CN117865802A - Preparation method of ethyl 4-bromobutyrate - Google Patents
Preparation method of ethyl 4-bromobutyrate Download PDFInfo
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- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 130
- 238000005893 bromination reaction Methods 0.000 claims abstract description 83
- 230000031709 bromination Effects 0.000 claims abstract description 82
- 238000005886 esterification reaction Methods 0.000 claims abstract description 67
- 230000032050 esterification Effects 0.000 claims abstract description 66
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 238000000746 purification Methods 0.000 claims abstract description 18
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 87
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
- 238000011282 treatment Methods 0.000 claims description 60
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 52
- 238000003756 stirring Methods 0.000 claims description 49
- 239000007788 liquid Substances 0.000 claims description 48
- 238000011221 initial treatment Methods 0.000 claims description 44
- 239000000126 substance Substances 0.000 claims description 40
- 239000000463 material Substances 0.000 claims description 38
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 32
- 239000012044 organic layer Substances 0.000 claims description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- 239000006087 Silane Coupling Agent Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 19
- 238000007599 discharging Methods 0.000 claims description 18
- 238000011049 filling Methods 0.000 claims description 17
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 17
- 230000014759 maintenance of location Effects 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 15
- 235000019441 ethanol Nutrition 0.000 claims description 15
- 239000004220 glutamic acid Substances 0.000 claims description 15
- 235000013922 glutamic acid Nutrition 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 14
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 14
- 150000001649 bromium compounds Chemical group 0.000 claims description 14
- 239000008367 deionised water Substances 0.000 claims description 14
- 229910021641 deionized water Inorganic materials 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- LHBNLZDGIPPZLL-UHFFFAOYSA-K praseodymium(iii) chloride Chemical compound Cl[Pr](Cl)Cl LHBNLZDGIPPZLL-UHFFFAOYSA-K 0.000 claims description 12
- 238000000498 ball milling Methods 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 10
- 239000007853 buffer solution Substances 0.000 claims description 10
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 238000002203 pretreatment Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims 3
- 238000001291 vacuum drying Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 8
- 238000010924 continuous production Methods 0.000 abstract description 6
- 239000002699 waste material Substances 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 25
- 230000001276 controlling effect Effects 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 3
- NVRVNSHHLPQGCU-UHFFFAOYSA-M 6-bromohexanoate Chemical compound [O-]C(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-M 0.000 description 3
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- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- UUQMNUMQCIQDMZ-UHFFFAOYSA-N betahistine Chemical compound CNCCC1=CC=CC=N1 UUQMNUMQCIQDMZ-UHFFFAOYSA-N 0.000 description 1
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- AYPJVXQBVHCUCJ-UHFFFAOYSA-N ethyl 4-hydroxybutanoate Chemical compound CCOC(=O)CCCO AYPJVXQBVHCUCJ-UHFFFAOYSA-N 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of ethyl 4-bromobutyrate, and belongs to the field of preparation of ethyl 4-bromobutyrate. The preparation method of the ethyl 4-bromobutyrate comprises the following steps: primary bromination, secondary bromination, primary esterification, secondary esterification, and purification. The preparation method of the ethyl 4-bromobutyrate can effectively solve the problems of difficult separation of catalyst components, low production safety, large reaction waste production amount, unstable reaction effect and product quality existing in the existing preparation of the ethyl 4-bromobutyrate, and can realize efficient and stable production of the ethyl 4-bromobutyrate under the condition of large-scale continuous production.
Description
Technical Field
The invention relates to the field of preparation of ethyl 4-bromobutyrate, in particular to a preparation method of ethyl 4-bromobutyrate.
Background
Ethyl 4-bromobutyrate, also known as Ethyl-4-bromobutyl ester, english name Ethyl 4-bromobutyl, CAS number: 2969-81-5 with chemical formula C 6 H 11 BrO 2 The molecular weight is 195.05. The ethyl 4-bromobutyrate is colorless to yellow transparent liquid, the relative density (25 ℃) is 1.363g/mL, and the boiling point is 80-82 ℃. In the prior art, the method comprises the steps of,ethyl 4-bromobutyrate is an important pesticide, pharmaceutical intermediate, for example, ethyl 4-bromobutyrate can be used in the preparation of intermediates of talinccable for parkinsonism, ezetimibe for hypercholesterolemia, betahistine for meniere's syndrome, and tolvaptan. Meanwhile, the ethyl 4-bromobutyrate is also widely applied in the fields of paint, printing ink, adhesives and cleaning agents; in the manufacture of coatings and inks, ethyl 4-bromobutyrate may be used as a solvent to dilute and mix pigments and resins; in the preparation of the adhesive, the ethyl 4-bromobutyrate can play roles in dissolving the adhesive, increasing the viscosity and the like. In the manufacture of cleaners, ethyl 4-bromobutyrate is effective as a cleaning ingredient to remove grease and stains. In addition, ethyl 4-bromobutyrate can also be used as a catalyst in partial cyclization reactions.
According to the related technical information disclosed in the prior art, the preparation method of the ethyl 4-bromobutyrate mainly comprises the following steps:
1. 4-bromobutyric acid is adopted as a raw material, p-toluenesulfonic acid or oxalyl chloride is adopted as a catalyst, and the esterification reaction is carried out with ethanol to prepare the ethyl 4-bromobutyrate. However, the method has the defects that the catalytic effect of the adopted catalyst of the p-toluenesulfonic acid or oxalyl chloride is general, the subsequent separation process of the catalyst components is complicated, post-treatment processes such as precipitation, filtration, neutralization, water washing and the like are needed, the generation amount of reaction waste is large, and the environmental pollution is easy to cause; meanwhile, the storage and transportation requirements of the adopted 4-bromobutyric acid are strict, the quality of the 4-bromobutyric acid purchased and obtained by different manufacturers is unstable, and the preparation effect and quality of the final product ethyl 4-bromobutyrate are easily influenced.
2. The ethyl 4-bromobutyrate is prepared by using gamma-butyrolactone and bromine as raw materials and red phosphorus as a catalyst. However, the method has the defects that the adopted catalyst red phosphorus has strong hygroscopicity, is easy to oxidize, has high corrosiveness to production equipment and has high fire hazard; in addition, in the preparation process, the byproduct ethyl 4-hydroxybutyrate and the like are easy to generate, so that the subsequent purification and post-treatment processes are complex, the production energy consumption is high, and the purity index of the product ethyl 4-bromobutyrate is not ideal.
3. And (3) carrying out bromination reaction on gamma-butyrolactone and hydrogen bromide, and then continuously reacting with absolute ethyl alcohol to prepare the ethyl 4-bromobutyrate. Although the method can obtain better purity and yield of the ethyl 4-bromobutyrate, the inventor tests that the method is still limited in small-scale preparation in a laboratory, the purity and yield index of the ethyl 4-bromobutyrate can be basically obtained only by batch preparation in the laboratory, the production scale is enlarged to be large-scale continuous production, the reaction effect is obviously reduced, the reaction rate is unstable, and the reaction rate is further reduced due to factors such as byproduct accumulation in a reaction system and the like along with the extension of the reaction time, and the quality of the ethyl 4-bromobutyrate is deteriorated; meanwhile, aiming at the fact that the post-treatment capacity of a reaction product gradually cannot meet the quality requirement of the ethyl 4-bromobutyrate, the sewage production amount in the post-treatment process is obviously increased, the production cost is increased, and the efficient and stable production of the ethyl 4-bromobutyrate cannot be realized.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides the preparation method of the ethyl 4-bromobutyrate, which can effectively avoid the problems of difficult separation of catalyst components (such as p-toluenesulfonic acid, red phosphorus and the like), low production safety, large reaction waste production amount, unstable reaction effect and product quality in the existing preparation of the ethyl 4-bromobutyrate, and can realize the efficient and stable production of the ethyl 4-bromobutyrate under the condition of large-scale continuous production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the preparation method of the ethyl 4-bromobutyrate comprises the following steps: primary bromination, secondary bromination, primary esterification, secondary esterification, and purification.
The primary bromination method is that gamma-butyrolactone is pumped into a feeding buffer tank, and is continuously fed into a primary micro-reaction module of a micro-channel reactor at a feeding rate of 0.009-0.01kg/s after being metered; simultaneously, a valve of a hydrogen bromide source is opened, and hydrogen bromide is continuously fed into a primary micro-reaction module of the micro-channel reactor after being metered; the temperature of the first-stage micro-reaction module (namely the first-stage bromination temperature) is controlled to be 40-45 ℃, the retention time of materials in the first-stage micro-reaction module (namely the first-stage bromination time) is controlled to be 480-600s, and the materials are discharged to obtain the first-stage bromide.
In the primary bromination, the feeding mole ratio of gamma-butyrolactone to hydrogen bromide in unit time is 1:1.03-1.08.
The first-stage micro-reaction module is filled with a reaction catalyst, and the filling amount of the reaction catalyst is 1.2-1.5% of the total weight of gamma-butyrolactone fed into the first-stage micro-reaction module in each hour.
The reaction catalyst is prepared by the following steps: pretreatment, primary treatment and secondary treatment.
The pretreatment method comprises the steps of uniformly mixing an ethanol solution with the volume concentration of 80-85%, gamma-alumina and mesoporous activated carbon, regulating the pH to 4-4.5 by adopting acetic acid, then putting into a ball mill, controlling the ball-material ratio to be 6-8:1, controlling the ball-milling rotation speed to be 150-200rpm, performing ball milling for 5-10min, simultaneously spraying a silane coupling agent KH-792 and a silane coupling agent KH-560, and continuously performing ball milling for 30-40min to obtain a ball-milled product; washing the ball-milled material by deionized water, and drying to obtain the pretreatment material.
In the pretreatment, the weight ratio of the ethanol solution to the gamma-alumina to the mesoporous activated carbon to the silane coupling agent KH-792 to the silane coupling agent KH-560 is 20-30:10-15:8-10:0.4-0.5:1-1.3.
The primary treatment method comprises the steps of putting a pretreatment object into primary treatment liquid with the volume of 18-20 times, stirring and heating to 40-50 ℃, preserving heat and stirring for 12-16 hours, and separating out solid objects; transferring the solid into a vacuum incubator, and drying at 70-80deg.C under vacuum degree of 0.08-0.09MPa for 6-8 hr to obtain primary treated product.
In the primary treatment, the primary treatment liquid is Na in which glutamic acid and leucine are dissolved 2 HPO 4 And NaH 2 PO 4 A buffer solution; the Na is 2 HPO 4 And NaH 2 PO 4 The pH value of the buffer solution is 7;
in the primary treatment liquid, the mass percentage content of glutamic acid is 0.6-0.8%, and the mass percentage content of leucine is 2-2.3%.
The secondary treatment method comprises the steps of putting the primary treatment object into anhydrous methanol with the volume of 5-6 times, uniformly dispersing, stirring and heating to 50-60 ℃ in a nitrogen atmosphere, and dripping salicylaldehyde with stirring at the dripping rate of 0.2-0.3 mL/min; after the salicylaldehyde is added dropwise, continuing to keep the temperature and stir for 60-90min; stirring and heating to 70-75 ℃, and stirring and dripping secondary treatment liquid at a dripping rate of 0.6-0.8 mL/min; after the secondary treatment is completed, continuing to keep the temperature and stir for 2-3 hours, separating out solid matters, drying in vacuum, and granulating to obtain the reaction catalyst.
In the secondary treatment, the secondary treatment liquid is anhydrous methanol in which copper chloride and praseodymium chloride are dispersed; in the secondary treatment liquid, the mass percentage content of copper chloride is 12-13%, and the mass percentage content of praseodymium chloride is 2.5-3%;
the mass ratio of the primary treatment substance to the salicylaldehyde to the secondary treatment liquid is 10-15:2-2.5:18-20.
The secondary bromination method is that primary bromide is continuously fed into a secondary micro-reaction module of a micro-channel reactor; the temperature of the secondary micro-reaction module (namely, the secondary bromination temperature) is controlled to be 30-35 ℃, the retention time of the materials in the secondary micro-reaction module (namely, the secondary bromination time) is controlled to be 240-300s, and the secondary bromide is obtained after discharging.
In the secondary bromination, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the secondary micro-reaction module, and the filling amount of the reaction catalyst is 1-1.2% of the total weight of gamma-butyrolactone fed into the primary micro-reaction module in each hour.
The primary esterification method is that secondary bromide is continuously fed into a tertiary micro-reaction module of a micro-channel reactor; simultaneously, continuously feeding absolute ethyl alcohol into a three-stage micro-reaction module of the micro-channel reactor by adopting a peristaltic pump; the temperature of the three-stage micro-reaction module (namely, the primary esterification temperature) is controlled to be 40-45 ℃, the retention time of the materials in the three-stage micro-reaction module (namely, the primary esterification time) is controlled to be 480-600s, and the materials are discharged to obtain the primary esterified material.
In the primary esterification, the feeding mole ratio of absolute ethyl alcohol to gamma-butyrolactone in the primary bromination in unit time is 1.02-1.05:1.
In the first-stage esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the first-stage bromination) is filled in the third-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.8-1.1% of the total weight of the absolute ethyl alcohol fed into the third-stage micro-reaction module in each hour.
The secondary esterification method is that the primary esterified substance is continuously fed into a four-stage micro-reaction module of a micro-channel reactor; controlling the temperature of the four-stage micro-reaction module (namely, the secondary esterification temperature) to be 35-40 ℃, keeping the residence time of the materials in the four-stage micro-reaction module (namely, the secondary esterification time) to be 300-360s, and discharging to obtain a secondary esterified substance; and (3) introducing the secondary esterified substance into a temporary storage tank for subsequent purification treatment.
In the secondary esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the four-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.6-0.8% of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
The purification method comprises the steps of adding the secondary esterified substance into deionized water with the volume of 1.2-1.5 times, stirring for 1-2 hours, standing for layering, and collecting a lower organic layer; then, adjusting the pH value of the organic layer to be neutral by adopting saturated sodium bicarbonate solution, standing for layering, and collecting a lower organic layer; adding the organic layer into deionized water with the volume of 1-1.2 times, stirring for 40-60min, standing for layering, and collecting the lower organic layer; extracting the organic layer with an equal volume of ethyl acetate for 2 times, and combining the extracted organic phases; the extracted organic phase is decompressed and rectified to prepare the ethyl 4-bromobutyrate.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of the ethyl 4-bromobutyrate adopts gamma-butyrolactone and hydrogen bromide gas as starting materials, and carries out primary bromination and secondary bromination in the presence of a reaction catalyst to prepare secondary bromide; then, adopting secondary bromide and absolute ethyl alcohol as raw materials, and carrying out primary esterification and secondary esterification in the presence of a reaction catalyst to prepare a secondary esterified product; purifying the second-level esterified substance to obtain ethyl 4-bromobutyrate; meanwhile, in the preparation of the reaction catalyst, a silane coupling agent KH-792 and a silane coupling agent KH-560 are adopted to treat gamma-alumina and mesoporous activated carbon in an acidic ethanol solution environment to prepare a pretreatment; in the primary treatment, a primary treatment liquid containing glutamic acid and leucine is adopted to treat a pretreatment object, and amino acid is grafted to the surface of the pretreatment object to prepare a primary treatment object; in the secondary treatment, salicylaldehyde is firstly adopted to treat the primary treatment object grafted with amino acid, after the salicylaldehyde is matched with the amino acid, the salicylaldehyde and metal active ions contained in the secondary treatment liquid are continuously formed into a complex, so that the effective catalysis of a reaction catalyst on the preparation process of the ethyl 4-bromobutyrate is realized, and the efficient and stable production of the ethyl 4-bromobutyrate is realized under the condition of large-scale continuous production; meanwhile, the problems that catalyst components (such as p-toluenesulfonic acid, red phosphorus and the like) in the existing preparation of the ethyl 4-bromobutyrate are not easy to separate, the production safety is low, the production amount of reaction wastes is large, and the reaction effect and the product quality are unstable are effectively avoided; further, good long-term catalytic performance and long-term storage stability of the reaction catalyst are effectively realized.
(2) The preparation method of the ethyl 4-bromobutyrate can effectively avoid the problems of difficult separation of catalyst components (such as p-toluenesulfonic acid, red phosphorus and the like), low production safety, large production amount of reaction waste, unstable reaction effect and product quality in the existing preparation of the ethyl 4-bromobutyrate; the reaction catalyst can realize the optimal reaction catalysis performance under the conditions of lower reaction temperature and shorter contact time in large-scale continuous production.
(3) According to the preparation method of the ethyl 4-bromobutyrate, the purity of the prepared ethyl 4-bromobutyrate is 99.2-99.5wt% and the yield is 98.8-99.1% (calculated by gamma-butyrolactone).
(4) In the preparation method of the ethyl 4-bromobutyrate, the reaction catalyst is adopted to continuously prepare the ethyl 4-bromobutyrate for 100 days, and the purity of the prepared ethyl 4-bromobutyrate is 99.0-99.4wt percent, and the yield is 98.0-98.6 percent (calculated by gamma-butyrolactone).
(5) In the preparation method of the ethyl 4-bromobutyrate, a reaction catalyst is adopted to be kept stand and stored for 180 days in an environment with the temperature of 40 ℃ and the relative humidity of 70 percent for continuous preparation of the ethyl 4-bromobutyrate, and the purity of the prepared ethyl 4-bromobutyrate is 99.5 weight percent and the yield is 99.0 percent (calculated by gamma-butyrolactone).
Detailed Description
Specific embodiments of the present invention will now be described in order to provide a clearer understanding of the technical features, objects and effects of the present invention.
Example 1
A preparation method of 4-bromoethyl butyrate comprises the following specific steps:
1. primary bromination
Pumping the gamma-butyrolactone into a feeding buffer tank, and continuously feeding the gamma-butyrolactone into a primary micro-reaction module of a micro-channel reactor at a feeding rate of 0.009kg/s after metering; simultaneously, a valve of a hydrogen bromide source is opened, and hydrogen bromide is continuously fed into a primary micro-reaction module of the micro-channel reactor after being metered; the temperature of the first-stage micro-reaction module (namely the first-stage bromination temperature) is controlled to be 40 ℃, the retention time of materials in the first-stage micro-reaction module (namely the first-stage bromination time) is controlled to be 480s, and the first-stage bromide is obtained after discharging.
In the primary bromination, the feeding mole ratio of gamma-butyrolactone to hydrogen bromide in unit time is 1:1.03.
The first-stage micro-reaction module is filled with a reaction catalyst, and the filling amount of the reaction catalyst is 1.2 percent of the total weight of gamma-butyrolactone fed into the first-stage micro-reaction module in each hour.
The preparation method of the reaction catalyst comprises the following steps:
1) Pretreatment of
Uniformly mixing an ethanol solution with the volume concentration of 80%, gamma-alumina and mesoporous activated carbon, regulating the pH to 4 by adopting acetic acid, then putting into a ball mill, controlling the ball-material ratio to be 6:1, ball milling at the speed of 150rpm for 5min, spraying a silane coupling agent KH-792 and a silane coupling agent KH-560 at the same time, and continuing ball milling for 30min to obtain a ball-milled product; washing the ball-milled material by deionized water, and drying to obtain the pretreatment material.
Wherein the weight ratio of the ethanol solution, the gamma-alumina, the mesoporous activated carbon, the silane coupling agent KH-792 and the silane coupling agent KH-560 is 20:10:8:0.4:1.
2) One-time treatment
Adding the pretreated substance into the primary treatment liquid with the volume of 18 times, stirring and heating to 40 ℃, preserving heat and stirring for 12 hours, and separating out solid substances; transferring the solid into a vacuum incubator, and drying at 70deg.C for 6h under the condition of vacuum degree of 0.08MPa to obtain the primary treated product.
Wherein the primary treatment liquid is Na with glutamic acid and leucine dissolved therein 2 HPO 4 And NaH 2 PO 4 A buffer solution; the Na is 2 HPO 4 And NaH 2 PO 4 The pH of the buffer solution was 7.
In the primary treatment liquid, the mass percentage content of glutamic acid is 0.6 percent, and the mass percentage content of leucine is 2 percent.
3) Secondary treatment
Adding the primary treated matter into anhydrous methanol with the volume of 5 times, uniformly dispersing, stirring and heating to 50 ℃ in a nitrogen atmosphere environment, and stirring and dripping salicylaldehyde at the dripping rate of 0.2 mL/min; after the salicylaldehyde is added dropwise, continuing to keep the temperature and stir for 60min; stirring and heating to 70 ℃, and stirring and dripping the secondary treatment liquid at the dripping rate of 0.6 mL/min; after the secondary treatment is completed, the mixture is continuously stirred for 2 hours under heat preservation, solid matters are separated out, and the mixture is dried in vacuum and granulated to prepare the reaction catalyst.
Wherein the secondary treatment liquid is anhydrous methanol in which copper chloride and praseodymium chloride are dispersed; in the secondary treatment liquid, the mass percentage content of copper chloride is 12%, and the mass percentage content of praseodymium chloride is 2.5%.
The mass ratio of the primary treatment substance to the salicylaldehyde to the secondary treatment liquid is 10:2:18.
2. Secondary bromination
The primary bromide is continuously fed into a secondary micro-reaction module of the micro-channel reactor; the temperature of the secondary micro-reaction module (namely, the secondary bromination temperature) is controlled to be 30 ℃, the retention time of the materials in the secondary micro-reaction module (namely, the secondary bromination time) is controlled to be 240s, and the secondary bromide is obtained after discharging.
In the secondary bromination, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the secondary micro-reaction module, and the filling amount of the reaction catalyst is 1% of the total weight of gamma-butyrolactone fed into the primary micro-reaction module in each hour.
3. First-stage esterification
The secondary bromide is continuously fed into a three-stage micro-reaction module of the micro-channel reactor; simultaneously, continuously feeding absolute ethyl alcohol into a three-stage micro-reaction module of the micro-channel reactor by adopting a peristaltic pump; the temperature of the three-stage micro-reaction module (namely, the primary esterification temperature) is controlled to be 40 ℃, the retention time of the materials in the three-stage micro-reaction module (namely, the primary esterification time) is controlled to be 480s, and the primary esterified material is obtained after discharging.
In the primary esterification, the feeding mole ratio of absolute ethyl alcohol to gamma-butyrolactone in the primary bromination in unit time is 1.02:1.
In the primary esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the three-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.8 percent of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
4. Second-order esterification
Continuously feeding the first-level esterified substance into a four-level micro-reaction module of the micro-channel reactor; controlling the temperature of the four-stage micro-reaction module (namely, the second-stage esterification temperature) to be 35 ℃, controlling the retention time of materials in the four-stage micro-reaction module (namely, the second-stage esterification time) to be 300s, and discharging to obtain a second-stage esterified substance; and (3) introducing the secondary esterified substance into a temporary storage tank for subsequent purification treatment.
In the second-stage esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the first-stage bromination) is filled in the four-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.6 percent of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
5. Purification
Adding the second-stage esterified substance into deionized water with the volume being 1.2 times that of the second-stage esterified substance, stirring for 1h, standing for layering, and collecting a lower organic layer; then, adjusting the pH value of the organic layer to be neutral by adopting saturated sodium bicarbonate solution, standing for layering, and collecting a lower organic layer; adding the organic layer into deionized water with the volume being 1 time, stirring for 40 minutes, standing for layering, and collecting the lower organic layer; extracting the organic layer with an equal volume of ethyl acetate for 2 times, and combining the extracted organic phases; the extracted organic phase is decompressed and rectified to prepare the ethyl 4-bromobutyrate.
In this example, the secondary esterified product was produced continuously by the steps of primary bromination, secondary bromination, primary esterification and secondary esterification every 1 hour, and after purification of the secondary esterified product, 73.0379kg of ethyl 4-bromobutyrate was produced, with a purity of 99.4wt% and a yield of 98.9% (based on γ -butyrolactone).
Example 2
A preparation method of 4-bromoethyl butyrate comprises the following specific steps:
1. primary bromination
Pumping the gamma-butyrolactone into a feeding buffer tank, and continuously feeding the gamma-butyrolactone into a primary micro-reaction module of a micro-channel reactor at a feeding rate of 0.0095kg/s after metering; simultaneously, a valve of a hydrogen bromide source is opened, and hydrogen bromide is continuously fed into a primary micro-reaction module of the micro-channel reactor after being metered; the temperature of the first-stage micro-reaction module (namely the first-stage bromination temperature) is controlled to be 42 ℃, the retention time of materials in the first-stage micro-reaction module (namely the first-stage bromination time) is controlled to be 540s, and the first-stage bromide is obtained after discharging.
In the primary bromination, the feeding mole ratio of gamma-butyrolactone to hydrogen bromide in unit time is 1:1.05.
The first-stage micro-reaction module is filled with a reaction catalyst, and the filling amount of the reaction catalyst is 1.3 percent of the total weight of gamma-butyrolactone fed into the first-stage micro-reaction module in each hour.
The preparation method of the reaction catalyst comprises the following steps:
1) Pretreatment of
Uniformly mixing an ethanol solution with the volume concentration of 83%, gamma-alumina and mesoporous activated carbon, regulating the pH to 4.2 by adopting acetic acid, then putting into a ball mill, controlling the ball-material ratio to be 7:1, and performing ball milling at the speed of 180rpm for 8min, spraying a silane coupling agent KH-792 and a silane coupling agent KH-560 at the same time, and continuing ball milling for 35min to obtain a ball-milled product; washing the ball-milled material by deionized water, and drying to obtain the pretreatment material.
Wherein the weight ratio of the ethanol solution, the gamma-alumina, the mesoporous activated carbon, the silane coupling agent KH-792 and the silane coupling agent KH-560 is 25:12:9:0.45:1.1.
2) One-time treatment
Adding the pretreated substance into primary treatment liquid with the volume of 19 times, stirring and heating to 45 ℃, preserving heat and stirring for 14 hours, and separating out solid substances; transferring the solid into a vacuum incubator, and drying at 75 ℃ for 7 hours under the condition of the vacuum degree of 0.085MPa to obtain the primary treated product.
Wherein the primary treatment liquid is Na with glutamic acid and leucine dissolved therein 2 HPO 4 And NaH 2 PO 4 A buffer solution; the Na is 2 HPO 4 And NaH 2 PO 4 The pH of the buffer solution was 7.
In the primary treatment liquid, the mass percentage content of glutamic acid is 0.7 percent, and the mass percentage content of leucine is 2.2 percent.
3) Secondary treatment
Adding the primary treated matter into anhydrous methanol with the volume of 5.5 times, uniformly dispersing, stirring and heating to 55 ℃ in a nitrogen atmosphere, and stirring and dripping salicylaldehyde at the dripping rate of 0.25 mL/min; after the salicylaldehyde is added dropwise, continuing to keep the temperature and stir for 75min; stirring and heating to 72 ℃, and stirring and dripping the secondary treatment liquid at the dripping rate of 0.7 mL/min; after the secondary treatment is completed, continuing to keep the temperature and stir for 2.5 hours, separating out solid matters, drying in vacuum, and granulating to obtain the reaction catalyst.
Wherein the secondary treatment liquid is anhydrous methanol in which copper chloride and praseodymium chloride are dispersed; in the secondary treatment liquid, the mass percentage content of copper chloride is 12.5%, and the mass percentage content of praseodymium chloride is 2.8%.
The mass ratio of the primary treatment substance to the salicylaldehyde to the secondary treatment liquid is 12:2.3:19.
2. Secondary bromination
The primary bromide is continuously fed into a secondary micro-reaction module of the micro-channel reactor; the temperature of the secondary micro-reaction module (namely, the secondary bromination temperature) is controlled to be 32 ℃, the retention time of the materials in the secondary micro-reaction module (namely, the secondary bromination time) is controlled to be 270s, and the secondary bromide is obtained after discharging.
In the secondary bromination, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the secondary micro-reaction module, and the filling amount of the reaction catalyst is 1.1 percent of the total weight of gamma-butyrolactone fed into the primary micro-reaction module in each hour.
3. First-stage esterification
The secondary bromide is continuously fed into a three-stage micro-reaction module of the micro-channel reactor; simultaneously, continuously feeding absolute ethyl alcohol into a three-stage micro-reaction module of the micro-channel reactor by adopting a peristaltic pump; the temperature of the three-stage micro-reaction module (namely, the first-stage esterification temperature) is controlled to be 42 ℃, the retention time of the materials in the three-stage micro-reaction module (namely, the first-stage esterification time) is controlled to be 540s, and the first-stage esterified material is obtained after discharging.
In the primary esterification, the feeding mole ratio of absolute ethyl alcohol to gamma-butyrolactone in the primary bromination in unit time is 1.03:1.
In the primary esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the three-stage micro-reaction module, and the filling amount of the reaction catalyst is 1% of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
4. Second-order esterification
Continuously feeding the first-level esterified substance into a four-level micro-reaction module of the micro-channel reactor; controlling the temperature of the four-stage micro-reaction module (namely, the second-stage esterification temperature) to be 38 ℃, controlling the residence time of the material in the four-stage micro-reaction module (namely, the second-stage esterification time) to be 330s, and discharging to obtain a second-stage esterified substance; and (3) introducing the secondary esterified substance into a temporary storage tank for subsequent purification treatment.
In the second-stage esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the first-stage bromination) is filled in the four-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.7 percent of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
5. Purification
Adding the second-stage esterified substance into deionized water with the volume being 1.3 times that of the second-stage esterified substance, stirring for 1.5 hours, standing for layering, and collecting a lower organic layer; then, adjusting the pH value of the organic layer to be neutral by adopting saturated sodium bicarbonate solution, standing for layering, and collecting a lower organic layer; adding the organic layer into deionized water with the volume being 1.1 times of that of the organic layer, stirring for 50min, standing for layering, and collecting the lower organic layer; extracting the organic layer with an equal volume of ethyl acetate for 2 times, and combining the extracted organic phases; the extracted organic phase is decompressed and rectified to prepare the ethyl 4-bromobutyrate.
In this example, the secondary esterified product was produced continuously by the steps of primary bromination, secondary bromination, primary esterification and secondary esterification every 1 hour, and after purification of the secondary esterified product, 77.1738kg of ethyl 4-bromobutyrate was produced with a purity of 99.5wt% and a yield of 99.1% (based on γ -butyrolactone).
Example 3
A preparation method of 4-bromoethyl butyrate comprises the following specific steps:
1. primary bromination
Pumping the gamma-butyrolactone into a feeding buffer tank, and continuously feeding the gamma-butyrolactone into a primary micro-reaction module of a micro-channel reactor at a feeding rate of 0.01kg/s after metering; simultaneously, a valve of a hydrogen bromide source is opened, and hydrogen bromide is continuously fed into a primary micro-reaction module of the micro-channel reactor after being metered; the temperature of the first-stage micro-reaction module (namely, the first-stage bromination temperature) is controlled to be 45 ℃, the retention time of materials in the first-stage micro-reaction module (namely, the first-stage bromination time) is 600s, and the first-stage bromide is obtained after discharging.
In the primary bromination, the feeding mole ratio of gamma-butyrolactone to hydrogen bromide in unit time is 1:1.08.
The first-stage micro-reaction module is filled with a reaction catalyst, and the filling amount of the reaction catalyst is 1.5 percent of the total weight of gamma-butyrolactone fed into the first-stage micro-reaction module in each hour.
The preparation method of the reaction catalyst comprises the following steps:
1) Pretreatment of
Uniformly mixing an ethanol solution with the volume concentration of 85%, gamma-alumina and mesoporous activated carbon, regulating the pH to 4.5 by adopting acetic acid, then putting into a ball mill, controlling the ball-material ratio to be 8:1, and performing ball milling at the ball milling rotating speed of 200rpm for 10min, spraying a silane coupling agent KH-792 and a silane coupling agent KH-560 at the same time, and continuing ball milling for 40min to obtain a ball-milled product; washing the ball-milled material by deionized water, and drying to obtain the pretreatment material.
Wherein the weight ratio of the ethanol solution, the gamma-alumina, the mesoporous activated carbon, the silane coupling agent KH-792 and the silane coupling agent KH-560 is 30:15:10:0.5:1.3.
2) One-time treatment
Adding the pretreated substance into primary treatment liquid with the volume of 20 times, stirring and heating to 50 ℃, preserving heat and stirring for 16 hours, and separating out solid substances; transferring the solid into a vacuum incubator, and drying at 80 ℃ for 8 hours under the condition that the vacuum degree is 0.09MPa to obtain the primary treated product.
Wherein the primary treatment liquid is Na with glutamic acid and leucine dissolved therein 2 HPO 4 And NaH 2 PO 4 A buffer solution; the Na is 2 HPO 4 And NaH 2 PO 4 The pH of the buffer solution was 7.
In the primary treatment liquid, the mass percentage content of glutamic acid is 0.8 percent, and the mass percentage content of leucine is 2.3 percent.
3) Secondary treatment
Adding the primary treated matter into anhydrous methanol with the volume of 6 times, uniformly dispersing, stirring and heating to 60 ℃ in a nitrogen atmosphere environment, and stirring and dripping salicylaldehyde at the dripping rate of 0.3 mL/min; after the salicylaldehyde is added dropwise, continuing to keep the temperature and stir for 90min; stirring and heating to 75 ℃, and stirring and dripping the secondary treatment liquid at the dripping rate of 0.8 mL/min; after the secondary treatment is completed, continuing to keep the temperature and stir for 3 hours, separating out solid matters, drying in vacuum, and granulating to obtain the reaction catalyst.
Wherein the secondary treatment liquid is anhydrous methanol in which copper chloride and praseodymium chloride are dispersed; in the secondary treatment liquid, the mass percentage content of copper chloride is 13%, and the mass percentage content of praseodymium chloride is 3%.
The mass ratio of the primary treatment substance to the salicylaldehyde to the secondary treatment liquid is 15:2.5:20.
2. Secondary bromination
The primary bromide is continuously fed into a secondary micro-reaction module of the micro-channel reactor; controlling the temperature of the secondary micro-reaction module (namely the secondary bromination temperature) to be 35 ℃, controlling the residence time of the materials in the secondary micro-reaction module (namely the secondary bromination time) to be 300s, and discharging to obtain the secondary bromide.
In the secondary bromination, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the secondary micro-reaction module, and the filling amount of the reaction catalyst is 1.2 percent of the total weight of gamma-butyrolactone fed into the primary micro-reaction module in each hour.
3. First-stage esterification
The secondary bromide is continuously fed into a three-stage micro-reaction module of the micro-channel reactor; simultaneously, continuously feeding absolute ethyl alcohol into a three-stage micro-reaction module of the micro-channel reactor by adopting a peristaltic pump; the temperature of the three-stage micro-reaction module (namely, the first-stage esterification temperature) is controlled to be 45 ℃, the retention time of the materials in the three-stage micro-reaction module (namely, the first-stage esterification time) is controlled to be 600s, and the first-stage esterified material is obtained after discharging.
In the primary esterification, the feeding mole ratio of absolute ethyl alcohol to gamma-butyrolactone in the primary bromination in unit time is 1.05:1.
In the primary esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the primary bromination) is filled in the three-stage micro-reaction module, and the filling amount of the reaction catalyst is 1.1 percent of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
4. Second-order esterification
Continuously feeding the first-level esterified substance into a four-level micro-reaction module of the micro-channel reactor; controlling the temperature of the four-stage micro-reaction module (namely, the second-stage esterification temperature) to be 40 ℃, keeping the retention time of the materials in the four-stage micro-reaction module (namely, the second-stage esterification time) to be 360s, and discharging to obtain a second-stage esterified substance; and (3) introducing the secondary esterified substance into a temporary storage tank for subsequent purification treatment.
In the second-stage esterification, a reaction catalyst (the adopted reaction catalyst is the same as that in the first-stage bromination) is filled in the four-stage micro-reaction module, and the filling amount of the reaction catalyst is 0.8 percent of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
5. Purification
Adding the second-stage esterified substance into deionized water with the volume being 1.5 times of that of the second-stage esterified substance, stirring for 2 hours, standing for layering, and collecting a lower organic layer; then, adjusting the pH value of the organic layer to be neutral by adopting saturated sodium bicarbonate solution, standing for layering, and collecting a lower organic layer; adding the organic layer into deionized water with the volume being 1.2 times of that of the organic layer, stirring for 60 minutes, standing for layering, and collecting the lower organic layer; extracting the organic layer with an equal volume of ethyl acetate for 2 times, and combining the extracted organic phases; the extracted organic phase is decompressed and rectified to prepare the ethyl 4-bromobutyrate.
In this example, the secondary esterified product was produced continuously by the steps of primary bromination, secondary bromination, primary esterification and secondary esterification every 1 hour, and after purification of the secondary esterified product, 81.2346kg of ethyl 4-bromobutyrate was produced with a purity of 99.2wt% and a yield of 98.8% (based on gamma-butyrolactone).
Comparative example 1
The technical scheme of the embodiment 2 is adopted, and the difference is that: 1) Omitting the steps of secondary bromination and secondary esterification, and directly purifying after the primary bromination and the primary esterification are sequentially carried out; 2) In the preparation of the reaction catalyst, the pretreatment step is omitted, and after the gamma-alumina and the mesoporous activated carbon are uniformly mixed, the mixture is used as a pretreatment substance for subsequent primary treatment.
In comparative example 1, the primary esterified product was continuously produced by the primary bromination and the primary esterification steps every 1 hour, and 73.9309kg of ethyl 4-bromobutyrate was obtained after purification of the primary esterified product, with a purity of 98.1wt% and a yield of 93.6% (based on gamma-butyrolactone).
It can be seen that in the technical scheme of comparative example 1, the steps of secondary bromination and secondary esterification are omitted, and the treatment of the silane coupling agent KH-792 and the silane coupling agent KH-560 is omitted in the pretreatment of the preparation of the reaction catalyst, so that the yield of the prepared ethyl 4-bromobutyrate is obviously reduced, and the purity index is also slightly reduced. After analysis, the pretreatment operation is omitted, the effective surface modification of the carrier component of the reaction catalyst cannot be carried out, so that the amino acid ligand cannot be stably grafted to the surface of the carrier in the subsequent primary treatment process, and further, the amino acid cannot be effectively matched with salicylaldehyde and form a complex with metal active ions in the subsequent secondary treatment process; the reaction catalyst cannot meet the rapid and efficient reaction environment in the microchannel reactor, and cannot effectively catalyze the primary bromination and primary esterification processes, so that the prepared ethyl 4-bromobutyrate is obviously reduced.
Comparative example 2
The technical scheme of the embodiment 2 is adopted, and the difference is that: 1) In the preparation of the reaction catalyst, glutamic acid is omitted from primary treatment liquid adopted in primary treatment; 2) In the secondary treatment, salicylaldehyde is omitted, and praseodymium chloride is contained in the secondary treatment liquid.
In comparative example 2, the secondary esterified product was produced continuously by the steps of primary bromination, secondary bromination, primary esterification and secondary esterification every 1 hour, and 73.1719kg of ethyl 4-bromobutyrate was obtained after purification of the secondary esterified product, the purity was 98.8% by weight, and the yield was 93.3% (based on gamma-butyrolactone).
It can be seen that in the technical scheme of comparative example 2, in the preparation of the reaction catalyst, the primary treatment liquid omits glutamic acid; after the salicylaldehyde is omitted in secondary treatment and praseodymium chloride is contained in secondary treatment liquid, the yield and purity index of the prepared ethyl 4-bromobutyrate are reduced to a certain extent; after glutamic acid is omitted in the primary treatment through analysis, only leucine is grafted on the surface of a carrier, and then the leucine is directly combined with copper ions in the secondary treatment process to prepare a reaction catalyst; the stability and the catalytic performance of the single amino acid in the reaction catalyst after being combined with copper ions are limited, multicomponent synergistic catalysis cannot be realized, and when the reaction catalyst is adopted for preparing the ethyl 4-bromobutyrate, the yield and the purity index of the prepared ethyl 4-bromobutyrate are reduced to a certain extent.
Further, the preparation of ethyl 4-bromobutyrate was continuously carried out for 100 days by using the methods for preparing ethyl 4-bromobutyrate of examples 1 to 3 and comparative examples 1 to 2 without changing the reaction catalyst, and the weight, purity and yield of ethyl 4-bromobutyrate prepared in examples 1 to 3 and comparative examples 1 to 2 were measured at 100 days, respectively. The specific results are shown in the following table:
it can be seen that the preparation method of the ethyl 4-bromobutyrate of the examples 1-3 is adopted to continuously prepare the ethyl 4-bromobutyrate, so that the high-efficiency and stable production of the ethyl 4-bromobutyrate can be realized for a long time; the preparation of the ethyl 4-bromobutyrate is continuously carried out for 100 days, and the better catalytic performance can be maintained, so that the yield and purity index of the prepared ethyl 4-bromobutyrate are not obviously reduced.
Further, the reaction catalysts prepared in example 2 and comparative examples 1 to 2 were placed in an environment having a temperature of 40℃and a relative humidity of 70%, and after standing and storage for 180 days, the preparation of ethyl 4-bromobutyrate was continuously performed by using the ethyl 4-bromobutyrate preparation method of example 2, and the weight, purity and yield of ethyl 4-bromobutyrate prepared in example 2 and comparative examples 1 to 2 were measured on the 2 nd day of continuous preparation, respectively. The specific results are shown in the following table:
it can be seen that the reaction catalyst adopted in the preparation method of the ethyl 4-bromobutyrate has good long-term storage stability, and can still realize good catalytic performance after standing and storing for 180 days in an environment with the temperature of 40 ℃ and the relative humidity of 70%.
In summary, the preparation method of the ethyl 4-bromobutyrate adopts gamma-butyrolactone and hydrogen bromide gas as starting materials, and carries out primary bromination and secondary bromination in the presence of a reaction catalyst to prepare secondary bromide; then, adopting secondary bromide and absolute ethyl alcohol as raw materials, and carrying out primary esterification and secondary esterification in the presence of a reaction catalyst to prepare a secondary esterified product; purifying the second-level esterified substance to obtain ethyl 4-bromobutyrate; meanwhile, in the preparation of the reaction catalyst, a silane coupling agent KH-792 and a silane coupling agent KH-560 are adopted to treat gamma-alumina and mesoporous activated carbon in an acidic ethanol solution environment to prepare a pretreatment; in the primary treatment, a primary treatment liquid containing glutamic acid and leucine is adopted to treat a pretreatment object, and amino acid is grafted to the surface of the pretreatment object to prepare a primary treatment object; in the secondary treatment, salicylaldehyde is firstly adopted to treat the primary treatment object grafted with amino acid, after the salicylaldehyde is matched with the amino acid, the salicylaldehyde and metal active ions contained in the secondary treatment liquid are continuously formed into a complex, so that the effective catalysis of a reaction catalyst on the preparation process of the ethyl 4-bromobutyrate is realized, and the efficient and stable production of the ethyl 4-bromobutyrate is realized under the condition of large-scale continuous production; meanwhile, the problems that catalyst components (such as p-toluenesulfonic acid, red phosphorus and the like) in the existing preparation of the ethyl 4-bromobutyrate are not easy to separate, the production safety is low, the production amount of reaction wastes is large, and the reaction effect and the product quality are unstable are effectively avoided; further, good long-term catalytic performance and long-term storage stability of the reaction catalyst are effectively realized.
The percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method of ethyl 4-bromobutyrate, which is characterized by comprising the following steps: primary bromination, secondary bromination, primary esterification, secondary esterification, and purification;
the primary bromination method comprises the steps of continuously feeding gamma-butyrolactone and hydrogen bromide gas into a primary micro-reaction module of a micro-channel reactor, carrying out primary bromination, and discharging to obtain primary bromide;
the primary micro-reaction module is filled with a reaction catalyst, and the reaction catalyst is prepared by the following steps: pretreatment, primary treatment and secondary treatment;
the pretreatment method comprises the steps of uniformly mixing gamma-alumina and mesoporous activated carbon, and performing ball milling treatment in an acidic ethanol solution by adopting a silane coupling agent KH-792 and a silane coupling agent KH-560 to obtain a pretreatment product;
the primary treatment method comprises the steps of adding a pretreatment object into primary treatment liquid, stirring and heating to 40-50 ℃, preserving heat and stirring for 12-16 hours, separating out solid objects, and vacuum drying to obtain the primary treatment object;
the primary treatment liquid is Na dissolved with glutamic acid and leucine 2 HPO 4 And NaH 2 PO 4 A buffer solution;
the secondary treatment method comprises the steps of putting the primary treated matter into absolute methanol, uniformly dispersing, heating to 50-60 ℃ in a nitrogen atmosphere environment, stirring and dripping salicylaldehyde; after the salicylaldehyde is added dropwise, continuing to keep the temperature and stir; stirring and heating to 70-75 ℃, stirring and dripping secondary treatment liquid; after the secondary treatment is completed, continuing to keep the temperature and stir, separating out solid matters, drying in vacuum, and granulating to obtain a reaction catalyst;
the secondary treatment liquid is anhydrous methanol in which copper chloride and praseodymium chloride are dispersed;
the secondary bromination method comprises the steps of continuously feeding primary bromide into a secondary micro-reaction module of a micro-channel reactor, performing secondary bromination, and discharging to obtain secondary bromide;
the secondary micro-reaction module is filled with a reaction catalyst which is the same as that in the primary bromination;
the primary esterification method comprises the steps of continuously feeding secondary bromide and absolute ethyl alcohol into a three-stage micro-reaction module of a micro-channel reactor, carrying out primary esterification, and discharging to obtain a primary esterified substance;
the three-stage micro-reaction module is internally filled with a reaction catalyst which is the same as that in the primary bromination;
the secondary esterification method comprises the steps of continuously feeding a primary esterified substance into a four-stage micro-reaction module of a micro-channel reactor, carrying out secondary esterification, and discharging to obtain a secondary esterified substance;
the four-stage micro-reaction module is internally filled with a reaction catalyst which is the same as that in the primary bromination;
the secondary esterified substance is purified to prepare the ethyl 4-bromobutyrate.
2. The method for preparing ethyl 4-bromobutyrate according to claim 1, wherein in the primary bromination, the temperature of the primary micro-reaction module is controlled to be 40-45 ℃, and the residence time of materials in the primary micro-reaction module is 480-600s;
in the secondary bromination, the temperature of the secondary micro-reaction module is controlled to be 30-35 ℃, and the retention time of materials in the secondary micro-reaction module is 240-300s;
in the primary esterification, the temperature of the three-stage micro-reaction module is controlled to be 40-45 ℃, and the retention time of materials in the three-stage micro-reaction module is 480-600s;
in the secondary esterification, the temperature of the four-stage micro-reaction module is controlled to be 35-40 ℃, and the retention time of materials in the four-stage micro-reaction module is 300-360s.
3. The method for preparing ethyl 4-bromobutyrate according to claim 1, wherein the loading amount of the reaction catalyst in the first-stage micro-reaction module is 1.2-1.5% of the total weight of gamma-butyrolactone fed to the first-stage micro-reaction module per hour;
in the secondary micro-reaction module, the filling amount of the reaction catalyst is 1-1.2% of the total weight of gamma-butyrolactone fed into the primary micro-reaction module in each hour;
in the three-stage micro-reaction module, the loading amount of the reaction catalyst is 0.8-1.1% of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour;
in the four-stage micro-reaction module, the loading of the reaction catalyst is 0.6-0.8% of the total weight of the absolute ethyl alcohol fed into the three-stage micro-reaction module in each hour.
4. The method for preparing ethyl 4-bromobutyrate according to claim 1, wherein in the primary bromination, the feeding mole ratio of gamma-butyrolactone to hydrogen bromide in unit time is 1:1.03-1.08;
in the primary esterification, the feeding mole ratio of absolute ethyl alcohol to gamma-butyrolactone in the primary bromination in unit time is 1.02-1.05:1.
5. The method for producing ethyl 4-bromobutyrate according to claim 1, wherein in the pretreatment, the acidic ethanol solution is adjusted to pH 4 to 4.5 with acetic acid;
the volume concentration of the ethanol solution is 80-85%;
the weight ratio of the ethanol solution, the gamma-alumina, the mesoporous activated carbon, the silane coupling agent KH-792 and the silane coupling agent KH-560 is 20-30:10-15:8-10:0.4-0.5:1-1.3.
6. The method for producing ethyl 4-bromobutyrate according to claim 1, wherein in the primary treatment, the volume ratio of the pretreatment substance to the primary treatment liquid is 1:18-20;
in the primary treatment liquid, na 2 HPO 4 And NaH 2 PO 4 The pH value of the buffer solution is 7;
in the primary treatment liquid, the mass percentage content of glutamic acid is 0.6-0.8%, and the mass percentage content of leucine is 2-2.3%.
7. The method for preparing ethyl 4-bromobutyrate according to claim 1, wherein, in the secondary treatment, the dripping speed of salicylaldehyde is 0.2-0.3mL/min, and the heat preservation stirring time after the salicylaldehyde dripping is completed is 60-90min;
the dropping speed of the secondary treatment liquid is 0.6-0.8mL/min, and the heat preservation stirring time after the completion of the dropping of the secondary treatment liquid is 2-3h.
8. The method for producing ethyl 4-bromobutyrate according to claim 1, wherein in the secondary treatment, the volume ratio of the primary treated matter to the anhydrous methanol is 1:5-6;
in the secondary treatment liquid, the mass percentage content of copper chloride is 12-13%, and the mass percentage content of praseodymium chloride is 2.5-3%;
the mass ratio of the primary treatment substance to the salicylaldehyde to the secondary treatment liquid is 10-15:2-2.5:18-20.
9. The method for preparing ethyl 4-bromobutyrate according to claim 1, wherein the purification method is that the secondary esterified substance is put into deionized water, stirred, and kept stand for layering, and then the lower organic layer is collected; then, adjusting the pH value of the organic layer to be neutral by adopting saturated sodium bicarbonate solution, standing for layering, and collecting a lower organic layer; adding the organic layer into deionized water, stirring, standing for layering, and collecting the lower organic layer; extracting the organic layer with ethyl acetate to obtain and extract an organic phase; the extracted organic phase is decompressed and rectified to prepare the ethyl 4-bromobutyrate.
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Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003066562A2 (en) * | 2002-02-06 | 2003-08-14 | Atofina | Method for preparing $g(v)-bromoalkylcarboxylic compounds |
| CN1453263A (en) * | 2003-05-19 | 2003-11-05 | 武汉大学 | Synthesis of gamma-ethyl bromo-butyrate |
| CN101041666A (en) * | 2006-12-29 | 2007-09-26 | 上海师范大学 | Antibiosis rare earth ternary complexes and preparation method and application thereof |
| CN101781325A (en) * | 2010-01-25 | 2010-07-21 | 北京师范大学 | Gallium salicylaldehyde amino acid Schiff base quaternary coordination compound, preparation method and application thereof |
| CN102180893A (en) * | 2010-07-06 | 2011-09-14 | 新疆农业大学 | Preparation method for copper complex of glycine-salicylaldehyde Schiff base |
| CN103193701A (en) * | 2013-03-14 | 2013-07-10 | 淮海工学院 | Functional ligand and preparation method thereof |
| CN113634283A (en) * | 2021-08-02 | 2021-11-12 | 西安凯立新材料股份有限公司 | Copper-based composite catalyst for acetylene hydrochlorination and method |
| CN113831761A (en) * | 2021-11-03 | 2021-12-24 | 东华大学 | Amino acid modified nano particle, preparation method and application thereof, and anti-fouling ultrafiltration membrane |
| CN114736119A (en) * | 2022-05-09 | 2022-07-12 | 迈奇化学股份有限公司 | One-step preparation method of ethyl 4-bromobutyrate |
| CN116875839A (en) * | 2023-09-06 | 2023-10-13 | 山东伟盛铝业有限公司 | Aluminum lithium alloy profile and preparation method thereof |
| CN116969535A (en) * | 2023-09-21 | 2023-10-31 | 寿光环保科技有限公司 | Sewage treatment agent containing polyaluminium chloride and preparation method thereof |
| CN117105769A (en) * | 2023-10-24 | 2023-11-24 | 山东顺成化学有限公司 | Preparation method of ethyl 2-bromopropionate |
-
2024
- 2024-03-11 CN CN202410268764.2A patent/CN117865802A/en not_active Withdrawn
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003066562A2 (en) * | 2002-02-06 | 2003-08-14 | Atofina | Method for preparing $g(v)-bromoalkylcarboxylic compounds |
| CN1453263A (en) * | 2003-05-19 | 2003-11-05 | 武汉大学 | Synthesis of gamma-ethyl bromo-butyrate |
| CN101041666A (en) * | 2006-12-29 | 2007-09-26 | 上海师范大学 | Antibiosis rare earth ternary complexes and preparation method and application thereof |
| CN101781325A (en) * | 2010-01-25 | 2010-07-21 | 北京师范大学 | Gallium salicylaldehyde amino acid Schiff base quaternary coordination compound, preparation method and application thereof |
| CN102180893A (en) * | 2010-07-06 | 2011-09-14 | 新疆农业大学 | Preparation method for copper complex of glycine-salicylaldehyde Schiff base |
| CN103193701A (en) * | 2013-03-14 | 2013-07-10 | 淮海工学院 | Functional ligand and preparation method thereof |
| CN113634283A (en) * | 2021-08-02 | 2021-11-12 | 西安凯立新材料股份有限公司 | Copper-based composite catalyst for acetylene hydrochlorination and method |
| CN113831761A (en) * | 2021-11-03 | 2021-12-24 | 东华大学 | Amino acid modified nano particle, preparation method and application thereof, and anti-fouling ultrafiltration membrane |
| CN114736119A (en) * | 2022-05-09 | 2022-07-12 | 迈奇化学股份有限公司 | One-step preparation method of ethyl 4-bromobutyrate |
| CN116875839A (en) * | 2023-09-06 | 2023-10-13 | 山东伟盛铝业有限公司 | Aluminum lithium alloy profile and preparation method thereof |
| CN116969535A (en) * | 2023-09-21 | 2023-10-31 | 寿光环保科技有限公司 | Sewage treatment agent containing polyaluminium chloride and preparation method thereof |
| CN117105769A (en) * | 2023-10-24 | 2023-11-24 | 山东顺成化学有限公司 | Preparation method of ethyl 2-bromopropionate |
Non-Patent Citations (2)
| Title |
|---|
| 付潮, 滕汉兵, 邱国福, 梁淑彩, 胡先明: "γ-溴代丁酸乙酯的合成", 化学试剂, no. 05, 28 October 2004 (2004-10-28), pages 29 - 30 * |
| 郭永学主编: "《制药设备与车间设计》", 31 December 2019, 中国医药科技出版社, pages: 101 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117886664A (en) * | 2024-03-12 | 2024-04-16 | 寿光市诚信盐业有限公司 | Method for preparing bromobenzene from poly-substituted bromobenzene mixture |
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