Production process and production system of quinoline carboxylic acid ethyl ester
Through the process process of the hyperlatic reaction, amino reaction, and ring synthesis response, combined with the tungsten acid composite catalyst, the problem of side reactions in the preparation of ethyloline carboxylic acid ethylis carboxylic acid, improved the output rate and purity, reduced production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs and production costs. Environmental pollution.
Patent Information
- Application Number
- CN202411497293.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-25
- Publication Date
- 2025-01-28
AI Technical Summary
In the existing preparation process of quinoline carboxylic acid ethyl ester, 2-furan formaldehyde is prone to side reactions, resulting in a decrease in product yield and purity.
The process process of the use of the hyacharine reactions, amine reactions, and ring syndrome reactions is used to react through the ketic kettle, amino kettle, and ring compound reaction kettle, and use tungstenate composite catalysts to improve the reaction efficiency and selectivity.
The yield and purity of ethyloline carboxylic acid ethyline is increased, reducing the production of by -products, and reducing production costs and environmental pollution.
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Figure CN119371355A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a production process and a production system of quinolinecarboxylic acid ethyl ester. Background Art
[0002] Ethyl quinolinecarboxylate (CAS No. 112811-71-9) is an important pharmaceutical synthesis intermediate with a chemical formula of C16H15F2NO4, a light yellow to white powder, and a melting point range of 182-186°C. Among them, ethyl quinolinecarboxylate is mainly used to synthesize antibiotic drugs such as moxifloxacin and gatifloxacin. In addition, ethyl quinolinecarboxylate is also used as an intermediate for the synthesis of quinoline heterocyclic compounds. A typical synthesis route for ethyl quinolinecarboxylate includes three main steps: first, 2-furaldehyde is converted into 5-hydroxyfuran-2(5H)-one through a photolysis reaction; second, 4,4-diethoxy-2-butenoic acid ethyl ester is generated through an acidolysis reaction; finally, 4,4-diethoxy-2-butenoic acid ethyl ester reacts with aniline in an acetic acid solvent to generate ethyl quinolinecarboxylate.
[0003] In the prior art, in the above-mentioned preparation process, 2-furan carboxaldehyde is prone to undergo side reactions such as cycloaddition reaction and oxidation reaction under light conditions, generating cyclized impurities, and reducing the yield and purity of the target product. In addition, a variety of side products are also generated during the acid hydrolysis reaction. The acid hydrolysis reaction of ethyl 4,4-diethoxy-2-butenoate involves multiple steps of nucleophilic addition and elimination, and side reactions are prone to occur under reaction conditions. Summary of the invention
[0004] In order to solve the problems mentioned in the above background technology, the present invention provides a production process and a production system of ethyl quinolinecarboxylate.
[0005] In order to achieve the above object, the present invention adopts the following technical solutions:
[0006] A production process and a production system of quinolinecarboxylic acid ethyl ester, comprising the following steps:
[0007] S1, acylation reaction: add toluene into a dry acylation kettle, start stirring, add tri-n-propylamine and N,N-dimethylamino ethyl acrylate, then add 2,4,5-trifluoro-3-methoxybenzoyl chloride, increase the temperature, and keep the temperature to react to obtain quinolinecarboxylic acid ethyl ester acylation product;
[0008] S2, amination reaction: quinolinecarboxylic acid ethyl ester acylate is introduced into an amination kettle, cyclopropylamine is added dropwise, and the addition is completed over 1.5-2h, the temperature is raised, and the reaction is kept warm (HPLC detection shows that the reaction is complete, otherwise cyclopropylamine is added until the reaction is complete), and after four washings and layering, quinolinecarboxylic acid ethyl ester amination is obtained;
[0009] S3, cyclization reaction: potassium carbonate and toluene are added to the cyclization reaction kettle, and the temperature is raised under stirring for azeotropic dehydration until there is no water. Under nitrogen protection, quinolinecarboxylic acid ethyl ester amide is added dropwise to the kettle, and a tungstate composite catalyst is added. The reaction temperature is controlled and the reaction is kept warm. The material is transferred to a concentration kettle, and toluene is distilled off at normal pressure. When the feed liquid is evaporated to a viscous state, water is added to the kettle, and distillation is continued until no toluene remains. After the distillation is completed, the temperature is lowered to below 30°C, and the crystallization is stirred for 1-2h. The centrifuge is placed in a centrifuge for centrifugation in batches, and the filter cake is washed with water first, and then with methanol to a white crystalline powder. The obtained filter cake is discharged and put into a spiral tapered vacuum dryer. The temperature is controlled to be 70-80°C and the vacuum degree is above -0.096MPa. After vacuum drying for 24h, a sample is taken to detect the moisture. When the dry loss is <0.5%, the material is discharged to obtain the finished product of quinolinecarboxylic acid ethyl ester.
[0010] The reaction equation is as follows:
[0011]
[0012]
[0013] Furthermore, in step S1, the stirring speed is 50-100 rpm, the temperature is raised to 55-65° C., and the insulation reaction time is 3-5 h.
[0014] Furthermore, in step S1, the feed mass ratio of toluene, tri-n-propylamine, ethyl N,N-dimethylaminoacrylate and 2,4,5-trifluoro-3-methoxybenzoyl chloride is (5.8-6.2):(3-4):(2-2.5):(0.8-1).
[0015] Furthermore, in step S2, the temperature is raised to 40-45° C., and the reaction time is kept warm for 2-3 hours.
[0016] Furthermore, in step S2, the feed mass ratio of quinolinecarboxylic acid ethyl ester acylate and cyclopropylamine is (1-1.1): (1.2-2).
[0017] Furthermore, the four washing and stratification in step S2 are specifically as follows:
[0018] After the reaction is completed, the upper organic phase 1 is supplemented with toluene and water for the first washing, stirred for 5-15 minutes, allowed to stand for 10-20 minutes, the aqueous phase 1 and the organic phase 2 are separated, the lower aqueous phase 1 is recovered, the upper organic phase 2 is transferred to the washing kettle 1, 20-30% hydrochloric acid and water are added, the second washing is carried out, stirred for 20-30 minutes, allowed to stand for 30-40 minutes, the aqueous phase 2 and the organic phase 3 are separated, the lower aqueous phase 2 is recovered, and 20-30% hydrochloric acid and water are added to the organic phase 3 to carry out the third washing. , stirring for 5-15min, standing for 10-20min, separating the aqueous phase three and the organic phase four, recovering the aqueous phase three, continuing to add water, sodium bicarbonate and sodium chloride to the organic phase four, stirring to dissolve, washing for the fourth time, stirring for 10-20min, standing for 10-20min, separating the aqueous phase four and the organic phase five, desalting the aqueous phase four, and passing the organic phase five into a concentration kettle under reduced pressure (-0.95-(-0.1)Mpa, 50-60°C) for azeotropic dehydration. After dehydration, the organic phase five is cooled to 30°C for standby use.
[0019] Furthermore, in step S3, the reaction temperature is 108-110° C., the reaction time is 3-4 h, and the feed mass ratio of potassium carbonate, toluene, ethyl quinolinecarboxylate amide and tungstate composite catalyst is (1-2): (2.5-3.5): 1: (0.03-0.07).
[0020] Furthermore, the tungstate composite catalyst in step S3 is prepared by the following steps:
[0021] Add vinylimidazole and sodium styrene sulfonate to dimethyl sulfoxide, stir until completely dissolved to form a uniform solution, add azobisisobutyronitrile under nitrogen protection, continue stirring for 10-20 minutes, heat to 70-80°C, react for 12-24 hours, and then dropwise add dimethyl sulfoxide solution containing 40-50wt% tungstate while stirring. After the dropwise addition is completed, react at room temperature for 6-12 hours, filter, wash and dry to obtain a tungstate composite catalyst.
[0022] Furthermore, the mass ratio of vinyl imidazole, sodium styrene sulfonate, azobisisobutyronitrile and tungstate is (20-23): (25-30): (0.1-0.3): (42-56), and the tungstate includes one of sodium tungstate and potassium tungstate.
[0023] According to another aspect of the present invention, a production system for producing quinolinecarboxylic acid ethyl ester is provided, comprising an acylation reaction unit, an amination reaction unit, a cyclization reaction unit and a post-processing unit, wherein the acylation reaction unit comprises an acylation kettle, a raw material storage tank and a stirrer, the acylation kettle is used for acylation reaction, and is provided with a stirring device, a heating device and a temperature control device, the raw material storage tanks respectively store toluene, tri-n-propylamine, N,N-dimethylamino ethyl acrylate and 2,4,5-trifluoro-3-methoxybenzoyl chloride, the feeding ratio is controlled by a metering pump, and the stirrer is arranged in the acylation kettle. The amination reaction unit comprises an amination kettle, a cyclopropylamine storage tank and a washing device, the amination kettle is used for amination reaction, and is provided with a stirring device, a heating device and a temperature control device, the cyclopropylamine storage tank stores cyclopropylamine, and the dripping speed is controlled by a metering pump, and the washing device comprises four washing kettles, which are respectively used for four washing processes, and are provided with a stirrer, a feeding port and a layering device. The cyclization reaction unit includes a cyclization reaction kettle, a second raw material storage tank and a catalyst preparation device. The cyclization reaction kettle is provided with a nitrogen inlet, an agitator, a heating device and a temperature control device. The second raw material storage tank stores potassium carbonate and toluene respectively. The catalyst preparation device is used to prepare a tungstate composite catalyst. The post-processing unit includes a concentration kettle, a centrifugal drying device and a discharging device. The concentration kettle is used to remove toluene and concentrate the reaction products. The centrifugal drying device is used for centrifugal separation and drying of the products. The discharging device collects and stores the final product, ethyl quinolinecarboxylate.
[0024] Compared with the prior art, the present invention has the following beneficial effects:
[0025] 1. In the technical solution of the present invention, azobisisobutyronitrile (AIBN) is used as a free radical initiator. The tert-butyl radical generated by the decomposition of AIBN triggers the polymerization reaction of vinyl imidazole and sodium styrene sulfonate to generate a polyvinyl imidazole-sodium styrene sulfonate copolymer. By introducing sodium tungstate, coordination bonds are formed with atoms such as oxygen and nitrogen in the copolymer molecules, thereby changing the electronic structure and spatial configuration of the copolymer. The amphiphilic surface properties of the composite catalyst enable it to be uniformly dispersed and stable in the reaction system, thereby improving the efficiency and selectivity of the catalytic reaction.
[0026] 2. In the technical scheme of the present invention, 2,4,5-trifluoro-3-methoxybenzoyl chloride first reacts with tri-n-propylamine and N,N-dimethylamino ethyl acrylate in toluene to generate quinolinecarboxylic acid ethyl ester acylate. The nitrogen of the carbonyl group (C=O) in the quinolinecarboxylic acid ethyl ester acylate is substituted to generate the corresponding amine compound. After the reaction, the unreacted raw materials and by-products are removed by washing and layering steps to purify the generated quinolinecarboxylic acid ethyl ester amide. Under the action of potassium carbonate and tungstate composite catalyst, the quinolinecarboxylic acid ethyl ester amide undergoes a cyclization reaction to generate a compound with a stable ring structure. The production process ensures the efficient progress of the reaction and the stability of the product, improves the yield and purity of quinolinecarboxylic acid ethyl ester, and reduces the generation of by-products, thereby reducing production costs and environmental pollution. Through four washing and layering operations, impurities and unreacted products in the reaction are effectively removed, and the purity of quinolinecarboxylic acid ethyl ester amide is improved. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, 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 invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0028] Figure 1 It is a process flow chart of the present invention. DETAILED DESCRIPTION
[0029] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0030] Unless otherwise specified, the raw materials used in the present invention are all conventional products purchased from the market.
[0031] Preparation Example 1
[0032] The tungstate composite catalyst is prepared by the following steps:
[0033] 2kg of vinyl imidazole and 2.5kg of sodium styrene sulfonate were added to 1L of dimethyl sulfoxide, and stirred until completely dissolved to form a uniform solution. Under nitrogen protection, 0.01kg of azobisisobutyronitrile was added, and stirring was continued for 10 minutes. The mixture was heated to 70°C. After the reaction time was 12 hours, 10.5kg of dimethyl sulfoxide solution containing sodium tungstate was added dropwise while stirring. After the addition was completed, the mixture was reacted at room temperature for 6 hours, filtered, washed, and dried to obtain a tungstate composite catalyst.
[0034] Preparation Example 2
[0035] The tungstate composite catalyst is prepared by the following steps:
[0036] 2.5 kg of vinyl imidazole and 2.8 kg of sodium styrene sulfonate were added to 1 L of dimethyl sulfoxide, and stirred until completely dissolved to form a uniform solution. Under nitrogen protection, 0.02 kg of azobisisobutyronitrile was added, and stirring was continued for 15 min. The mixture was heated to 75 ° C. After the reaction time was 18 h, 12.3 kg of dimethyl sulfoxide solution containing potassium tungstate was added dropwise while stirring. After the addition was completed, the mixture was reacted at room temperature for 10 h, filtered, washed, and dried to obtain a tungstate composite catalyst.
[0037] Preparation Example 3
[0038] The tungstate composite catalyst is prepared by the following steps:
[0039] 3.3 kg of vinyl imidazole and 3 kg of sodium styrene sulfonate were added to 1 L of dimethyl sulfoxide, and stirred until completely dissolved to form a uniform solution. Under nitrogen protection, 0.03 kg of azobisisobutyronitrile was added, and stirring was continued for 20 min. The mixture was heated to 80 ° C. After the reaction time was 24 h, 14 kg of dimethyl sulfoxide solution containing sodium tungstate was added dropwise while stirring. After the addition was completed, the mixture was reacted at room temperature for 12 h, filtered, washed, and dried to obtain a tungstate composite catalyst.
[0040] Example 1
[0041] A production process and a production system of quinolinecarboxylic acid ethyl ester, comprising the following steps:
[0042] S1, acylation reaction: add 58 kg of toluene into a dry acylation kettle, add 30 kg of tri-n-propylamine and 20 kg of N,N-dimethylamino ethyl acrylate at a stirring speed of 50 rpm, then add 8 kg of 2,4,5-trifluoro-3-methoxybenzoyl chloride, heat to 55 ° C, keep warm for 3-5 hours to obtain quinolinecarboxylic acid ethyl ester acylation;
[0043] S2, amination reaction: 10kg of quinolinecarboxylic acid ethyl ester acylate was introduced into an amination kettle, 12kg of cyclopropylamine was added dropwise, and the addition was completed within 1.5 hours. The temperature was raised to 40°C and the reaction time was kept warm for 2 hours. After the reaction was completed, toluene and water were added to the upper organic phase 1 for the first washing, stirred for 5 minutes, allowed to stand for 10 minutes, the aqueous phase 1 and the organic phase 2 were separated, the lower aqueous phase 1 was recovered, the upper organic phase 2 was transferred to a washing kettle 1, 20% hydrochloric acid and excess water were added, the second washing was carried out, stirred for 20 minutes, allowed to stand for 30 minutes, the aqueous phase 2 and the organic phase 3 were separated, the lower aqueous phase 2 was recovered, and the reaction was continued. 20% hydrochloric acid and excess water were added to the organic phase three for the third washing, stirred for 5 min, allowed to stand for 10 min, the aqueous phase three and the organic phase four were separated, the aqueous phase three was recovered, and excess water, 10 wt % sodium bicarbonate and 5 wt % sodium chloride were added to the organic phase four to stir and dissolve, and the fourth washing was carried out, stirred for 10 min, allowed to stand for 10 min, the aqueous phase four and the organic phase five were separated, the aqueous phase four was desalted, and the organic phase five was passed into a concentration kettle under reduced pressure (-0.95 MPa, 50° C.) for azeotropic dehydration. After the dehydration was completed, the organic phase five was cooled to 30° C. for standby use to obtain quinolinecarboxylic acid ethyl ester amide;
[0044] S3, cyclization reaction: 10kg potassium carbonate and 25kg toluene are added to the cyclization reaction kettle, and the temperature is raised under stirring for azeotropic dehydration until there is no water. Under nitrogen protection, 10kg quinolinecarboxylic acid ethyl ester amide is added dropwise to the kettle, and 0.3kg tungstate composite catalyst prepared in Preparation Example 1 is added. The reaction temperature is controlled to be 108°C, and the reaction is carried out for 3h. The material is transferred to a concentration kettle, and toluene is distilled off at normal pressure. When the feed liquid is evaporated to a viscous state, water is added to the kettle, and distillation is continued until no toluene remains. After the distillation is completed, the temperature is lowered to below 30°C, and the crystallization is stirred for 1h. The centrifuge is placed in batches for centrifugation, and the filter cake is washed with water first, and then with methanol to a white crystalline powder. The obtained filter cake is discharged and put into a spiral tapered vacuum dryer, and the temperature is controlled to be 70°C and the vacuum degree is -0.096MPa. After vacuum drying for 24h, a sample is taken to detect the moisture. When the dry loss is <0.5%, the material is discharged to obtain the finished product of quinolinecarboxylic acid ethyl ester.
[0045] Example 2
[0046] A production process and a production system of quinolinecarboxylic acid ethyl ester, comprising the following steps:
[0047] S1, acylation reaction: add 60 kg of toluene into a dry acylation kettle, add 35 kg of tri-n-propylamine and 22.5 kg of N,N-dimethylamino ethyl acrylate at a stirring speed of 70 rpm, then add 8.8 kg of 2,4,5-trifluoro-3-methoxybenzoyl chloride, heat to 60°C, keep warm for 4 hours to obtain quinolinecarboxylic acid ethyl ester acylation;
[0048] S2, amination reaction: 10.4 kg of quinolinecarboxylic acid ethyl ester acylate was introduced into an amination kettle, 15.5 kg of cyclopropylamine was added dropwise, and the addition was completed within 1.5 hours. The temperature was raised to 42°C, and the reaction time was kept warm for 2.5 hours. After the reaction was completed, toluene and water were added to the upper organic phase 1 for the first washing, stirred for 10 minutes, allowed to stand for 15 minutes, the aqueous phase 1 and the organic phase 2 were separated, the lower aqueous phase 1 was recovered, the upper organic phase 2 was transferred to a washing kettle 1, 25% hydrochloric acid and excess water were added, the second washing was carried out, stirred for 25 minutes, allowed to stand for 35 minutes, the aqueous phase 2 and the organic phase 3 were separated, and the lower aqueous phase 2 was recovered. The organic phase 3 was collected, 25% hydrochloric acid and excess water were added to the organic phase 3, and the third washing was performed, the mixture was stirred for 10 min, and the mixture was allowed to stand for 15 min. The aqueous phase 3 and the organic phase 4 were separated, and the aqueous phase 3 was recovered. Excess water, 10 wt % sodium bicarbonate and 5 wt % sodium chloride were added to the organic phase 4 to stir and dissolve, and the mixture was washed for the fourth time, stirred for 15 min, and the mixture was allowed to stand for 15 min. The aqueous phase 4 and the organic phase 5 were separated, and the aqueous phase 4 was desalted. The organic phase 5 was passed into a concentration kettle under reduced pressure (-0.98 Mpa, 56 ° C) and azeotropically dehydrated. After the dehydration was completed, the organic phase 5 was cooled to 30 ° C for standby use to obtain quinolinecarboxylic acid ethyl ester amination;
[0049] S3, cyclization reaction: 13.5kg potassium carbonate and 28.6kg toluene were added to the cyclization reaction kettle, and the temperature was raised under stirring to azeotropic dehydration until anhydrous. Under nitrogen protection, 10kg quinolinecarboxylic acid ethyl ester amide was added dropwise to the kettle, and 0.45kg tungstate composite catalyst prepared in Preparation Example 2 was added. The reaction temperature was controlled to 109°C, and the reaction was carried out for 3.5h. The material was transferred to a concentration kettle, and the toluene was distilled off at normal pressure. When the feed liquid was evaporated to a viscous state, water was added to the kettle, and then Continue distilling until no toluene remains. After the distillation is completed, cool to below 30°C, stir and crystallize for 1.5 hours, centrifuge in batches, dry, wash the filter cake with water, and then wash the filter cake with methanol until it becomes a white crystalline powder. Discharge the obtained filter cake and put it into a spiral tapered vacuum dryer. Control the temperature to 75°C and the vacuum degree to -0.096MPa. After vacuum drying for 24 hours, take a sample to detect the moisture. When the dry loss is <0.5%, discharge the material to obtain the finished product of ethyl quinolinecarboxylate.
[0050] Example 3
[0051] A production process and a production system of quinolinecarboxylic acid ethyl ester, comprising the following steps:
[0052] S1, acylation reaction: add 62 kg of toluene into a dry acylation kettle, add 40 kg of tri-n-propylamine and 25 kg of N,N-dimethylamino ethyl acrylate at a speed of 100 rpm, then add 10 kg of 2,4,5-trifluoro-3-methoxybenzoyl chloride, heat to 65 ° C, keep warm for 5 hours to obtain quinolinecarboxylic acid ethyl ester acylation;
[0053] S2. Amination reaction: 11 kg of quinolinecarboxylic acid ethyl ester acylate was introduced into an amination kettle, and 20 kg of cyclopropylamine was added dropwise. The addition was completed within 2 hours, and the temperature was raised to 45°C. The reaction time was kept warm for 3 hours. After the reaction was completed, toluene and water were added to the upper organic phase 1 for the first washing, stirred for 15 minutes, and allowed to stand for 20 minutes. The aqueous phase 1 and the organic phase 2 were separated, and the lower aqueous phase 1 was recovered. The upper organic phase 2 was transferred to a washing kettle 1, 30% hydrochloric acid and excess water were added, and the second washing was carried out. The mixture was stirred for 30 minutes, and allowed to stand for 40 minutes. The aqueous phase 2 and the organic phase 3 were separated, and the lower aqueous phase 2 was recovered. 30% hydrochloric acid and excess water were added to the organic phase three for the third washing, stirred for 15 min, allowed to stand for 20 min, the aqueous phase three and the organic phase four were separated, the aqueous phase three was recovered, and excess water, 10 wt % sodium bicarbonate and 5 wt % sodium chloride were added to the organic phase four to stir and dissolve, and the fourth washing was carried out, stirred for 20 min, allowed to stand for 20 min, the aqueous phase four and the organic phase five were separated, the aqueous phase four was desalted, and the organic phase five was passed into a concentration kettle under reduced pressure (-0.1 MPa, 60° C.) for azeotropic dehydration. After the dehydration was completed, the organic phase five was cooled to 30° C. for standby use to obtain quinolinecarboxylic acid ethyl ester amination;
[0054] S3, cyclization reaction: 20kg potassium carbonate and 35kg toluene are added to the cyclization reaction kettle, and the temperature is raised under stirring for azeotropic dehydration until there is no water. Under nitrogen protection, 10kg quinolinecarboxylic acid ethyl ester amide is added dropwise to the kettle, and 0.7kg tungstate composite catalyst prepared in Preparation Example 3 is added. The reaction temperature is controlled to be 110°C, and the reaction is carried out for 4h. The material is transferred to a concentration kettle, and toluene is distilled off at normal pressure. When the feed liquid is evaporated to a viscous state, water is added to the kettle, and distillation is continued until no toluene remains. After the distillation is completed, the temperature is lowered to below 30°C, and the crystallization is stirred for 2h. The centrifuge is placed in batches for centrifugation, and the filter cake is washed with water first, and then with methanol to a white crystalline powder. The obtained filter cake is discharged and put into a spiral tapered vacuum dryer, and the temperature is controlled to be 80°C and the vacuum degree is -0.096MPa. After vacuum drying for 24h, a sample is taken to detect the moisture. When the dry loss is <0.5%, the material is discharged to obtain the finished product of quinolinecarboxylic acid ethyl ester.
[0055] Comparative Example 1
[0056] The difference between this comparative example and Example 1 is that polyvinyl imidazole is used instead of the tungstate composite catalyst, and the remaining steps are the same as those in Example 1.
[0057] Comparative Example 2
[0058] The difference between this comparative example and Example 2 is that sodium polystyrene sulfonate is used instead of the tungstate composite catalyst, and the remaining steps are the same as those in Example 2.
[0059] Comparative Example 3
[0060] The difference between this comparative example and Example 3 is that sodium tungstate is used instead of the tungstate composite catalyst, and the remaining steps are the same as those in Example 3.
[0061] The purity and weight yield of Examples 1-3 and Comparative Examples 1-3 were determined by HPLC. The results are shown in Table 1:
[0062] Table 1. Purity and weight yield results of Examples 1-3 and Comparative Examples 1-3
[0063] serial number purity(%) Weight yield (%) Example 1 99.6 139.5 Example 2 99.7 140.4 Example 3 99.7 137.9 Comparative Example 1 97.5 112.7 Comparative Example 2 96.1 128.4 Comparative Example 3 99.6 117.8
[0064] As shown in Table 1, Examples 1-3 used tungstate composite catalysts, and the purity reached 99.6% or 99.7%. This shows that the tungstate composite catalyst played an effective catalytic role in the reaction and was helpful in generating high-purity ethyl quinolinecarboxylate. Comparative Examples 1-3 used different catalysts or did not use composite catalysts, resulting in decreased purity. Although sodium tungstate was used in Comparative Example 3, the catalytic effect was not as good as that of the tungstate composite catalyst in the embodiment, probably because no composite catalyst was formed.
[0065] The weight yields of Examples 1-3 all exceeded 137%, indicating that the tungstate composite catalyst also has a significant effect in improving the yield. It may be due to the synergistic effect of the components in the composite catalyst, which improves the efficiency and selectivity of the reaction. The weight yields of Comparative Examples 1-3 are all lower than those of the embodiments. It proves that the tungstate composite catalyst has the advantage of improving the yield. Although sodium tungstate is used in Comparative Example 3, its catalytic effect is limited because no composite catalyst is formed, resulting in a low yield.
[0066] Tungstate composite catalysts may accelerate the cyclization reaction by providing active sites, stabilizing reaction intermediates, or promoting electron transfer. Composite catalysts may improve the efficiency and selectivity of the reaction through synergistic effects.
[0067] In summary, the production process of ethyl quinolinecarboxylate in Examples 1-3 improves the yield and purity of the product, further reduces the production cost, and at the same time recovers the by-products, reduces environmental pollution, and has economic and environmental benefits.
[0068] In the description of the specification, the description with reference to the terms "preparation example", "embodiment", "various embodiments" and the like means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or preparation example are included in at least one embodiment or preparation example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or preparation example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or preparation examples in a suitable manner.
[0069] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A production process for ethyl quinolinecarboxylate, characterized in that: The following steps are involved: S1, adding toluene to an acylation kettle, adding tri-n-propylamine and ethyl N,N-dimethylaminoacrylate while stirring, and then adding 2,4,5-trifluoro-3-methoxybenzoyl chloride, heating, and keeping the temperature for reaction to obtain ethyl quinolinecarboxylate; S2, passing quinolinecarboxylic acid ethyl ester acylate into an amination kettle, adding cyclopropylamine dropwise, heating, and keeping warm for reaction, washing and layering four times to obtain quinolinecarboxylic acid ethyl ester amination; S3. Potassium carbonate and toluene are added into the cyclization reaction kettle. Under nitrogen protection, quinolinecarboxylic acid ethyl ester amide is added dropwise into the kettle. After the addition is completed, a tungstate composite catalyst is added. The reaction temperature is controlled to react. The reaction is transferred to a concentration kettle to remove toluene, the temperature is lowered for crystallization, and the material is discharged after centrifugal drying.
2. A production process for ethyl quinolinecarboxylate according to claim 1, characterized in that, In step S1, the stirring speed is 50-100 rpm, the temperature is raised to 55-65° C., and the insulation reaction time is 3-5 hours.
3. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, In step S1, the feed mass ratio of toluene, tri-n-propylamine, ethyl N,N-dimethylaminoacrylate and 2,4,5-trifluoro-3-methoxybenzoyl chloride is (5.8-6.2):(3-4):(2-2.5):(0.8-1).
4. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, In step S2, the temperature is raised to 40-45° C. and the reaction time is kept at this temperature for 2-3 hours.
5. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, In step S2, the feed mass ratio of quinolinecarboxylic acid ethyl ester acylate and cyclopropylamine is (1-1.1): (1.2-2).
6. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, The four washing and layering steps in step S2 are specifically as follows: After the reaction is completed, the upper organic phase 1 is added with toluene and water for the first washing, stirred for 5-15 minutes, allowed to stand for 10-20 minutes, the aqueous phase 1 and the organic phase 2 are separated, the lower aqueous phase 1 is recovered, the upper organic phase 2 is transferred to the washing kettle 1, 20-30% hydrochloric acid and water are added, the second washing is carried out, stirred for 20-30 minutes, allowed to stand for 30-40 minutes, the aqueous phase 2 and the organic phase 3 are separated, the lower aqueous phase 2 is recovered, and 20-30% hydrochloric acid and water are added to the organic phase 3. Hydrochloric acid and water, wash for the third time, stir for 5-15min, let stand for 10-20min, separate the aqueous phase three and the organic phase four, recover the aqueous phase three, continue to add water, sodium bicarbonate and sodium chloride to the organic phase four, stir and dissolve, wash for the fourth time, stir for 10-20min, let stand for 10-20min, separate the aqueous phase four and the organic phase five, desalt the aqueous phase four, pass the organic phase five into a concentration kettle for azeotropic dehydration under reduced pressure, and after the dehydration is completed, cool the organic phase five to 30°C for standby use.
7. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, In step S3, the reaction temperature is 108-110° C., the reaction time is 3-4 hours, and the feed mass ratio of potassium carbonate, toluene, ethyl quinolinecarboxylate amide and tungstate composite catalyst is (1-2): (2.5-3.5): 1: (0.03-0.07).
8. A production process for quinolinecarboxylic acid ethyl ester according to claim 1, characterized in that, The tungstate composite catalyst in step S3 is prepared by the following steps: Add vinylimidazole and sodium styrene sulfonate to dimethyl sulfoxide, stir until completely dissolved to form a uniform solution, add azobisisobutyronitrile under nitrogen protection, continue stirring for 10-20 minutes, heat to 70-80°C, react for 12-24 hours, and then dropwise add dimethyl sulfoxide solution containing tungstate while stirring. After the dropwise addition is completed, react at room temperature for 6-12 hours, filter, wash and dry to obtain a tungstate composite catalyst.
9. A production process for quinolinecarboxylic acid ethyl ester according to claim 8, characterized in that, The mass ratio of vinyl imidazole, sodium styrene sulfonate, azobisisobutyronitrile and tungstate is (20-23): (25-30): (0.1-0.3): (42-56), and the tungstate includes one of sodium tungstate and potassium tungstate.
10. A production system for producing quinolinecarboxylic acid ethyl ester according to any one of claims 1 to 9, characterized in that: The invention comprises an acylation reaction unit, an amination reaction unit, a cyclization reaction unit and a post-processing unit, wherein the acylation reaction unit comprises an acylation kettle, a raw material storage tank 1 and a stirrer, the amination reaction unit comprises an amination kettle, a cyclopropylamine storage tank and a washing device, the cyclization reaction unit comprises a cyclization reaction kettle, a raw material storage tank 2 and a catalyst preparation device, and the post-processing unit comprises a concentration kettle, a centrifugal drying device and a discharging device.