Preparation method of 1, 4-dioxane-2-ketone

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a preparation method of 1, 4-dioxane-2-ketone, which comprises the following steps: reacting ethylene glycol and tert-butyl bromoacetate under the alkaline condition of potassium tert-butoxide to directly synthesize 1, 4-dioxane-2-ketone, and carrying out reduced pressure distillation to obtain high-purity 1, 4-dioxane-2-ketone. On the basis of the prior art, the raw materials are easy to obtain, so that the cost is low, in addition, the design is ingenious, only one-step reaction is needed, the reaction steps are greatly simplified, the product is easy to separate, the selectivity is high, the operation is simple, and the requirement of industrial mass production is met.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for preparing 1,4-dioxane-2-one. Background Art

[0002] 1,4-dioxane-2-one is an important organic chemical product with a wide range of uses. It can be used directly as a flavor additive, preservative, etc., and as a monomer for synthesizing a class of bioabsorbable and degradable materials, poly-1,4-dioxane-2-one and its derivatives, and plays an important role in the fields of medicine, materials science, and daily necessities chemistry. Poly-1,4-dioxane-2-one is an ideal surgical suture material, bone tissue repair material, drug sustained-release material, green biodegradable plastic, etc. This determines the important role of the purity of the monomer 1,4-dioxane-2-one in the synthesis of poly-1,4-dioxane-2-one with excellent performance.

[0003] At present, there are generally two methods for synthesizing 1,4-dioxane-2-one: one is to use diethylene glycol as a raw material and prepare it through catalytic oxidation and dehydrogenation cyclization reaction with a metal catalyst. For this method, the current literature reports have achieved excellent activity and selectivity for the oxidative lactonization of diethylene glycol using a metal catalyst Cu / nitro catalyst system, but for factory production, its production investment is large, there is loss and reduction of catalytic activity in the recycling of the catalyst, and a lot of waste liquid and solid waste are generated, and the treatment cost is high, which is not conducive to factory mass production.

[0004] The other is to use ethylene glycol as raw material, use ethylene glycol, chloroacetic acid or chloroacetate to obtain hydroxy acid salt, and then obtain it by acidification and cyclization. For example, the early patent US4502988 discloses the use of ethylene glycol, chloroacetic acid, and metallic sodium as raw materials for preparation, and other patents such as EP1138664 and CN101628909 disclose the use of ethylene glycol, sodium hydroxide, and sodium chloroacetate as raw materials to prepare β-hydroxyethoxyacetic acid sodium salt, and then obtain it by inorganic acid acidification and cyclization. The main disadvantage of this process is that it uses lactonization and cyclization under acidic conditions, the purity of the reacted product is not high, and it needs to be cumbersomely refined, and the acid residue has a great influence on the purity of the product in the later storage.

[0005] Another patent CN102731469 discloses a process for performing a cyclization reaction under neutral conditions, but the reaction steps are complicated. Summary of the invention

[0006] In view of the above technical problems, the present invention proposes a new process for preparing (2,5-dimethoxypyridin-4-yl)boric acid in a simple and high yield manner, which is achieved by the following technical scheme:

[0007] The preparation method of 1,4-dioxane-2-one, the reaction formula of which is as follows:

[0008]

[0009] The following steps are involved:

[0010] S1. Add ethylene glycol and solvent into a four-necked flask and control the temperature in an ice-water bath at 0-10 degrees;

[0011] S2, add potassium tert-butoxide, and control the temperature at 0-10 degrees;

[0012] S3, after adding, keep warm at 0-10 degrees, stir and react for 1 hour;

[0013] S4, add tert-butyl bromoacetate dropwise, and control the temperature at 0-10 degrees;

[0014] S5. After the dripping is completed, the temperature is naturally restored to room temperature and the reaction is carried out for 2 hours;

[0015] S6, after the reaction is finished, the reaction is quenched and the pH in the system is adjusted to neutral;

[0016] S7, adding water and DCM, stirring, extracting and stratifying, and washing the organic phase with water twice;

[0017] S8, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oil;

[0018] S9. The light yellow oil is distilled under reduced pressure, and the oil bath temperature is controlled at 90-105 degrees to obtain the fraction 1,4-dioxane-2-one.

[0019] Preferably, in S1, the solvent is N,N-dimethylformamide.

[0020] Preferably, the molar ratio of the added ethylene glycol, tert-butyl bromoacetate and potassium tert-butoxide is 3:1:1.05.

[0021] Preferably, the weight (g) to volume (ml) ratio of the added tert-butyl bromoacetate and N,N-dimethylformamide is 1:4.

[0022] Preferably, the quenching reaction in S6 is carried out using a saturated aqueous ammonium chloride solution.

[0023] More preferably, the room temperature in S5 is 30 degrees.

[0024] The beneficial effects of the present invention are as follows: on the basis of the prior art, the raw materials are easily available, the cost is low, the steps are simplified, only one step of reaction is required, and the lactonization reaction is directly completed. At the same time, the reaction treatment operation is simpler, the yield of the obtained product 1,4-dioxane-2-one is high, the amount of solvent used and the amount of waste liquid generated are less, the product is easy to separate, the selectivity is high, the operation is simple, and it is suitable for the requirements of large-scale industrial production. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only 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.

[0026] At the same time, the meaning of "and / or" or "and / or" appearing in the full text includes three options. Taking "A and / or B" as an example, it includes option A, or option B, or a option in which both A and B are satisfied.

[0027] In addition, in the present invention, descriptions such as "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0028] Example 1, a method for preparing 1,4-dioxane-2-one, the reaction formula of which is shown below:

[0029]

[0030] The specific steps are:

[0031] S1. Add 286.4 g of ethylene glycol and 1.2 L of N,N-dimethylformamide into a 3 L four-necked flask and control the temperature at 0-10 degrees in an ice-water bath;

[0032] S2, add 181.2g of potassium tert-butoxide, and control the temperature at 0-10 degrees;

[0033] S3, after addition, keep the temperature at 0-10 degrees and stir to react for 1 hour;

[0034] S4, start to dropwise add 300.0 g of tert-butyl bromoacetate, and control the temperature at 0-10 degrees;

[0035] S5. After the dripping is completed, the temperature is naturally restored to room temperature (30 degrees) and reacted for 2 hours;

[0036] S6. After the reaction is monitored, a saturated aqueous solution of ammonium chloride is added dropwise to quench the reaction, and the pH of the system is adjusted to neutral;

[0037] S7, add 2.4L water and 1.5L DCM, stir and separate the layers, wash the organic phase with 600ml water and 300ml water respectively;

[0038] S8, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 180 g of a light yellow oil;

[0039] S9. 180 g of the light yellow oil was distilled under reduced pressure at an oil bath temperature of 90-105 degrees to obtain 1,4-dioxane-2-one as a white semi-solid fraction of 133.3 g. The fraction was stored in a refrigerator at 2-8 degrees and turned into a white powdery solid overnight. The yield was 85% and the GC purity was 99.9%.

[0040] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0041] Comparative Scheme 1: Adjustment of the reaction solvent selection in Example 1: Use an equal amount of tetrahydrofuran to replace N,N-dimethylformamide, and keep the other raw material feeding amounts, reaction temperature, reaction steps and other conditions unchanged to obtain 36.1 g of the product 1,4-dioxane-2-one as a white semisolid with a yield of 23% and a GC purity of 99.1%.

[0042] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0043] Comparative Scheme 2: Adjustment of the reaction solvent selection in Example 1: Use an equal amount of tert-butanol instead of N,N-dimethylformamide as the reaction solvent, and keep the other raw material feeding amounts, reaction temperature, reaction steps and other conditions unchanged to obtain the product 1,4-dioxane-2-one 106.8 g white semi-solid with a yield of 68% and a GC purity of 99.7%.

[0044] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0045] It can be seen from Comparative Schemes 1 and 2 that the type of solvent has a significant impact on the reaction, so choosing N,N-dimethylformamide as the reaction solvent is the best solution, which is also the technical solution proposed by the present invention.

[0046] Comparative Scheme 3: Adjustment of the amount of ethylene glycol in Example 1: The amount of ethylene glycol was adjusted to 190.9 g, and the amounts of other raw materials, reaction temperature, reaction steps and other conditions remained unchanged, to obtain 95.8 g of the product 1,4-dioxane-2-one as a white semisolid, with a yield of 61% and a GC purity of 99.4%.

[0047] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0048] Comparative Scheme 4: Adjustment of the amount of ethylene glycol in Example 1: The amount of ethylene glycol was adjusted to 477.3 g, and the amounts of other raw materials, reaction temperature, reaction steps and other conditions remained unchanged to obtain 134.5 g of the product 1,4-dioxane-2-one as a white semisolid with a yield of 85.7% and a GC purity of 99.7%.

[0049] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0050] It can be seen from Comparative Schemes 3 and 4 that when the amount of ethylene glycol used is too small, the by-product impurities of the reaction increase and the reaction yield decreases. When the amount of ethylene glycol used is too large, the reaction yield does not change much. Therefore, 286.4 g of ethylene glycol should be selected as the optimal solution.

[0051] Comparative Scheme 5: Adjustment of the amount of potassium tert-butoxide in Example 1: The amount of potassium tert-butoxide was adjusted to 207.1 g, and the amount of other raw materials, reaction temperature, reaction steps and other conditions remained unchanged to obtain 124.0 g of the product 1,4-dioxane-2-one as a white semi-solid with a yield of 79% and a GC purity of 99.6%.

[0052] 1 HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0053] Comparative Scheme 6: Adjustment of the amount of potassium tert-butoxide in Example 1: The amount of potassium tert-butoxide was adjusted to 241.6 g, and the amount of other raw materials, reaction temperature, reaction steps and other conditions remained unchanged to obtain 100.5 g of white semi-solid 1,4-dioxane-2-one with a yield of 64% and a GC purity of 99.3%.

[0054] 1HNMR (400MHz, CDCl3): δ3.88 (t, J = 4.0 Hz, 2H), 4.38 (s, 2H), 4.50 (t, J = 4.0 Hz, 2H).

[0055] It can be seen from Comparative Schemes 5 and 6 that when the dosage of potassium tert-butoxide increases, the stability of the raw material tert-butyl bromoacetate is significantly affected, so selecting 181.2 g of potassium tert-butoxide is the optimal solution.

[0056] That is, the present invention adopts the above technical scheme, and only needs one step of reaction, that is, ethylene glycol and tert-butyl bromoacetate react under alkaline conditions of potassium tert-butoxide, the reaction directly synthesizes 1,4-dioxane-2-one, and high-purity 1,4-dioxane-2-one is obtained by reduced pressure distillation. At the same time, the reaction treatment operation is simpler, the yield of the obtained product 1,4-dioxane-2-one is high, the amount of solvent used and the amount of waste liquid generated are less, the process and production cost are further simplified, the product has significant economic value, and is easier to be produced in a factory.

[0057] It should be understood that the purpose of these embodiments is only to illustrate the present invention and is not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and / or variations to the present invention, and all of these equivalent forms also fall within the protection scope defined by the appended claims of this application.

Claims

1. A method for preparing 1,4-dioxane-2-one, characterized in that: The reaction formula is as follows: The following steps are involved: S1. Add ethylene glycol and solvent into a four-necked flask and control the temperature in an ice-water bath at 0-10 degrees; S2, add potassium tert-butoxide, and control the temperature at 0-10 degrees; S3, after adding, keep warm at 0-10 degrees, stir and react for 1 hour; S4, add tert-butyl bromoacetate dropwise, and control the temperature at 0-10 degrees; S5. After the dripping is completed, the temperature is naturally restored to room temperature and the reaction is carried out for 2 hours; S6, after the reaction is finished, the reaction is quenched and the pH in the system is adjusted to neutral; S7, adding water and DCM, stirring, extracting and stratifying, and washing the organic phase with water twice; S8, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow oil; S9. The light yellow oil is distilled under reduced pressure, and the oil bath temperature is controlled at 90-105 degrees to obtain the fraction 1,4-dioxane-2-one.

2. The method for preparing 1,4-dioxane-2-one according to claim 1, characterized in that: In S1, the solvent is N,N-dimethylformamide.

3. The method for preparing 1,4-dioxane-2-one according to claim 1, characterized in that: The molar ratio of the added ethylene glycol, tert-butyl bromoacetate and potassium tert-butoxide is 3:1:1.

05.

4. The method for preparing 1,4-dioxane-2-one according to claim 2, characterized in that: The weight (g) to volume (ml) ratio of the added tert-butyl bromoacetate and N,N-dimethylformamide was 1:

4.

5. The method for preparing 1,4-dioxane-2-one according to claim 1, characterized in that: In S6, the reaction is quenched with saturated aqueous ammonium chloride solution.

6. The method for preparing 1,4-dioxane-2-one according to claim 1, characterized in that: The room temperature in S5 is 30 degrees.

Images