One-pot preparation method of ethyl 4-bromobutyrate

Abstract

The present invention provides a one-pot preparation method of ethyl 4-bromobutyrate, which is characterized by comprising: Step 1: adding γ-butyrolactone into an organic solvent, and carrying out reflux and water separation while dropwise adding an aqueous hydrobromic acid solution; Step 2: detecting the content of γ-butyrolactone, if it is less than 0.5% by mass fraction, then proceed to Step 3, if it is above 0.5% by mass fraction, then proceed to the following Step 4; Step 3: dropwise adding absolute ethanol, and continue to carry out reflux and water separation until the water content is below 0.2% by mass fraction to obtain a crude product solution of ethyl 4-bromobutyrate, and carry out distillation and rectification to obtain a purified ethyl 4-bromobutyrate solution; Step 4: detecting the water in the system, if it is less than 0.5% by mass fraction, then continue to supplement and dropwise add an aqueous hydrobromic acid solution, and continue to carry out reflux and water separation, repeating Step 2; if the water content is above 0.5% by mass fraction, continue to carry out reflux and water separation, repeating Step 2.

Description

Technical Field

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

[0002] Ethyl 4-bromobutyrate is a very important intermediate for pesticides and pharmaceuticals and is widely used in organic synthesis.

[0003] In the synthesis route of ethyl 4-bromobutyrate, the most economical method is to react γ-butyrolactone with a brominating reagent. Synthesis, 1982, P963 reported that boron tribromide reacts with γ-butyrolactone in dichloromethane to form 4-bromobutyric acid, which is then esterified to obtain ethyl 4-bromobutyrate. However, this method uses equimolar boron tribromide, which has a very high cost, and a large amount of boride will be generated during the production process, and the treatment of the three wastes is quite difficult. Therefore, this method has no value in industry.

[0004] The main method for preparing ethyl 4-bromobutyrate in China is to slowly introduce dry hydrogen bromide gas into γ-butyrolactone, and after the reaction is completed, anhydrous ethanol is added. Currently, in the method for preparing ethyl 4-bromobutyrate using this method, there is a technical prejudice, that is, in the reaction of using hydrogen bromide, γ-butyrolactone and ethanol to produce ethyl 4-bromobutyrate, the raw materials are required to be absolutely anhydrous.

[0005] For example, in Patent Document 1 with the application number 202210499719.9 and the invention name "A one-step preparation method of ethyl 4-bromobutyrate", after controlling the reaction temperature by introducing dry hydrogen bromide gas into γ-butyrolactone for reaction, anhydrous ethanol is added to produce 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 reacts with γ-butyrolactone to obtain 4-bromobutyric acid, which is then esterified with anhydrous ethanol to obtain ethyl 4-bromobutyrate. In the prior art, the use of dry hydrogen bromide gas has a high cost, and there are 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 method for preparing ethyl 4-bromobutyrate suitable for industrial production with lower cost, simplicity and safety. Summary of the Invention

[0007] Problems to be Solved by the Invention

[0008] In view of the problems in the above-mentioned prior art, the present invention boldly overcomes the above-mentioned technical prejudice, abandons the use of dry hydrogen bromide gas, and proposes a one-pot preparation method of ethyl 4-bromobutyrate with simple and safe process and easy to scale up production.

[0009] The object of the present invention is to provide a one-pot preparation method of ethyl 4-bromobutyrate with inexpensive reaction starting materials, simple and safe process, and easy for large-scale production. Another object of the present invention is to provide a one-pot preparation method of ethyl 4-bromobutyrate with both high yield and high product purity.

[0010] Method for solving the problem

[0011] 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 preparation method of ethyl 4-bromobutyrate, characterized by comprising:

[0013] Step 1: Add γ-butyrolactone to one or more organic solvents selected from toluene, benzene, xylene, n-heptane, and cyclohexane. The mass ratio of the organic solvent to γ-butyrolactone is 2:1 to 10:1. After stirring evenly, while stirring, dropwise add an aqueous hydrobromic acid solution with a molar ratio of hydrobromic acid to γ-butyrolactone of 1.0:1 to 2.0:1 and carry out reflux water separation at 50-120 °C until no water is visually observed to be separated. At this time, the reaction solution 1 is in the container.

[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% mass fraction, then proceed to the following step 3. If the content of unreacted γ-butyrolactone is 0.5% mass fraction or more, then 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% mass fraction, then dropwise add absolute ethanol to the reaction solution 1 with a molar ratio of ethanol to unreacted γ-butyrolactone of 1.0:1 to 2.0:1, and continue to carry out reflux water separation until the water content is below 0.2% mass fraction. The reflux water separation conditions are the same as those in step 1, to obtain a crude solution of ethyl 4-bromobutyrate. Distill and rectify the obtained crude solution of ethyl 4-bromobutyrate to obtain a purified solution of ethyl 4-bromobutyrate.

[0016] Step 4: If the content of unreacted γ-butyrolactone measured in step 2 is 0.5% mass fraction or more, then simultaneously detect the water content. If the water content is less than 0.5% mass fraction, then supplement and dropwise add an aqueous hydrobromic acid solution with 0.05-0.2 equivalents of hydrobromic acid, continue to carry out reflux water separation, and then repeat step 2. If the water content is 0.5% mass fraction or more, then continue to carry out reflux water separation, and then repeat step 2.

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

[0018] [3] The one-pot preparation method of ethyl 4-bromobutyrate according to [1], characterized in that in step 1, the mass ratio of the 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], 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], characterized in that in steps 1 to 4, the reflux and water separation temperature is 60 to 85 °C.

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

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

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

[0024] Advantages of the Invention

[0025] The present invention provides a one-pot preparation method of ethyl 4-bromobutyrate. By this method, an aqueous solution of hydrobromic acid can be directly added to the raw material γ-butyrolactone for reaction, and then ethanol can be directly added to the reaction solution to obtain the target product. The present invention overcomes the technical prejudice that absolute anhydrous conditions are required in the raw materials when preparing ethyl 4-bromobutyrate from hydrogen bromide and γ-butyrolactone in the prior art. Moreover, the process is simple and safe, and the target compound can be obtained in a relatively high yield. The raw materials used are cheap and easily available, easy to operate, and convenient for industrial production, with broad application prospects. Brief Description of the Drawings

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

[0027] Figure 21H NMR spectrum of ethyl 4-bromobutyrate obtained in Example 1. Detailed implementation mode

[0028] The following will further explain and illustrate the specific implementation mode of the present invention in combination with specific embodiments. However, this 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] A one-pot preparation method of ethyl 4-bromobutyrate of the present invention is characterized by including the following steps 1 to 4.

[0030] Step 1: Add γ-butyrolactone to an organic solvent. The mass ratio of the organic solvent to γ-butyrolactone is 2:1 to 10:1. After stirring evenly, while stirring, add an aqueous hydrobromic acid solution with a molar ratio of hydrobromic acid to γ-butyrolactone of 1.0:1 to 2.0:1, and carry out reflux water separation at 50 to 120 °C, preferably 60 - 80 °C, until no water is visually observed to be separated. At this time, the solution in the container is reaction solution 1. "No water is visually observed to be separated" means that there is no obvious increase in the water in the container for receiving the separated water during visual observation, rather than actually 0 water being separated. The organic solvent is a water-insoluble and density-smaller-than-water water-separating solvent with a boiling point of about 100 °C, that is, a water-carrying solvent during reflux, such as one or several of alkanes, cycloalkanes, aromatic hydrocarbons, etc. Among them, preferably one or several of toluene, benzene, xylene, n-heptane, cyclohexane, etc. From the perspectives of obtaining better yield, higher product purity, energy consumption, and cost, the above-mentioned molar ratio of hydrobromic acid to 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 to γ-butyrolactone is preferably 3:1 to 5:1.

[0031] Step 2: Detect the content of unreacted γ-butyrolactone in reaction solution 1. If the content of unreacted γ-butyrolactone is less than 0.5% by mass fraction, proceed to the following step 3. If the content of unreacted γ-butyrolactone is 0.5% by mass fraction or more, proceed to the following step 4. The content of unreacted γ-butyrolactone can be determined by a 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 fraction, it is judged that the γ-butyrolactone initially added as a raw material has completely reacted. When the content of unreacted γ-butyrolactone is 0.5% by mass fraction or more, it is judged that the γ-butyrolactone initially added as a raw material has not completely reacted and needs to continue the reaction. When detecting the content of unreacted γ-butyrolactone in reaction solution 1, it can be detected every 0.5 hours 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 fraction, 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 refluxing with water separation is continued until the water content is below 0.2% by mass fraction. The conditions for refluxing with water separation are the same as those in Step 1, obtaining a crude product solution of ethyl 4-bromobutyrate as a colorless transparent liquid. The obtained crude product solution of ethyl 4-bromobutyrate is distilled and rectified to obtain a purified ethyl 4-bromobutyrate solution. The method for measuring the above water content is not particularly limited and can be detected by the Karl Fischer method. Since ethyl 4-bromobutyrate will hydrolyze into 4-bromobutyric acid under acidic conditions with water, and 4-bromobutyric acid is prone to cyclize to remove hydrogen bromide to form γ-butyrolactone. Therefore, from the perspective of obtaining a higher yield and purity of the target product, the water content needs to be controlled below 0.2% by mass fraction in Step 3. The above distillation is used to recover the solvent and can be carried out by a conventional distillation method, such as vacuum distillation method, etc. The distillation temperature can be a temperature above the boiling point of the organic solvent used. The above rectification is carried out by controlling the reflux ratio of 8:2 to 1:1 under a vacuum of 10 Torr (water pump) for the distilled solution and collecting the fraction at 90-120°C. To obtain a higher purity ethyl 4-bromobutyrate solution, it is preferred to collect the fraction at 110-115°C.

[0033] Step 4: If the content of unreacted γ-butyrolactone measured in Step 2 is 0.5% by mass fraction or more, the water content is detected simultaneously. If the water content is less than 0.5% by mass fraction, an aqueous solution of hydrobromic acid equivalent to 0.05-0.2 equivalents based on hydrobromic acid is added dropwise, and after continuing refluxing with water separation, Step 2 is repeated; if the water content is 0.5% by mass fraction or more, refluxing with water separation is continued, and then Step 2 is repeated. The refluxing with water separation is not particularly limited and can be, for example, 1 h, 2 h, etc.

[0034] The 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, it reacts with hydrobromic acid to form 4-bromobutyric acid, and the formed 4-bromobutyric acid reacts with ethanol to form ethyl 4-bromobutyrate. In the present invention, when the content of unreacted γ-butyrolactone in the system is above 0.5% by mass fraction, the residual moisture is beneficial to the hydrolysis reaction of the unreacted γ-butyrolactone. At this time, in the reaction system, when the moisture content is less than 0.5% by mass fraction, 4-bromobutyric acid is likely to remove hydrobromic acid and revert to γ-butyrolactone. In contrast, at this time, in the reaction system, when the moisture content is above 0.5% by mass fraction, the moisture can protonate the lactone carbonyl better, and γ-butyrolactone undergoes ring-opening under the attack of hydrobromic acid, which can effectively promote the ring-opening efficiency of γ-butyrolactone, and the yield of the target product also increases. Therefore, starting from obtaining a better yield of ethyl 4-bromobutyrate, it is necessary to control the moisture content in the system to be above 0.5% by mass fraction.

[0037] The one-pot preparation method of ethyl 4-bromobutyrate of the present invention can directly add an aqueous solution of hydrobromic acid to react in the raw material γ-butyrolactone, and then directly add ethanol to the reaction solution to obtain the target product. The present invention overcomes the technical prejudice that absolute anhydrous conditions are required in the raw materials 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 in a relatively high yield, and the raw materials used are cheap and easy to obtain, easy to operate, convenient for industrial production, and have a wide application prospect.

[0038] Examples

[0039] In the examples, the instruments used are:

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

[0041] Nuclear magnetic resonance spectrometer: Bruker Avance III 400MHz nuclear magnetic resonance spectrometer,

[0042] High performance gas chromatograph: Agilent GC8890

[0043] The measured contents of γ-butyrolactone and moisture are both mass fractions relative to the entire system.

[0044] Example 1

[0045] In a 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (7.68 mol) of benzene. After stirring evenly, while stirring, add 680 g (4.08 mol) of 48% hydrobromic acid aqueous solution dropwise and reflux for water separation at 80 - 85 °C. After 18 h of water separation, when no water is visually observed to be separated, the content of unreacted γ-butyrolactone in the system detected by GC is 0.82% mass fraction. Then, the water content detected by the Karl Fischer method is 1.22% mass fraction. Continue refluxing for water separation for 1 h. Use a chromatograph to detect the content of unreacted γ-butyrolactone in the system by GC (temperature: 300 - 150(2) - 15 - 280(8) - 300, column model: SE-54), and the content is 0.35% mass fraction. Add 220 g (4.78 mol) of ethanol dropwise, and continue refluxing for water separation at 80 - 85 °C while adding. It takes about 1 h to finish dropping. After dropping, continue water separation for 24 h. Then, use a Karl Fischer moisture titrator to detect the water content in the system, and the water content is 0.12% mass fraction. The reaction is completed. Then, carry out solvent stripping under reduced pressure at an external temperature of 50 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and a reflux ratio of 6:4, to obtain 622 g of colorless transparent liquid 1.

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

[0047] 1 H NMR (400 MHz, CDCl3): δ 4.23–4.08 (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 from this 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 is 91.5%, and the purity is 99.1% (gas chromatography analysis).

[0050] Example 2

[0051] In a 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (6.52 mol) of toluene. After stirring evenly, while stirring, add 660 g (3.96 mol) of 48% hydrobromic acid aqueous solution dropwise and reflux to separate water at a temperature of 100 - 110 °C. After 12 hours of water separation, when no water is visually observed to be separated, use a chromatograph to detect the content of unreacted γ-butyrolactone in the system by GC (temperature: 300 - 150(2) - 15 - 280(8) - 300, column model: SE-54), and the content of unreacted γ-butyrolactone is 0.38% by mass fraction. Then add 220 g (4.78 mol) of ethanol dropwise, and continue to reflux and separate water at 100 - 110 °C while adding. It takes about 1 hour to finish dropping, and then continue to separate water for 14 hours. Use a Karl Fischer moisture titrator to detect the water content in the system by the Karl Fischer method, and the water content is 0.12% by mass fraction, and the reaction is completed. Then, under reduced pressure distillation to remove the solvent at an external temperature of 80 °C, the obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and a reflux ratio of 6:4, to obtain 642 g of a colorless transparent liquid 2.

[0052] Analyze in the same way as in Example 1 to determine that the colorless transparent liquid 2 is 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 chromatographic analysis).

[0054] Example 3

[0055] In a 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (5.25 mol) of n-heptane. After stirring evenly, while stirring, add 700 g (4.20 mol) of 48% hydrobromic acid aqueous solution dropwise and carry out reflux water separation at a temperature of 95 - 105 °C. After 16 h of water separation, when no water is visually observed to be separated, use a chromatograph through GC (temperature: 300 - 150(2) - 15 - 280(8) - 300 column model: SE-54) to detect that the content of unreacted γ-butyrolactone in the system is 0.46% by mass fraction. Then, add 240 g (5.21 mol) of ethanol dropwise, and continue reflux water separation at 95 - 105 °C while adding. It takes about 1 h to finish the dropwise addition. After finishing the dropwise addition and continuing water separation for 16 h, use a Karl Fischer moisture titrator to detect that the moisture content in the system is 0.33% by mass fraction. Continue reflux reaction for 1 h, and detect that the moisture content in the system is 0.17%. The reaction is completed. Then, carry out solvent stripping under reduced pressure at an external temperature of 70 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and controlling the reflux ratio of 6:4, to obtain 627 g of colorless transparent liquid 3.

[0056] Analyze in the same way as in Example 1 to determine that the colorless transparent liquid 3 is 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 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (6.96 mol) of n-hexane. After stirring evenly, while stirring, add 700 g (4.20 mol) of 48% hydrobromic acid aqueous solution dropwise and reflux and separate water at 60 - 70 °C. After 20 h of water separation, when no water is visually observed to be separated, the content of unreacted γ-butyrolactone in the system detected by GC is 3.65% mass fraction. Then, the water content detected by the Karl Fischer method is 0.46% mass fraction. Add 70 g of 48% hydrobromic acid aqueous solution and continue reflux and separate water for 4 h. When no water is visually observed to be distilled out, use a chromatograph to detect the content of unreacted γ-butyrolactone in the system by GC (temperature: 300 - 150(2) - 15 - 280(8) - 300 column model: SE-54), and the content is 1.21% mass fraction. The water content detected by the Karl Fischer method is 0.33% mass fraction. Add 70 g of 48% hydrobromic acid aqueous solution and continue reflux and separate water for 4 h. When no water is visually observed to be distilled out, use a chromatograph to detect the content of unreacted γ-butyrolactone in the system by GC (temperature: 300 - 150(2) - 15 - 280(8) - 300 column model: SE-54), and the content is 0.41% mass fraction. Add 240 g (5.21 mol) of ethanol dropwise, and while dropping, continue to reflux and separate water under the condition of 65 - 75 °C. The dropping is completed in about 1 h. After the dropping is completed, continue to separate water for 20 h. Then, use a Karl Fischer moisture titrator to detect the water content in the system, and the water content is 0.15% mass fraction, and the reaction is completed. Then, distill off the solvent under reduced pressure at an external temperature of 40 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and a reflux ratio of 6:4, and 633 g of a colorless transparent liquid 4 is obtained.

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

[0061] It can be seen from this 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 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 450 g (4.89 mol) of toluene. After stirring evenly, while stirring, add 660 g (3.96 mol) of 48% hydrobromic acid aqueous solution dropwise and reflux and separate water at a temperature of 100 - 110 °C. After 20 hours of water separation, no obvious water is separated out. Using a chromatograph, the content of unreacted γ-butyrolactone in the system detected by GC is 2.2% mass fraction, and the water content detected by a Karl Fischer moisture titrator using the Karl Fischer method is 5.6% mass fraction. Continue refluxing for 1 h, and using a chromatograph, the content of unreacted γ-butyrolactone in the system detected by GC is 1.2%, and the water content detected by a Karl Fischer moisture titrator using the Karl Fischer method is 2.6% mass fraction. Continue refluxing for 1 h, and using a chromatograph, the content of unreacted γ-butyrolactone in the system detected by GC is 1.1%, and the water content detected by a Karl Fischer moisture titrator using the Karl Fischer method is 2.2% mass fraction. Add 220 g (4.78 mol) of ethanol dropwise, and while adding, continue to reflux and separate water under the condition of 100 - 110 °C. It takes about 1 h to finish dropping. After finishing dropping and continuing to separate water for 16 h, the water content of the system detected by a Karl Fischer moisture titrator using the Karl Fischer method is 3.7% mass fraction. Continue reacting for 1 h, the water content of the system detected by a Karl Fischer moisture titrator using the Karl Fischer method is 3.2% mass fraction. Continue reacting for 1 h, the water content of the system detected by a Karl Fischer moisture titrator using the Karl Fischer method is 3.1% mass fraction, and the water basically no longer changes. Then, under reduced pressure, distill off the solvent at an external temperature of 80 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and controlling the reflux ratio of 6:4, to obtain 520 g of a colorless transparent liquid 1'.

[0065] Analyze in the same way as in Example 1 to determine that the colorless transparent liquid 1' is ethyl 4-bromobutyrate.

[0066] By calculation, the yield of this transparent ethyl 4-bromobutyrate is 76.5%, and the purity is 94.3% (gas chromatographic analysis).

[0067] The yield and purity of Comparative Example 1 are poorer than those of the example. The reason is presumably that when the amount of toluene is too small, the hydrolysis reaction between γ-butyrolactone and water cannot proceed to completion, and when the amount of toluene is too small, the water-carrying during reflux and water separation is insufficient, and the esterification reaction between ethyl 4-bromobutyrate and ethanol cannot proceed completely.

[0068] Comparative Example 2

[0069] In a 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (6.52 mol) of toluene. After stirring evenly, while stirring, add 660 g (3.96 mol) of 48% hydrobromic acid aqueous solution dropwise and carry out reflux water separation at a temperature of 100 - 110 °C. After about 10 h of water separation, use a chromatograph to detect the content of unreacted γ-butyrolactone in the system by GC (temperature: 300 - 150(2) - 15 - 280(8) - 300, column model: SE-54), and the content is 1.66%. Then add 220 g (4.78 mol) of ethanol dropwise, and continue reflux water separation at a temperature of 100 - 110 °C while adding. It takes about 1 h to finish adding. After continuing water separation for 14 h, when the water content in the system is detected to be 0.15% by the Karl Fischer method using a Karl Fischer moisture titrator, the reaction is completed. Then, carry out solvent stripping under reduced pressure at an external temperature of 80 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and controlling the reflux ratio of 6:4 to obtain a colorless transparent liquid 2'.

[0070] Analyze in the same way as in Example 1 to determine that the colorless transparent liquid 2' is ethyl 4-bromobutyrate.

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

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

[0073] Comparative Example 3

[0074] In a 2000 ml three-necked flask equipped with a magnetic stirrer, a thermometer, and a simple water separator, add 300 g (3.48 mol) of γ-butyrolactone and 600 g (6.52 mol) of toluene. After stirring evenly, while stirring, add 600 g (3.60 mol) of 48% hydrobromic acid aqueous solution dropwise and carry out reflux water separation at a temperature of 100 - 110 °C. After 10 h of water separation, when no water is visually observed to be separated out, use a chromatograph through GC (temperature: 300 - 150(2) - 15 - 280(8) - 300, column model: SE-54) to detect that the content of unreacted γ-butyrolactone in the system is 1.75% mass fraction. Then, use a Karl Fischer moisture titrator to detect the water content in the system to be 0.88% mass fraction through the Karl Fischer method. Continue reflux water separation at 100 - 110 °C for 1 h. Then, detect that the content of unreacted γ-butyrolactone in the system is 1.02% mass fraction. Then, use a Karl Fischer moisture titrator to detect the water content in the system to be 0.40% mass fraction through the Karl Fischer method. Add 220 g (4.78 mol) of ethanol dropwise, and continue reflux water separation at 100 - 110 °C while adding. It takes about 1 h to finish dropping. After finishing dropping and continuing water separation for 14 h, use a Karl Fischer moisture titrator to detect the water content in the system to be 0.14% through the Karl Fischer method, and the reaction is completed. Then, carry out solvent stripping under reduced pressure at an external temperature of 80 °C. The obtained crude product is rectified by collecting the fraction at 110 - 115 °C under a vacuum of 10 Torr, an external temperature of 120 °C, and a reflux ratio of 6:4, to obtain 625 g of a colorless transparent liquid 3'.

[0075] Analyze in the same way as in Example 1 to determine that the colorless transparent liquid 3' is ethyl 4-bromobutyrate.

[0076] By calculation, the yield of ethyl 4-bromobutyrate is 91.2%, and the purity is 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% mass fraction and no hydrobromic acid aqueous solution is added, the yield and purity of ethyl 4-bromobutyrate are relatively 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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