Method for producing mecobalamin by using microchannel reactor
The production of methylcobalamin through a microchannel reactor, combined with strictly controlled reaction temperature and light-proof conditions, solves the problem of easy decomposition of methylcobalamin in traditional methods and achieves efficient, automated, high-quality production of methylcobalamin.
Patent Information
- Application Number
- CN202410331417.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-22
- Publication Date
- 2025-09-23
AI Technical Summary
Traditional methylcobalamin production methods result in poor product quality, many by-products, low yield, long reaction time, and the inability to effectively protect against light, which makes methylcobalamin easy to decompose.
A microchannel reactor is used to carry out cyanocobalamin reduction and methylation reactions, combined with a purification post-treatment process, strictly controlling the reaction temperature and light-shielding conditions, to produce methylcobalamin through the first and second microchannel reactors, and subsequently undergoing purification treatment.
The production efficiency and product quality of methylcobalamin are improved, by-products are reduced, high-yield and high-purity methylcobalamin production is achieved, human errors are avoided, and fully automated production is supported.
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Figure CN120682282A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for producing methylcobalamin by utilizing a microchannel reactor. Background Art
[0002] Methylcobalamin is an important vitamin B12 derivative that plays an important role in promoting nerve growth and repairing nerve damage. It is widely used in medicine, biology and other fields.
[0003] Microchannel reaction technology is a continuous flow reaction technology with microreactors as core components. This technology has the characteristics of efficient heat transfer, efficient mass transfer, and rapid reaction. In addition, the reaction speed is controllable and the reaction scale can be flexibly adjusted, making it very suitable for chemical synthesis.
[0004] Traditional methylcobalamin production methods primarily utilize chemical synthesis. However, due to its light sensitivity, conventional production equipment lacks effective light protection, resulting in some methylcobalamin being susceptible to photodecomposition. This leads to shortcomings such as poor product quality, numerous byproducts, and low yields. Furthermore, conventional production methods also have long reaction times, which also impact production efficiency. Therefore, developing an efficient, reliable, and rapid synthesis method is of great significance. Summary of the Invention
[0005] The present invention provides a method for producing methylcobalamin using a microchannel reactor. By carrying out a cyanocobalamin reduction reaction in a first microchannel reactor and a methylation reaction in a second microchannel reactor, combined with a post-purification treatment process, the reaction temperature can be precisely controlled, the generation of impurities is greatly suppressed, and the quality of the product is effectively improved.
[0006] In order to achieve the above object, the technical solution adopted by the present invention is:
[0007] A method for producing methylcobalamin using a microchannel reactor, characterized by comprising:
[0008] S1: Passing a reaction mixture of cyanocobalamin, cobalt chloride, sodium borohydride, and purified water into a first microchannel reactor for reduction reaction to obtain a reduced cyanocobalamin solution;
[0009] S2: passing the reduced cyanocobalamin solution into a second microchannel reactor for methylation reaction with a trimethylsulfoxide iodide solution to obtain a methylcobalamin solution;
[0010] S3: The methylcobalamin solution is subjected to post-purification treatment, including a concentration step after adding acetic acid to adjust the pH value, a macroporous resin adsorption and analysis step, and an acetone recrystallization step to obtain a methylcobalamin product.
[0011] Wherein, steps S1-S2 are carried out under nitrogen and light-proof conditions, and step S3 is carried out under light-proof conditions.
[0012] In step S1, the weight ratio of cyanocobalamin: cobalt chloride: sodium borohydride: purified water is 1 kg: 0.1-0.5 kg: 0.1-1.0 kg: 20-40 kg.
[0013] Wherein, the reduction reaction temperature in step S1 is 20-30° C., and the flow rate is 40-50 L / min.
[0014] Wherein, the methylation reaction temperature in step S2 is 20-30° C., and the flow rate is 40-50 L / min.
[0015] The concentration of the trimethylsulfoxide iodide solution is 1.5% (w / v), the feed flow rate is 5-10 L / min, and the feed volume is 20-30 L.
[0016] Wherein, the centrifuge speed in step S3 is 500-1000 rpm.
[0017] Wherein, in step S3, the pH value of the methylcobalamin clear solution is adjusted to 4.0-7.0.
[0018] The temperature of evaporation and concentration in step S3 is 50-70°C.
[0019] Wherein, in step S3, the crystallization time is 5-10 hours and the crystallization temperature is -10 to -20°C.
[0020] Wherein, in step S3, the drying temperature of the wet methylcobalamin crystals is 50-70° C. and the drying time is 5-10 h.
[0021] The technical solution of the present invention has at least the following beneficial technical effects:
[0022] 1. By utilizing microchannel reaction to produce methylcobalamin, the reaction temperature and residence time are strictly controlled, the production efficiency of methylcobalamin is improved, and the reaction by-products are reduced. At the same time, the post-processing of the reaction is greatly simplified, and the losses caused by each post-processing step are reduced, thereby effectively improving the synthesis efficiency;
[0023] 2. The selected microchannel reactor can enhance mass transfer and heat transfer performance, maintain a constant reaction temperature, avoid temperature fluctuations, reduce the generation of by-products, and improve the safety of the reaction process;
[0024] 3. The compact structure of the microchannel reactor can significantly reduce reaction time and production costs. The microchannel reactor can be combined flexibly (parallel or series), and the production scale can be easily scaled up. The device has good light protection, high yield, and good product quality. It can achieve fully automated production, reduce human error, and process data can be recorded and transmitted in real time, facilitating operator control.
[0025] 4. The production method provided by the present invention effectively improves the content and yield of the target product, while reducing single impurities. The experimental results show that the single impurity content of the product is less than 0.2%, the yield is more than 95%, and the purity is more than 99%. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 Schematic diagram of the process flow of the production method of the present invention DETAILED DESCRIPTION
[0027] The present invention is described below with reference to examples. It should be understood that the examples are for the purpose of illustrating the present invention rather than limiting the present invention. The scope and core content of the present invention are determined by reference to the claims.
[0028] In the following embodiments, microchannel reactor c is the first microchannel reactor, and microchannel reactor e is the second microchannel reactor.
[0029] Example 1
[0030] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.1kg:0.1kg:20kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0031] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0032] 3. Set the temperature of microchannel reactor c to 20°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0033] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 5 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen should be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 20°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0034] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0035] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 4.0 with acetic acid, and then evaporated and concentrated at 50° C. to obtain a methylcobalamin concentrate.
[0036] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0037] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0038] 9. Dry the wet methylcobalamin crystals in step 8 at 50° C. for 5 h, and sieve to obtain the finished methylcobalamin product.
[0039] Strictly avoid light during steps 2 to 9.
[0040] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 99.21% and a single impurity of 0.15% (the standard is no more than 0.5%). The yield of methylcobalamin in this case was 95.68%.
[0041] Example 2
[0042] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.1kg:0.1kg:20kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0043] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0044] 3. Set the temperature of microchannel reactor c to 30°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0045] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 5 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen should be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 20°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0046] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0047] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 4.0 with acetic acid, and then evaporated and concentrated at 50° C. to obtain a methylcobalamin concentrate.
[0048] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0049] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0050] 9. Dry the wet methylcobalamin crystals in step 8 at 50° C. for 5 h, and sieve to obtain the finished methylcobalamin product.
[0051] Strictly avoid light during steps 2 to 9.
[0052] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, and the content was 99.25%, and the single impurity was 0.12% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 96.14%.
[0053] Example 3
[0054] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.1kg:0.1kg:20kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0055] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0056] 3. Set the temperature of microchannel reactor c to 20°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0057] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 5 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen must be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 30°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0058] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0059] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 5.0 with acetic acid, and then evaporated and concentrated at 50° C. to obtain a methylcobalamin concentrate.
[0060] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0061] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0062] 9. Dry the wet methylcobalamin crystals in step 8 at 50° C. for 5 h, and sieve to obtain the finished methylcobalamin product.
[0063] Strictly avoid light during steps 2 to 9.
[0064] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 99.78% and a single impurity of 0.14% (the standard is no more than 0.5%). The yield of methylcobalamin in this case was 96.15%.
[0065] Example 4
[0066] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.1kg:0.1kg:20kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0067] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0068] 3. Set the temperature of microchannel reactor c to 20°C and the flow rate to 50 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0069] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 5 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen should be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 20°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0070] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0071] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 5.0 with acetic acid, and then evaporated and concentrated at 60° C. to obtain a methylcobalamin concentrate.
[0072] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0073] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0074] 9. Dry the wet methylcobalamin crystals in step 8 at 60° C. for 5 h, and sieve to obtain the finished methylcobalamin.
[0075] Strictly avoid light during steps 2 to 9.
[0076] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 98.98% and a single impurity of 0.10% (the standard is no more than 0.5%). The yield of methylcobalamin in this case was 97.22%.
[0077] Example 5
[0078] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.5kg:1.0kg:40kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0079] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0080] 3. Set the temperature of microchannel reactor c to 20°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0081] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 10 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen should be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 20°C and the flow rate to 50 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0082] 5. The methylation reaction solution of step 4 was centrifuged at 1000 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0083] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 6.0 with acetic acid, and then evaporated and concentrated at 60° C. to obtain a methylcobalamin concentrated solution.
[0084] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0085] 8. The purified methylcobalamin solution of step 7 was crystallized at -20°C for 10 h and centrifuged at 1000 rpm to obtain wet methylcobalamin crystals.
[0086] 9. Dry the wet methylcobalamin crystals in step 8 at 60° C. for 10 h, and sieve to obtain the finished methylcobalamin.
[0087] Strictly avoid light during steps 2 to 9.
[0088] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 99.75% and a single impurity of 0.17% (the standard is no more than 0.5%). The yield of methylcobalamin in this case was 95.34%.
[0089] Example 6
[0090] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.5kg:1.0kg:40kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0091] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0092] 3. Set the temperature of microchannel reactor c to 30°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0093] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 10 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen must be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 30°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0094] 5. The methylation reaction solution of step 4 was centrifuged at 1000 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0095] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 6.0 with acetic acid, and then evaporated and concentrated at 60° C. to obtain a methylcobalamin concentrated solution.
[0096] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0097] 8. The purified methylcobalamin solution of step 7 was crystallized at -20°C for 10 h and centrifuged at 1000 rpm to obtain wet methylcobalamin crystals.
[0098] 9. Dry the wet methylcobalamin crystals in step 8 at 60° C. for 10 h, and sieve to obtain the finished methylcobalamin.
[0099] Strictly avoid light during steps 2 to 9.
[0100] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 99.34% and a single impurity of 0.15% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 95.22%.
[0101] Example 7
[0102] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.5kg:1.0kg:40kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0103] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0104] 3. Set the temperature of microchannel reactor c to 30°C and the flow rate to 50 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0105] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 10 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen must be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 30°C and the flow rate to 40 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0106] 5. The methylation reaction solution of step 4 was centrifuged at 1000 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0107] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 7.0 with acetic acid, and then evaporated and concentrated at 70° C. to obtain a methylcobalamin concentrate.
[0108] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0109] 8. The purified methylcobalamin solution of step 7 was crystallized at -20°C for 10 h and centrifuged at 1000 rpm to obtain wet methylcobalamin crystals.
[0110] 9. Dry the wet methylcobalamin crystals in step 8 at 70° C. for 10 h, and sieve to obtain the finished methylcobalamin product.
[0111] Strictly avoid light during steps 2 to 9.
[0112] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 99.26% and a single impurity of 0.16% (the standard is no more than 0.5%). The yield of methylcobalamin in this case was 96.78%.
[0113] Example 8
[0114] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in the ratio of 1kg:0.5kg:1.0kg:40kg to preparation tank a and dissolve them to prepare a reaction mixture.
[0115] 2. Pump the reaction mixture into premixer b for mixing, and at the same time, introduce high-purity nitrogen into premixer b for deoxygenation. Nitrogen must be introduced continuously throughout the process.
[0116] 3. Set the temperature of microchannel reactor c to 30°C and the flow rate to 40 L / min, and pump the reaction solution into microchannel reactor c for reduction reaction.
[0117] 4. Pump a 1.5% trimethylsulfoxide iodide solution into premixer d at a feed rate of 10 L / min and a feed volume of 30 L. Simultaneously, introduce high-purity nitrogen into premixer d to remove oxygen. Nitrogen should be continuously introduced throughout the entire process. Set the temperature of microchannel reactor e to 30°C and the flow rate to 50 L / min. Pump the reaction solution into microchannel reactor e for the methylation reaction.
[0118] 5. The methylation reaction solution of step 4 was centrifuged at 1000 rpm for separation, and the supernatant was collected in a supernatant tank f to obtain a methylcobalamin supernatant.
[0119] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 7.0 with acetic acid, and then evaporated and concentrated at 70° C. to obtain a methylcobalamin concentrate.
[0120] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0121] 8. The purified methylcobalamin solution of step 7 was crystallized at -20°C for 10 h and centrifuged at 1000 rpm to obtain wet methylcobalamin crystals.
[0122] 9. Dry the wet methylcobalamin crystals in step 8 at 70° C. for 10 h, and sieve to obtain the finished methylcobalamin product.
[0123] Strictly avoid light during steps 2 to 9.
[0124] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, and the content was 99.11%, and the single impurity was 0.11% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 95.12%.
[0125] Comparative Example 1
[0126] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in a ratio of 1kg:0.1kg:0.1kg:20kg into a preparation tank and dissolve them to form a reaction mixture.
[0127] 2. Pump the reaction mixture into the reaction tank and introduce high-purity nitrogen to remove oxygen.
[0128] 3. Set the temperature of the reaction tank to 20°C, start stirring, and carry out the reduction reaction.
[0129] 4. Pump 30 L of 1.5% trimethylsulfoxide iodide solution into the reaction tank, and simultaneously introduce high-purity nitrogen to remove oxygen. Nitrogen must be introduced continuously throughout the process. Set the reaction temperature to 20° C. for methylation reaction.
[0130] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank to obtain a methylcobalamin supernatant.
[0131] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 4.0 with acetic acid, and then evaporated and concentrated at 50° C. to obtain a methylcobalamin concentrate.
[0132] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0133] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0134] 9. Dry the wet methylcobalamin crystals in step 8 at 50° C. for 5 h, and sieve to obtain the finished methylcobalamin product.
[0135] Strictly avoid light during steps 2 to 9.
[0136] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, with a content of 97.15% and a single impurity of 0.49% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 93.61%.
[0137] Comparative Example 2
[0138] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in a ratio of 1kg:0.1kg:0.1kg:30kg into a preparation tank and dissolve them to form a reaction mixture.
[0139] 2. Pump the reaction mixture into the reaction tank and introduce high-purity nitrogen to remove oxygen.
[0140] 3. Set the temperature of the reaction tank to 25°C, start stirring, and carry out the reduction reaction.
[0141] 4. Pump 30 L of 1.5% trimethylsulfoxide iodide solution into the reaction tank, and simultaneously introduce high-purity nitrogen to remove oxygen. Nitrogen should be introduced continuously throughout the process. Set the reaction temperature to 25° C. for methylation reaction.
[0142] 5. The methylation reaction solution of step 4 was centrifuged at 500 rpm for separation, and the supernatant was collected in a supernatant tank to obtain a methylcobalamin supernatant.
[0143] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 6.0 with acetic acid, and then evaporated and concentrated at 60° C. to obtain a methylcobalamin concentrated solution.
[0144] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0145] 8. The purified methylcobalamin solution of step 7 was crystallized at -10°C for 5 h and centrifuged at 500 rpm to obtain wet methylcobalamin crystals.
[0146] 9. Dry the wet methylcobalamin crystals in step 8 at 60° C. for 5 h, and sieve to obtain the finished methylcobalamin.
[0147] Strictly avoid light during steps 2 to 9.
[0148] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, and the content was 96.15%, and the single impurity was 0.46% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 90.12%.
[0149] Comparative Example 3
[0150] 1. Add cyanocobalamin, cobalt chloride, sodium borohydride and purified water in a ratio of 1kg:0.1kg:0.1kg:40kg into a preparation tank and dissolve them to form a reaction mixture.
[0151] 2. Pump the reaction mixture into the reaction tank and introduce high-purity nitrogen to remove oxygen.
[0152] 3. Set the temperature of the reaction tank to 30°C, start stirring, and carry out the reduction reaction.
[0153] 4. Pump 30 L of 1.5% trimethylsulfoxide iodide solution into the reaction tank, and simultaneously introduce high-purity nitrogen to remove oxygen. Nitrogen must be introduced continuously throughout the process. Set the reaction temperature to 30° C. for methylation reaction.
[0154] 5. The methylation reaction solution of step 4 was centrifuged at 1000 rpm for separation, and the supernatant was collected in a supernatant tank to obtain a methylcobalamin supernatant.
[0155] 6. The pH value of the methylcobalamin solution in step 5 was adjusted to 7.0 with acetic acid, and then evaporated and concentrated at 70° C. to obtain a methylcobalamin concentrate.
[0156] 7. The methylcobalamin concentrate of step 6 is purified by macroporous adsorption resin-acetone to obtain a purified methylcobalamin solution.
[0157] 8. The purified methylcobalamin solution of step 7 was crystallized at -20°C for 10 h and centrifuged at 1000 rpm to obtain wet methylcobalamin crystals.
[0158] 9. Dry the wet methylcobalamin crystals in step 8 at 70° C. for 10 h, and sieve to obtain the finished methylcobalamin product.
[0159] Strictly avoid light during steps 2 to 9.
[0160] The methylcobalamin obtained in this example was tested according to the method of the 2020 edition of the Chinese Pharmacopoeia, and the content was 95.98%, and the single impurity was 0.48% (the standard is not more than 0.5%). The yield of methylcobalamin in this case was 91.25%.
[0161] Effect comparison:
[0162]
Claims
1. A method for producing methylcobalamin using a microchannel reactor, characterized in that: include: S1: Passing a reaction mixture of cyanocobalamin, cobalt chloride, sodium borohydride, and purified water into a first microchannel reactor for reduction reaction to obtain a reduced cyanocobalamin solution; S2: passing the reduced cyanocobalamin solution into a second microchannel reactor for methylation reaction with a trimethylsulfoxide iodide solution to obtain a methylcobalamin solution; S3: The methylcobalamin solution is subjected to post-purification treatment, including a concentration step after adding acetic acid to adjust the pH value, a macroporous resin adsorption and analysis step, and an acetone recrystallization step to obtain a methylcobalamin product.
2. The method according to claim 1, characterized in that Steps S1-S3 are performed under nitrogen and light-shielding conditions.
3. The method according to claim 1, characterized in that In step S1, the weight ratio of cyanocobalamin: cobalt chloride: sodium borohydride: purified water is 1 kg: 0.1-0.5 kg: 0.1-1.0 kg: 20-40 kg.
4. The method according to claim 1, characterized in that The reduction reaction temperature in step S1 is 20° C.-30° C., and the flow rate is 40-50 L / min.
5. The method according to claim 1, characterized in that The reduction reaction temperature in step S1 is 20° C.-30° C., and the flow rate is 40-50 L / min.
6. The method according to claim 1, characterized in that In step S2, the feed flow rate of trimethyl sulfoxide iodide is 5-10 L / min, and the feed volume is 20-30 L.
7. The method according to claim 1, characterized in that In step S3, the centrifuge speed is 500-1000 rpm.
8. The method according to claim 1, characterized in that In step S3, the pH value of the methylcobalamin clear solution is adjusted to 4.0-7.
0.
9. The method according to claim 1, characterized in that The temperature of evaporation and concentration in step S3 is 50-70°C.
10. The method according to claim 1, characterized in that The crystallization time in step S3 is 5-10 hours, and the crystallization temperature is -10 to -20°C; the drying temperature of the wet methylcobalamin crystals in step S3 is 50-70°C, and the drying time is 5-10 hours.