CN119977937A - Preparation method of 1,4-dioxane-2-one - Google Patents

Preparation method of 1,4-dioxane-2-one Download PDF

Info

Publication number
CN119977937A
CN119977937A CN202510145370.2A CN202510145370A CN119977937A CN 119977937 A CN119977937 A CN 119977937A CN 202510145370 A CN202510145370 A CN 202510145370A CN 119977937 A CN119977937 A CN 119977937A
Authority
CN
China
Prior art keywords
dioxane
reaction
temperature
ketone
preparing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202510145370.2A
Other languages
Chinese (zh)
Inventor
周瑜斌
孙光明
刘冬平
顾玉龙
徐�明
詹谦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Aikang Biotechnology Co ltd
Original Assignee
Nanjing Aikang Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Aikang Biotechnology Co ltd filed Critical Nanjing Aikang Biotechnology Co ltd
Priority to CN202510145370.2A priority Critical patent/CN119977937A/en
Publication of CN119977937A publication Critical patent/CN119977937A/en
Pending legal-status Critical Current

Links

Landscapes

  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明属于涉及药物化学合成技术领域，尤其涉及1，4‑二氧六环‑2‑酮的制备方法，包括以下步骤：将乙二醇、溴乙酸叔丁酯在叔丁醇钾碱性条件下反应，反应直接合成1，4‑二氧六环‑2‑酮，并通过减压蒸馏得到高纯度的1，4‑二氧六环‑2‑酮。本发明在现有技术的基础上原料易得，从而成本低，此外，设计巧妙，仅需一步反应即可，从而大大简化反应步骤，且产物易于分离，选择性高，操作简单，因此，适合工业大生产的要求。The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing 1,4-dioxane-2-ketone, comprising the following steps: reacting ethylene glycol and tert-butyl bromoacetate under alkaline conditions of potassium tert-butoxide, directly synthesizing 1,4-dioxane-2-ketone by reaction, and obtaining high-purity 1,4-dioxane-2-ketone by reduced pressure distillation. The invention is based on the prior art, and the raw materials are easily available, so the cost is low. In addition, the invention is cleverly designed, and only one-step reaction is required, thereby greatly simplifying the reaction steps, and the product is easy to separate, the selectivity is high, and the operation is simple, so it is suitable for the requirements of large-scale industrial production.

Description

Preparation method of 1, 4-dioxane-2-ketone
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of 1, 4-dioxane-2-ketone.
Background
The 1, 4-dioxane-2-ketone is an important organic chemical product, has wide application, can be directly used as a spice additive, a preservative and the like, and also can be used as a monomer for synthesizing a type of bioabsorbable and degradable material poly 1, 4-dioxane-2-ketone and derivatives thereof, and has important effects in the fields of medicine, materialics and commodity chemistry. The poly-1, 4-dioxane-2-ketone is an ideal surgical suture material, bone tissue repair material, drug slow release material, green biodegradable plastic and the like. This determines the important role of the purity of the monomer 1, 4-dioxane-2-one for the synthesis of poly 1, 4-dioxane-2-one with good properties.
At present, two general methods for synthesizing 1, 4-dioxane-2-ketone are adopted, wherein one method is to take diethylene glycol as a raw material and prepare the catalyst through catalytic oxidation and dehydrocyclization reactions of a metal catalyst. For the method, the report of the current literature already realizes that a metal catalyst Cu/nitro catalyst system has excellent activity and selectivity for the oxidation and lactonization of diethylene glycol, but for factory production, the production investment is large, loss exists in the recycling of the catalyst and the reduction of the catalytic activity, the generated waste liquid and solid waste are large, the treatment cost is high, and the method is unfavorable for the mass production of factory production.
The other is to take ethylene glycol as raw material, adopt ethylene glycol, chloroacetic acid or chloroacetate to obtain hydroxy acid salt, and obtain the hydroxy acid salt through acidification and cyclization. For example, the earlier patent US4502988 discloses the preparation of ethylene glycol, chloroacetic acid and metallic sodium as raw materials, and the other patent EP1138664, CN101628909 discloses the preparation of beta-hydroxyethoxy acetic acid sodium salt by using ethylene glycol, sodium hydroxide and sodium chloroacetate as raw materials, and then the beta-hydroxyethoxy acetic acid sodium salt is obtained by acid ring-closure with inorganic acid. The process has the main defects that lactonization is adopted to form a ring under the acidic condition, the purity of the reacted product is low, tedious refining is needed, and the acid residue has great influence on the later-period preservation purity of the product.
Another patent CN102731469 discloses a process that can carry out the cyclization reaction under neutral conditions, but the reaction steps are cumbersome.
Disclosure of Invention
Aiming at the technical problems, the invention provides a novel process for preparing (2, 5-dimethoxy pyridine-4-yl) boric acid simply and with high yield, which is realized by the following technical scheme:
the preparation method of the 1, 4-dioxane-2-ketone has the following reaction formula:
The method comprises the following steps:
s1, adding ethylene glycol and a solvent into a four-neck flask, and controlling the temperature of an ice water bath to be 0-10 ℃;
S2, adding potassium tert-butoxide, and controlling the temperature to be 0-10 ℃;
s3, after the addition is finished, preserving the temperature to be 0-10 ℃, and stirring and reacting for 1h;
s4, dropwise adding tert-butyl bromoacetate, and controlling the temperature to be 0-10 ℃;
S5, naturally recovering to room temperature after dripping, and reacting for 2 hours;
s6, after the reaction is finished, quenching reaction is carried out, and the PH in the system is adjusted to be neutral;
s7, adding water and DCM, stirring, extracting and layering, and washing an organic phase twice by using water;
S8, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating filtrate under reduced pressure to obtain a light yellow oily substance;
S9, carrying out reduced pressure distillation on the light yellow oily matter, and controlling the temperature of an oil bath at 90-105 ℃ to obtain fraction 1, 4-dioxane-2-ketone.
Preferably, in S1, the solvent is N, N-dimethylformamide.
Preferably, the molar ratio of ethylene glycol, tert-butyl bromoacetate and potassium tert-butoxide added is 3:1:1.05.
Preferably, the weight (g) to volume (ml) ratio of t-butyl bromoacetate and N, N-dimethylformamide added is 1:4.
Preferably, the quenching reaction in S6 is performed with saturated aqueous ammonium chloride.
More preferably, the room temperature in S5 is 30 degrees.
The invention has the advantages that the raw materials are easy to obtain, the cost is low, the steps are simplified, the lactonization reaction is directly completed by only one-step reaction, meanwhile, the treatment operation of the reaction is simpler and more convenient, the yield of the obtained product 1, 4-dioxane-2-ketone is high, the consumption of the solvent and the production amount of waste liquid are less, the product is easy to separate, the selectivity is high, and the operation is simple, thereby being suitable for the requirements of industrial mass production.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Meanwhile, the meaning of "and/or" and/or "appearing throughout the text is to include three schemes, taking" a and/or B "as an example, including a scheme, or B scheme, or a scheme that a and B satisfy simultaneously.
Furthermore, descriptions such as those referred to as "first," "second," and the like, are provided for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying an order of magnitude of the indicated technical features in the present disclosure. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be considered to be absent and not within the scope of protection claimed in the present invention.
Example 1, 4-Dioxahexacyclic-2-one preparation method, the reaction formula is shown as follows:
The specific operation steps are as follows:
S1, adding 286.4g of ethylene glycol and 1.2L of N, N-dimethylformamide into a 3L four-neck flask, and controlling the temperature of an ice water bath to be 0-10 ℃;
S2, adding 181.2g of potassium tert-butoxide, and controlling the temperature to be 0-10 ℃;
s3, after the addition is finished, preserving the temperature to be 0-10 ℃ and stirring to react for 1h;
s4, beginning to dropwise add 300.0g of tert-butyl bromoacetate, and controlling the temperature to be 0-10 ℃;
S5, naturally recovering to room temperature (30 ℃) after the dripping is finished, and reacting for 2 hours;
S6, monitoring the end of the reaction, dropwise adding a saturated ammonium chloride aqueous solution to quench the reaction, and regulating the pH value in the system to be neutral;
s7, adding 2.4L of water and DCM1.5L L of water, stirring and layering, and washing the organic phase once by using 600ml of water and 300ml of water respectively;
S8, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating filtrate under reduced pressure to obtain 180g of light yellow oily matter;
S9, 180g of light yellow oily matter is distilled under reduced pressure, the oil bath temperature is 90-105 ℃, 133.3g of white semisolid of fraction 1, 4-dioxane-2-one is obtained, the mixture is put into a refrigerator with the temperature of 2-8 ℃ for storage, the white powdery solid is obtained after the mixture is converted into the white powdery solid, the yield is 85%, and the GC purity is 99.9%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
Comparative scheme 1 selection and adjustment of the reaction solvent in example 1, namely, using equivalent tetrahydrofuran to replace N, N-dimethylformamide, the addition amount of the rest raw materials, the reaction temperature, the reaction step and other conditions are unchanged, thus obtaining 36.1g of the 1, 4-dioxane-2-one white semisolid with the yield of 23% and the GC purity of 99.1%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
Compared with the scheme 2, the method is adjusted according to the selection of the reaction solvent in the example 1, namely, the same amount of tertiary butanol is used for replacing N, N-dimethylformamide as the reaction solvent, the feeding amount of the other raw materials, the reaction temperature, the reaction step and other conditions are unchanged, and 106.8g of white semi-solid of the product 1, 4-dioxane-2-one is obtained, the yield is 68%, and the GC purity is 99.7%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
As can be seen from comparative schemes 1 and 2, the influence of the type of solvent on the reaction is remarkable, so that the selection of N, N-dimethylformamide as the reaction solvent is an excellent solution, i.e., the technical scheme proposed by the present invention.
In the comparison scheme 3, the dosage of the ethylene glycol in the example 1 is adjusted to 190.9g, the conditions of the dosage, the reaction temperature, the reaction step and the like of the other raw materials are unchanged, and the product 1, 4-dioxane-2-one is 95.8g white semi-solid, the yield is 61%, and the GC purity is 99.4%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
In comparison scheme 4, the dosage of the ethylene glycol in the example 1 is adjusted to 477.3g, the conditions of the dosage, the reaction temperature, the reaction step and the like of the other raw materials are unchanged, and 134.5g of white semisolid of the product 1, 4-dioxane-2-one is obtained, the yield is 85.7%, and the GC purity is 99.7%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
As is clear from the comparison of the schemes 3 and 4, when the amount of ethylene glycol is small, the impurity content of the by-product of the reaction increases, the reaction yield decreases, and when the amount of ethylene glycol is large, the reaction yield does not change much, so that 286.4g of ethylene glycol is the preferred solution.
In comparison scheme 5, the dosage of the potassium tert-butoxide in the example 1 is adjusted to 207.1g, the conditions of the dosage, the reaction temperature, the reaction steps and the like of the other raw materials are unchanged, and 124.0g of white semisolid of the product 1, 4-dioxane-2-one is obtained, the yield is 79%, and the GC purity is 99.6%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
In comparison scheme 6, the dosage of the potassium tert-butoxide in the example 1 is adjusted to 241.6g, the conditions of the dosage, the reaction temperature, the reaction step and the like of the other raw materials are unchanged, and 100.5g of white semisolid of the product 1, 4-dioxane-2-one is obtained, the yield is 64%, and the GC purity is 99.3%.
1HNMR(400MHz,CDCl3):δ3.88(t,J=4.0Hz,2H),4.38(s,2H),4.50(t,J=4.0Hz,2H)。
As is clear from comparative examples 5 and 6, when the amount of potassium t-butoxide is increased, the stability of the starting material t-butyl bromoacetate is significantly affected, so that 181.2g of potassium t-butoxide is selected as the optimal solution.
The invention adopts the technical scheme that only one-step reaction is needed, namely, glycol and bromobutyl acetate react under the alkaline condition of tertiary butanol potassium, the reaction is directly carried out to synthesize 1, 4-dioxane-2-ketone, the high-purity 1, 4-dioxane-2-ketone is obtained through reduced pressure distillation, meanwhile, the treatment operation of the reaction is simpler and more convenient, the yield of the obtained product 1, 4-dioxane-2-ketone is high, the consumption of a solvent and the production amount of waste liquid are less, the process and the production cost are further simplified, the economic value is remarkable, and the industrialized production is easier.
It should be understood that these examples are for the purpose of illustrating the application only and are not intended to limit the scope of the application. Furthermore, it is to be understood that various changes, modifications and/or variations may be made by those skilled in the art after reading the technical content of the present application, and that all such equivalents are intended to fall within the scope of the present application as defined in the appended claims.

Claims (6)

  1. The preparation method of the 1, 4-dioxane-2-ketone is characterized in that the reaction formula is as follows:
    The method comprises the following steps:
    s1, adding ethylene glycol and a solvent into a four-neck flask, and controlling the temperature of an ice water bath to be 0-10 ℃;
    S2, adding potassium tert-butoxide, and controlling the temperature to be 0-10 ℃;
    s3, after the addition is finished, preserving the temperature to be 0-10 ℃, and stirring and reacting for 1h;
    s4, dropwise adding tert-butyl bromoacetate, and controlling the temperature to be 0-10 ℃;
    S5, naturally recovering to room temperature after dripping, and reacting for 2 hours;
    s6, after the reaction is finished, quenching reaction is carried out, and the PH in the system is adjusted to be neutral;
    s7, adding water and DCM, stirring, extracting and layering, and washing an organic phase twice by using water;
    S8, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating filtrate under reduced pressure to obtain a light yellow oily substance;
    S9, carrying out reduced pressure distillation on the light yellow oily matter, and controlling the temperature of an oil bath at 90-105 ℃ to obtain fraction 1, 4-dioxane-2-ketone.
  2. 2. The process for preparing 1, 4-dioxane-2-one according to claim 1, wherein the solvent in S1 is N, N-dimethylformamide.
  3. 3. The method for preparing 1, 4-dioxane-2-one according to claim 1, wherein the molar ratio of the added glycol, the bromoacetic acid tert-butyl ester and the potassium tert-butoxide is 3:1:1.05.
  4. 4. A process for preparing 1, 4-dioxane-2-one according to claim 2, wherein the weight (g) to volume (ml) ratio of the tert-butyl bromoacetate and N, N-dimethylformamide added is 1:4.
  5. 5. The process for preparing 1, 4-dioxane-2-one according to claim 1, wherein the quenching reaction in S6 is performed by using a saturated aqueous ammonium chloride solution.
  6. 6. The process for preparing 1, 4-dioxane-2-one according to claim 1, wherein the room temperature in S5 is 30 ℃.
CN202510145370.2A 2025-02-10 2025-02-10 Preparation method of 1,4-dioxane-2-one Pending CN119977937A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202510145370.2A CN119977937A (en) 2025-02-10 2025-02-10 Preparation method of 1,4-dioxane-2-one

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202510145370.2A CN119977937A (en) 2025-02-10 2025-02-10 Preparation method of 1,4-dioxane-2-one

Publications (1)

Publication Number Publication Date
CN119977937A true CN119977937A (en) 2025-05-13

Family

ID=95625834

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202510145370.2A Pending CN119977937A (en) 2025-02-10 2025-02-10 Preparation method of 1,4-dioxane-2-one

Country Status (1)

Country Link
CN (1) CN119977937A (en)

Similar Documents

Publication Publication Date Title
CN108546258B (en) A kind of method that simple and effective synthesizes esterdiol in Corey
CN110790721B (en) Synthetic method of ceftazidime side chain ethyl ester
CN117903131A (en) Improved synthesis method of non-neridrones
US5350868A (en) ω-hydroxy-(ω-3)-ketonitrile and method for preparing ω-hydroxyaliphatic acid
CN106995411A (en) A kind of preparation method of the formyl imidazoles of 2 normal-butyl, 4 chlorine 5
CN119977937A (en) Preparation method of 1,4-dioxane-2-one
CN105017229A (en) Method for preparing Fludioxonil
CN114163323A (en) Synthetic method of 3-oxocyclobutanecarboxylic acid
CN115557928B (en) Synthesis method of 2-chlorothiophene-5-formic acid
RO121737B1 (en) Process for preparing 5-carboxyphthalide and use thereof for producing citalopram
FR2803846A1 (en) 3- (1-HYDROXY-PENTYLIDENE) -5-NITRO-3H-BENZOFURAN-2-ONE, PROCESS FOR PREPARING THE SAME AND USE THEREOF
CN114213343B (en) Preparation and purification methods of celecoxib intermediate
SU504489A3 (en) Method for preparing 4n-benzo (4,5) cyclohepta- (1,2-b) -thiophene derivatives
JPH0311036A (en) Production of omega-hydroxy-(omega-3)-ketofatty acid
CN112979555A (en) Process for synthesizing cimetidine
CN108084093B (en) Method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by one-pot method
CN116063163B (en) Preparation method of 7- (benzyloxy) -2,4,5, 6-tetrahydro-1H-cyclobutadiene [ f ] indene-1-one
CN114478229B (en) Preparation method of azelaic acid
CN111233707A (en) Synthesis and refining method of 4-fluorobenzoylacetonitrile
CN114213398B (en) Preparation method of polysubstituted furan derivative, bactericide and application
CN113912544B (en) Preparation method of 5-bromo-1-methylindazole
CN110862311B (en) Synthesis method of 1-hydroxycyclopropanecarboxylic acid and carboxylate
SK59893A3 (en) Method of production of tetronic acid alkylester
CN112521397B (en) Preparation method of 2, 6-dioxabicyclo- (3.3.0) -octane-3, 7-dione
CN102786511B (en) Improved method for preparing fupentixol dihydrochloride intermediate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination