A process for the preparation of a 2-chloronicotinic acid intermediate

Abstract

This invention relates to a method for preparing 2-chloronicotinic acid intermediates, belonging to the technical field of organic chemistry. The invention employs a fixed-bed reactor, using propynyl alcohol and dimethylamine as raw materials, to generate 3-dimethylaminopropenal under manganese dioxide catalysis. To control the further reaction of 3-dimethylaminopropenal with dimethylamine to generate impurities, 0.1%–0.5% sodium hydroxide is added to the reaction system. After the 3-dimethylaminopropenal reacts with ethyl cyanoacetate, HCl is introduced to close the ring, yielding ethyl 2-chloronicotinic acid. This invention uses a fixed-bed reactor instead of a batch reactor, improving the safety of the reaction equipment and reducing the generation of peroxide impurities. Simultaneously, the addition of a small amount of sodium hydroxide to the reaction system controls the impurity content during the reaction process and enhances the reactivation effect of manganese dioxide.

Description

Technical Field

[0001] This invention relates to the technical field of organic chemistry, and specifically to a method for preparing a 2-chloronicotinic acid intermediate. Background Technology

[0002] 2-Chloronicotinic acid is an important intermediate in the synthesis of boscalid, nicosulfuron, and pyrifluquinazon. Currently, the industrial synthesis process uses the nicotinic acid N-oxidative chlorination method. This method uses nicotinic acid as a raw material, oxidizes it with peroxide to nicotinic acid nitrogen oxides, then chlorinates it with phosphorus oxychloride to 2-chloronicotinyl chloride, and finally hydrolyzes it to obtain 2-chloronicotinic acid. The specific route is as follows: .

[0003] Although the above method has a high yield, it generates a large amount of phosphorus-containing wastewater, which is difficult to treat.

[0004] Another industrial process is the oxidative hydrolysis of 2-chloro-3-methylpyridine. First, 2-chloro-3-methylpyridine is chlorinated with chlorine gas to 2-chloro-3-trichloromethylpyridine, which is then hydrolyzed to obtain 2-chloronicotinic acid. The specific route is as follows: .

[0005] However, the above method has many side reactions. During the hydrolysis process, the chlorine at position 2 dissolves and hydrolyzes, and the resulting chlorine-containing wastewater is difficult to treat.

[0006] The emerging synthetic route is the ring-closure method, using triphosgene, DMF, vinyl ether, and methyl cyanoacetate as raw materials. First, triphosgene and DMF form a Vilsmeier salt, which reacts with vinyl ether to generate a chloroacetal intermediate. This intermediate then reacts with dimethylamine to form an amine-substituted intermediate, which combines with ethyl cyanoacetate and undergoes ring closure to yield ethyl 2-chloronicotinate. Hydrolysis then yields 2-chloronicotinic acid. While this method has low raw material costs, it involves numerous steps, side reactions, and low yields, making it unsuitable for industrial production at present. Summary of the Invention

[0007] To address the problems of difficult wastewater treatment and low yield in existing methods for synthesizing 2-chloronicotinic acid intermediates, this invention provides a method for preparing 2-chloronicotinic acid intermediates to solve these problems. This invention employs a fixed-bed reactor, using propynyl alcohol and dimethylamine as raw materials to generate 3-dimethylaminopropenal under manganese dioxide catalysis. To control the further reaction of 3-dimethylaminopropenal with dimethylamine to generate impurities, 0.1%–0.5% sodium hydroxide is added to the reaction system. After the 3-dimethylaminopropenal reacts with ethyl cyanoacetate, HCl is introduced to achieve ring closure, yielding ethyl 2-chloronicotinic acid. This invention uses a fixed-bed reactor instead of a batch reactor, improving the safety of the reaction equipment and reducing the generation of peroxide impurities. Simultaneously, the addition of a small amount of sodium hydroxide to the reaction system controls the impurity content during the reaction process and enhances the reactivation effect of manganese dioxide.

[0008] The technical solution of this invention is as follows: A method for preparing a 2-chloronicotinic acid intermediate, the reaction formula is as follows: ; Includes the following steps: (1) Manganese dioxide catalyst is packed in the reaction tube bundle of a fixed bed reactor. A methanol solution containing propynyl alcohol and sodium hydroxide is mixed with dimethylamine and continuously fed into the fixed bed reactor. The reaction pressure and reaction temperature are controlled to obtain intermediate I (3-dimethylaminopropenal). (2) Intermediate I reacts with ethyl cyanoacetate to obtain intermediate II; (3) Intermediate II cyclizes under the action of hydrogen chloride to form ethyl 2-chloronicotinic acid.

[0009] Furthermore, the specific steps of step (1) are as follows: (A) Add sodium hydroxide to methanol, stir to dissolve, add propynyl alcohol, then pass dimethylamine gas into the methanol solution, and maintain the solution temperature below 20°C to obtain a methanol solution of propynyl alcohol / dimethylamine. When preparing the raw material mixture, a small amount of sodium hydroxide needs to be added. This serves two purposes: firstly, it enhances the reactivation effect of the manganese dioxide catalyst; secondly, it prevents intermediate I from continuing to react with dimethylamine to generate impurity I during the reaction process. The pathway for the formation of impurity I is as follows: .

[0010] (B) The fixed bed is heated to 75℃~80℃, and air with an oxygen content of 25%~30% is introduced to make the pressure of the fixed bed reactor reach 3.0~3.2Mpa; the methanol solution of propynyl alcohol / dimethylamine obtained in step (A) is continuously introduced, and the pressure of the fixed bed is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve to ensure the online activation effect of the catalyst. (C) The solvent is removed from the qualified reaction solution to obtain intermediate I; the removed methanol is recovered and reused.

[0011] Furthermore, the manganese dioxide catalyst content in the reaction tube bundle of the fixed-bed reactor is 90%–92%, with a bulk density of 0.4–0.5 g / ml. The manganese dioxide is processed into spherical particles with a diameter of 1–1.5 mm using a water-insoluble silicate binder. Appropriate content and bulk density of manganese dioxide powder are selected to ensure the hardness of the catalyst and the strong adhesion of the powder after molding. Spherical particles matching the inner diameter of the fixed-bed reaction tube bundle are prepared to avoid liquid feed deviation.

[0012] In some specific embodiments, the diameter of the reaction tube bundle in the fixed-bed reactor is 40 mm, the length is 10 m, and the catalyst packing height is 9.7~9.8 m.

[0013] Furthermore, the mass ratio of the methanol solution feed rate of propynyl alcohol / dimethylamine to the air intake rate is 4~5:3~4.

[0014] Furthermore, in step (A), the amount of sodium hydroxide added is 0.1% to 0.5% based on the mass of methanol. Sodium hydroxide can be used in various forms such as granules, flakes, and powder.

[0015] Furthermore, in step (A), the mass ratio of propynyl alcohol to methanol is 1:4~6.

[0016] Furthermore, in step (A), the molar ratio of dimethylamine to propynyl alcohol is 1.1~1.2:1.

[0017] Furthermore, the specific steps of step (2) are as follows: Toluene was added to intermediate I, followed by ethyl cyanoacetate. The temperature was raised to 110°C-115°C, and a sodium carbonate aqueous solution with a mass concentration of 20%-30% was added dropwise at a temperature of 80°C-90°C. After the addition was complete, the reaction was maintained at this temperature until the reactants were completely reacted. The reaction system was then cooled to 20°C-30°C, and water was added to adjust the pH of the aqueous phase to 5-7. After washing with water again, the mixture was separated to obtain a toluene solution containing intermediate II. The amount of toluene used is 4-5 kg / kg based on the mass of intermediate I; the molar ratio of ethyl cyanoacetate to intermediate I is 1.2-1.3:1; the molar ratio of sodium carbonate to intermediate I in the sodium carbonate solution is 0.2-0.3:1. Further, step (3) is as follows: hydrogen chloride gas is continuously introduced into the toluene solution containing intermediate II under controlled temperature. When the pressure reaches 0.3~0.4MPa, the pressure is maintained for 2 hours and the reaction ends. After the reaction ends, the pH is adjusted, the solution is washed with water, and the solution is concentrated to obtain ethyl 2-chloronicotinic acid.

[0018] The beneficial effects of this invention are as follows: (1) The present invention uses a fixed bed instead of a traditional batch reaction vessel, which not only significantly improves the operational safety of the reaction equipment, but also effectively reduces the generation of peroxide impurities and optimizes the purity of the reaction products. Adding a small amount of sodium hydroxide to the reaction system can effectively inhibit the further reaction of intermediate I with dimethylamine to generate impurities and reduce the occurrence of side reactions. At the same time, it can also enhance the reactivation effect of manganese dioxide catalyst and further extend the cycle of catalyst use.

[0019] (2) By selecting manganese dioxide powder with qualified content and bulk density, this invention effectively ensures the hardness of the catalyst after molding and the strong adhesion between powders, extends the service life of the catalyst, and avoids abnormal reaction caused by catalyst damage. By preparing spherical particles that match the inner diameter of the fixed bed reaction tube bundle, the problem of flow deviation during liquid feeding can be effectively avoided, ensuring that the reactants and catalyst are in full contact, and improving the uniformity and stability of the reaction.

[0020] (3) The present invention uses oxygen-enriched air with an oxygen content of 25%~30%, which can effectively improve the reaction efficiency and the reactivation efficiency of manganese dioxide catalyst, shorten the reaction cycle, and reduce production energy consumption. The condensation reaction is carried out by adding sodium carbonate solution at high temperature and under reflux conditions with water, which effectively improves the condensation reaction rate. At the same time, by reasonably controlling the concentration of sodium carbonate solution, the water pressure of the system is reduced, and the solubility of sodium carbonate in the reaction system is ensured, avoiding reaction abnormalities caused by sodium carbonate precipitation, and further ensuring the smooth progress of the reaction and the stability of product quality.

[0021] In summary, this technical solution, through the synergistic effect of various technical measures, has achieved significant progress in improving reaction efficiency, reducing impurity content, ensuring equipment safety, extending catalyst lifespan, and reducing production costs, and has good industrial application value. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 The image shows the high-performance liquid chromatography (HPLC) chromatogram of intermediate I prepared in Example 1; in the image, RT=3.916 min represents 3-dimethylaminopropenal, and RT=5.062 min represents impurity I.

[0024] Figure 2 The figure shows the high performance liquid chromatography (HPLC) chromatogram of intermediate I prepared in Comparative Example 1; in the figure, RT=3.916 min represents 3-dimethylaminopropenal, and RT=5.056 min represents impurity I.

[0025] Figure 3 The image shows the high-performance liquid chromatography (HPLC) chromatogram of intermediate II prepared in Example 1. In the chromatogram, RT=3.966 min represents 3-dimethylaminopropenal, RT=5.647 min represents intermediate II, and RT=6.421 min represents toluene.

[0026] Figure 4The image shows the high-performance liquid chromatography (HPLC) chromatogram for the preparation of intermediate II in Comparative Example 2. In the chromatogram, RT=3.919 min represents 3-dimethylaminopropenal, RT=4.952 min represents impurity I, RT=5.659 min represents intermediate II, and RT=6.427 min represents toluene. Detailed Implementation

[0027] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0028] Example 1 A method for preparing a 2-chloronicotinic acid intermediate, the reaction formula is as follows: ; The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml was processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble silicate binder. 200 g of manganese dioxide powder was added to a rolling baller, and a silicate binder solution was sprayed while rolling. 50 g of manganese dioxide powder was added every 10 min. The balls were rolled at 50℃~60℃. The binder was 5%~6% of the mass of manganese dioxide. After the required particle size was achieved, the catalyst was gradient dried to 200℃ and then activated at 300℃~350℃. The catalyst was then loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor had a diameter of 40 mm and a length of 10 m. The catalyst packing height was 9.7~9.8 m.

[0029] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0030] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0031] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 34.4 kg. The content of intermediate I is 97.3% (area normalized) by HPLC detection, the content of impurity I is 1.3% (area normalized), the content of impurity I is 94.7% by HPLC quantitative detection, and the yield is 92.1%.

[0032] (5) Take 30 kg of intermediate I, add 120 kg of toluene and 38.9 kg of ethyl cyanoacetate. Heat the reaction system to 110℃~115℃, then add 15.9 kg of 25% sodium carbonate aqueous solution at 80℃~90℃. After the addition is complete, continue to keep warm for 1 hour. The residue of intermediate I is 0.31%, indicating that the condensation reaction is complete. Cool the reaction solution to 20℃, add 100 kg of water to the reaction solution, stir and separate the liquids. Add another 100 kg of water to the organic phase, adjust the pH of the aqueous phase to 6 with 30% hydrochloric acid, stir and separate the liquids. Add another 100 kg of water to the organic phase for washing, separate the liquids, and weigh the organic phase to 170 kg. Take a sample for testing. The quantitative content of intermediate II is 31.2%, and the yield is 95.3%.

[0033] (6) HCl was introduced into the toluene solution containing intermediate II obtained in step (5). When the pressure reached 0.3 MPa, the pressure was maintained at 0.3~0.4 MPa and the reaction continued for 2 hours. After the reaction was completed, water was added to the reaction solution and the pH was adjusted to 3~4 with 30% liquid alkali. The solution was separated, the organic phase was washed with water, and the organic phase was concentrated to obtain 48.9 kg of 2-chloronicotinic acid ethyl ester. The purity was 95% (area normalized) as determined by HPLC.

[0034] Example 2 Following the synthesis method disclosed in Example 1, the effect of the amount of dimethylamine (1.2:1) on the quality of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0035] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propynyl alcohol, and pass 19.3 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propynyl alcohol is 1.20:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0036] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0037] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 34.8 kg. The content of intermediate I is 95.8% (area normalized) according to HPLC. The content of impurity I is 2.7% (area normalized). The content of impurity I is 92.8% according to HPLC quantitative detection. The yield is 91.3%.

[0038] Example 3 Following the synthesis method disclosed in Example 1, the effect of the amount of sodium hydroxide (0.2%) in methanol on the mass of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0039] (2) Take 100 kg of methanol, add 0.2 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0040] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0041] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 34.5 kg. The content of intermediate I is 96.3% (area normalized) by HPLC and the content of impurity I is 1.9% (area normalized). The content of intermediate I is 93.8% by HPLC quantitative detection and the yield is 91.5%.

[0042] Example 4 Following the synthesis method disclosed in Example 1, the effect of the bulk density of manganese dioxide catalyst in a fixed-bed reactor on the mass of intermediate I was investigated. The specific steps are as follows: A catalyst was prepared by mixing manganese dioxide powder with a content of 90%–92% and a bulk density of 0.9–1.1 g / ml using a non-water-soluble binder. However, due to the high bulk density and fine powder morphology of the manganese dioxide powder, it was impossible to form spherical catalysts, resulting in severe powder shedding and an inability to fill the solid bed reactor. Therefore, the experiment failed.

[0043] Example 5 Following the synthesis method disclosed in Example 1, the effect of heating temperature in the fixed-bed reactor on the quality of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0044] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propynyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propynyl alcohol is 1.20:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0045] (3) The fixed bed reactor is heated to 50℃~55℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 3%~5% and the intermediate I content is >86% by online infrared display. After extending the reaction by 1h, the propynyl alcohol residue is no longer reduced. The reaction is stopped and the receiving tank is switched.

[0046] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 31.2 kg. The content of intermediate I is 94.3% (area normalized) by HPLC and the content of impurity I is 4.1% (area normalized). The content of impurity I is 91.7% by HPLC quantitative detection and the yield is 80.92%.

[0047] Example 6 Following the synthesis method disclosed in Example 1, the effect of the reaction pressure (1.0~1.2 MPa) in the fixed-bed reactor on the mass of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0048] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0049] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 1.0~1.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0050] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 32.1 kg. The content of intermediate I is 96.2% (area normalized) by HPLC and the content of impurity I is 1.4% (area normalized). The content of intermediate I is 93.7% by HPLC quantitative detection and the yield is 85.07%.

[0051] Example 7 Following the synthesis method disclosed in Example 1, the effect of the reaction pressure (2.0~2.2 MPa) in the fixed-bed reactor on the mass of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0052] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0053] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 2.0~2.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0054] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 33.6 kg. The content of intermediate I is 96.4% (area normalized) by HPLC and the content of impurity I is 1.3% (area normalized). The content of impurity I is 94.2% by HPLC quantitative detection and the yield is 89.52%.

[0055] Example 8 Following the synthesis method disclosed in Example 1, the effect of the air-to-liquid ratio (4:4.5) on the mass of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0056] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0057] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. Then, the methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 45kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0058] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 34.2 kg. The content of intermediate I is 97.2% (area normalized) according to HPLC. The content of impurity I is 1.2% (area normalized). The content of impurity I is 94.8% according to HPLC quantitative detection. The yield is 91.70%.

[0059] Example 9 Following the synthesis method disclosed in Example 1, the effect of the air-to-liquid ratio (4:2.5) on the quality of intermediate I was investigated. The specific steps are as follows: (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0060] (2) Take 100 kg of methanol, add 0.5 kg of sodium hydroxide granules, stir and dissolve at room temperature, cool down to 10°C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10°C to 20°C during the gas passage process.

[0061] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 25kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 3%~5% and the intermediate I content is >86% by online infrared display. After extending the reaction by 1h, the propynyl alcohol residue is no longer reduced. The reaction is stopped and the receiving tank is switched.

[0062] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain intermediate I 31.8 kg. The content of intermediate I is 96.3% (area normalized) according to HPLC. The content of impurity I is 1.5% (area normalized). The content of impurity I is 90.9% according to HPLC quantitative detection. The yield is 81.75%.

[0063] Based on the experimental results of Examples 3-9, it is recommended to reduce the amount of sodium hydroxide, reduce the fixed-bed reaction temperature, and increase the dimethylamine ratio. This will increase the amount of impurity I. Reducing the fixed-bed pressure will not have a significant effect on impurity I, but it will affect the yield of intermediate I. Reducing the oxygen-enriched air flux will also affect the yield of intermediate I.

[0064] Comparative Example 1 The effect of not adding sodium hydroxide to the reaction system during the preparation of intermediate I was investigated.

[0065] (1) Manganese dioxide powder with a content of 90%~92% and a bulk density of 0.4~0.5 g / ml is processed into spherical particles with a diameter of 1~1.5 mm using a non-water-soluble binder and loaded into the reaction tube bundle of a fixed-bed reactor. The reaction tube bundle of the fixed-bed reactor has a diameter of 40 mm, a length of 10 m, and a catalyst packing height of 9.7~9.8 m.

[0066] (2) Take 100 kg of methanol, cool it to 10 °C, add 20 kg of propargyl alcohol, and pass 18.5 kg of dimethylamine gas under sealed conditions. The molar ratio of dimethylamine to propargyl alcohol is 1.15:1. Maintain the solution temperature at 10 °C to 20 °C during the gas passage process.

[0067] (3) The fixed bed reactor is heated to 75℃~80℃ with hot water and oxygen-enriched air with an oxygen content of 25%~30% is introduced to make the fixed bed pressure reach 3.0~3.2MPa. The methanol solution of propynyl alcohol / dimethylamine is introduced into the fixed bed reactor. The liquid feed rate is stabilized at 40kg / h and the oxygen-enriched air rate is 30kg / h. The fixed bed pressure is stabilized by adjusting the opening of the fixed bed tail gas valve. At the same time, the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve. The propynyl alcohol residue is 0.2%~1% and the intermediate I content is >96% by online infrared display. After the reaction is stable, the receiving tank is switched.

[0068] (4) After the feeding is completed, the reaction solution that has passed the reaction is heated to 80°C and the solvent is removed under reduced pressure. Methanol is recovered to obtain 32 kg of intermediate I. The content of intermediate I is 82.9% (area normalized) according to HPLC. The content of impurity I is 16.3% (area normalized). The content of intermediate I is 85.7% according to HPLC quantitative detection.

[0069] It can be seen that without adding sodium hydroxide during the preparation of intermediate I, the content of impurity I in the prepared intermediate I is very high. Some intermediate I will continue to react with dimethylamine to generate impurity I, which will ultimately affect the purity of intermediate I.

[0070] Comparative Example 2 (1) Take 4 kg of intermediate I prepared in Example 1, add 16 kg of toluene and 5.2 kg of ethyl cyanoacetate. Heat the reaction system to 110℃~115℃, then add 2.12 kg of sodium carbonate aqueous solution with a mass concentration of 25% at 80℃~90℃. After the addition is complete, continue to keep warm for 1 h. The residual content of intermediate I is detected to be 2.42%. After continuing the reaction for 1 h, the content of intermediate I no longer decreases, and the condensation reaction is complete. Cool the reaction solution to 20℃, add 13.5 kg of water to the reaction solution, stir and separate the liquid. Add another 13.5 kg of water to the organic phase, adjust the pH of the aqueous phase to 6 with 30% hydrochloric acid, stir and separate the liquid. Add another 13.5 kg of water to the organic phase for washing, separate the liquid, and weigh the organic phase to be 22.9 kg. Take a sample for testing. The quantitative content of intermediate II is 25.6%, and the yield is 87.4%.

[0071] (2) HCl was introduced into the toluene solution containing intermediate II obtained in step (1). When the pressure reached 0.3 MPa, the pressure was maintained at 0.3~0.4 MPa and the reaction continued for 2 hours. After the reaction was completed, the reaction solution was washed with water and the organic phase was concentrated to obtain 41.5 kg of ethyl 2-chloronicotinic acid. The purity was 88.2% (area normalized) as determined by HPLC.

[0072] It can be seen that if sodium carbonate aqueous solution is added all at once during the preparation of intermediate II, the reaction of intermediate I will be incomplete, affecting the purity and yield of intermediate II. Consequently, the yield and purity of the product will be affected during the subsequent preparation of ethyl 2-chloronicotinic acid.

[0073] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing a 2-chloronicotinic acid intermediate, characterized in that, The reaction formula is as follows: ； Includes the following steps: (1) Manganese dioxide catalyst is packed in the reaction tube bundle of a fixed bed reactor. A methanol solution containing propynyl alcohol and sodium hydroxide is mixed with dimethylamine and continuously fed into the fixed bed reactor. The reaction pressure and reaction temperature are controlled to obtain intermediate I. (2) Intermediate I reacts with ethyl cyanoacetate to obtain intermediate II; (3) Intermediate II cyclizes under the action of hydrogen chloride to form ethyl 2-chloronicotinic acid.

2. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 1, characterized in that, The specific steps of step (1) are as follows: (A) Add sodium hydroxide to methanol, stir to dissolve, add propynyl alcohol, then pass dimethylamine gas into the methanol solution, and maintain the solution temperature below 20°C to obtain a methanol solution of propynyl alcohol / dimethylamine. (B) The fixed bed is heated to 75℃~80℃, and air with an oxygen content of 25%~30% is introduced to make the pressure of the fixed bed reactor reach 3.0~3.2Mpa; the methanol solution of propynyl alcohol / dimethylamine obtained in step (A) is continuously introduced, and the oxygen content in the tail gas is ensured to be >20% by adjusting the oxygen-enriched air inlet valve; (C) The solvent is removed from the qualified reaction solution to obtain intermediate I.

3. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 1, characterized in that, The reaction tube bundle of the fixed-bed reactor is filled with a manganese dioxide catalyst content of 90%~92% and a bulk density of 0.4~0.5g / ml. The manganese dioxide is processed into spherical particles with a diameter of 1~1.5mm using a non-water-soluble binder.

4. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 2, characterized in that, The mass ratio of the methanol solution feed rate of propargyl alcohol / dimethylamine to the air intake rate is 4~5:3~4.

5. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 2, characterized in that, In step (A), the amount of sodium hydroxide added is 0.1% to 0.5% based on the mass of methanol.

6. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 2, characterized in that, In step (A), the mass ratio of propynyl alcohol to methanol is 1:4~6.

7. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 2, characterized in that, In step (A), the molar ratio of dimethylamine to propynyl alcohol is 1.1~1.2:

1.

8. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 1, characterized in that, The specific steps of step (2) are as follows: Toluene was added to intermediate I, followed by ethyl cyanoacetate. The temperature was raised to 110℃~115℃, and a sodium carbonate aqueous solution with a mass concentration of 20%~30% was added dropwise at a temperature of 80℃~90℃. After the addition was complete, the reaction was maintained at the temperature until the reactants were completely reacted. The reaction system was then cooled to 20℃~30℃, and water was added to adjust the pH of the aqueous phase to 5~7. After washing with water again, the solution was separated to obtain a toluene solution containing intermediate II.

9. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 8, characterized in that, The amount of toluene used is 4-5 kg / kg based on the mass of intermediate I; the molar ratio of ethyl cyanoacetate to intermediate I is 1.2-1.3:1; the molar ratio of sodium carbonate to intermediate I in the sodium carbonate solution is 0.2-0.3:

1.

10. The method for preparing a 2-chloronicotinic acid intermediate as described in claim 1, characterized in that, Step (3) is as follows: hydrogen chloride gas is continuously introduced into the toluene solution containing intermediate II under controlled temperature. When the pressure reaches 0.3~0.4MPa, the pressure is maintained for 2 hours and the reaction ends. After the reaction is completed, the solution is washed with water and concentrated to obtain ethyl 2-chloronicotinic acid.

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