A method for preparing calcium gluconate using microchannel continuous flow reaction technology

Abstract

This invention relates to a method for preparing calcium gluconate using microchannel continuous flow reaction technology. Employing a Corning microchannel reactor for continuous production of calcium gluconate represents a breakthrough from conventional batch oxidation reaction processes. Under sodium nitrite / nitric acid reaction conditions, this invention utilizes a microchannel continuous flow reactor for oxidation followed by a salt conversion reaction to obtain calcium gluconate, achieving a total yield of over 90%. Compared to traditional processes, this technology offers faster reaction rates and shorter production times for calcium gluconate, solving the problem of uncontrolled exothermic reactions during scale-up in traditional batch batch reactors. It is simple to operate, significantly improves yield, allows for seamless scale-up, and minimizes environmental pollution, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug preparation technology, specifically relating to a microchannel continuous flow reaction technology for preparing calcium gluconate. Background Technology

[0002] Calcium gluconate (compound I) is a complex ion containing four chiral carbon atoms. It generally exists as a tetrahydrate and is easily converted into gluconate in the human body.

[0003] Gluconic acid has wide applications in various fields such as industry, medicine, health care, and food, leading to a significant increase in societal demand. It can not only enhance the body's natural defense mechanisms, eliminate carcinogens, and reduce the risk of cancer, but also serve as a precursor for nylon materials. With in-depth research in the pharmaceutical field, fortified milk powder and dairy products containing added calcium D-gluconate have been commercialized, and pharmaceutical formulations are under development. In 2004, due to the wide range of applications of gluconic acid and its derivatives, it was hailed by the U.S. Department of Energy as "the most valuable biorefined product."

[0004] The key to synthesizing calcium gluconate is the synthesis of gluconic acid. Currently, the main methods for synthesizing calcium gluconate are nitric acid oxidation and TEMPO oxidation. The traditional nitric acid oxidation method generates large amounts of nitrogen oxides, causing severe environmental pollution. Furthermore, the exothermic reaction is difficult to control, resulting in low yields and hindering industrial production. The TEMPO oxidation method is complex, requiring strict control of reaction temperature and pH, making it unsuitable for large-scale production. Therefore, there is an urgent need to find a new synthetic method to prepare potassium gluconate in high yield, with low cost, minimal environmental pollution, safe operation, and the ability to achieve industrial production. The structure of calcium gluconate is shown below:

[0005]

[0006] Existing reported preparation processes and advantages / disadvantages of calcium gluconate:

[0007] Patent WO9507303A1 uses glucose as a starting material, and through a TEMPO-NaClO-NaBr co-catalytic oxidation reaction, it produces sodium gluconate, which is then converted to potassium gluconate monosodium phosphate, and finally converted to calcium gluconate. The disadvantages of this method are that the reaction temperature needs to be controlled between 0℃ and 5℃, making the reaction conditions difficult to control; the post-processing is complex, and it is not suitable for large-scale production.

[0008]

[0009] Patent CN109678695B describes a catalytic oxidation reaction using glucose, oxygen, and a metal catalyst, palladium-vanadium ammonium, in a high-pressure reactor. A potassium-containing alkali is added, and gluconic acid is converted into potassium gluconic acid. The reaction is carried out through metal catalytic oxidation. However, the reaction requires the introduction of oxygen into the high-pressure reactor. Furthermore, literature reports that this method has poor product selectivity and high catalyst cost, which is not conducive to industrial production.

[0010]

[0011] Patent US2809989A describes the preparation of gluconic acid from glucose by oxidizing it with concentrated nitric acid. The advantages of nitric acid oxidation are that nitric acid acts as both a solvent and a reagent in the reaction, and the post-reaction processing is simple and easy to operate. The disadvantages are a low yield of only 20-30%, the release of a large amount of yellow-brown nitrogen dioxide toxic gas during the reaction, and the rapid exothermic temperature rise during the reaction, making scale-up uncontrollable and posing a risk of material spillage or even explosion.

[0012]

[0013] Based on a comprehensive analysis of the advantages and disadvantages of the above routes, it is necessary to invent a route that is highly productive, less polluting to the environment, safe to operate, and suitable for industrial production. Summary of the Invention

[0014] The purpose of this invention is to overcome the defects in the prior art and provide a method for preparing calcium gluconate using a microchannel continuous flow reactor.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0016] This invention provides a microchannel continuous flow reaction technique for preparing calcium gluconate, specifically including the following steps:

[0017]

[0018] S1 oxidation reaction

[0019] Glucose and purified water were added to the reaction flask, heated and stirred to dissolve, sodium nitrite was added and stirred until dissolved, resulting in mixture A. Mixture A and nitric acid solution were fed into the microreactor via a feed pump for rapid mixing to initiate the reaction. Purified water was added to the effluent, and the pH was adjusted to 9-11 with alkali. The mixture was heated and stirred, then cooled, and acid was added to adjust the pH to 3-4. The mixture was kept at the same temperature and stirred, filtered, and post-treated to obtain a white solid compound III.

[0020] S2 salt conversion reaction

[0021] Compound III and purified water were added to the reaction flask. Nitric acid was slowly added under controlled temperature, and the mixture was kept warm and stirred. Calcium hydroxide was added, and the pH was adjusted to 7-9 with alkali. The mixture was then stirred under controlled temperature, filtered, and dried after post-treatment to obtain calcium gluconate.

[0022] As a further improvement of the present invention, the molar ratio of glucose, nitric acid and sodium nitrite in step S1 is 1:2 to 6:0.03 to 0.2.

[0023] As a further improvement of the present invention, in step S1, the mass ratio of purified water to glucose in mixture A is 75-220:200, and the concentration of the nitric acid solution is 65%.

[0024] As a further improvement of the present invention, in step S1, the back pressure at the tail end of the microchannel continuous flow reactor is set to 4.5 to 5.5 bar, the temperature of the circulating liquid in the reactor jacket is 105 to 115°C, the flow rate of the mixture A is 12.5 to 13 g / min, and the flow rate of the nitric acid solution is 18.6 to 19.2 g / min.

[0025] As a further improvement of the present invention, in step S1, purified water equivalent to 60-80% of the mass of the raw glucose is added to the effluent.

[0026] As a further improvement of the present invention, in step S1, the pH is adjusted to 9-11, the temperature is raised to 55-65℃ and stirred for 0.5-1.5h, the temperature is lowered to 0℃-10℃, acid is added to adjust the pH to 3-4, and the temperature is maintained and stirred for 1.5-2.5h.

[0027] As a further improvement of the present invention, in step S2, the weight ratio of compound III to calcium hydroxide is 1:0.2 to 1:0.4; the weight ratio of compound III to nitric acid is 1:0.25 to 1:0.3; and the weight ratio of compound III to purified water is 1:8 to 1:10.

[0028] As a further improvement of the present invention, in step S2, the reaction temperature of step S2 is 25℃~35℃.

[0029] As a further improvement of the present invention, the post-treatment of step S1 is to add the filter cake to purified water, stir and filter, wash the filter cake with purified water first, then wash it with acetone, dry the filter cake, and obtain a white solid compound III.

[0030] In step S2, the post-treatment involves adding the filter cake to purified water, keeping it warm and stirring, filtering, washing with purified water, and drying the filter cake to obtain compound I.

[0031] As a further improvement of the present invention, in step S1, the alkali is selected from potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, and sodium carbonate; the acid is selected from concentrated nitric acid, concentrated sulfuric acid, hydrochloric acid, and phosphoric acid; in step S2, the alkali is sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0032] The beneficial effects of adopting the above technical solution are as follows:

[0033] (1) This invention utilizes a Corning microchannel reactor to continuously produce calcium gluconate, representing a breakthrough from conventional batch oxidation processes. To date, there have been no reports on process research and equipment technology for the continuous flow reaction of glucose to produce calcium gluconate.

[0034] (2) Through design and research, this application has developed a technical solution for the continuous production of calcium gluconate in microchannels by adjusting the reaction temperature, material concentration and flow rate. It has the advantages of fast reaction speed, short reaction time, and excellent mass and heat transfer characteristics, which solves the problem of difficult heat control in large-scale production. It is simple to operate, has a high yield, and can achieve seamless scale-up. The entire production process has less environmental pollution and is suitable for industrial production.

[0035] (3) The present invention has mild conditions, simple operation, and a total yield of over 90%. Attached Figure Description

[0036] Figure 1 The 1H NMR spectrum of calcium gluconate obtained in Example 1 of this invention;

[0037] Figure 2 This is the carbon spectrum of calcium gluconate obtained in Example 1 of the present invention. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of the present invention clearer, the invention will be described clearly and completely below in conjunction with specific embodiments.

[0039] Example 1

[0040] S1 oxidation reaction

[0041] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain mixture A. Add 440.0g 65% nitric acid to a 1L reaction flask for later use.

[0042] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 110°C in the reactor jacket. Mixture A and nitric acid solution were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, controlling the flow rate of mixture A at 12.7 g / min and the flow rate of nitric acid solution at 18.9 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 95.0%.

[0043] S2 salt conversion reaction

[0044] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The mixture was kept at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. Then, 18.0 g of calcium hydroxide was added at 30 °C, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. The mixture was then filtered again, washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I (calcium gluconate), with a yield of 98.0%. 1 H-NMR, 400MHz, D2O) δ: 3.977-3.998 (m, 1H), 4.147-4.164 (m, 1H), 4.367-4.377 (m, 1H), 4.488-4.493 (m, 1H), spectrum is as follows Figure 1 ;( 13 C-NMR, 400MHz, DMSO-d6) δ: 72.54, 72.64, 72.93, 74.33, 176.80, 177.12, spectral values ​​are as follows Figure 2 The content (titration method) is 100.0%, and the calcium content (ion chromatography method) is 99.9%.

[0045] Example 2

[0046] S1 oxidation reaction

[0047] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 2.1g sodium nitrite and stir until dissolved to obtain solution A. Add 193.8g nitric acid to a 1L reaction flask to obtain solution B.

[0048] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 110°C in the reactor jacket. Solutions A and B were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, with the flow rates of solution A controlled at 12.7 g / min and solution B at 18.9 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 94.3%.

[0049] S2 salt conversion reaction

[0050] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 15.0 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. At 30 °C, 12.0 g of calcium hydroxide was added, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 25 °C–35 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. The mixture was filtered again, washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I, with a yield of 97.6%, a purity (titration method) of 99.5%, and a calcium content (ion chromatography method) of 99.7%.

[0051] Example 3

[0052] S1 oxidation reaction

[0053] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 65℃, stir until dissolved, then add 14.0g sodium nitrite and stir until dissolved to obtain solution A. Add 581.0g nitric acid to a 1L reaction flask to obtain solution B.

[0054] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 110°C in the reactor jacket. Solutions A and B were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, with the flow rates of solution A controlled at 12.7 g / min and solution B at 18.9 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, and concentrated nitric acid was added to adjust the pH to 3.5. The mixture was then stirred at 5°C for 2 hours. After filtration, the filter cake was added to 2000 g of purified water and stirred at 5°C for 1 hour. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain compound III, with a yield of 94.0%.

[0055] S3 salt conversion reaction

[0056] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The mixture was kept at 30 °C, and 18.0 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. Then, 24.0 g of calcium hydroxide was added at 30 °C, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. The mixture was then filtered again, washed with 120.0 g of purified water, and the filter cake was vacuum dried at 45 °C to obtain calcium gluconate. The yield was 97.4%, the content (titration method) was 99.5%, and the calcium content (ion chromatography method) was 99.6%.

[0057] Example 4

[0058] S1 oxidation reaction

[0059] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 65℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain solution A. Add 440.0g nitric acid to a 1L reaction flask to obtain solution B.

[0060] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 110°C in the reactor jacket. Solutions A and B were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, with the flow rates of solution A controlled at 12.7 g / min and solution B at 18.9 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 9 using a 10% potassium carbonate aqueous solution. The temperature was raised to 60°C and stirred for 1 h. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.0, and the mixture was stirred for 2 h at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 h at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain compound III, with a yield of 93.9%.

[0061] S2 salt conversion reaction

[0062] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. At 30 °C, 18.0 g of calcium hydroxide was added, followed by adjustment of the pH to 7 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. The mixture was filtered again, washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I, with a yield of 97.9%, a purity (titration method) of 99.7%, and a calcium content (ion chromatography method) of 99.6%.

[0063] Example 5

[0064] S1 oxidation reaction

[0065] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 65℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain solution A. Add 440.0g nitric acid to a 1L reaction flask to obtain solution B.

[0066] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 105°C in the reactor jacket. Solutions A and B were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, with the flow rates of solution A controlled at 12.5 g / min and solution B at 18.6 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 9 using a 10% potassium carbonate aqueous solution. The temperature was raised to 65°C and stirred for 1 hour. The temperature was lowered to 3°C, concentrated nitric acid was added to adjust the pH to 3.0, and the mixture was stirred at 5°C for 2 hours. After filtration, the filter cake was added to 2000 g of purified water and stirred at 3°C ​​for 1 hour. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain compound III, with a yield of 93.5%.

[0067] S2 salt conversion reaction

[0068] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The mixture was kept at 25 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. At 25 °C, 18.0 g of calcium hydroxide was added, followed by adjustment of the pH to 7 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 25 °C for 1 h. The mixture was then filtered again, washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I, with a yield of 97.2%, a purity (titration method) of 99.4%, and a calcium content (ion chromatography method) of 99.4%.

[0069] Comparative Example 1

[0070] S1 oxidation reaction

[0071] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain mixture A. Add 440.0g 65% nitric acid to a 1L reaction flask for later use.

[0072] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 95°C in the reactor jacket. Mixture A and nitric acid solution were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, controlling the flow rate of mixture A at 12.7 g / min and the flow rate of nitric acid solution at 18.9 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 93.3%.

[0073] S2 salt conversion reaction

[0074] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. Then, 18.0 g of calcium hydroxide was added at 30 °C, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. After filtration, the mixture was washed with 120.0 g of purified water. The filter cake was dried under vacuum at 45 °C to obtain compound I (calcium gluconate), with a yield of 97.8%, a purity (titration method) of 99.7%, and a calcium content (ion chromatography method) of 99.6%.

[0075] Comparative Example 2

[0076] S1 oxidation reaction

[0077] Add 200.0g glucose and 100.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain mixture A. Add 440.0g 65% nitric acid (concentration 14.4mol / L) to a 1L reaction flask for later use.

[0078] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 105°C in the reactor jacket. Mixture A and nitric acid solution were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, controlling the flow rate of mixture A at 12.0 g / min and the flow rate of nitric acid solution at 18.5 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 93.0%.

[0079] S2 salt conversion reaction

[0080] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. At 30 °C, 18.0 g of calcium hydroxide was added, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. The mixture was filtered again, washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I (calcium gluconate), with a yield of 97.7%, a purity (titration method) of 99.6%, and a calcium content (ion chromatography method) of 99.6%.

[0081] Comparative Example 3

[0082] S1 oxidation reaction

[0083] Add 200.0g glucose and 110.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain mixture A. Add 440g 65% nitric acid to a 1L reaction flask for later use.

[0084] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 116°C in the reactor jacket. Mixture A and nitric acid solution were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, controlling the flow rate of mixture A at 13.1 g / min and the flow rate of nitric acid solution at 19.3 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 92.5%.

[0085] S2 salt conversion reaction

[0086] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. Then, 18.0 g of calcium hydroxide was added at 30 °C, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. After filtration, the mixture was washed with 120.0 g of purified water. The filter cake was dried under vacuum at 45 °C to obtain compound I (calcium gluconate), with a yield of 97.1%, a purity (titration method) of 99.2%, and a calcium content (ion chromatography method) of 99.3%.

[0087] Comparative Example 4

[0088] S1 oxidation reaction

[0089] Add 200.0g glucose and 90.0g purified water to a 1L reaction flask, heat to 60℃, stir until dissolved, then add 6.8g sodium nitrite and stir until dissolved to obtain mixture A. Add 440g 65% nitric acid to a 1L reaction flask for later use.

[0090] The Corning G1 microchannel continuous flow reactor was set with a back pressure of 5 bar at the tail end and a circulating liquid temperature of 104°C in the reactor jacket. Mixture A and nitric acid solution were pumped into the first mixing plate of the Corning G1 reactor using a feed pump, controlling the flow rate of mixture A at 12.4 g / min and the flow rate of nitric acid solution at 18.5 g / min. The reaction liquid flowing out from the 10th plate was collected. After collection, 140.0 g of purified water was added to the effluent, and the pH of the reaction liquid was adjusted to 10 using a 10% potassium hydroxide aqueous solution. The temperature was raised to 60°C and stirred for 1 hour. The temperature was lowered to 5°C, concentrated nitric acid was added to adjust the pH to 3.5, and the mixture was stirred for 2 hours at 5°C. After filtration, the filter cake was added to 2000 g of purified water and stirred for 1 hour at 5°C. After filtration, the filter cake was washed with 200 g of purified water and then with 100 g of acetone. The filter cake was vacuum dried at 55°C to obtain a white solid compound III, with a yield of 92.1%.

[0091] S2 salt conversion reaction

[0092] 60.0 g of compound III and 540.0 g of purified water were added to a 1 L reaction flask. The temperature was maintained at 30 °C, and 16.8 g of nitric acid was slowly added. The mixture was stirred at 30 °C for 0.5 h. Then, 18.0 g of calcium hydroxide was added at 30 °C, followed by adjustment of the pH to 8 with 10% potassium hydroxide solution. After adjustment, the mixture was stirred at 30 °C for 2 h. The mixture was filtered, and the filter cake was added to 600.0 g of purified water. The mixture was stirred at 30 °C for 1 h. After filtration, the mixture was washed with 120.0 g of purified water, and the filter cake was dried under vacuum at 45 °C to obtain compound I (calcium gluconate) with a yield of 97.0%. The purity (titration method) was 99.3%, and the calcium content (ion chromatography method) was 99.3%.

[0093] As can be seen from the above embodiments, the method provided by the present invention can not only realize the industrial production of calcium gluconate, but also improve the yield of the final product and reduce environmental pollution.

[0094] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing calcium gluconate using microchannel continuous flow reaction technology, characterized in that, Specifically, the steps include the following: ； S1 oxidation reaction Glucose and purified water were added to the reaction flask, heated and stirred to dissolve, sodium nitrite was added and stirred to dissolve, resulting in mixture A. Mixture A and nitric acid solution were fed into the microreactor through a feed pump for rapid mixing to initiate the reaction. Purified water was added to the effluent, and the pH was adjusted to 9-11 with potassium hydroxide. The mixture was heated and stirred, cooled, and acid was added to adjust the pH to 3-4. The mixture was kept at the temperature and stirred, filtered, and post-treated to obtain white solid compound III. S2 salt conversion reaction Compound III and purified water were added to the reaction flask. Nitric acid was slowly added under controlled temperature, and the mixture was kept warm and stirred. Calcium hydroxide was added, and the pH was adjusted to 7-9 with potassium hydroxide. The mixture was kept warm and stirred, filtered, and then dried after post-treatment to obtain calcium gluconate.

2. The method according to claim 1, characterized in that, In step S1, the molar ratio of glucose, nitric acid, and sodium nitrite is 1:2~6:0.03~0.

2.

3. The method according to claim 1, characterized in that, In step S1, the ratio of purified water to glucose in mixture A is 75-220:200, and the concentration of the nitric acid solution is 65%.

4. The method according to claim 1, characterized in that, In step S1, the microchannel continuous flow reactor is set with a tail back pressure of 4.5~5.5 bar, the temperature of the circulating liquid in the reactor jacket is 105~115℃, the flow rate of the mixture A is 12.5~13 g / min, and the flow rate of the nitric acid solution is 18.6~19.2 g / min.

5. The method according to claim 1, characterized in that, In step S1, purified water equivalent to 60-80% of the mass of the raw glucose is added to the effluent.

6. The method according to claim 1, characterized in that, In step S1, the pH is adjusted to 9-11, the temperature is raised to 55-65℃ and stirred for 0.5-1.5 hours, the temperature is lowered to 0℃-10℃, acid is added to adjust the pH to 3-4, and the mixture is kept warm and stirred for 1.5-2.5 hours.

7. The method according to claim 1, characterized in that, In step S2, the weight ratio of compound III to calcium hydroxide is 1:0.2 to 1:0.4; the weight ratio of compound III to nitric acid is 1:0.25 to 1:0.3; and the weight ratio of compound III to purified water is 1:8 to 1:

10.

8. The method according to claim 1, characterized in that, In step S2, the reaction temperature is 25℃~35℃.

9. The method according to claim 1, characterized in that, The post-processing of step S1 involves adding the filter cake to purified water, stirring and filtering, washing the filter cake with purified water first, then washing it with acetone, and drying the filter cake to obtain a white solid compound III. In step S2, the post-treatment involves adding the filter cake to purified water, keeping it warm and stirring, filtering, washing with purified water, and drying the filter cake to obtain compound I.

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