阅读说明：本技术 α-乙酰基-γ-丁内酯的制备方法 (Preparation method of alpha-acetyl-gamma-butyrolactone ) 是由 郭官安 李全国 袁玉坤 夏雨 万挺峰 司玉贵 于 2020-07-23 设计创作，主要内容包括：本发明涉及有机合成领域,公开了一种α-乙酰基-γ-丁内酯的制备方法,该方法包括以下步骤：(1)使γ-丁内酯、CH<Sub>3</Sub>COOR<Sup>1</Sup>和R<Sup>2</Sup>ONa发生酰化反应以得到含α-乙酰基-γ-丁内酯钠盐的物料,其中,R<Sup>1</Sup>和R<Sup>2</Sup>各自独立地为C1-C4的烷基；(2)在水存在的条件下,使所述含α-乙酰基-γ-丁内酯钠盐的物料与CO<Sub>2</Sub>气体接触发生中和反应。本发明提供的方法在确保安全性的情况下还具备收率较高的优势,为α-乙酰基-γ-丁内酯的规模化生产提供了便利。(The invention relates to the field of organic synthesis, and discloses a preparation method of α -acetyl-gamma-butyrolactone, which comprises the following steps of (1) reacting gamma-butyrolactone and CH 3 COOR 1 And R 2 Acylation of ONa to obtain a material comprising α -acetyl-gamma-butyrolactone sodium salt, wherein R 1 And R 2 Each independently being a C1-C4 alkyl group, (2) reacting the α -acetyl-gamma-butyrolactone-sodium salt-containing material with CO in the presence of water 2 The method provided by the invention has the advantage of higher yield under the condition of ensuring safety, and provides convenience for large-scale production of α -acetyl-gamma-butyrolactone.)

1. A preparation method of alpha-acetyl-gamma-butyrolactone is characterized by comprising the following steps:

(1) by reacting gamma-butyrolactone, CH₃COOR¹And R²Acylation of ONa to obtain a material comprising α -acetyl-gamma-butyrolactone sodium salt, wherein R¹And R²Each independently is a C1-C4 alkyl group;

(2) reacting the α -acetyl-gamma-butyrolactone sodium salt-containing material with CO in the presence of water₂The gas contact generates a neutralization reaction.

2. The method of claim 1, wherein R¹And R²Each independently is a C1-C2 alkyl group.

3. The method according to claim 1 or 2, wherein in step (1), the step (c) is performed by a chemical vapor deposition methodThe gamma-butyrolactone, CH₃COOR¹And R²The molar ratio of ONa is 1: (2-15): (0.5-2), preferably 1: (3-12): (1-1.5).

4. The process according to any one of claims 1 to 3, wherein in step (1), the temperature of the acylation reaction is 60 ℃ to 100 ℃, preferably 80 ℃ to 90 ℃;

and/or the pressure of the acylation reaction is 0.01-0.6MPa, preferably 0.1-0.3 MPa;

and/or the time of the acylation reaction is 1 to 30 hours, preferably 3 to 15 hours.

5. The process according to any one of claims 1 to 4, wherein the process further comprises a step (1) of distilling and recovering CH during the acylation reaction₃COOR¹And R formed during the acylation reaction¹OH or R²OH。

6. The method according to any one of claims 1 to 5, wherein in step (2), water and R in step (1) are added²The molar ratio of ONa is (0.3-1): 1, preferably (0.55-1): 1.

7. the method according to any one of claims 1 to 6, wherein in step (2), CO is used₂The pressure of the gas is 0.01 to 5MPa, preferably 0.01 to 1 MPa.

8. The process according to any one of claims 1 to 7, wherein in step (2), the temperature of the neutralization reaction is from-10 ℃ to 80 ℃, preferably from 5 ℃ to 35 ℃; the time of the neutralization reaction is 0.1 to 10 hours, preferably 0.5 to 5 hours.

9. The method according to any one of claims 1-8, wherein the method further comprises step (3): and (3) carrying out reduced pressure rectification separation on the alpha-acetyl-gamma-butyrolactone crude product in the step (2) to obtain the alpha-acetyl-gamma-butyrolactone.

10. The method according to claim 9, wherein in the step (3), the vacuum degree of the reduced pressure rectification is less than 1000 Pa.

Technical Field

The invention relates to the field of organic synthesis, in particular to a preparation method of alpha-acetyl-gamma-butyrolactone.

Background

The alpha-acetyl-gamma-butyrolactone is an important intermediate in the field of pharmaceutical chemical production, and can be used for producing and preparing various medicaments. The current process routes mainly include two types: one is a process route of ring opening, re-esterification and ring closing of ethylene oxide by methyl (or ethyl) acetoacetate; the other is an acylation process route which adopts gamma-butyrolactone and methyl (or ethyl) acetate as raw materials. The boiling point of ethylene oxide used in the methyl (or ethyl) acetoacetate route is 10.8 ℃, the ethylene oxide belongs to a first-grade flammable and explosive chemical, and serious potential safety hazards are caused in storage, transportation and production links, so the process route is gradually eliminated at present, and the mainstream production of domestic enterprises is shifted to an acylation process route using gamma-butyrolactone and methyl (or ethyl) acetate as raw materials.

The acylation process route starting from gamma-butyrolactone and acetate in the presence of a strong basic species (sodium metal, potassium metal, sodium alkoxide, sodium amide, etc.) was originally reported by f.korte et al (angelwan patent Chemie,71,1959,23, 709-. The subsequent processes are mostly improvements on the basis.

CN103304519A discloses a preparation method of alpha-acetyl-gamma-butyrolactone by recycling reaction materials, which has the following reaction formula:

the method comprises the following steps: (1) acylation reaction: adding gamma-butyrolactone (I), methyl acetate (II), sodium methoxide and an inert solvent into a reaction kettle, slowly heating the reaction materials to 70-90 ℃, reacting to generate sodium salt of alpha-acetyl-gamma-butyrolactone and a byproduct methanol, and removing the byproduct methanol through azeotropic distillation to obtain sodium salt of alpha-acetyl-gamma-butyrolactone; the inert solvent is a solvent which does not generate azeotropy with methyl acetate and methanol and is selected from one or more of dimethylbenzene, ethylbenzene, nonane, decane, undecane and trimethylbenzene, the molar ratio of gamma-butyrolactone to the inert solvent is 1: 3-8, the molar ratio of gamma-butyrolactone to sodium methoxide is 1: 1.1-2, and the molar ratio of gamma-butyrolactone to methyl acetate is 1: 2-8; (2) separation of reaction materials: performing acylation reaction until the content of gamma-butyrolactone (I) in the reaction material is less than 2% by gas chromatography detection, stopping heating, and distilling out the solvent, wherein the distilled out solvent comprises unreacted methyl acetate, a byproduct methanol and a small amount of inert solvent in the step (1); (3) and (3) neutralization reaction: adjusting the sodium salt of the alpha-acetyl-gamma-butyrolactone obtained in the step (2) to a weakly acidic state with pH of 3-4 by using sulfuric acid or phosphoric acid, and separating a water phase to obtain a solution of the alpha-acetyl-gamma-butyrolactone; wherein the phosphate aqueous phase is extracted with an inert solvent, wherein the inert solvent is the solvent in the step (1); (4) desolventizing and rectifying treatment: combining the organic phases obtained in the step (3), evaporating the solvent to obtain a crude product of the alpha-acetyl-gamma-butyrolactone, and performing reduced pressure rectification to obtain a pure product of the alpha-acetyl-gamma-butyrolactone; (5) and (3) recovery treatment of the waste solvent: mixing the rest inert solvent, methyl acetate and the byproduct methanol mixed waste solvent after the reaction is completed, separating the inert solvent by common distillation, and separating excessive methyl acetate and the byproduct methanol by extractive distillation; (6) and (3) recycling: and (3) directly feeding the methyl acetate and the inert solvent recovered in the step (5) into the step (1) for recycling, and recovering the obtained methanol for preparing sodium methoxide to re-feed into the step (1).

CN108129423A discloses a method for preparing α -acetyl- γ -butyrolactone, which comprises the following steps: (1) under the condition of a first organic solvent, solid sodium methoxide is used as a catalyst, gamma-butyrolactone and ethyl acetate are used as initial raw materials, acetylation reaction is carried out, and after the reaction is finished, reaction liquid is concentrated to separate out alpha-acetyl-gamma-butyrolactone sodium salt solid; (2) subjecting the α -acetyl- γ -butyrolactone sodium salt solids to a pulping wash using a second organic solvent that is insoluble in the α -acetyl- γ -butyrolactone sodium salt solids; and (3) placing the washed alpha-acetyl-gamma-butyrolactone sodium salt solid in a third organic solvent, adjusting the pH value to 6-7 by using an acid solution, stirring, filtering, and distilling the filtrate under reduced pressure to obtain the alpha-acetyl-gamma-butyrolactone. Wherein the acid is selected from one or more of sulfuric acid and hydrochloric acid, the concentration of the acid solution is 50-80%, the concentration of the preferable acid solution is 60-75%, and the solvent of the acid solution is selected from one or more of methanol, ethanol and ethyl acetate; when the pH value is adjusted by using the acid solution, the temperature is controlled to be-10-15 ℃, the preferable temperature is controlled to be-5 ℃, the stirring time is 4.5-6 hours, and the preferable stirring time is 5 hours.

The method adopts sodium methoxide to replace sodium metal, solves the safety problem caused by using sodium metal, but the yield of the method is lower and is not less than 85 percent. Therefore, there is a need for a process for preparing α -acetyl- γ -butyrolactone in higher yield.

Disclosure of Invention

In view of the above problems in the prior art, an object of the present invention is to provide a method for producing α -acetyl- γ -butyrolactone, which has the advantage of high yield while ensuring safety.

In order to achieve the above objects, the present invention provides a method for preparing α -acetyl- γ -butyrolactone, which comprises the steps of:

(1) by reacting gamma-butyrolactone, CH₃COOR¹And R²Acylation of ONa to obtain a material comprising α -acetyl-gamma-butyrolactone sodium salt, wherein R¹And R²Each independently is a C1-C4 alkyl group;

(2) reacting the α -acetyl-gamma-butyrolactone sodium salt-containing material with CO in the presence of water₂The gas contact generates a neutralization reaction.

According to the method provided by the invention, the weak acid such as carbonic acid (carbon dioxide) is adopted for neutralization reaction, compared with the medium strong acid and the strong acid such as phosphoric acid and sulfuric acid in the prior art, the hydrolysis of the product is effectively reduced, the generation of phosphorus-containing wastewater and waste salt is thoroughly abolished, and the process is environment-friendly and green; the method provided by the invention has few side reactions and a simple separation system, the yield of the alpha-acetyl-gamma-butyrolactone can reach 95%, the product purity can reach 99.5%, and convenience is provided for large-scale production of the alpha-acetyl-gamma-butyrolactone.

Specifically, the preparation method of the alpha-acetyl-gamma-butyrolactone provided by the invention has the following advantages:

(1) according to the method provided by the invention, sodium alkyl alkoxide is adopted as alkali in the acylation reaction of the gamma-butyrolactone, no hydrogen is generated in the whole process, and the potential safety hazard existing in the process of using sodium metal does not exist;

(2) according to the method provided by the invention, a high-boiling point solvent is not introduced into the whole process flow, so that the problem of azeotropic separation of alkyl acetate, alkyl alcohol and the high-boiling point solvent is avoided, and the energy consumption is greatly reduced;

(3) the method provided by the invention has few side reactions and simple separation system, the yield of the alpha-acetyl-gamma-butyrolactone can reach 95%, and the product purity can reach 99.5%;

(4) according to the method provided by the invention, in the presence of water, carbon dioxide is adopted for neutralization reaction, so that hydrolysis of products is avoided, generation of phosphorus-containing wastewater and waste salt is thoroughly abolished, the process is environment-friendly and green, and the influence on the environment is hardly caused;

(5) according to the method provided by the invention, the recovered alkyl acetate and alkyl alcohol can be directly recycled, the recovery operation is convenient, the energy consumption is low, and the production cost is greatly reduced;

(6) the method provided by the invention has the advantages that the operation of the whole process flow does not need high-pressure operation, the common reaction tank or the rectifying tower can meet the requirements, special equipment or a safe buffer system is not involved, the operation is safe and convenient, and the industrialization is facilitated.

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

The invention provides a preparation method of alpha-acetyl-gamma-butyrolactone, which comprises the following steps:

(1) by reacting gamma-butyrolactone, CH₃COOR¹And R²Acylation of ONa to obtain a material comprising α -acetyl-gamma-butyrolactone sodium salt, wherein R¹And R²Each independently is a C1-C4 alkyl group;

(2) reacting the α -acetyl-gamma-butyrolactone sodium salt-containing material with CO in the presence of water₂The gas contact generates a neutralization reaction.

According to the process of the present invention, preferably, in step (1), R¹And R²Each independently preferably is a C1-C2 alkyl group such as methyl, ethyl. R¹And R²May be the same or different.

According to the process of the present invention, in step (1), the acylation reaction is generally carried out under dry conditions, and the acylation reaction is preferably carried out in a reaction tank equipped with a reflux and distillation apparatus, the reaction tank being preferably provided with a liquid dropping head tank and a solid feed hopper.

According to the process of the invention, in step (1), the gamma-butyrolactone, CH₃COOR¹And R²The molar ratio of ONa is preferably 1: (2-15): (0.5-2), more preferably 1: (3-12): (1-1.5).

In step (1), CH₃COOR¹The method is used as a raw material of the acylation reaction and a solvent of the reaction, and no additional high-boiling point solvent is introduced, so that the cost can be saved, and the azeotropic formation of the high-boiling point solvent, the alkyl acetate and the alkyl alcohol generated by the acylation reaction can be avoided.

According to the method, the feeding mode and the feeding speed of the acylation reaction only need to meet the condition that the heat of a reaction system can be timely withdrawn to ensure the temperature required by the reaction; preferably, the γ -butyrolactone and sodium alkyl alkoxide may be fed in portions while maintaining the temperature of the acylation reaction system during the feeding within the temperature range required for the acylation reaction.

According to the process of the present invention, in step (1), the temperature of the acylation reaction may be 60 ℃ to 100 ℃, preferably 80 ℃ to 90 ℃.

According to the process of the present invention, in the step (1), the pressure of the acylation reaction may be 0.01 to 0.6MPa, preferably 0.1 to 0.3 MPa.

In the present invention, the pressure is a gauge pressure unless otherwise specified.

According to the process of the present invention, the time of the acylation reaction may be 1 to 30 hours, preferably 3 to 15 hours.

According to the method of the present invention, preferably, the method further comprises: in step (1), CH is distilled and recovered during the acylation reaction₃COOR¹And R formed during the acylation reaction¹OH or R²And (5) OH. In order to allow the acylation reaction to be smoothly performed, the reflux ratio of the distillation process may be (3-4): 1.

CH recovered in step (1)₃COOR¹Can be directly recycled, and in addition, R is added¹OH or R²OH is distilled out, which is beneficial to more complete conversion of gamma-butyrolactone, and meanwhile, the distilled alkyl alcohol can be used for preparing sodium alkyl alcohol, so that the production cost is greatly reduced.

In the present invention, when CH is distilled off in the step (1)₃COOR¹And R formed by acylation¹OH or R²When OH is used, a certain amount of CH can be supplemented into the acylation reaction system₃COOR¹(ii) a Preferably, CH is present per gram of gamma-butyrolactone₃COOR¹The amount of the additive (b) is 0.5 to 5g, more preferably 1 to 3 g.

According to the process of the invention, in step (2), water and R in step (1)²The molar ratio of ONa may be (0.3-1): 1, preferably (0.55-1): 1.

according to the process of the invention, in general, in step (2), the neutralization is carried out by means of CO₂The tank provides CO under pressure₂Gas, preferably CO₂The pressure of the gas may be 0.01 to 5MPa, preferably 0.01 to 1 MPa.

According to the process of the present invention, in the step (2), the temperature of the neutralization reaction may be-10 ℃ to 80 ℃, preferably 5 ℃ to 35 ℃.

According to the method of the present invention, in the step (2), the time for the neutralization reaction may be 0.1 to 10 hours, preferably 0.5 to 5 hours.

According to the method of the present invention, preferably, the method may further comprise the step (3): and (3) carrying out reduced pressure rectification separation on the alpha-acetyl-gamma-butyrolactone crude product in the step (2) to obtain the alpha-acetyl-gamma-butyrolactone.

According to the method of the present invention, the rectification may preferably be pressure swing rectification or azeotropic rectification.

Wherein the vacuum degree of the pressure swing distillation or the azeotropic distillation is preferably less than 1000 Pa.

According to a preferred embodiment of the present invention, the method for preparing α -acetyl- γ -butyrolactone provided by the present invention comprises the steps of:

(1) acylation reaction: by reacting gamma-butyrolactone, CH₃COOR¹And R²ONa is subjected to heat preservation reaction for 3-15h at the temperature of 80-90 ℃ and under the pressure of 0.1-0.3MPa to obtain a material containing α -acetyl-gamma-butyrolactone sodium salt, and CH is distilled and recovered in the process of acylation reaction₃COOR¹And R formed during the acylation reaction¹OH or R²OH, wherein, gamma-butyrolactone, CH₃COOR¹And R²The molar ratio of ONa is 1: (3-12): (1-1.5); r¹And R²Each independently is a C1-C2 alkyl group;

(2) a neutralization reaction, namely leading the material containing α -acetyl-gamma-butyrolactone sodium salt to be in CO of 0.01-1MPa at the temperature of 5-35 DEG C₂Mixing with water in gas atmosphere, and reacting for 0.5-5h under heat preservation, wherein the water and R in the step (1)²The molar ratio of ONa is (0.55-1): 1;

(3) separation: and (3) carrying out reduced pressure rectification separation on the alpha-acetyl-gamma-butyrolactone crude product in the step (2) under the condition of high vacuum (less than 2000Pa) to obtain the alpha-acetyl-gamma-butyrolactone.

In the present invention, the material containing the sodium salt of α -acetyl- γ -butyrolactone in step (2) is the material obtained by the reaction in step (1), and is not subjected to an additional separation step, such as an extraction step of the prior art, i.e., the process of the present invention does not include an additional separation step, such as an extraction step, between the completion of step (1) and step (2). Therefore, the method greatly saves the working procedures, reduces the production cost and also reduces the material loss caused by additional operation.

The route for preparing the alpha-acetyl-gamma-butyrolactone by the invention is as follows:

the present invention will be described in detail below by way of examples.

The raw materials, acids, bases, solvents, etc. used in the following examples and comparative examples were all obtained commercially. Purity was measured by gas chromatography and yield was calculated as actual/theoretical yield 100%.