Method for producing hydroxycobalamin salt by using microchannel reactor
By combining a microchannel reactor with a post-processing process, the problems of low efficiency, high impurities and high risk in the production of hydroxocobalamin have been solved, and efficient, safe and low-cost production of hydroxocobalamin has been achieved, with product purity and yield significantly improved.
Patent Information
- Application Number
- CN202410344074.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-25
- Publication Date
- 2025-09-26
AI Technical Summary
Existing methods for producing hydroxocobalamin have problems such as multi-step synthesis, high impurities, high risk, low yield, and high cost. Traditional methods are inefficient and unsafe.
A microchannel reactor is used for light-induced reaction, combined with post-processing processes such as centrifugal separation, resin adsorption and recrystallization to control reaction temperature and impurity generation, thereby improving product purity and yield.
Through the use of microchannel reactors, efficient and safe production of hydroxocobalamin is achieved, impurity generation is reduced, yield and product quality are improved, and production costs are reduced.
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Figure CN120699079A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for producing hydroxocobalamin salt by utilizing a microchannel reactor. Background Art
[0002] Hydroxocobalamin is the hydroxylated active form of vitamin B12, also known as long-acting vitamin B12. It is commonly used to treat diseases such as neuropathy, pernicious anemia, and growth retardation. Hydroxocobalamin can also be used as a cyanide antidote. It is safe and fast-acting. It is a new cyanide antidote and has been approved by many countries for the treatment of known or suspected cyanide poisoning. In recent years, microchannel reaction technology has developed rapidly. 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 rate is controllable and the reaction scale can be flexibly adjusted, making it very suitable for chemical synthesis.
[0003] Traditional methods for producing hydroxocobalamin include:
[0004] (1) Using cyanocobalamin as a precursor, the CN- group is first eliminated from the cyanocobalamin molecule in an acidic medium and replaced by another anion (e.g., Cl-), which is then converted into hydroxocobalamin. However, this process uses a multi-step synthesis, a large amount of solvents and reagents, and a solvent method (i.e., phenol-chloroform) for product separation, which produces a large amount of process impurities. In addition, the reaction yield is very low and the occupational hazard is high.
[0005] (2) Cyanocobalamin is catalytically hydrogenated to convert it into cobalamin, which is then oxidized to obtain hydroxocobalamin. This method comprises: reacting cyanocobalamin with a sulfite ion source of water-soluble sulfite and SO2 in an aqueous medium to form sulfite reductase; thereafter reacting the sulfite reductase with a nitrite ion source of water-soluble nitrite and N2O to form nitrite reductase; and then reacting the nitrite reductase with a substance decomposed from urea and sulfamic acid to form hydroxocobalamin. The disadvantages of this method are: more steps, resulting in more impurities; the use of expensive catalysts, and the generation of hydrogen gas, which is highly dangerous.
[0006] (3) Enzymatic production of hydroxocobalamin: The method of obtaining hydroxocobalamin from coenzyme vitamin B12 has no advantages in terms of yield and production cost.
[0007] (4) Using Zn particles and HCl to generate hydrogen, cyanocobalamin is reduced to cobalamin, and then oxygen is introduced to oxidize the reduced cobalamin to hydroxocobalamin. This method uses hydrogen and oxygen, and the chemical synthesis process is highly hazardous and is not recommended.
[0008] (5) Using methylcobalamin to produce hydroxocobalamin. The traditional method is to dissolve methylcobalamin and then use light to convert methylcobalamin into hydroxocobalamin. However, this method has disadvantages such as uneven light, low reaction efficiency, low yield, and high impurity content.
[0009] Therefore, it is of great significance to develop an efficient, reliable and rapid method for the synthesis of hydroxocobalamin. Summary of the Invention
[0010] The present invention provides a method for producing hydroxocobalamin salt using a microchannel reactor. The method comprises performing a light irradiation reaction in the microchannel reactor and combining it with a post-treatment process, thereby being able to precisely control the reaction temperature, greatly suppressing the generation of impurities, and effectively improving the quality of the product.
[0011] In order to achieve the above object, the technical solution adopted by the present invention is:
[0012] A method for producing hydroxocobalamin salt using a microchannel reactor, characterized by comprising:
[0013] S1: adjusting the pH value of the reaction mixture of methylcobalamin, zinc powder, and purified water to 2-6, and passing it into a microchannel reactor for light-induced reaction to obtain a hydroxocobalamin salt solution;
[0014] S2: performing a post-processing of the hydroxocobalamin salt solution by centrifugation, comprising a centrifugation concentration step and a macroporous resin adsorption and desorption step, to obtain a hydroxocobalamin salt desorption solution;
[0015] S3: performing post-purification treatment on the purified hydroxocobalamin salt solution, including an acetone recrystallization step and a drying step, to obtain a finished hydroxocobalamin salt product.
[0016] In step S1, the weight ratio of methylcobalamin, zinc powder and purified water is 1 kg: 0.001-0.005 kg: 30-50 kg.
[0017] In step S1, the pH value is adjusted by hydrochloric acid or acetic acid, and the pH value adjustment range is 2.0-6.0.
[0018] Wherein, in step S1, the illumination reaction temperature is 30-40°C, the flow rate is 20-30 L / min, and the illumination intensity is 400-600 Lx.
[0019] Wherein, the centrifuge speed in steps S2 and S3 is 500-1000 rpm.
[0020] Wherein, the evaporation concentration temperature in step S2 is 50-70°C.
[0021] Wherein, in step S2, the macroporous adsorption resin is LX-920 type, and the macroporous resin eluent is acetone.
[0022] Wherein, in step S3, the crystallization temperature is -10 to -20°C and the crystallization time is 5 to 10 hours.
[0023] Wherein, in step S3, the drying temperature is 50-70° C. and the drying time is 5-10 h.
[0024] Wherein, the hydroxocobalamin salt in step S3 is hydrochloric acid or hydroxocobalamin acetate.
[0025] The technical solution of the present invention has at least the following beneficial technical effects:
[0026] 1. By utilizing the microchannel reaction method to produce hydroxocobalamin salts, the reaction temperature and residence time are strictly controlled, the production efficiency of methylcobalamin is improved, and the reaction by-products are reduced, thereby effectively improving the synthesis efficiency;
[0027] 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;
[0028] 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.
[0029] 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 total impurities of the product are less than 2.0%, the yield is more than 95%, and the content is more than 98%. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 Schematic diagram of the process flow of the production method of the present invention DETAILED DESCRIPTION
[0031] 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.
[0032] Example 1
[0033] 1. Add methylcobalamin, zinc powder, and purified water to preparation tank a in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.001kg:30kg. Stir and dissolve, then adjust the pH to 2.0 with hydrochloric acid to prepare a reaction mixture.
[0034] 2. Pump the reaction mixture from step 1 into premixer b for mixing.
[0035] 3. Turn on the light source, set the light intensity to 400 Lx, set the pump flow rate to 20 L / min, set the temperature of microchannel reactor c to 30°C, pump the reaction mixture in step 2 into microchannel reactor c, carry out light reaction, and collect the light reaction liquid - hydroxocobalamin salt solution.
[0036] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 500 rpm for centrifugation, and the supernatant was collected in a supernatant tank d to obtain a hydroxocobalamin supernatant.
[0037] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 50° C. to obtain a hydroxocobalamin salt concentrate.
[0038] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0039] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -10°C for 5 h and then centrifuged at 500 rpm to obtain hydroxocobalamin salt wet crystals.
[0040] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 50° C. for 5 h, mix, and sieve to obtain the finished product.
[0041] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 99.03%, and the total impurities were 2.4% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 96.15%.
[0042] Example 2
[0043] 1. Add methylcobalamin, zinc powder, and purified water to preparation tank a in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.002kg:30kg. Stir and dissolve, then adjust the pH to 2.0 with hydrochloric acid to prepare a reaction mixture.
[0044] 2. Pump the reaction mixture from step 1 into premixer b for mixing.
[0045] 3. Turn on the light source, set the light intensity to 400 Lx, set the pump flow rate to 20 L / min, set the temperature of microchannel reactor c to 30°C, pump the reaction mixture in step 2 into microchannel reactor c, carry out light reaction, and collect the light reaction liquid - hydroxocobalamin salt solution.
[0046] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 500 rpm for centrifugation, and the supernatant was collected in a supernatant tank d to obtain a hydroxocobalamin supernatant.
[0047] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 50° C. to obtain a hydroxocobalamin salt concentrate.
[0048] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0049] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -10°C for 5 h and then centrifuged at 500 rpm to obtain hydroxocobalamin salt wet crystals.
[0050] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 50° C. for 5 h, mix, and sieve to obtain the finished product.
[0051] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 98.24%, and the total impurities were 1.9% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 97.03%.
[0052] Example 3
[0053] 1. Add methylcobalamin, zinc powder, and purified water to preparation tank a in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.003kg:40kg. Stir and dissolve, then adjust the pH to 4.0 with hydrochloric acid to prepare a reaction mixture.
[0054] 2. Pump the reaction mixture from step 1 into premixer b for mixing.
[0055] 3. Turn on the light source, set the light intensity to 500 Lx, set the pump flow rate to 25 L / min, set the temperature of microchannel reactor c to 35°C, pump the reaction mixture in step 2 into microchannel reactor c, carry out light reaction, and collect the light reaction liquid - hydroxocobalamin salt solution.
[0056] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 700 rpm for centrifugal separation, and the supernatant was collected in a supernatant tank d to obtain a hydroxocobalamin supernatant.
[0057] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 60° C. to obtain a hydroxocobalamin salt concentrate.
[0058] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0059] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -15°C for 7 hours and then centrifuged at 700 rpm to obtain hydroxocobalamin salt wet crystals.
[0060] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 60° C. for 7 h, mix, and sieve to obtain the finished product.
[0061] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 98.15%, and the total impurities were 2.8% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 95.18%.
[0062] Example 4
[0063] 1. Add methylcobalamin, zinc powder, and purified water to preparation tank a in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.004kg:50kg. After stirring and dissolving, adjust the pH to 6.0 with hydrochloric acid to prepare a reaction mixture.
[0064] 2. Pump the reaction mixture from step 1 into premixer b for mixing.
[0065] 3. Turn on the light source, set the light intensity to 600 Lx, set the pump flow rate to 30 L / min, set the temperature of microchannel reactor c to 40°C, pump the reaction mixture in step 2 into microchannel reactor c, carry out light reaction, and collect the light reaction liquid - hydroxocobalamin salt solution.
[0066] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 1000 rpm for centrifugal separation, and the supernatant was collected in a supernatant tank d to obtain a hydroxocobalamin supernatant.
[0067] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 70° C. to obtain a hydroxocobalamin salt concentrate.
[0068] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0069] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -20°C for 10 h and then centrifuged at 1000 rpm to obtain hydroxocobalamin salt wet crystals.
[0070] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 70° C. for 10 h, mix, and sieve to obtain the finished product.
[0071] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 97.89%, and the total impurities were 2.2% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 97.89%.
[0072] Example 5
[0073] 1. Add methylcobalamin, zinc powder, and purified water to preparation tank a in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.005kg:50kg. Stir and dissolve, then adjust the pH to 6.0 with acetic acid to prepare a reaction mixture.
[0074] 2. Pump the reaction mixture from step 1 into premixer b for mixing.
[0075] 3. Turn on the light source, set the light intensity to 600 Lx, set the pump flow rate to 30 L / min, set the temperature of microchannel reactor c to 40°C, pump the reaction mixture in step 2 into microchannel reactor c, carry out light reaction, and collect the light reaction liquid - hydroxocobalamin salt solution.
[0076] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 1000 rpm for centrifugal separation, and the supernatant was collected in a supernatant tank d to obtain a hydroxocobalamin supernatant.
[0077] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 70° C. to obtain a hydroxocobalamin salt concentrate.
[0078] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0079] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -20°C for 10 h and then centrifuged at 1000 rpm to obtain hydroxocobalamin salt wet crystals.
[0080] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 70° C. for 10 h, mix, and sieve to obtain the finished product.
[0081] The hydroxocobalamin salt (hydroxocobalamin acetate) obtained in this example was tested according to the European Pharmacopoeia 10.0 method, and the content was 98.89%, and the total impurities were 1.8% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 96.38%.
[0082] Comparative Example 1
[0083] 1. Add methylcobalamin, zinc powder, and purified water to a preparation tank in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.001kg:30kg. Stir to dissolve and adjust the pH to 2.0 with hydrochloric acid to prepare a reaction mixture.
[0084] 2. Pump the reaction mixture from step 1 into the reaction tank and stir to mix.
[0085] 3. Turn on the light source, set the light intensity to 400 Lx, set the temperature of the reaction tank to 30°C, carry out light reaction for 3 hours, and obtain a hydroxocobalamin salt solution.
[0086] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 500 rpm for centrifugation, and the supernatant was collected in a supernatant tank to obtain a hydroxocobalamin supernatant.
[0087] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 50° C. to obtain a hydroxocobalamin salt concentrate.
[0088] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0089] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -10°C for 5 h and then centrifuged at 500 rpm to obtain hydroxocobalamin salt wet crystals.
[0090] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 50° C. for 5 h, mix, and sieve to obtain the finished product.
[0091] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 96.01%, and the total impurities were 4.8% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 92.45%.
[0092] Comparative Example 2
[0093] 1. Add methylcobalamin, zinc powder, and purified water to a preparation tank in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.003kg:40kg. Stir to dissolve and adjust the pH to 4.0 with hydrochloric acid to prepare a reaction mixture.
[0094] 2. Pump the reaction mixture from step 1 into the reaction tank and stir to mix.
[0095] 3. Turn on the light source, set the light intensity to 500 Lx, set the temperature of the reaction tank to 35°C, carry out light reaction for 3 hours, and obtain a hydroxocobalamin salt solution.
[0096] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 700 rpm for centrifugal separation, and the supernatant was collected in a supernatant tank to obtain a hydroxocobalamin supernatant.
[0097] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 60° C. to obtain a hydroxocobalamin salt concentrate.
[0098] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0099] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -15°C for 7 hours and then centrifuged at 700 rpm to obtain hydroxocobalamin salt wet crystals.
[0100] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 60° C. for 7 h, mix, and sieve to obtain the finished product.
[0101] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 94.35%, and the total impurities were 5.1% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 90.65%.
[0102] Comparative Example 3
[0103] 1. Add methylcobalamin, zinc powder, and purified water to a preparation tank in a ratio of methylcobalamin: zinc powder: purified water = 1kg:0.005kg:50kg. Stir to dissolve and adjust the pH to 6.0 with hydrochloric acid to prepare a reaction mixture.
[0104] 2. Pump the reaction mixture from step 1 into the reaction tank and stir to mix.
[0105] 3. Turn on the light source, set the light intensity to 600 Lx, set the temperature of the reaction tank to 40°C, carry out light reaction for 3 hours, and obtain a hydroxocobalamin salt solution.
[0106] 4. The hydroxocobalamin solution of step 3 was pumped into a centrifuge at 1000 rpm for centrifugal separation, and the supernatant was collected in a supernatant tank to obtain a hydroxocobalamin supernatant.
[0107] 5. The hydroxocobalamin solution of step 4 was evaporated and concentrated at 70° C. to obtain a hydroxocobalamin salt concentrate.
[0108] 6. The hydroxocobalamin salt concentrate of step 5 is purified by adsorption with LX-920 macroporous adsorption resin and desorption with acetone to obtain a purified hydroxocobalamin salt solution.
[0109] 7. The purified hydroxocobalamin salt solution of step 6 was treated with pure acetone at -20°C for 10 h and then centrifuged at 1000 rpm to obtain hydroxocobalamin salt wet crystals.
[0110] 8. Dry the hydroxocobalamin salt wet crystals obtained in step 7 at 70° C. for 10 h, mix, and sieve to obtain the finished product.
[0111] The hydroxocobalamin salt (hydroxocobalamin hydrochloride) obtained in this example was tested according to the method of European Pharmacopoeia 10.0, and the content was 5.66%, and the total impurities were 5.4% (the standard is not more than 5.0%). The yield of the hydroxocobalamin salt in this case was 90.22%.
[0112] Effect comparison:
[0113]
Claims
1. A method for producing hydroxocobalamin salt using a microchannel reactor, characterized in that: include: S1: adjusting the pH value of the reaction mixture of methylcobalamin, zinc powder, and purified water to 2-6, and passing it into a microchannel reactor for light-induced reaction to obtain a hydroxocobalamin salt solution; S2: performing post-separation treatment on the hydroxocobalamin salt solution, including a centrifugal separation and concentration step and a macroporous resin adsorption and desorption step, to obtain a hydroxocobalamin salt desorption solution; S3: performing post-purification treatment on the purified hydroxocobalamin salt solution, including an acetone recrystallization step and a drying step, to obtain a finished hydroxocobalamin salt product.
2. The method according to claim 1, characterized in that In step S1, the weight ratio of methylcobalamin, zinc powder and purified water is 1 kg: 0.001-0.005 kg: 30-50 kg.
3. The method according to claim 1, characterized in that In step S1, the pH value is adjusted by hydrochloric acid or acetic acid, and the pH value adjustment range is 2.0-6.
0.
4. The method according to claim 1, characterized in that In step S1, the illumination reaction temperature is 30-40° C., the flow rate is 20-30 L / min, and the illumination intensity is 400-600 Lx.
5. The method according to claim 1, characterized in that The centrifuge speed in steps S2 and S3 is 500-1000 rpm.
6. The method according to claim 1, characterized in that The evaporation concentration temperature in step S2 is 50-70°C.
7. The method according to claim 1, characterized in that In step S2, the macroporous adsorption resin is LX-920 type, and the macroporous resin eluent is acetone.
8. The method according to claim 1, characterized in that In step S3, the crystallization temperature is -10 to -20°C and the crystallization time is 5 to 10 hours.
9. The method according to claim 1, characterized in that In step S3, the drying temperature is 50-70° C. and the drying time is 5-10 h.
10. The method according to claim 1, characterized in that In step S3, the hydroxocobalamin salt is hydrochloric acid or hydroxocobalamin acetate.