One-pot preparation method of ethyl 4-bromobutyrate

Abstract

The invention provides a one-pot preparation method of ethyl 4-bromobutyrate, which is characterized by comprising the following steps: step 1, adding gamma-butyrolactone into an organic solvent, and carrying out reflux water separation while dropwise adding a hydrobromic acid aqueous solution, step 2, detecting the content of gamma-butyrolactone, if the content is less than 0.5% by mass fraction, carrying out step 3, and if the content is more than 0.5% by mass fraction, carrying out step 4; 3, dropwise adding absolute ethyl alcohol, continuing to carry out reflux water separation until the water content is less than 0.2% by mass fraction to obtain a crude product solution of the ethyl 4-bromobutyrate, and carrying out distillation and rectification to obtain a purified ethyl 4-bromobutyrate solution, and 4, detecting the water in the system, and if the water content is less than 0.5% by mass fraction, carrying out the step 3, and if the water content is less than 0.5% by mass fraction, carrying out the step 4. If not, continuously supplementing and dripping the hydrobromic acid aqueous solution, continuously carrying out reflux water diversion, and repeating the step 2; when the water content is 0.5% or above by mass fraction, continuing to carry out reflux water separation, and repeating the step 2.

Description

Technical Field

[0001] The invention relates to a one-pot preparation method of ethyl 4-bromobutyrate. Background Art

[0002] Ethyl 4-bromobutyrate is a very important pesticide and pharmaceutical intermediate, widely used in organic synthesis.

[0003] Among the synthetic routes of ethyl 4-bromobutyrate, the most economical one is to use γ-butyrolactone as raw material and react with a brominating agent. Synthesis, 1982, P963 reported that in dichloromethane, boron tribromide and γ-butyrolactone react to generate 4-bromobutyric acid, which is then esterified to obtain ethyl 4-bromobutyrate. However, this method uses an equimolar amount of boron tribromide, which is very expensive, and a large amount of boride is produced during the production process, making the treatment of the three wastes quite difficult. Therefore, this method is of no value in industry.

[0004] The domestic method for preparing ethyl 4-bromobutyrate is mainly to slowly pass dry hydrogen bromide gas into γ-butyrolactone, and after the reaction is completed, add anhydrous ethanol. At present, there is a technical bias in the method for preparing ethyl 4-bromobutyrate using this method, that is, in the reaction of using hydrogen bromide, γ-butyrolactone and ethanol to generate ethyl 4-bromobutyrate, the raw materials are required to be absolutely anhydrous.

[0005] For example, in patent document 1, application number 202210499719.9, the invention name is "a one-step preparation method of ethyl 4-bromobutyrate", after the reaction temperature is controlled by passing dry hydrogen bromide gas into γ-butyrolactone for reaction, anhydrous ethanol is added to generate ethyl 4-bromobutyrate. Non-patent document 1 Journal of the Chemical Society. Perkin transactions I, 1981, p. 336-343 reported that dry hydrogen bromide gas and γ-butyrolactone were reacted to obtain 4-bromobutyric acid, which was then esterified with anhydrous ethanol to obtain ethyl 4-bromobutyrate. The use of dry hydrogen bromide gas in the prior art is relatively costly, and has special requirements for equipment, transportation, etc., and the reaction is more dangerous.

[0006] Based on the above situation, there is an urgent need for a low-cost, simple and safe method suitable for the industrial preparation of ethyl 4-bromobutyrate. Summary of the invention

[0007] Problems to be Solved by the Invention

[0008] In view of the above problems in the prior art, the present invention boldly overcomes the above technical prejudices, abandons the use of dry hydrogen bromide gas, and proposes a one-pot preparation method of ethyl 4-bromobutyrate which is simple, safe and easy to mass produce.

[0009] The object of the present invention is to provide a one-pot preparation method of ethyl 4-bromobutyrate, which has low-cost reaction starting materials, simple and safe process, and is easy to produce on a large scale. Another object of the present invention is to provide a one-pot preparation method of ethyl 4-bromobutyrate with high yield and product purity.

[0010] Methods for solving problems

[0011] In order to solve the above technical problems, the present invention provides the following one-pot preparation method of ethyl 4-bromobutyrate.

[0012] [1] A one-pot method for preparing ethyl 4-bromobutyrate, characterized in that it comprises:

[0013] Step 1: adding γ-butyrolactone to one or more organic solvents selected from toluene, benzene, xylene, n-heptane, and cyclohexane, wherein the mass ratio of the organic solvent to γ-butyrolactone is 2:1 to 10:1, stirring evenly, and then dripping hydrobromic acid aqueous solution at a molar ratio of hydrobromic acid to γ-butyrolactone of 1.0:1 to 2.0:1 under stirring, and reflux and separate water at 50 to 120° C. until no water is separated by naked eye observation, at which time the container is a reaction solution 1,

[0014] Step 2: Detect the content of unreacted γ-butyrolactone in the reaction solution 1. If the content of unreacted γ-butyrolactone is less than 0.5% by mass, proceed to the following step 3. If the content of unreacted γ-butyrolactone is greater than 0.5% by mass, proceed to the following step 4.

[0015] Step 3: If the content of unreacted γ-butyrolactone measured in step 2 is less than 0.5% by mass, anhydrous ethanol is added dropwise to the reaction solution 1 at a molar ratio of ethanol: unreacted γ-butyrolactone of 1.0:1 to 2.0:1, and reflux water separation is continued until the water content is less than 0.2% by mass. The reflux water separation conditions are the same as those in step 1 to obtain a crude solution of ethyl 4-bromobutyrate, and the crude solution of ethyl 4-bromobutyrate is distilled and rectified to obtain a purified ethyl 4-bromobutyrate solution.

[0016] Step 4: If the content of unreacted γ-butyrolactone measured in step 2 is 0.5% by mass or more, the water content is detected at the same time. If the water content is less than 0.5% by mass, a hydrobromic acid aqueous solution is added dropwise in an amount of 0.05 to 0.2 equivalents of hydrobromic acid, and reflux water separation is continued, and step 2 is repeated; if the water content is 0.5% by mass or more, reflux water separation is continued, and then step 2 is repeated.

[0017] [2] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in step 1, the molar ratio of hydrobromic acid:γ-butyrolactone is 1.1:1 to 1.5:1.

[0018] [3] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in step 1, the mass ratio of organic solvent to γ-butyrolactone is 3:1 to 5:1.

[0019] [4] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in step 3, the molar ratio of ethanol to unreacted γ-butyrolactone is 1.2:1 to 1.5:1.

[0020] [5] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in steps 1 to 4, the reflux water separation temperature is 60 to 85°C.

[0021] [6] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in the step 3, the distillation is carried out by controlling the reflux ratio of the distilled solution to 8:2 to 1:1 under a vacuum of 10 Torr and collecting a fraction at 90 to 120°C.

[0022] [7] The one-pot preparation method of ethyl 4-bromobutyrate according to [6] is characterized in that in step 3, during the distillation, a fraction of 110 to 115°C is collected.

[0023] [8] The one-pot preparation method of ethyl 4-bromobutyrate according to [1] is characterized in that in step 2, the content of unreacted γ-butyrolactone is determined by gas chromatography.

[0024] Effects of the Invention

[0025] The invention provides a one-pot preparation method of ethyl 4-bromobutyrate. According to the method, a hydrobromic acid aqueous solution can be directly added to a raw material gamma-butyrolactone for reaction, and then ethanol is directly added to the reaction solution to obtain a target product. The invention overcomes the technical prejudice that the raw materials need to be absolutely anhydrous when preparing ethyl 4-bromobutyrate from hydrogen bromide and gamma-butyrolactone in the prior art, and the process is simple and safe, and the target compound can be obtained with a higher yield. The raw materials used are cheap and easily available, easy to operate, convenient for industrial production, and have broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a schematic flow diagram of the one-pot preparation method of ethyl 4-bromobutyrate.

[0027] Figure 2H NMR spectrum of ethyl 4-bromobutyrate obtained in Example 1. DETAILED DESCRIPTION

[0028] The specific embodiments of the present invention will be further explained and illustrated below in conjunction with specific examples, but the explanation and illustration do not limit the technical solution of the present invention. In the present invention, the target product is ethyl 4-bromobutyrate.

[0029] The one-pot preparation method of ethyl 4-bromobutyrate of the present invention is characterized by comprising the following steps 1 to 4.

[0030] Step 1: Add γ-butyrolactone to an organic solvent, wherein the mass ratio of the organic solvent to γ-butyrolactone is 2:1 to 10:1, and after stirring evenly, add a hydrobromic acid aqueous solution dropwise at a molar ratio of hydrobromic acid to γ-butyrolactone of 1.0:1 to 2.0:1 under stirring, and reflux and separate water at 50 to 120°C, preferably 60-80°C until no water is separated by naked eye observation, and the container is the reaction solution 1 at this time. "No water separation and separation by naked eye observation" means that the water content in the container receiving the separated water does not increase significantly under naked eye observation, and it is not substantially 0 water separation. The organic solvent is a water separation solvent with a density lower than that of water and a boiling point of about 100°C that is insoluble in water, that is, the reflux can carry a water-type solvent, one or more of alkanes, cycloalkanes, aromatic hydrocarbons, etc. Among them, one or more of toluene, benzene, xylene, n-heptane, cyclohexane, etc. are preferred. From the perspective of obtaining better yield, higher product purity, energy consumption and cost, the molar ratio of hydrobromic acid:γ-butyrolactone is preferably 1.1:1 to 1.5:1, the temperature of reflux water separation is preferably 60 to 85°C, and the mass ratio of the organic solvent:γ-butyrolactone is preferably 3:1 to 5:1.

[0031] Step 2: Detect the content of unreacted γ-butyrolactone in the reaction solution 1. If the content of unreacted γ-butyrolactone is less than 0.5% by mass, proceed to the following step 3. If the content of unreacted γ-butyrolactone is greater than 0.5% by mass, proceed to the following step 4. The content of unreacted γ-butyrolactone can be measured by conventional gas chromatography (GC) (temperature: 300-150 (2)-15-280 (8)-300 column model: SE-54). When the content of unreacted γ-butyrolactone is less than 0.5% by mass, it is determined that the γ-butyrolactone initially added as a raw material has reacted completely. When the content of unreacted γ-butyrolactone is greater than 0.5% by mass, it is determined that the γ-butyrolactone initially added as a raw material has not reacted completely and needs to be continued to react. When detecting the content of unreacted γ-butyrolactone in the reaction solution 1, the detection can be performed every 0.5 hour or 1 hour according to actual needs.

[0032] Step 3: If the content of unreacted γ-butyrolactone measured in step 2 is less than 0.5% by mass, anhydrous ethanol is added dropwise to the reaction solution 1 at a molar ratio of ethanol: unreacted γ-butyrolactone of 1.0:1 to 2.0:1, preferably 1.2:1 to 1.5:1, and reflux water separation is continued until the water content is less than 0.2% by mass. The reflux water separation conditions are the same as those in step 1, and a crude solution of colorless transparent liquid 4-bromobutyric acid ethyl ester is obtained. The crude solution of 4-bromobutyric acid ethyl ester is distilled and rectified to obtain a purified 4-bromobutyric acid ethyl ester solution. The above-mentioned method for determining the water content is not particularly limited and can be detected by the Karl Fischer method. Since 4-bromobutyric acid ethyl ester is hydrolyzed to 4-bromobutyric acid under acidic conditions with water, and 4-bromobutyric acid is easily removed by cyclization to generate γ-butyrolactone by removing hydrogen bromide. Therefore, from the perspective of obtaining a higher yield and purity of the target product, the water content needs to be controlled to be less than 0.2% by mass in step 3. The above-mentioned distillation is used to recover the solvent, and can be carried out by a common distillation method, such as a vacuum distillation method, and the distillation temperature can be a temperature above the boiling point of the organic solvent used. The above-mentioned distillation is carried out by controlling the reflux ratio of 8:2 to 1:1 to the distilled solution under a vacuum of 10Torr (water pump), and collecting a 90-120°C fraction. From the perspective of obtaining a higher purity 4-bromobutyric acid ethyl ester solution, it is preferred to collect a fraction of 110 to 115°C.

[0033] Step 4: If the content of unreacted γ-butyrolactone measured in step 2 is 0.5% by mass or more, the water content is detected at the same time. If the water content is less than 0.5% by mass, a hydrobromic acid aqueous solution is added dropwise in an amount of 0.05 to 0.2 equivalents of hydrobromic acid, and reflux water separation is continued, and step 2 is repeated; if the water content is 0.5% by mass or more, reflux water separation is continued, and then step 2 is repeated. There is no particular limitation on the reflux water separation, and for example, it can be 1h, 2h, etc.

[0034] Reaction equation of the present invention is as follows:

[0035]

[0036] As shown in the above reaction equation, after the γ-butyrolactone as a raw material undergoes a hydrolysis ring-opening reaction with water, 4-bromobutyric acid is generated with hydrobromic acid, and the generated 4-bromobutyric acid reacts with ethanol to generate 4-bromobutyric acid ethyl ester. It is believed that in the present invention, when the content of unreacted γ-butyrolactone in the system is more than 0.5% mass fraction, the residual moisture is beneficial to the hydrolysis reaction of unreacted γ-butyrolactone, and at this time in the reaction system, the moisture content is less than 0.5% mass fraction, then 4-bromobutyric acid is easy to remove hydrobromic acid and turn back to γ-butyrolactone, relative to this, at this time in the reaction system, when the moisture content is more than 0.5% mass fraction, moisture can make the lactone carbonyl better protonated, and γ-butyrolactone is attacked by hydrobromic acid and open-looped, which can effectively promote the ring-opening efficiency of γ-butyrolactone, and the yield of the target product is also increased. Therefore, from the perspective of obtaining a better yield of 4-bromobutyric acid ethyl ester, it is necessary to control the system moisture to be more than 0.5% mass fraction.

[0037] The one-pot preparation method of ethyl 4-bromobutyrate can directly add a hydrobromic acid aqueous solution to a raw material γ-butyrolactone for reaction, and then directly add ethanol to the reaction solution to obtain a target product. The method overcomes the technical prejudice that the raw materials need to be absolutely anhydrous when preparing ethyl 4-bromobutyrate from hydrogen bromide and γ-butyrolactone in the prior art, and the process is simple and safe, and the target compound can be obtained with a higher yield. The raw materials used are cheap and easily available, easy to operate, convenient for industrial production, and have broad application prospects.

[0038] Example

[0039] In the embodiment, the instrument used is:

[0040] Moisture titrator: Shanghai Anting Electronic Automatic Moisture Titrator, ZSD-2J",

[0041] NMR instrument: Bruker Avance III 400MHz NMR instrument,

[0042] High performance gas chromatograph: Agilent GC8890

[0043] The measured γ-butyrolactone content and water content are both mass fractions relative to the entire system.

[0044] Example 1

[0045] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer and a simple water separator, add 300g (3.48mol) of γ-butyrolactone and 600g (7.68mol) of benzene. After stirring evenly, add 680g (4.08mol) of 48% hydrobromic acid aqueous solution dropwise while reflux and separate the water at 80-85°C under stirring. After 18 hours of water separation, when no water was observed with the naked eye, the unreacted γ-butyrolactone content of the system was 0.82% by mass by GC detection. Then, the water content was detected by Karl Fischer method and was 1.22% by mass. Reflux water separation was continued for 1 hour. The unreacted γ-butyrolactone content of the system was detected by GC (temperature: 300-150(2)-15-280(8)-300, column model: SE-54) using a chromatograph and was 0.35% by mass. 220 g (4.78 mol) of ethanol was added dropwise while reflux water separation was continued at 80-85°C. The addition was completed in about 1 hour. After the addition was completed, water separation was continued for 24 hours. Then, the water content of the system was detected by Karl Fischer method using a water titrator and was 0.12% by mass. The reaction was completed. Then, the solvent was removed by vacuum distillation at an external temperature of 50°C, and the crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4, and the 110-115°C fraction was collected to obtain 622 g of colorless transparent liquid 1.

[0046] The colorless transparent liquid 1 was analyzed using a nuclear magnetic resonance instrument, and the obtained hydrogen spectrum was shown in FIG. Figure 2 .

[0047] 1 H NMR (400MHz, CDCl3): δ4.23–4.08(m,2H), 3.56–3.39(m,2H), 2.60–2.41(m,2H), 2.27–2.08(m,2H), 1.36–1.15(m,3H).

[0048] It can be seen that the colorless transparent liquid 1 is the target compound ethyl 4-bromobutyrate.

[0049] By calculation, in Example 1, the yield of ethyl 4-bromobutyrate was 91.5% and the purity was 99.1% (gas chromatography analysis).

[0050] Example 2

[0051] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (6.52mol) of toluene were added and stirred evenly. Then, 660g (3.96mol) of 48% hydrobromic acid aqueous solution was added dropwise under stirring and refluxed at 100-110°C for water separation. After 12h of water separation, when no water was separated by naked eye observation, the chromatograph was used to analyze the GC (temperature: 30 0-150(2)-15-280(8)-300 column model: SE-54), the unreacted γ-butyrolactone content of the detection system is 0.38% by mass, 220g (4.78mol) of ethanol is added dropwise, and reflux and water separation is continued at 100-110°C. The addition is completed in about 1h, and then water separation is continued for 14h. The water content of the system is 0.12% by mass using a moisture titrator by Karl Fischer method, and the reaction is complete. Then, the solvent is removed by reduced pressure distillation at an external temperature of 80°C. The crude product is distilled under a vacuum of 10Torr, an external temperature of 120°C, and a reflux ratio of 6:4. The fraction of 110-115°C is collected and distilled to obtain 642g of colorless transparent liquid 2.

[0052] The colorless transparent liquid 2 was analyzed in the same manner as in Example 1, and was confirmed to be ethyl 4-bromobutyrate.

[0053] By calculation, in Example 2, the yield of ethyl 4-bromobutyrate is 94.5% and the purity is 99.5% (gas chromatography analysis).

[0054] Example 3

[0055] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (5.25mol) of n-heptane were added and stirred evenly. Then, 700g (4.20mol) of a 48% aqueous hydrobromic acid solution was added dropwise while stirring at 95-105°C for reflux separation. After 16h of separation, when no water was observed to be separated by naked eyes, the content of unreacted γ-butyrolactone in the detection system was 0.46% by mass by GC (temperature: 300-150(2)-15-280(8)-300, column model: SE-54). Then, 240 g (5.21 mol) of ethanol was added dropwise, and reflux and water separation was continued at 95-105°C. The addition was completed in about 1 hour. After the addition was completed, water separation was continued for 16 hours. The water content of the system was detected by Karl Fischer method using a moisture titrator, which was 0.33% by mass. The reflux reaction was continued for 1 hour. The water content of the system was detected to be 0.17%, and the reaction was completed. Then, the solvent was removed by vacuum distillation at an external temperature of 70°C. The crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4. The fraction of 110-115°C was collected for rectification to obtain 627 g of colorless transparent liquid 3.

[0056] The same analysis as in Example 1 confirmed that the colorless transparent liquid 3 was ethyl 4-bromobutyrate.

[0057] By calculation, in Example 3, the yield of ethyl 4-bromobutyrate is 92.3% and the purity is 99.1% (gas chromatography analysis).

[0058] Example 4

[0059] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (6.96mol) of n-hexane were added, and after being stirred evenly, 700g (4.20mol) of a 48% aqueous hydrobromic acid solution was added dropwise while reflux water separation was performed at 60-70°C. After 20h of water separation, when no water was separated by naked eye, the unreacted γ-butyrolactone content was 3.65% by mass by the GC detection system. Then, the water content was detected by Karl Fischer method and was 0.46% by mass. 70 g of 48% hydrobromic acid aqueous solution was added and refluxed for 4 h. When no water was distilled out by naked eye, the unreacted γ-butyrolactone content of the system was 1.21% by mass using GC (temperature: 300-150 (2) -15-280 (8) -300 column model: SE-54) and the water content was 0.33 by Karl Fischer method. % mass fraction, add 70g of 48% hydrobromic acid aqueous solution, continue to reflux and separate water for 4h, when no water is distilled out by naked eye observation, use chromatograph to detect the unreacted γ-butyrolactone content of the system by GC (temperature: 300-150(2)-15-280(8)-300 column model: SE-54) to find that it is 0.41% mass fraction, add 240g (5.21mol) of ethanol, and continue to reflux and separate water at 65-75℃ while adding. The addition is completed in about 1h, and after the addition is completed, the water separation is continued for 20h. The water content of the system is 0.15% mass fraction using a water titrator by Karl Fischer method, and the reaction is completed. Then, desolventize by reduced pressure distillation at an external temperature of 40℃, and the obtained crude product is distilled by collecting the 110-115℃ fraction under vacuum of 10Torr, external temperature of 120℃, and controlling the reflux ratio of 6:4 to obtain 633g of colorless transparent liquid 4.

[0060] The colorless transparent liquid 4 was analyzed using a nuclear magnetic resonance instrument, and the obtained hydrogen spectrum was shown in FIG. Figure 2 .

[0061] It can be seen that the colorless transparent liquid 4 is the target compound ethyl 4-bromobutyrate.

[0062] By calculation, in Example 4, the yield of ethyl 4-bromobutyrate is 93.1% and the purity is 98.6% (gas chromatography analysis).

[0063] Comparative Example 1

[0064] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 450g (4.89mol) of toluene were added, stirred evenly, and then 660g (3.96mol) of a 48% aqueous solution of hydrobromic acid was added dropwise under stirring while reflux water separation was performed at 100-110°C. After 20 hours of water separation, no obvious water was separated. The unreacted γ-butyrolactone content of the system was 2.2% by mass using a chromatograph through the GC detection system, and the water content was 5.6% by mass using a moisture titrator by the Karl Fischer method. The reflux reaction was continued for 1h. The unreacted γ-butyrolactone content of the system was 1.2% by mass using a chromatograph through the GC detection system, and the water content was 2.6% by mass using a moisture titrator by the Karl Fischer method. The reflux reaction was continued for 1h. The unreacted γ-butyrolactone content of the system was 1.1% by mass using a chromatograph through the GC detection system, and the water content was 2.2% by mass using a moisture titrator by the Karl Fischer method. 220g (4.78mol) of ethanol was added dropwise, and reflux water was continued at 100-110°C while adding dropwise. The addition was completed in about 1 hour. After the addition was completed, water separation was continued for 16 hours. The water content of the system was detected by Karl Fischer method using a moisture titrator, which was 3.7% by mass. The reaction was continued for 1 hour. The water content of the system was detected by Karl Fischer method using a moisture titrator, which was 3.2% by mass. The reaction was continued for 1 hour. The water content of the system was detected by Karl Fischer method using a moisture titrator, which was 3.1% by mass. The water content basically did not change. Then, it was desolvated by reduced pressure distillation at an external temperature of 80°C. The crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4. The fraction of 110-115°C was collected for distillation to obtain 520g of colorless transparent liquid 1'.

[0065] The same analysis as in Example 1 confirmed that the colorless transparent liquid 1' was ethyl 4-bromobutyrate.

[0066] The yield of the transparent 4-bromobutyric acid ethyl ester was calculated to be 76.5% and the purity was 94.3% (gas chromatography analysis).

[0067] The yield and purity of Comparative Example 1 are inferior to those of the embodiment. The reasons are presumably that when toluene is too little, the hydrolysis reaction of γ-butyrolactone and water cannot be carried out to the end, and when toluene is too little, water is not sufficiently carried during reflux water separation, and the esterification reaction of ethyl 4-bromobutyrate and ethanol cannot be carried out completely.

[0068] Comparative Example 2

[0069] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (6.52mol) of toluene were added, and after being uniformly stirred, 660g (3.96mol) of a 48% aqueous hydrobromic acid solution was added dropwise while refluxed and separated at a temperature of 100-110°C under stirring. After about 10h of separation, the unreacted γ-butyrolactone content of the system was detected by GC (temperature: 300-150(2)-15-280(8)-300, column model: SE-54) using a chromatograph, and the content was 1.66%. 220g (4.78mol) of ethanol was added dropwise, and refluxed and separated at a temperature of 100-110°C while adding dropwise. After about 1h of addition, the separation was continued for 14h. When the water content of the system was 0.15% by Karl Fischer method using a water titrator, the reaction was completed. Then, the solvent was removed by vacuum distillation at an external temperature of 80°C. The crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4. The fractions at 110-115°C were collected and rectified to obtain a colorless transparent liquid 2'.

[0070] The same analysis as in Example 1 confirmed that the colorless transparent liquid 2' was ethyl 4-bromobutyrate.

[0071] By calculation, 615 g of ethyl 4-bromobutyrate was produced, with a yield of 90.5% and a purity of 95.5% (gas chromatography analysis).

[0072] In the one-pot preparation method of ethyl 4-bromobutyrate of the present invention, in step 4, when the value of the unreacted γ-butyrolactone content in the system is greater than 0.5%, after adding ethanol, the yield and purity, especially the purity, are relatively low.

[0073] Comparative Example 3

[0074] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (6.52mol) of toluene were added and stirred evenly. Then, 600g (3.60mol) of a 48% aqueous solution of hydrobromic acid was added dropwise while stirring at 100-110°C for reflux separation. After 10h of separation, when no water was observed by naked eyes, the body was detected by GC (temperature: 300-150(2)-15-280(8)-300, column model: SE-54). The unreacted γ-butyrolactone content is 1.75% by mass. Then, the water content of the system is 0.88% by mass by using a water titrator according to the Karl Fischer method. Reflux and water separation is continued for 1 hour at 100-110°C. Then, the unreacted γ-butyrolactone content of the system is 1.02% by mass. Then, the water content of the system is 0.40% by mass by using a water titrator according to the Karl Fischer method. 220g (4.78mol) of ethanol is added dropwise, and reflux and water separation is continued at 100-110°C. The addition is completed in about 1 hour. After the addition is completed and the water separation is continued for 14 hours, the water content of the system is 0.14% by using a water titrator according to the Karl Fischer method, and the reaction is completed. Then, the solvent was removed by vacuum distillation at an external temperature of 80°C. The crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4. The fractions at 110-115°C were collected and rectified to obtain 625 g of a colorless transparent liquid 3'.

[0075] The same analysis as in Example 1 confirmed that the colorless transparent liquid 3' was ethyl 4-bromobutyrate.

[0076] According to calculation, the yield of ethyl 4-bromobutyrate was 91.2% and the purity was 96.8% (gas chromatography analysis).

[0077] In the one-pot preparation method of ethyl 4-bromobutyrate of the present invention, when the water content in step 4 is less than 0.5% by mass, the hydrobromic acid aqueous solution is not supplemented, and the yield and purity of ethyl 4-bromobutyrate are low.

[0078] Comparative Example 4

[0079] In a 2000ml three-necked flask equipped with a magnetic stirrer, a thermometer and a simple water separator, 300g (3.48mol) of γ-butyrolactone and 600g (5.25mol) of n-heptane were added, and after being stirred evenly, 700g (4.20mol) of a 48% aqueous hydrobromic acid solution was added dropwise while stirring and refluxed at 95-105°C. After 16h of water separation, when no water was separated by naked eye observation, the content of unreacted γ-butyrolactone in the detection system was 0.42% by GC (temperature: 300-150(2)-15-280(8)-300, column model: SE-54), 240g (5.21mol) of ethanol was added dropwise, and refluxed at 95-105°C while adding dropwise. The addition was completed in about 1 hour, and then the water separation was continued for 12 hours. The water content of the system was detected by Karl Fischer method using a moisture titrator and was 0.42%, and the reaction was terminated. Then, the solvent was removed by vacuum distillation at an external temperature of 70°C. The crude product was distilled under a vacuum of 10 Torr, an external temperature of 120°C, and a reflux ratio of 6:4, and the fraction of 110-115°C was collected for rectification to obtain 568g of colorless transparent liquid 4'.

[0080] The same analysis as in Example 1 confirmed that the colorless transparent liquid 4' was ethyl 4-bromobutyrate.

[0081] By calculation, in Comparative Example 4, the yield of ethyl 4-bromobutyrate was 83.6% and the purity was 95.3% (gas chromatography analysis).

[0082] In the one-pot preparation method of ethyl 4-bromobutyrate of the present invention, when the water content in step 3 is greater than 0.2% by mass and the reaction is terminated, the second reflux time is shortened, the water content is large, and the yield and purity of ethyl 4-bromobutyrate are lower than those in Example 3.

[0083] It can be seen from the above embodiments and comparative examples that the one-pot preparation method of 4-bromobutyric acid ethyl ester of the present invention can directly add hydrobromic acid aqueous solution to the raw material γ-butyrolactone for reaction, and then directly add ethanol to the reaction solution to obtain the target product. The present invention overcomes the technical prejudice that the raw material needs to be absolutely anhydrous when hydrogen bromide and γ-butyrolactone are used to prepare 4-bromobutyric acid ethyl ester in the prior art. The process of the present invention is simple and safe, and the yield and purity that can be obtained are both high. The present invention uses cheap raw materials, is easy to operate, is convenient for industrial production, and has a wide range of application prospects.

[0084] It should also be noted that the above-listed embodiments are only specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and similar changes or modifications made therewith can be directly derived or easily associated with the contents disclosed by those skilled in the art from the present invention, and all should belong to the protection scope of the present invention.

Claims

1. A one-pot preparation method of ethyl 4-bromobutyrate, characterized in that: include: Step 1: adding γ-butyrolactone to one or more organic solvents selected from toluene, benzene, xylene, n-heptane, and cyclohexane, wherein the mass ratio of the organic solvent to γ-butyrolactone is 2:1 to 10:1, stirring evenly, and then dripping hydrobromic acid aqueous solution at a molar ratio of hydrobromic acid to γ-butyrolactone of 1.0:1 to 2.0:1 under stirring, and reflux and separate water at 50 to 120° C. until no water is separated by naked eye observation, at which time the container is a reaction solution 1, Step 2: Detect the content of unreacted γ-butyrolactone in the reaction solution 1. If the content of unreacted γ-butyrolactone is less than 0.5% by mass, proceed to the following step 3. If the content of unreacted γ-butyrolactone is greater than 0.5% by mass, proceed to the following step 4. Step 3: If the content of unreacted γ-butyrolactone measured in step 2 is less than 0.5% by mass, anhydrous ethanol is added dropwise to the reaction solution 1 at a molar ratio of ethanol: unreacted γ-butyrolactone of 1.0:1 to 2.0:1, and reflux water separation is continued until the water content is less than 0.2% by mass. The reflux water separation conditions are the same as those in step 1 to obtain a crude solution of ethyl 4-bromobutyrate, and the crude solution of ethyl 4-bromobutyrate is distilled and rectified to obtain a purified ethyl 4-bromobutyrate solution. Step 4: If the content of unreacted γ-butyrolactone measured in step 2 is 0.5% by mass or more, the water content is detected at the same time. If the water content is less than 0.5% by mass, a hydrobromic acid aqueous solution is added dropwise in an amount of 0.05 to 0.2 equivalents of hydrobromic acid, and reflux water separation is continued, and step 2 is repeated; if the water content is 0.5% by mass or more, reflux water separation is continued, and then step 2 is repeated.

2. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that In the step 1, the molar ratio of hydrobromic acid to γ-butyrolactone is 1.1:1 to 1.5:

1.

3. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that, In the step 1, the mass ratio of the organic solvent to γ-butyrolactone is 3:1 to 5:

1.

4. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that In the step 3, the molar ratio of ethanol to unreacted γ-butyrolactone is 1.2:1 to 1.5:

1.

5. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that, In the steps 1 to 4, the reflux water separation temperature is 60 to 85°C.

6. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that In the step 3, the distillation is performed by controlling the reflux ratio of the distilled solution to 8:2 to 1:1 under a vacuum of 10 Torr and collecting a fraction at 90 to 120°C.

7. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 6, characterized in that: In the step 3, during the distillation, the fraction at 110-115° C. is collected.

8. The one-pot preparation method of ethyl 4-bromobutyrate according to claim 1, characterized in that In the step 2, the content of unreacted γ-butyrolactone is determined by gas chromatography.

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