Method for continuously synthesizing 8-methylquinoline

Abstract

The invention belongs to the field of preparation of organic compounds, and particularly relates to a method for continuously synthesizing 8-methylquinoline. Glycerin or acrolein and o-toluidine are subjected to a Skraup condensation reaction in a continuous reaction device in the presence of a catalyst, a stabilizer and a sulfuric acid solution, and 8-methylquinoline is continuously generated. According to the present invention, the glycerol (or acrolein), the stabilizer, the sulfuric acid solution, the catalyst and the o-toluidine are continuously added, such that the stable ratio of the sulfuric acid to the glycerol is maintained, the generation of the high polymer and the tar is further controlled through the addition of the catalyst and the stabilizer, the synthesis yield is improved, the purity of the 8-methylquinoline achieves more than 99.5%, and the production cost is reduced. Meanwhile, continuous production is realized; compared with a traditional synthesis method, the method has the characteristics of simple process, stable control, less tar generation, high product purity and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic compound preparation, and particularly relates to a method for continuously synthesizing 8-methylquinoline. Background Art

[0002] 8-Methylquinoline is an important fine chemical intermediate, which can be used as a raw material for the production of 8-quinoline formaldehyde, 5-bromoquinoline-8-carboxylic acid methyl ester, 5-chloro-8-methylquinoline, 8-quinolinecarboxylic 2-acetylenicotinic acid, 7-chloro-8-methylquinoline and other products. The main synthesis methods of 8-methylquinoline are as follows:

[0003] The first method is the acrolein diethyl acetal method: Ramann, Ginelle A.; Cowen, Bryan J. [Tetrahedron Letters, 2015, vol. 56, #46, p. 6436-6439] reported a method of obtaining 8-methylquinoline by reflux reaction of o-toluidine hydrochloric acid solution with excess acrolein diethyl acetal. The method is reported in the literature to have a yield of 83%, but the purity is poor and needs to be purified by column chromatography.

[0004] The second method is the 1,2,3,4-tetrahydroquinoline dehydrogenation method: Bang, Saet Byeol; Kim, Jinho [Synthetic Communications, 2018, vol. 48, #11, p. 1291-1298] reported that 1,2,3,4-tetrahydroquinoline was used as the raw material, water was used as the solvent, and oxygen was used as the oxidant to perform dehydrogenation to obtain 8-methylquinoline with a yield of 97%. However, the raw material 1,2,3,4-tetrahydroquinoline in this method is difficult to obtain and the raw material cost is high;

[0005] The third method is the 1,3-propylene glycol method: Khusnutdinov; Bayguzina; Aminov [Russian Journal of General Chemistry, 2015, vol. 85, #12, p 2725-2727][Zh.Obshch.Khim., 2015, vol. 85, #12, p. 1993-1995, 3] reported the use of o-toluidine and 1,3-propylene glycol in carbon tetrachloride solvent, using FeCl 3 6H 2 O is used as a catalyst to react to obtain 8-methylquinoline. This method requires high temperature and high pressure, and 1,3-propylene glycol needs to be greatly excessive.

[0006] The fourth method is the glycerol method: O'Murchu, C. [Synthesis, 1989, #11, p.880-882] reported that glycerol (or acrolein) was added dropwise to o-toluidine, sodium iodide and 80% sulfuric acid, and reacted at 140-145°C to obtain 8-methylquinoline. The mechanism is that o-toluidine forms o-toluidine sulfate in sulfuric acid solution, and glycerol generates acrolein in situ under the action of sulfuric acid. The two condense and close the ring in the presence of sulfuric acid, and then dehydrogenate under the action of sulfuric acid and sodium iodide to obtain 8-methylquinoline. Some documents also use acrolein to replace glycerol for synthesis. In the synthesis process of this method, the synthesis yield is usually around 80-90%. Due to the presence of more tar (acrolein polymerization, etc.) in the synthesis process, there are many impurities in the product, and it is difficult to separate in the distillation process. The purity of the obtained 8-methylquinoline is about 98%, which is difficult to reach 99.5%, and cannot meet the impurity control requirements of high-specification downstream products. Summary of the invention

[0007] In order to solve the shortcomings of the existing glycerol method for synthesizing 8-methylquinoline, the present invention provides a method for continuously synthesizing high-purity 8-methylquinoline.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] Glycerol or acrolein undergoes a Skraup condensation reaction with o-toluidine in the presence of a catalyst, a stabilizer and a sulfuric acid solution in a continuous reaction device to continuously generate 8-methylquinoline.

[0010] Furthermore, under nitrogen protection, a substrate is added to a continuous reaction device, heated to 80-155° C., and glycerol or acrolein, a stabilizer, a sulfuric acid solution, a catalyst, and o-toluidine are added to the reaction device simultaneously and continuously to cause a Skraup condensation reaction, thereby continuously preparing 8-methylquinoline.

[0011] The substrate is a sulfuric acid solution or a sulfuric acid solution and one or two of a stabilizer and a catalyst.

[0012] The amount of substrate added is determined according to the volume of the continuous reaction device and the feed ratio of the materials.

[0013] During the continuous reaction, the dropping speed ratio of sulfuric acid: glycerol (or acrolein): catalyst: stabilizer: o-toluidine is 2.0-5.0: 1.0-3.0: 0.001-1.0: 0.001-0.02: 1 in mole. Preferably, the dropping speed ratio of the catalyst to o-toluidine is 0.001-0.01: 1 in mole.

[0014] The continuous reaction device is one or a combination of single-stage or multi-stage series-connected kettle reactors, tubular reactors, and series-connected circulating loop reactors. The number of stages of the reactors is 1 to 20; the continuous reaction temperature of each stage is 80-155° C.; the continuous reaction time of each stage is 1 to 20 hours, and the total continuous reaction time is the sum of the reaction time of each stage.

[0015] The end of the continuous reaction device is connected with a synthetic liquid receiving bottle.

[0016] The concentration of the sulfuric acid solution is 70-98%, preferably 80-93%.

[0017] The catalyst can be one or more of elemental iodine, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, sodium toluene sulfonate, potassium ethylbenzene sulfonate, and sodium nitrobenzene sulfonate.

[0018] The stabilizer is one or more of 2,6-di-tert-butyl-p-cresol, hydroquinone and tert-butyl-hydroquinone.

[0019] The reaction solution obtained after the reaction is finished is dissolved in water, an inorganic base solution is added to adjust the pH value to 7-9, an organic solvent is added to extract, desolventize, and then distilled to obtain 8-methylquinoline; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., with a mass concentration of 20-50%; the organic solvent is toluene, petroleum ether, and a fatty alcohol with 4-8 carbon atoms.

[0020] The distillation temperature is 110-120°C, and the distillation pressure is 0.30-0.50 kPa absolute pressure.

[0021] The purity of 8-methylquinoline is above 99.5%.

[0022] Beneficial effects of the present invention:

[0023] In the traditional intermittent glycerin synthesis process, glycerin (or acrolein) is added dropwise to o-toluidine, sodium iodide and 80% sulfuric acid. Due to the lack of stabilizer in the system, acrolein generated in the reaction process or added dropwise to the system is easily oxidized and polymerized to form tar in a large amount of sulfuric acid system. The present invention maintains a stable ratio of sulfuric acid and glycerin by continuously adding glycerin (or acrolein), stabilizer, sulfuric acid solution, catalyst and o-toluidine, and further controls the generation of polymers and tar by adding catalysts and stabilizers. While the synthesis yield is improved, the purity of 8-methylquinoline reaches more than 99.5%, and continuous production is realized. Compared with the traditional synthesis method, the present invention has the characteristics of simple process, stable control, less tar generation, and high product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1It is a two-stage continuous reaction device used in the embodiment of the present invention. DETAILED DESCRIPTION

[0025] The specific implementation of the technical solution of the present invention is described in detail below, but the present invention is not limited to the following description:

[0026] The present invention will be described below in conjunction with specific embodiments:

[0027] Embodiment 1:

[0028] Pour 1013 g of water into a 5000 ml four-necked bottle, stir to control the temperature below 40°C, add 4500 g of 98% sulfuric acid dropwise while stirring, and after the addition is completed, maintain the temperature below 40°C for 20 minutes to obtain 80% sulfuric acid by mass for use.

[0029] Put 100g of 80% sulfuric acid, 0.07g of solid potassium iodide, and 0.45g of 2,6-di-tert-butyl-p-cresol into a 500ml four-necked bottle with overflow (effective volume 400ml), stir, and heat to 90℃ under nitrogen protection. Add materials to the reaction container continuously at the following flow rate: 55.2g / h of glycerol, 0.8g / h of 2,6-di-tert-butyl-p-cresol, 175.5g / h of 80% sulfuric acid, 0.11g / h of potassium iodide, and 53.5g / h of o-toluidine, and react for 20 hours. After the overflow of the first four-necked bottle, enter the four-necked bottle with an effective volume of 1000ml and maintain the temperature at 135℃ for insulation reaction. After the overflow of the second four-necked bottle, enter the synthetic liquid receiving bottle.

[0030] After the reaction is completed, the synthetic liquid in the first and second four-necked bottles and the synthetic liquid receiving bottle is combined and cooled to below 60°C, 2200g of water is added to dissolve, 30% sodium hydroxide is added dropwise to adjust the pH to 7-8, and after the pH is adjusted, 3000ML of petroleum ether is added for extraction and stratification. 3000ml of petroleum ether is added to the water layer for secondary extraction, the oil layers are combined, and the crude 8-methylquinoline is desolventized to obtain a purity of 97.5% and a yield of 95.2%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120°C. The distillation yields refined 8-methylquinoline with a purity of 99.60%.

[0031] Embodiment 2:

[0032] Pour 1013 g of water into a 5000 ml four-necked bottle, stir to control the temperature below 40°C, add 4500 g of 98% sulfuric acid dropwise while stirring, and after the addition is completed, maintain the temperature below 40°C for 20 minutes to obtain 80% sulfuric acid by mass.

[0033] Put 100g of 80% sulfuric acid, 0.13g of solid sodium iodide, and 0.5g of tert-butyl hydroquinone into a 500ml four-necked bottle with overflow (effective volume 400ml), stir, and heat to 90℃ under nitrogen protection. Add materials to the reaction container continuously at the following flow rate: 75.0g / h of glycerol, 1.0g / h of tert-butyl hydroquinone, 200g / h of 80% sulfuric acid, 0.25g / h of sodium iodide, and 53.5g / h of o-toluidine. Add dropwise for 20 hours. After the overflow of the first four-necked bottle, enter the four-necked bottle with an effective volume of 2000ml and maintain the temperature at 145℃ for insulation reaction. After the overflow of the second four-necked bottle, enter the synthetic liquid receiving bottle.

[0034] After the reaction is completed, the synthetic liquid in the first and second four-necked bottles and the synthetic liquid receiving bottle is combined and cooled to below 60°C, 2000g of water is added to dissolve, 48% potassium hydroxide is added dropwise to adjust the pH to 7-8, and after the pH is adjusted, 3000ML of petroleum ether is added for extraction and stratification. 3000ml of petroleum ether is added to the water layer for secondary extraction, the oil layers are combined, and the crude 8-methylquinoline is desolventized to obtain a purity of 97.3% and a yield of 94.9%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120°C. The distillation yields refined 8-methylquinoline with a purity of 99.72%.

[0035] Embodiment 3:

[0036] Add 242 g of water, stir to control the temperature below 40°C, add 4500 g of 98% sulfuric acid dropwise while stirring, and after the addition is completed, maintain the temperature below 40°C for 20 minutes to obtain 93% sulfuric acid by mass for use.

[0037] Put 100g of 93% sulfuric acid, 0.3g of sodium p-nitrobenzene sulfonate, and 0.15g of 2,6-di-tert-butyl-p-cresol into a 500ml four-necked bottle with overflow (effective volume 400ml), stir, and heat to 110℃ under nitrogen protection. Add materials to the reaction container continuously at the following flow rate: 92.0g / h of glycerol, 0.25g / h of 2,6-di-tert-butyl-p-cresol, 162.0g / h of 93% sulfuric acid, 0.5g / h of sodium p-nitrobenzene sulfonate, and 53.5g / h of o-toluidine. Add dropwise for 20 hours. After the overflow of the first four-necked bottle, enter the four-necked bottle with an effective volume of 1500ml and maintain the temperature at 135℃ for insulation reaction. After the overflow of the second four-necked bottle, enter the synthetic liquid receiving bottle.

[0038] After the reaction is completed, the synthetic liquids in the first and second four-necked bottles and the synthetic liquid receiving bottle are combined and cooled to below 60°C, 2500g of water is added to dissolve, and 20% sodium carbonate solution is continued to be added dropwise to adjust the pH to 7-8. After the pH is adjusted, 3500ml of 1-pentanol is added for extraction and stratification. 3500ml of 1-pentanol is added to the water layer for secondary extraction, the oil layers are combined, and the crude 8-methylquinoline is desolventized to obtain a purity of 96.0% and a yield of 93.1%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120°C. The distillation yields refined 8-methylquinoline with a purity of 99.54%.

[0039] Embodiment 4:

[0040] Pour 1013 g of water into a 5000 ml four-necked bottle, stir and control the temperature below 40°C, add 4500 g of 98% sulfuric acid dropwise while stirring, and keep warm for 20 minutes after the addition is completed to obtain 80% sulfuric acid by mass.

[0041] Put 100g of 80% sulfuric acid, 0.3g of potassium p-ethylbenzenesulfonate, and 0.15g of p-cresol into a 500ml four-necked bottle with overflow (effective volume 400ml), stir, and heat to 145℃ under nitrogen protection. Add materials to the reaction container continuously at the following flow rate: 36.5g / h of acrolein, 0.25g / h of hydroquinone, 160g / h of 80% sulfuric acid, 1.25g / h of potassium p-ethylbenzenesulfonate, and 53.5g / h of o-toluidine, and react for 20 hours. After the overflow of the first four-necked bottle, enter the four-necked bottle with an effective volume of 1000ml to maintain the temperature at 145℃ for insulation reaction. After the overflow of the second four-necked bottle, enter the synthetic liquid receiving bottle.

[0042] After the reaction is completed, the synthetic liquids in the first and second four-necked bottles and the synthetic liquid receiving bottle are combined and cooled to below 60°C. The synthetic liquid is cooled to below 60°C, 2000g of water is added to dissolve, and 30% potassium carbonate solution is continued to be added dropwise to adjust the pH to 7-8. After the pH is adjusted, 3500ml of 1-pentanol is added for extraction and stratification. 3500ml of 1-pentanol is added to the water layer for secondary extraction, and the oil layers are combined and desolventized to obtain crude 8-methylquinoline with a purity of 96.0% and a yield of 92.7%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120°C. The distillation yields refined 8-methylquinoline with a purity of 99.50%.

[0043] Comparative Example 1:

[0044] Add 101.3 g of water, stir to control the temperature below 40°C, add 450 g of 98% sulfuric acid dropwise while stirring, and after the addition is completed, maintain the temperature below 40°C for 20 minutes to obtain 551.3 g of 80% sulfuric acid by mass.

[0045] Put 107g o-toluidine (1mol), 2.0g sodium iodide (0.013mol), 551.3g 80% sulfuric acid (4.5mol) into a round-bottom flask, stir and heat to 140℃ under nitrogen protection, maintain the temperature at 140℃, and start to drop 110.4g glycerol (1.2mol). The drop time is 1hr. After the drop addition is completed, maintain 140℃ for 2.5hr. The synthetic liquid is below 60℃, 25% sodium hydroxide is added dropwise to adjust the pH to 7-8, 500ML toluene is added for extraction, and the layers are separated. Toluene is added to the water layer for secondary extraction, the oil layers are combined, and the solvent is removed to obtain crude 8-methylquinoline with a purity of 93.4% and a yield of 87.2%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120℃. The distillation is refined 8-methylquinoline with a purity of 98.2%.

[0046] Comparative Example 2

[0047] Add 8.3 g of water into a round-bottom flask, stir and control the temperature below 40°C, then add 153.7 g of 98% sulfuric acid dropwise while stirring. After the addition is completed, maintain the temperature below 40°C for 20 minutes.

[0048] Add 0.25g of 2,6-di-tert-butyl-p-cresol and 0.5g of sodium p-nitrobenzenesulfonate, stir and heat to 110°C under nitrogen protection, and simultaneously drop 92.0g of glycerol and 53.5g of o-toluidine for about 1 to 2 hours. After the dropwise addition is completed, heat to 140°C and keep warm for 1 to 2 hours.

[0049] After the reaction is completed, the four-necked bottle is cooled to below 60°C, 125g of water is added to dissolve, and 48% potassium hydroxide is continued to be added dropwise to adjust the pH to 7-8. After the pH is adjusted, 175ml of 1-pentanol is added for extraction and stratification. 175ml of 1-pentanol is added to the water layer for secondary extraction, and the oil layers are combined and desolventized to obtain crude 8-methylquinoline with a purity of 94.5% and a yield of 90.1%. The crude 8-methylquinoline is heated and distilled under negative pressure through a 10cm separation column, with an absolute pressure of 0.4kpa and a final temperature of 120°C. The distillation yields refined 8-methylquinoline with a purity of 99.15%.

[0050] The above examples are only for illustrating the technical concept and technical features of the present invention, and cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the essence of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for continuously synthesizing 8-methylquinoline, characterized in that: Glycerol or acrolein undergoes a Skraup condensation reaction with o-toluidine in the presence of a catalyst, a stabilizer and a sulfuric acid solution in a continuous reaction device to continuously generate 8-methylquinoline.

2. The method according to claim 1, characterized in that: Under nitrogen protection, a substrate is added to a continuous reaction device, heated to 80-155° C., and glycerol or acrolein, a stabilizer, a sulfuric acid solution, a catalyst, and o-toluidine are added to the reaction device simultaneously and continuously to cause a Skraup condensation reaction, thereby continuously preparing 8-methylquinoline.

3. The method according to claim 2, characterized in that: The substrate is a sulfuric acid solution or a sulfuric acid solution and one or two of a stabilizer and a catalyst.

4. The synthesis method according to claim 2, characterized in that: During the continuous reaction, the dropping speed ratio of sulfuric acid: glycerol or acrolein: catalyst: stabilizer: o-toluidine is 2.0-5.0:1.0-3.0:0.001-1.0:0.001-0.02:1 in mole.

5. The method according to claim 1, characterized in that: The continuous reaction device is one or a combination of single-stage or multi-stage series-connected kettle reactors, tubular reactors, and series-connected circulating loop reactors. The number of stages of the reactors is 1 to 20; the continuous reaction temperature of each stage is 80-155° C.; the continuous reaction time of each stage is 1 to 20 hours, and the total continuous reaction time is the sum of the reaction time of each stage.

6. The method according to claim 1, characterized in that: The concentration of the sulfuric acid solution is 70-98%.

7. The method according to claim 2, characterized in that: The catalytic catalyst can be one or more of elemental iodine, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, sodium toluene sulfonate, potassium ethylbenzene sulfonate, and sodium nitrobenzene sulfonate.

8. The synthesis method according to claim 2, characterized in that: The stabilizer is one or more of 2,6-di-tert-butyl-p-cresol, hydroquinone and tert-butyl-hydroquinone.

9. The method according to claim 2, characterized in that: After the reaction is completed, the reaction solution obtained is dissolved in water, an inorganic base solution is added to adjust the pH value to 7-9, an organic solvent is added to extract, desolventize, and then distill to obtain 8-methylquinoline.

10. The synthesis method according to claim 2, characterized in that: The purity of 8-methylquinoline is above 99.5%.

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