Synthetic method of isopropyl acetoacetate

Abstract

The invention provides a synthesis method of isopropyl acetoacetate, and belongs to the technical field of synthesis of drug intermediates. Methyl acetoacetate and isopropanol are used as raw materials, reaction is completed under the catalytic action of concentrated sulfuric acid and a molecular sieve, isopropyl acetoacetate is obtained through rectification, the addition amount of the concentrated sulfuric acid is 1-5% of the mass of the methyl acetoacetate, and the addition amount of the molecular sieve is 3-10% of the mass of the methyl acetoacetate. According to the synthesis method, isopropyl acetoacetate can be efficiently synthesized, synthesis is simple, raw materials are cheap and stable, sources are wide, reaction safety is high, product purity is high, industrialization is facilitated, and continuous production of isopropyl acetoacetate is easy to achieve.

Description

Technical Field

[0001] The present application relates to a method for synthesizing isopropyl acetoacetate, and belongs to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002] Isopropyl acetoacetate, also known as isopropyl 3-oxobutyrate and isopropyl 3-ketobutyrate, is an important intermediate for medicine and pesticides. It is mainly used in the synthesis of antihypertensive drugs including azelnidipine and nimodipine, and can also be used in the synthesis of dichlorvos insecticides.

[0003]

[0004] In recent years, due to the increasing industrial requirements such as safety and environmental protection, as well as some market monopolies and capital operations, the supply of isopropyl acetoacetate is limited and the price is high, which poses a great challenge to the stable production of corresponding pharmaceutical and pesticide final products.

[0005] At present, the method for synthesizing isopropyl acetoacetate mainly includes the following:

[0006] 1. Prepared by Claisen condensation of isopropyl acetate

[0007] Isopropyl acetoacetate can be obtained by Claisen condensation of two molecules of isopropyl acetate. The reaction is as follows:

[0008]

[0009] The direct preparation of isopropyl acetoacetate by Claisen condensation generally requires a strong base (such as sodium) as a catalyst and high temperature conditions. The reaction is violent and the by-product hydrogen has great safety risks. In addition, when this method is used to directly condense isopropyl acetoacetate, side reactions are prone to occur under strong base and high temperature conditions, generating impurities such as acetone, isopropyl ether, and polymers.

[0010] 2. Prepared from isopropyl alcohol and diketene

[0011] "Synthesis of Isopropyl Acetoacetate" (Jia Beihuan et al., Journal of Hebei Normal University (Natural Science Edition), 1990, No. 1, pp. 101-103) Isopropyl acetoacetate is obtained by reacting diketene, isopropanol and concentrated sulfuric acid under reflux conditions, and the reaction is as follows:

[0012]

[0013] "Catalytic reaction of diketene and isopropanol" (Song Lixian et al., Chemical Reagents, 1995, No. 3, 169-170) uses phosphoric acid and triethylamine as reaction catalysts to achieve the esterification-ring-opening reaction of diketene and isopropanol to obtain isopropyl acetoacetate. Through the synthesis of this experimental route, the author found that the reaction would suddenly and violently release heat during the heating process, causing the experimental materials to rush, and the stability and safety of the reaction were insufficient.

[0014] In addition, diketene has poor stability and is relatively active. It requires transportation and storage conditions of 0 to 8°C, which has great restrictions on large-scale production. Under high temperature and alkaline conditions, diketene is prone to self-hydrolysis and condensation degradation:

[0015]

[0016] The use of diketene to synthesize isopropyl acetoacetate is troublesome in transportation and storage of materials. Diketene is a highly toxic chemical with strong tear-inducing and pungent irritation, which is inconvenient to use. In addition, the synthesis of isopropyl acetoacetate using diketene generally requires purification of the raw materials to achieve a good conversion rate. The raw materials have many side reactions and are greatly restricted in industrialization.

[0017] 3. Chloroacetone + CO + isopropanol reaction

[0018] "PdCl2 / Bu4NI: An efficient and ligand-free catalyst for the alkoxycarbonylation of organic chlorides" (Lei, Yizhu, et al, Journal of Molecular Catalysis A: Chemical, 2014, 392: 105-111) uses PdCl2 and tetrabutylammonium iodide as composite catalysts to achieve the alkoxycarbonylation reaction of chlorinated compounds, that is, chloroacetone is efficiently synthesized from CO and isopropanol under the catalysis of PdCl2 / Bu4NI. The reaction is as follows:

[0019]

[0020] The conversion rate of the reaction is 72.3%. Considering the high price of the chloroacetone reagent used in the reaction, the expensive catalyst, the excessive amount of alkali and other factors, the synthesis cost is high and the industrial application value is almost negligible.

[0021] 4. Reaction of methyl acetoacetate with isopropanol

[0022] "BF3-OEt2: An Efficient Catalyst for Transesterification of β-Ketoesters" mentions that using boron trifluoride-ether as a catalyst, methyl acetoacetate and isopropanol can be reacted under toluene reflux conditions to obtain isopropyl acetoacetate through ester exchange. The reaction is as follows:

[0023]

[0024] This scheme uses 0.15 equivalents of BF3-OEt2 to react for 5 hours, and the conversion rate can reach 87%. However, in the reproducible experiment, the applicant found that there was not a very complete conversion, and more acids and other components were generated in the system, which caused great corrosion to the equipment. Considering that BF3 and isopropanol can react to generate boric esters and HF, the equipment material requirements are high and the industrial significance is not great.

[0025] 5. Reaction of ethyl acetoacetate with isopropanol

[0026] PL159100B1 mentions a method for preparing acetoacetate of a higher secondary alcohol from acetoacetate of a lower primary alcohol by transesterification. In the example, ethyl acetoacetate and isopropanol are reacted for a long time and then distilled repeatedly to remove ethanol to obtain isopropyl acetoacetate. The reaction is as follows:

[0027]

[0028] The method does not describe the use of a catalyst, so the transesterification reaction time is long, up to 50 to 70 hours, and the long reaction time cannot guarantee the conversion rate of ethyl acetoacetate, and a relatively considerable conversion rate can only be achieved through multiple distillation separation methods. Obviously, this method is not suitable for industrial scale-up application due to its low efficiency and low conversion rate.

[0029] In summary, the existing methods for synthesizing isopropyl acetoacetate mainly have the following technical disadvantages: insufficient raw material stability, low safety, many side reactions, low conversion rate, difficulty in industrial conversion, expensive catalysts used in some processes, high cost and high technology, which also limit the industrial production of isopropyl acetoacetate. Summary of the invention

[0030] In view of this, the present application provides a method for synthesizing isopropyl acetoacetate, which can not only efficiently synthesize isopropyl acetoacetate, but also has a simple synthesis process, high reaction safety, high product purity, and cheap and stable raw materials.

[0031] Specifically, the present application is implemented through the following scheme:

[0032] A method for synthesizing isopropyl acetoacetate is characterized in that methyl acetoacetate and isopropyl alcohol are used as raw materials, react under the catalytic action of concentrated sulfuric acid and molecular sieves, and distill to obtain isopropyl acetoacetate, wherein the amount of concentrated sulfuric acid added is 1-5% of the mass of methyl acetoacetate, and the amount of molecular sieve added is 3-10% of the mass of methyl acetoacetate.

[0033] The reaction equation of the above process is as follows:

[0034]

[0035] Methyl acetoacetate is used as a raw material, reacted with isopropanol, reacted for a period of time under the catalytic action of concentrated sulfuric acid and molecular sieves, and then obtained by distillation method with high purity isopropyl acetoacetate, and the overall yield reaches about 80%.

[0036] Further, as a preference:

[0037] The mass ratio of the isopropanol to methyl acetoacetate is 5 to 20: 1. Excess isopropanol recovered by continuous distillation after the reaction can be recycled, so preferably, the mass ratio of the isopropanol to methyl acetoacetate is 8 to 15: 1.

[0038] In the synthesis reaction of isopropyl acetoacetate, concentrated sulfuric acid-molecular sieve is used as a catalyst for transesterification, the reagents are simple, and the post-processing operation is convenient. Therefore, the amount of concentrated sulfuric acid added is preferably 2% of the mass of methyl acetoacetate, and the amount of molecular sieve added is preferably 5% of the mass of methyl acetoacetate.

[0039] In order to obtain a better reaction effect, it is better to use the molecular sieve after crushing, so the molecular sieve is 4A molecular sieve powder.

[0040] The synthetic method of above-mentioned isopropyl acetoacetate can also be specifically the following steps:

[0041] Step 1, build equipment: the equipment mainly includes a reactor, a scraped film evaporator, a distillation tower kettle, a front portion tank and a positive portion tank. One side of the reactor is connected to a feed pipe, and the other side is connected to the scraped film evaporator through a feed liquid pipe; the bottom of the scraped film evaporator is connected to the distillation tower kettle with a discharge pipe, and the top is connected to the reactor with a reflux pipe; the distillation tower of the distillation tower kettle is connected to two diversion pipes, which are respectively connected to the front portion tank and the positive portion tank;

[0042] Step 2: methyl acetoacetate, isopropanol, concentrated sulfuric acid and molecular sieve enter the reactor through the feed pipe, heat up to an internal temperature of 80-85° C., react and evaporate by-products (mainly methanol), and the resulting reaction liquid continuously enters the scraped film evaporator through the feed pipe, the concentrated and evaporated isopropanol returns to the reactor through the reflux pipe, and the concentrated liquid enters the distillation tower kettle through the discharge pipe;

[0043] Step 3: When it is detected that the residual methyl acetoacetate in the reaction solution is less than 8%, the discharge pipe and the shunt pipe corresponding to the positive portion tank are closed, and the shunt pipe corresponding to the front portion tank is opened. The temperature of the distillation tower kettle is raised to 100-110° C., and the distillation is stopped at atmospheric pressure until the top temperature is greater than 95° C. The low-boiling point components separated from the top of the tower (mainly excess isopropanol, methyl acetoacetate, isopropyl ether, etc.) are sent to the front portion tank as the front portion, and the temperature of the distillation tower kettle is lowered to 60-70° C., and the negative pressure distillation is continued until there is no distillate, and the front portion is received;

[0044] Step 4, close the diverter pipe corresponding to the front portion tank, open the diverter pipe corresponding to the positive portion tank, heat the distillation tower kettle to 120-130°C, first heat it to the temperature inside the distillation tower kettle at normal pressure>100°C, switch to the clean positive portion tank fraction receiving bottle, slowly open the negative pressure to a stable vacuum degree ≤-0.095MPa, and send the fraction at 98-105°C on the top of the tower as the positive portion (this is the positive portion of isopropyl acetoacetate, and the main component detected by GC is>97%) into the positive portion tank, concentrate until there is no fraction on the top of the tower, stop heating and vacuum, and after the fraction is cooled, protect it with nitrogen, put it into a container containing solid acid, seal it, and the collected material is isopropyl acetoacetate.

[0045] In order to achieve high vacuum degree of distillation during industrial scale-up, it is best to use a combination of screw vacuum pump + Roots pump to meet the high vacuum requirements.

[0046] The positive portion tank is filled with solid acid which inhibits the degradation and polymerization of isopropyl acetoacetate.

[0047] Preferably, the solid acid is a styrene-sulfonic acid type resin.

[0048] Adding solid acid can effectively reduce the proportion of enol form and further degradation. Since the acidity of keto methylene is stronger than that of enol form, adding a small amount of solid acid can enhance the acidity of the system and make the configuration stay more on the stable keto structure. Therefore, the amount of solid acid added is 0.2-2% of the mass of isopropyl acetoacetate, and preferably 0.5%. In the storage of isopropyl acetoacetate, adding a small amount of solid acid can effectively reduce the enol tautomerism, inhibit the degradation and polymerization of isopropyl acetoacetate, and further reduce the decomposition of the ester bond produced by the enol tautomerism and the self-condensation. When using, just filter and separate the solid acid.

[0049] Based on the above improved synthesis method of isopropyl acetoacetate, the main materials and products are all liquids, the ester exchange reaction is a balanced reaction, and the process only has the steps of reaction, distillation and rectification. Therefore, it is easy to realize continuous operation in production, simple industrial continuous production, sufficient guarantee for production control and safety, simple synthesis steps, easy operation, and better product quality.

[0050] Obviously, the above scheme is also applicable to the synthesis of isobutyl acetoacetate, n-butyl acetoacetate or benzyl acetoacetate. At this time, in step 4, after switching to the clean positive fraction receiving bottle,

[0051] Under normal atmospheric pressure, collect the fraction at 213.9°C at the top of the tower as the positive fraction and send it to the positive fraction tank to collect n-butyl acetoacetate.

[0052] Or under normal atmospheric pressure, collect the fraction at 177-179°C at the top of the tower as the positive fraction and send it to the positive fraction tank to collect isobutyl acetoacetate;

[0053] Or under a vacuum of -0.098 MPa, collect the fraction at 156-159°C at the top of the tower as the positive fraction and send it into the positive fraction tank to collect benzyl acetoacetate.

[0054] Likewise, methyl acetoacetate can also be replaced by inexpensive ethyl acetoacetate as a reaction raw material. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0056] Figure 1 It is a structural schematic diagram of the device involved in this application;

[0057] Figure 2 This is a schematic diagram of the process flow of this application.

[0058] Numbers in the figure: 1. Reactor; 11. Feed pipe; 12. Feed liquid pipe; 2. Wiped film evaporator; 21. Reflux pipe; 22. Discharge pipe; 3. Distillation tower kettle; 4. Distillation tower; 5. Front portion tank; 51. Branch pipe one; 6. Main portion tank; 62. Branch pipe two; 7. Methanol tower; 71. Methanol receiving tank. DETAILED DESCRIPTION

[0059] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0060] It should be noted that when a component is referred to as being "fixed to" or "disposed on" another component, it may be directly or indirectly located on the other component. When a component is referred to as being "connected to" another component, it may be directly or indirectly connected to the other component. The directions or positions indicated by the terms "upper", "lower", "left", "right", "front", "back", "vertical", "horizontal", "top", "bottom", "inside", "outside", etc. are based on the directions or positions shown in the accompanying drawings and are only for the convenience of description and should not be construed as limitations on the present technical solution.

[0061] In addition, the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features. "Multiple" means two or more, unless otherwise clearly and specifically defined.

[0062] Example 1

[0063] The synthesis of isopropyl acetoacetate in this embodiment is combined with Figure 1 , Figure 2 , the process is as follows:

[0064] (1) Material preparation: Add 0.375 kg of 4A molecular sieve, 7.5 kg of methyl acetoacetate, 75.0 kg of isopropanol, and 0.15 kg of concentrated sulfuric acid (98%) into the reactor 1, and connect the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4, the front portion tank 5, the main portion tank 6, the methanol tower 7 and the methanol receiving tank 71.

[0065] (2) Ester exchange reaction: The reactor 1 is subjected to an esterification reaction at normal pressure, and the temperature inside the reactor 1 is controlled to be about 82°C (because all the equipment are connected, at this time, the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4 are basically at a temperature equivalent to the temperature inside the reactor 1, i.e., about 82°C). A low boiling point fraction is continuously distilled out from the top of the reactor 1 (mainly methanol, which is sent to the methanol receiving tank 71 through the methanol tower 7). The reactor 1 is kept warm for about 24 hours. The GC detection shows that the methyl acetoacetate in the reaction liquid is 6.42% (at this time, the reaction is considered to be over because the residual methyl acetoacetate is less than 8%. If it is higher than 8%, the reaction is continued to be kept warm until the reaction is complete).

[0066] The reaction liquid produced in the above esterification reaction process is continuously fed into the scraped film evaporator 2 through the feed liquid pipe 12 as the reaction proceeds, and a fraction (mainly isopropanol) is continuously distilled out from the top of the scraped film evaporator 2, and the fraction is refluxed into the reactor 1 through the reflux pipe 21 for recycling), and the concentrated liquid obtained in the scraped film evaporator 2 is fed into the distillation tower kettle 3 through the bottom discharge pipe 22.

[0067] (3) Distillation of the front portion: After the esterification reaction is completed, the external temperature of the distillation tower kettle 3 is controlled at 105°C, and atmospheric distillation is carried out in the distillation tower 4. When the top temperature of the distillation tower 4 exceeds 95°C, the atmospheric distillation of the distillation tower 4 is stopped, and the low-boiling point components (mainly excessive isopropanol solvent, methyl acetoacetate, isopropyl ether, etc.) are separated from the top of the tower, and vacuum distillation is changed to control the internal temperature of the distillation tower 4 to be about 65°C. The splitter pipe 51 is connected to the clean front portion tank 5, and the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa. Under this negative pressure condition, distillation is continued until there is no fraction, completing the distillation of the front portion. During this process, the low-boiling point components continuously enter the front portion tank 5 through the splitter pipe 51.

[0068] (4) Distillation of isopropyl acetoacetate: After the pre-fraction is completed, the external temperature of the distillation tower kettle 3 is controlled to be about 125°C, and the temperature is first raised to >100°C at normal pressure until the internal temperature of the distillation tower 4 is higher than 100°C, and then the negative pressure is slowly opened until the stable vacuum degree in the distillation kettle 4 is ≤-0.095Mpa. The second splitter pipe 61 is connected to the clean positive fraction tank 6, which receives the fraction at 98-105°C at the top of the tower, and 6.98kg of isopropyl acetoacetate is obtained, with a molar yield of 75%. The isopropyl acetoacetate (including enol structure) detected by GC is 98.2%.

[0069] Example 2

[0070] The synthesis of isopropyl acetoacetate in this embodiment is combined with Figure 1 , Figure 2 , the process is as follows:

[0071] (1) Material preparation: Add 0.375 kg of 4A molecular sieve powder, 7.5 kg of methyl acetoacetate, 75.0 kg of isopropanol, and 0.15 kg of concentrated sulfuric acid (98%) into the reactor 1, and connect the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4, the front portion tank 5, the main portion tank 6, the methanol tower 7 and the methanol receiving tank 71.

[0072] (2) Transesterification reaction: The reactor 1 is subjected to an esterification reaction at normal pressure, and the temperature inside the reactor 1 is controlled to be about 82° C. (Since all the equipment are connected, the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4 are basically at a temperature equivalent to the temperature inside the reactor 1, i.e., about 82° C.). A low boiling point fraction is continuously distilled out from the top of the reactor 1 (mainly methanol, which is sent to the methanol receiving tank 71 through the methanol tower 7). The reactor 1 is kept warm for about 30 hours. The GC detection shows that the content of methyl acetoacetate in the reaction liquid is 4.88% (at this time, the reaction is considered to be over because the residual methyl acetoacetate is less than 8%. If it is higher than 8%, the reaction is continued to be kept warm until the reaction is complete).

[0073] The reaction liquid produced in the above esterification reaction process is continuously fed into the scraped film evaporator 2 through the feed liquid pipe 12 as the reaction proceeds, and a fraction (mainly isopropanol) is continuously distilled out from the top of the scraped film evaporator 2, and the fraction is refluxed into the reactor 1 through the reflux pipe 21 for recycling), and the concentrated liquid obtained in the scraped film evaporator 2 is fed into the distillation tower kettle 3 through the bottom discharge pipe 22.

[0074] (3) Distillation of the front portion: After the esterification reaction is completed, the external temperature of the distillation tower kettle 3 is controlled at 105°C, and atmospheric distillation is carried out in the distillation tower 4. When the top temperature of the distillation tower 4 exceeds 95°C, the atmospheric distillation of the distillation tower 4 is stopped, and the low-boiling point components (mainly excessive isopropanol solvent, methyl acetoacetate, isopropyl ether, etc.) are separated from the top of the tower, and vacuum distillation is changed to control the internal temperature of the distillation tower 4 to be about 65°C. The splitter pipe 51 is connected to the clean front portion tank 5, and the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa. Under this negative pressure condition, distillation is continued until there is no fraction, completing the distillation of the front portion. During this process, the low-boiling point components continuously enter the front portion tank 5 through the splitter pipe 51.

[0075] (4) Distillation of isopropyl acetoacetate: After the pre-fraction is completed, the external temperature of the distillation tower kettle 3 is controlled to be about 125°C, and the temperature is first raised to >100°C at normal pressure to the internal temperature of the distillation tower 4, and then the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095 MPa in the distillation kettle 4. The splitter pipe 61 is connected to the clean positive fraction tank 6, which receives the fraction at 98-105°C at the top of the tower, and 7.26 kg of isopropyl acetoacetate is obtained, with a molar yield of 78%. The isopropyl acetoacetate (including enol structure) detected by GC is 97.4%.

[0076] Example 3

[0077] The synthesis of isopropyl acetoacetate in this embodiment is combined with Figure 1 , Figure 2 , the process is as follows:

[0078] (1) Material preparation: Add 0.75 kg of 4A molecular sieve powder, 15.0 kg of methyl acetoacetate, 180.0 kg of isopropanol, and 0.3 kg of concentrated sulfuric acid (98%) into the reactor 1, and connect the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4, the front portion tank 5, the main portion tank 6, the methanol tower 7 and the methanol receiving tank 71.

[0079] (2) Ester exchange reaction: The reactor 1 is subjected to an esterification reaction at normal pressure, and the temperature inside the reactor 1 is controlled to be about 82° C. (Since all the equipment are connected, the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4 are basically at a temperature equivalent to the temperature inside the reactor 1, i.e., about 82° C.). A low-boiling-point fraction is continuously distilled out from the top of the reactor 1 (mainly methanol, which is sent to the methanol receiving tank 71 via the methanol tower 7). The reactor 1 is kept warm for reaction for about 36 hours. The GC detection shows that the methyl acetoacetate in the reaction solution is 5.06%, and the reaction is completed.

[0080] The reaction liquid produced in the above esterification reaction process is continuously fed into the scraped film evaporator 2 through the feed liquid pipe 12 as the reaction proceeds, and a fraction (mainly isopropanol) is continuously distilled out from the top of the scraped film evaporator 2, and the fraction is refluxed into the reactor 1 through the reflux pipe 21 for recycling), and the concentrated liquid obtained in the scraped film evaporator 2 is fed into the distillation tower kettle 3 through the bottom discharge pipe 22.

[0081] (3) Distillation of the front portion: After the esterification reaction is completed, the external temperature of the distillation tower kettle 3 is controlled at 105°C, and atmospheric distillation is carried out in the distillation tower 4. When the top temperature of the distillation tower 4 exceeds 95°C, the atmospheric distillation of the distillation tower 4 is stopped, and the low-boiling point components (mainly excessive isopropanol solvent, methyl acetoacetate, isopropyl ether, etc.) are separated from the top of the tower, and vacuum distillation is changed to control the internal temperature of the distillation tower 4 to be about 65°C. The splitter pipe 51 is connected to the clean front portion tank 5, and the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa. Under this negative pressure condition, distillation is continued until there is no fraction, completing the distillation of the front portion. During this process, the low-boiling point components continuously enter the front portion tank 5 through the splitter pipe 51.

[0082] (4) Distillation of isopropyl acetoacetate: After the pre-fraction is completed, the external temperature of the distillation tower kettle 3 is controlled to be about 125°C, and the temperature is first raised to >100°C at normal pressure to the internal temperature of the distillation tower 4, and then the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa in the distillation kettle 4. The second splitter pipe 61 is connected to the clean positive fraction tank 6, which receives the fraction at 98-105°C at the top of the tower, and 10.5kg of isopropyl acetoacetate is obtained, with a molar yield of 81%. The isopropyl acetoacetate (including enol form) detected by GC is 98.0%.

[0083] Example 4

[0084] The synthesis of isopropyl acetoacetate in this embodiment is combined with Figure 1 , Figure 2 , the process is as follows:

[0085] (1) Material preparation: Add 0.75 kg of 4A molecular sieve powder, 15.0 kg of methyl acetoacetate, 150.0 kg of isopropanol, and 0.3 kg of concentrated sulfuric acid (98%) into the reactor 1, and connect the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4, the front portion tank 5, the main portion tank 6, the methanol tower 7 and the methanol receiving tank 71.

[0086] (2) Ester exchange reaction: Esterification reaction was carried out in reactor 1 under normal pressure, and the temperature in reactor 1 was controlled to be about 82°C (because all equipment were connected, at this time, the scraped film evaporator 2, the distillation tower kettle 3 and the distillation tower 4 were basically at a temperature equivalent to the temperature in reactor 1, i.e., about 82°C). Low-boiling-point fractions were continuously distilled out from the top of reactor 1 (mainly methanol, which was sent to methanol receiving tank 71 through methanol tower 7). The reaction was kept warm in reactor 1 for about 24 hours. GC detected that methyl acetoacetate was 5.68% in the reaction solution.

[0087] The reaction liquid produced in the above esterification reaction process is continuously fed into the scraped film evaporator 2 through the feed liquid pipe 12 as the reaction proceeds. The concentrated fraction of the scraped film evaporator 2 is collected and recycled. The concentrated liquid obtained in the scraped film evaporator 2 is fed into the distillation tower kettle 3 through the bottom discharge pipe 22.

[0088] (3) Distillation of the front portion: After the esterification reaction is completed, the external temperature of the distillation tower kettle 3 is controlled at 105°C, and atmospheric distillation is carried out in the distillation tower 4. When the top temperature of the distillation tower 4 exceeds 95°C, the atmospheric distillation of the distillation tower 4 is stopped, and the low-boiling point components (mainly excessive isopropanol solvent, methyl acetoacetate, isopropyl ether, etc.) are separated from the top of the tower, and vacuum distillation is changed to control the internal temperature of the distillation tower 4 to be about 65°C. The splitter pipe 51 is connected to the clean front portion tank 5, and the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa. Under this negative pressure condition, distillation is continued until there is no fraction, completing the distillation of the front portion. During this process, the low-boiling point components continuously enter the front portion tank 5 through the splitter pipe 51.

[0089] (4) Distillation of isopropyl acetoacetate: After the pre-fraction is completed, the external temperature of the distillation tower kettle 3 is controlled to be about 125°C, and the temperature is first raised to >100°C at normal pressure in the distillation tower 4, and then the negative pressure is slowly opened to a stable vacuum degree of ≤-0.095Mpa in the distillation kettle 4. The second splitter pipe 61 is connected to the clean positive fraction tank 6, which receives the fraction at 98-105°C at the top of the tower, and 10.6kg of isopropyl acetoacetate is obtained, with a molar yield of 82.25%. The isopropyl acetoacetate (including enol form) detected by GC is 98.1%.

[0090] In the above embodiments, isopropyl acetoacetate is synthesized by transesterification of methyl acetoacetate with isopropanol under the action of concentrated sulfuric acid-molecular sieve, and the molar yield of isopropyl acetoacetate reaches about 80%, and the GC detection of isopropyl acetoacetate (including enol form) is about 98% or more.

[0091] Taking isopropyl acetoacetate prepared in Example 4 as a control sample, a comparative study of different storage conditions was performed on the sample. The final GC test results are shown in Table 1.

[0092] Table 1: Effects of different storage conditions on isopropyl acetoacetate

[0093]

[0094]

[0095] By comparing the GC test results of samples in different storage conditions with those of the newly collected samples, we can see that:

[0096] 1) By comparing serial numbers 1 and 2 with the control group, it can be seen that the storage temperature has little effect on the quality of isopropyl acetoacetate known in the present application. It can be seen that the method of this case not only obtains isopropyl acetoacetate with high purity and a yield of about 80%, but the obtained isopropyl acetoacetate is relatively stable under conditions of 10-30°C. Compared with the positive sample just collected, the proportion of iPAc keto form dropped from 89.72% and stabilized at around 85%, and the proportion of iPAc enol form increased from 8.41% and stabilized at around 12%.

[0097] 2) Comparing No. 3 and No. 4 with No. 1, it can be seen that after adding solid acid, the ratio of keto form to enol form is significantly higher, the product is more conducive to conversion into keto form, further reducing the decomposition of ester bonds and self-condensation produced by enol interconversion, and the isopropanol content is basically maintained at around 0.3%. In particular, when comparing No. 4 with No. 1, at the same storage time and temperature, after adding solid acid, the proportion of iPAc keto form increased by nearly 10%, and the proportion of iPAc enol form decreased from 12.82 to 5.48, a decrease of nearly half, and the content of isopropanol decreased from 1.72% to 0.4%, a decrease of nearly 80%.

[0098] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for synthesizing isopropyl acetoacetate, characterized in that: Methyl acetoacetate and isopropanol are used as raw materials, react under the catalytic action of concentrated sulfuric acid and molecular sieves, and then distill to obtain isopropyl acetoacetate. The amount of concentrated sulfuric acid added is 1-5% of the mass of methyl acetoacetate, and the amount of molecular sieve added is 3-10% of the mass of methyl acetoacetate.

2. The method for synthesizing isopropyl acetoacetate according to claim 1, wherein: The added mass ratio of isopropanol to methyl acetoacetate is 5-20:

1.

3. A method for synthesizing isopropyl acetoacetate according to claim 1, characterized in that: The added mass ratio of isopropanol to methyl acetoacetate is 8-15:

1.

4. A method for synthesizing isopropyl acetoacetate according to claim 1, characterized in that: The amount of concentrated sulfuric acid added is 2% of the mass of methyl acetoacetate, and the amount of molecular sieve added is 5% of the mass of methyl acetoacetate.

5. A method for synthesizing isopropyl acetoacetate according to claim 1, characterized in that: The molecular sieve is 4A molecular sieve powder.

6. The method for synthesizing isopropyl acetoacetate according to claim 1, characterized in that: Here are the steps: Step 1, build equipment: the equipment mainly includes a reactor, a scraped film evaporator, a distillation tower kettle, a front portion tank and a positive portion tank. One side of the reactor is connected to a feed pipe, and the other side is connected to the scraped film evaporator through a feed liquid pipe; the bottom of the scraped film evaporator is connected to the distillation tower kettle with a discharge pipe, and the top is connected to the reactor with a reflux pipe; the distillation tower of the distillation tower kettle is connected to two diversion pipes, which are respectively connected to the front portion tank and the positive portion tank; Step 2: methyl acetoacetate, isopropanol, concentrated sulfuric acid and molecular sieve enter the reactor through the feed pipe, heat up to an internal temperature of 80-85°C, react and evaporate by-products, and the resulting reaction liquid continuously enters the scraped film evaporator through the feed liquid pipe, the concentrated and evaporated isopropanol returns to the reactor through the reflux pipe, and the concentrated liquid enters the distillation tower kettle through the discharge pipe; Step 3: When the residual methyl acetoacetate in the reaction solution is detected to be less than 8%, the discharge pipe and the diverter corresponding to the positive portion tank are closed, and the diverter corresponding to the front portion tank is opened. The temperature of the distillation tower kettle is raised to 100-110°C, and the distillation is stopped at atmospheric pressure until the top temperature is greater than 95°C. The low-boiling point component separated from the top of the tower is sent to the front portion tank as the front portion, and the distillation tower kettle is cooled to 60-70°C, and the negative pressure distillation is continued until there is no distillate, and the front portion is received; Step 4: Close the diverter pipe corresponding to the front portion tank, open the diverter pipe corresponding to the positive portion tank, raise the temperature of the distillation tower kettle to 120-130°C, first raise the temperature at normal pressure to a temperature inside the distillation tower kettle >100°C, switch to the clean positive portion tank fraction receiving bottle, slowly open the negative pressure to a stable vacuum degree of ≤-0.095MPa, and send the fraction at 98-105°C at the top of the tower into the positive portion tank as the positive portion, concentrate until there is no fraction at the top of the tower, stop heating and vacuum, and protect with nitrogen after the fraction is cooled. The collection in the positive portion tank is isopropyl acetoacetate.

7. A method for synthesizing isopropyl acetoacetate according to claim 6, characterized in that: In step 4, the positive portion tank is filled with a solid acid that inhibits the degradation and polymerization of isopropyl acetoacetate.

8. The method for synthesizing isopropyl acetoacetate according to claim 7, wherein: The solid acid is a styrene-sulfonic acid type resin.

9. The method for synthesizing isopropyl acetoacetate according to claim 7, wherein: The added amount of the solid acid is 0.2-2% of the mass of isopropyl acetoacetate.

10. A method for synthesizing isopropyl acetoacetate according to any one of claims 1 to 9, characterized in that: In step four, Under normal atmospheric pressure, collect the fraction at 213.9°C at the top of the tower as the positive fraction and send it to the positive fraction tank to collect n-butyl acetoacetate. Alternatively, under normal atmospheric pressure, the fraction at 177-179° C. at the top of the tower is collected as the positive fraction and sent to the positive fraction tank to collect isobutyl acetoacetate; Alternatively, under a vacuum of -0.098 MPa, the fraction at 156-159° C. at the top of the tower is collected as a positive fraction and sent to a positive fraction tank to collect benzyl acetoacetate.

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