one or more of acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane and dichloromethane.

[0010] Preferably, the solvent is acetonitrile.

[0011] Preferably, the inert gas is nitrogen.

[0012] Preferably, the reaction temperature is room temperature and the reaction time is 16-28 hours.

[0013] Preferably, the molar ratio of diethylene glycol to trichloroisocyanuric acid is 1:0.8-1.2; the molar ratio of diethylene glycol to acidic substance is 1:2-5; and the molar ratio of diethylene glycol to 2,2,6,6-tetramethylpiperidinyl oxide is 1:0.1-0.2.

[0014] Preferably, the method for preparing p-dioxanone with diethylene glycol comprises the following steps: mixing diethylene glycol, 2,2,6,6-tetramethylpiperidinoxide, an acidic substance, trichloroisocyanuric acid and a solvent, and reacting under a nitrogen atmosphere to obtain the p-dioxanone.

[0015] Preferably, in the process of mixing diethylene glycol, 2,2,6,6-tetramethylpiperidinyl oxide, an acidic substance, trichloroisocyanuric acid and a solvent, 2,2,6,6-tetramethylpiperidinyl oxide and diethylene glycol are first mixed, and then the mixture of the acidic substance and the solvent is added, stirred, and then the mixture of trichloroisocyanuric acid and the solvent is added and stirred to mix.

[0016] Preferably, the method further comprises adding sodium thiosulfate to the product after the reaction.

[0017] Preferably, the usage ratio of sodium thiosulfate to trichloroisocyanuric acid is 24 mg:1 mmol.

[0018] Preferably, both the diethylene glycol and the liquid acidic substance are pre-dried with molecular sieves to remove water; and the acetonitrile is ultra-dry acetonitrile.

[0019] The chemical equation for preparing p-dioxanone from diethylene glycol in the present invention is as follows:

[0020]

[0021] The advantages of the present invention are:

[0022] The present invention provides a new method for preparing p-dioxanone, wherein the target product is obtained by one-step oxidation and cyclization of diethylene glycol. The required raw materials are easily available and inexpensive, no metal is involved in catalysis, the yield is good, the reaction conditions are mild, and the method has the prospect of industrialization.

[0023] In the present invention, the acidic substance auxiliary agent provides an acidic environment, so that the reaction forms a hemiacetal product during the reaction, and finally PDO is obtained under the action of TEMPO and TCCA. The reaction greatly increases the yield of PDO from 15% to 42-88%; the reagent is low-cost, the process is simple, the operation is convenient, the conditions are mild, and the post-treatment is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the NMR spectrum of PDO prepared in Example 1 of the present invention;

[0025] Figure 2 is the NMR spectrum of the reaction solution in Example 1 of the present invention;

[0026] Figure 3 The NMR spectrum of the reaction solution in Comparative Example 1 of the present invention;

[0027] Figure 4 is the nuclear magnetic resonance spectrum of the reaction solution in Example 2 of the present invention in which the acidic substance is nitrobenzene;

[0028] Figure 5 This is the nuclear magnetic spectrum of the reaction solution in Example 2 of the present invention where the acidic substance is trifluoroethanol;

[0029] Figure 6 This is the nuclear magnetic resonance spectrum of the reaction solution in Example 2 of the present invention where the acidic substance is hexafluoroisopropanol;

[0030] Figure 7 is the nuclear magnetic spectrum of the reaction solution in Example 2 of the present invention in which the acidic substance is benzoic acid;

[0031] Figure 8 is the nuclear magnetic resonance spectrum of the reaction solution in Example 2 of the present invention in which the acidic substance is citric acid;

[0032] Fig. 9 The NMR spectrum of the reaction solution in Comparative Example 3 of the present invention;

[0033] Fig.10 This is the NMR spectrum of the reaction solution (without TEMPO) in Comparative Example 2 of the present invention;

[0034] Fig.11 This is the NMR spectrum of the reaction solution (without TCCA) in Comparative Example 2 of the present invention;

[0035] Fig.12 The NMR spectrum of Example 3 of the present invention in which the solvent is ethyl acetate;

[0036] Fig.13 This is the NMR spectrum of tetrahydrofuran as the solvent in Example 3 of the present invention;

[0037] Fig.14This is the NMR spectrum of the solvent 1,4-dioxane in Example 3 of the present invention;

[0038] Fig.15 This is the NMR spectrum of dichloromethane as the solvent in Example 3 of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0040] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0041] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0042] The diethylene glycol and liquid acidic substances used below are all dehydrated and dried using molecular sieves in advance; the acetonitrile is ultra-dry acetonitrile.

[0043] Example 1

[0044] The synthesis method of dioxanone, the steps are as follows:

[0045] 15.63 mg TEMPO (0.1 mmol) was added to the Shrek tube, and the double-row tube was used to evacuate and replenish nitrogen three times. Under a nitrogen atmosphere, 106.12 mg DEG (1 mmol) was added, and then 122.08 mg MeNO2 (2 mmol) and 0.5 mL acetonitrile were mixed and added to the Shrek tube, and stirred at 0°C for 30 min; 232.41 mg TCCA (1 mmol) was dissolved in 0.5 mL acetonitrile and slowly added dropwise into the above Shrek tube under a nitrogen atmosphere, maintained at 0°C and stirred for 1 h, and then transferred to room temperature for reaction for 24 h. After the reaction, 24 mg of sodium thiosulfate was added and stirred for 1 h to ensure that the oxidant was completely removed. The filtrate was collected by filtration and subjected to silica gel column chromatography (200-300 mesh silica gel was added to the silica gel column, and the column was compacted with petroleum ether. The mobile phase was petroleum ether: ethyl acetate in a volume ratio of 8:1, and the polarity was gradually increased to a volume ratio of 3:1. The product flowed out) to obtain PDO. The silica gel column yield was 84%. The PDO NMR spectrum is shown as follows Figure 1 As shown, the NMR yield is 88%, as Figure 2When acetonitrile is used as the reaction solvent, the NMR spectrum of the reaction solution (i.e., the filtrate collected by filtration) is relatively "clean", that is, there are no excessive impurity peaks around the characteristic peaks of the product, and fewer side reactions occur.

[0046] Example 2

[0047] The synthesis method of dioxanone, the steps are as follows:

[0048] 15.63 mg TEMPO (0.1 mmol) was added to the Shrek tube, and the double-row tube was used to evacuate and replenish nitrogen three times. Under a nitrogen atmosphere, 106.12 mg DEG (1 mmol) was added, and then the acidic substance (2 mmol) and 0.5 mL acetonitrile were mixed and added to the Shrek tube, and stirred at 0°C for 30 min; 232.41 mg TCCA (1 mmol) was dissolved in 0.5 mL acetonitrile, and slowly added dropwise into the above Shrek tube under a nitrogen atmosphere, kept at 0°C and stirred for 1 h, and then transferred to room temperature for reaction for 24 h. After the reaction was completed, 24 mg sodium thiosulfate was added and stirred for 1 h to ensure that the oxidant was completely removed, and the filtrate was collected by filtration. The PDO yield was detected by NMR, as shown in the following table:

[0049] Components Acidic substances NMR yield (%) 1 Nitrobenzene 69 (see Figure 4 ) 2 Trifluoroethanol 62 (see Figure 5 ) 3 Hexafluoroisopropanol 76 (see Figure 6 ) 4 benzoic acid 70 (see Figure 7 ) 5 Citric Acid 42 (see Figure 8 )

[0050] Depend on Figure 4-8 It can be seen that there are no excessive impurity peaks around the characteristic peaks of the filtrate products obtained from different acidic substances, and the NMR spectrum of the reaction liquid is relatively "clean", indicating that there are fewer side reactions in the reaction system.

[0051] Comparative Example 1

[0052] The synthesis method of dioxanone (without the presence of acidic substances) is as follows:

[0053] 15.63 mg TEMPO (0.1 mmol) was added to the Shrek tube, and the mixture was evacuated and nitrogen was added three times using a double-row tube. Under a nitrogen atmosphere, 106.12 mg DEG (1 mmol) was added, and the mixture was stirred at 0°C for 30 min. 232.41 mg TCCA (1 mmol) was dissolved in 0.5 mL acetonitrile, and the mixture was slowly added dropwise into the Shrek tube under a nitrogen atmosphere, and the mixture was kept at 0°C and stirred for 1 h, and then transferred to room temperature for reaction for 24 h. After the reaction was completed, 24 mg sodium thiosulfate was added, and the mixture was stirred for 1 h to ensure that the oxidant was completely removed. The filtrate was collected by filtration, and the PDO yield was about 15% as determined by NMR (see Figure 3 ).

[0054] Comparative Example 2

[0055] According to the conditions in Example 1, no TEMPO or TCCA was involved in the reaction, and other reaction conditions were unchanged. The reaction did not occur and no dioxanone was obtained. Its NMR spectrum is as follows Figure 10-11 shown.

[0056] Example 3

[0057] According to the conditions in Example 1, the reaction solvent was changed, and other reaction conditions remained unchanged. The results are shown in the following table

[0058] Components Solvents NMR yield (%) 1 Ethyl acetate 21 (see Fig.12 ) 2 Tetrahydrofuran 33 (see Fig.13 ) 3 1,4-Dioxane 25 (see Fig.14 ) 4 Dichloromethane 69 (see Fig.15 )

[0059] Figure 12-15 In the reaction, when the reaction solvent was replaced by ethyl acetate, tetrahydrofuran, 1,4-dioxane and dichloromethane, the side reaction occurred more frequently, and the impurity peaks in the NMR spectrum increased. Compared with Example 1, when acetonitrile was used as the solvent, the side reaction could be reduced, and the positive reaction could be promoted to a certain extent.

[0060] Comparative Example 3

[0061] The synthesis method of dioxanone, the steps are as follows:

[0062] 106.12 mg DEG (1 mmol), 15.63 mg TEMPO (0.1 mmol) and 1220.8 mg MeNO2 (20 mmol) were added to a single-necked flask and stirred at 0°C for 30 min; 232.41 mg TCCA (1 mmol) was dissolved in 1220.8 mg MeNO2 (20 mmol) and slowly added to the above single-necked flask at 0°C for 1 h, and then transferred to room temperature for 24 h; after the reaction, 24 mg sodium thiosulfate was added and stirred to ensure that the oxidant was completely removed, and the filtrate was collected by filtration. The PDO yield was about 31% as determined by NMR (see Fig. 9 ), it can be seen that when nitromethane is used as the solvent, the yield is only 31%, which is far lower than the 88% yield of Example 1.

[0063] Comparative Example 4

[0064] When 1,4-dioxane was used in an equal molar amount to replace DEG in Example 1, p-dioxanone was not obtained.

[0065] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing p-dioxanone using diethylene glycol, characterized in that: The method uses diethylene glycol as a raw material, 2,2,6,6-tetramethylpiperidinyl oxide as a catalyst, and trichloroisocyanuric acid as an oxidant, and reacts in a solvent in the presence of an acidic substance and an inert gas to obtain the p-dioxanone.

2. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The acidic substance is a mixture of one or more of nitromethane, nitrobenzene, trifluoroethanol, hexafluoroisopropanol, benzoic acid and citric acid.

3. The method for preparing p-dioxanone with diethylene glycol according to claim 2, characterized in that: The acidic substance is hexafluoroisopropanol or nitromethane, or a mixture of the two.

4. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The solvent is a mixture of one or more of acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane and dichloromethane.

5. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The inert gas is nitrogen.

6. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The reaction temperature is room temperature and the reaction time is 16-28 hours.

7. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The molar ratio of diethylene glycol to trichloroisocyanuric acid is 1:0.8-1.2; the molar ratio of diethylene glycol to acidic substance is 1:2-5; the molar ratio of diethylene glycol to 2,2,6,6-tetramethylpiperidinyl oxide is 1:0.1-0.

2.

8. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The following steps are involved: Diethylene glycol, 2,2,6,6-tetramethylpiperidinoxide, an acidic substance, trichloroisocyanuric acid and a solvent are mixed, and reacted under a nitrogen atmosphere to obtain the p-dioxanone.

9. The method for preparing p-dioxanone with diethylene glycol according to claim 1, characterized in that: The method also includes adding sodium thiosulfate to the product after the reaction.

10. The method for preparing p-dioxanone with diethylene glycol according to claim 9, characterized in that: The dosage ratio of sodium thiosulfate to trichloroisocyanuric acid is 24 mg:1 mmol.

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