CN102391340A - Preparation method of mecobalamin - Google Patents
Preparation method of mecobalamin Download PDFInfo
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- CN102391340A CN102391340A CN2011103362797A CN201110336279A CN102391340A CN 102391340 A CN102391340 A CN 102391340A CN 2011103362797 A CN2011103362797 A CN 2011103362797A CN 201110336279 A CN201110336279 A CN 201110336279A CN 102391340 A CN102391340 A CN 102391340A
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Abstract
The invention discloses a preparation method of mecobalamin. The preparation method includes the steps: A.dissolving cyanocobalamine, cobalt chloride and trimethylsulfoxonium iodide in deionized water to obtain a liquid to react; B. dissolving sodium borohydride in absolute ethyl alcohol and adding the liquid to react which is obtained from the step A so as to generate reaction; C. adjusting the PH of the solution to 5.0-7.0; D. conducting centrifugation to obtain filtrate; E. conducting vacuum evaporation on the filtrate to obtain a concentrate; and F. absorbing the concentrate with a macroporous resin column and then conducting washing, layer developing and resolution, thus obtaining crystallization stock solution; adding acetone in the crystallization stock solution; and after dynamic and static crystallization, conducting filtration, washing and drying, thus obtaining the finished product of the mecobalamin. In the invention, low-concentration reaction liquid is adopted and by the steps of centrifugation, resin extraction, crystallization and the like, the mecobalamin with high yield, high purity and low cost is obtained; and the preparation method belongs to an industrial preparation method.
Description
Technical field
The present invention relates to the chemical pharmaceutical field, specifically, is a kind of method for preparing mecobalamin.
Background technology
Mecobalamin is one of cobalamin series product, and chemistry is by name: cobalt-α-[α-5,6-dimethylbenzimidazole base]-cobalt-Beta-methyl cobamide is an octahedral bodily form cobaltamine complex.Molecular formula is: C
63H
91CoN
13O
14P, molecular weight is: 1344.41.Mecobalamin is garnet crystallization or crystalline powder, and water absorbability is strong, sees that light is prone to decompose, and it is cobalamin one of two kinds of coenzyme activity forms in vivo.Mecobalamin has good transitivity for nervous tissue in vivo, impels nucleic acid, protein, lipid metabolism through the methyl conversion reaction, repairs the nervous tissue that is damaged, and belongs to bulk drug, is recorded by Japanese Pharmacopoeia.
At present, the preparation method of mecobalamin mainly comprises following several kinds:
Japanese Patent JPA-49-47899: the method that vitamin B12a and mono methyl dicarboxylate are reacted in the presence of metal-powder;
German Patent 2,149,150 (offen): the method that the methylation reaction of hydroxocobalamin is prepared mecobalamin with methyl-mercuric iodide or methyl hexafluorosilicic acid ammonia;
Japanese Patent JP-A50-41900: in the presence of metal-powder, containing the aqueous phase of methyl alcohol, the method for Vitral and oxalic acid mono-methyl prepared in reaction mecobalamin;
German Patent 2,058,892: prepare the method for mecobalamin with methylating with methyl tosylate behind the sodium borohydride reduction Vitral;
Japanese Patent JP-B-45-38059: prepare the method for mecobalamin with methylating with methyl iodide behind the sodium borohydride reduction Vitral;
Chinese patent CN1409723A: prepare mecobalamin in Vitral that contains the methyl sulfur derivatives or hydroxocobalamin solution, adding Peng Qinghuana in the presence of molysite or the cobalt salt, adopt crystallisation by cooling, acetone, dissolve with hydrochloric acid solution crystallization, acetone crystallization to prepare the method for mecobalamin afterwards;
Chinese patent CN100352829C: in the presence of molysite or cobalt salt with sodium borohydride reduction Vitral or hydroxocobalamin; Add the trimethylammonium sulfur derivatives and accomplish methylation reaction, adopt crystallisation by cooling, acetone, dissolve with hydrochloric acid solution crystallization, acetone crystallization to prepare the method for mecobalamin afterwards;
Chinese patent CN101175764A: in the presence of reductive agent, with methylcarbonate Vitral or hydroxocobalamin are methylated, adopt crystallisation by cooling afterwards, the acetone crystallization prepares the method for mecobalamin after resin extraction, the methanol-eluted fractions.
Wherein, used can not be through reagent (methyl oxalate, mono methyl dicarboxylate, methyl hexafluorosilicic acid ammonia) or toxic reagent (methyl iodide, methyl tosylate) and the pollutent that is purchased acquisition for method 1-5: methyl-mercuric iodide is difficult for carrying out suitability for industrialized production;
Method 6 is only different at the addition sequence of step of reaction methylating reagent and reductive agent with method 7; Method 6 is under the situation that methylating reagent exists, to add Peng Qinghuana; This technology in the advantage of reaction process is: after the sodium borohydride reduction that Vitral or hydroxocobalamin are added into is active B12S; Exist the methylating reagent reaction in the question response liquid to generate mecobalamin with excessive at once; Therefore the by product of reaction is few, but shortcoming is to be prone to generate the dimethyl sulfide with stink; The advantage in reaction process of method 7 is less for the dimethyl sulfide that produces, but because Vitral or hydroxocobalamin are reduced to active B12S earlier, therefore in the process that adds methylating reagent, is prone to generate by product.But two method common shortcomings are:
1. the first step owing to its extraction precipitates the acquisition bullion for cooling with the solubleness that reduces mecobalamin, because mecobalamin still has the solubleness of 8000ug/ml in 12 ℃ water, higher solubleness is arranged in alcohol; Therefore; When first extracts, have an appointment 10% yield losses in liquid, when adopting this kind extracting mode, for obtaining high yield; Need to adopt high density Vitral reaction solution, easy dissolving not exclusively causes reaction not exclusively;
2. in the building-up process that adopts divalent cobalt to react with promotion as the cryanide ion sequestering agent; When being deposited in crystallisation by cooling, the cobaltous cyanide that generates gets into the mecobalamin bullion with the mecobalamin coprecipitation; Must cause the operation of many places contact cyanogen root through follow-up technology through adding concentrated hydrochloric acid and adding heat abstraction;
3. the building-up reactions of mecobalamin is to accomplish under greater than 10 alkaline condition at PH, and the cooling of about 24h is deposited under this high PH mecobalamin is damaged;
4. adopt the crystallization processes of recrystallization, make the starting material that in building-up reactions, add, the by product of reaction can adhere to, be wrapped in mecobalamin crystalline surface and inner, so product purity is low;
There is the drawback of the yield losses that low temperature crystallization causes equally in method 8; In the extraction stage; Only adopted simple resin operation; And introduced methyl alcohol, two kinds of solvents of acetone at refining stage, not only increase the solvent recovery system, and the high occupational hazards of methyl alcohol becomes the limiting factor of suitability for industrialized production.
Summary of the invention
The technical problem that the present invention will solve provides a kind of preparation method of mecobalamin; Solve the deficiency of prior art; In reaction, adopt the reaction solution of lower concentration, adopt steps such as centrifugal, vacuum-evaporation, resin extraction, crystallization to obtain high yield, high purity, mecobalamin industrialized process for preparing cheaply.
For solving the problems of the technologies described above, the technical scheme that the present invention taked is following.
A kind of preparation method of mecobalamin, its step comprises:
A, Vitral, NSC 51149, Trimethylsulfoxonium Iodide are dissolved in the deionized water, fully stir, question response liquid;
B, Peng Qinghuana is dissolved in absolute ethyl alcohol, the gained ethanol solution of sodium borohydride adds to be gone up step gained question response liquid and reacts;
C, go up after the step, reaction finished, the PH of regulator solution is 5.0-7.0;
D, on go on foot the gained reaction solution through centrifugal filtered liq;
Go on foot the gained filtered liq in E, the vacuum-evaporation and get liquid concentrator;
F, on go on foot the gained liquid concentrator through macroporous resin column absorption, washing, exhibition layer, resolve crystallization stoste; In crystallization stoste, add acetone, through dynamically, behind the stationary crystallization, filtration, washing, dry mecobalamin finished product.
As a kind of optimal technical scheme of the present invention; In the steps A; The concentration of said Vitral is 0.010-0.013g/ml, and the consumption weight ratio of said NSC 51149 and Vitral is (0.12-0.17): 1, and the consumption weight ratio of said Trimethylsulfoxonium Iodide and Vitral is (0.25-0.32): 1.
As a kind of optimal technical scheme of the present invention, in the steps A, gained question response liquid is at first used the nitrogen deoxygenation, carries out next step reaction again.
As a kind of optimal technical scheme of the present invention, among the step B, the consumption weight ratio of said Peng Qinghuana and Vitral is (0.34-0.39): 1, and the weightmeasurement ratio of Peng Qinghuana and absolute ethyl alcohol (0.042-0.048) g: 1ml.
As a kind of optimal technical scheme of the present invention, among the step B, Peng Qinghuana is dissolved in absolute ethyl alcohol after, the gained ethanol solution of sodium borohydride is at first used the nitrogen deoxygenation, carries out next step reaction again; Temperature when ethanol solution of sodium borohydride and steps A gained question response liquid react is 20-40 ℃.
As a kind of optimal technical scheme of the present invention, among the step C, the used reagent of regulator solution PH is acetic acid.
As a kind of optimal technical scheme of the present invention, developing agent described in the step F is that proportion is the aqueous acetone solution of 0.980-0.990g/ml.
As a kind of optimal technical scheme of the present invention, resolving agent described in the step F is the aqueous acetone solution of 0.920-0.940g/ml.
As a kind of optimal technical scheme of the present invention; In the step F; Obtain after the crystallization stoste to its carry out dynamically, the concrete operation method of stationary crystallization is that under agitation the acetone of adding 0.79-0.80g/ml in crystallization stoste makes that the density of solution is 0.820-0.840g/ml; Stir 1-2h and carry out dynamic crystallization, leave standstill 2-4h and carry out stationary crystallization.
As a kind of optimal technical scheme of the present invention, in the step F, the concrete model of said macroporous resin column is CAD45 or XAD1180.
Adopt the beneficial effect that technique scheme produced to be: the present invention adopts the Vitral reaction solution of lower concentration in step of reaction; Assurance is reflected under the liquid phase to be carried out; Under the situation that methylating reagent exists, add Peng Qinghuana; Finish in reaction and to adjust back reaction solution PH immediately, guaranteed the high conversion of reaction to the stable PH of mecobalamin; In the extraction stage; Increase the extraction process that high speed centrifugation, vacuum-evaporation and lower concentration reaction solution are complementary; At refining stage, used to have a little the polar macroporous resin, remove the mineral ion of introducing in the reaction in absorption, washing stage; Unreacted Vitral is separated with different colour bands on resin with mecobalamin with the by product hydroxocobalamin with developing agent in the exhibition layer stage, improved product purity; Adopt dynamic and static crystallization bonded crystallization processes simultaneously, and whole extraction treating process only introduces a kind of solvent, whole technology easy handling, stability is high, and product yield is high, and impurity is few, and cost is low.Its concrete beneficial effect can be listed below:
1. the present invention adopts high speed centrifugation to separate the technology of removal reaction precipitation, vacuum-evaporation removal organic solvent, resin extraction removal inorganic salt and mecobalamin resemblance; Replace low temperature sedimentation crystallization processes; Got rid of the yield losses that the solubleness of mecobalamin 8000ug/ml in the time of 12 ℃ causes; Make product yield greater than 92%, avoided the reaction precipitation cobaltous cyanide behind extraction stage and mecobalamin coprecipitation, to need to add the foreign matter that the concentrated hydrochloric acid heat-treatment process is introduced simultaneously; When resin extracts, in absorption, the washing stage removed various mineral ions,, the resemblance of mecobalamin is separated in an exhibition layer stage, significantly improved the quality of crystallization stoste, make content>=99% of the finished product, related substance≤1%;
2. the reaction density of the present invention's employing is a little less than Vitral solubleness at normal temperatures; Assurance is reflected under the full liquid-phase condition to be carried out; The incomplete problem of dissolving of having avoided low temperature sedimentation extraction process middle and high concentration reaction solution to be brought reaches the low-conversion that causes thus; Reaction conversion ratio of the present invention reaches more than 98%, for the high yield of product is laid a good foundation;
3. after methylation reaction is accomplished, when the PH of reaction solution is finished by reaction greater than 10 adjust to mecobalamin stable PH:5.0-7.0, reduced the destruction of long-time high PH to mecobalamin;
4. in resin extraction, Crystallization Procedure, only use a kind of solvent of acetone, cut down, in suitability for industrialized production, only need be equipped with a cover solvent recovery system, and effectively reduce the degree of Occupational health harm with the evaporation operation after the methyl alcohol parsing.
Embodiment
Following examples have specified the present invention.Various raw material used in the present invention and items of equipment are conventional commercially available prod, all can buy directly through market to obtain.
Embodiment 1
A kind of preparation method of mecobalamin, its step comprises:
A, in retort, 50g Vitral, 6g NSC 51149,13g Trimethylsulfoxonium Iodide are dissolved in the 4L deionized water, fully stir, question response liquid, feed nitrogen deoxygenation 40 minutes, the purity of nitrogen >=99.99%;
B, the 17g Peng Qinghuana is dissolved in the 400ml absolute ethyl alcohol, moisture in this absolute ethyl alcohol≤3%, the nitrogen deoxygenation added retort with it again and reacts after 25 minutes, the purity of nitrogen>=99.99% wherein, temperature of reaction is controlled at 20-40 ℃;
C, go up after the step, reaction finished, PH is 10.43, and the acetic acid with 20% is adjusted to 5.85 with reaction solution PH;
D, on to go on foot the gained reaction solution be that the whizzer of 12000rpm is crossed and filtered filtered liq through rotating speed;
E, on go on foot the gained filtered liq and under 65-70 ℃ temperature condition, carry out vacuum-evaporation, obtain the 3250ml liquid concentrator;
F, will go up step gained liquid concentrator be adsorbed on the flow velocity of 1L/h on the macroporous resin column of dress 4L CAD45; Washing back is that the aqueous acetone solution of 0.990g/ml is opened up layer with the flow of 500ml/h with density; After liquid to be exported becomes colorless; Flow with 700ml/h uses density to resolve as the aqueous acetone solution of 0.930g/ml, obtains 1620ml crystallization stoste; Under agitation, in crystallization stoste, adding density is that the density of acetone to the solution of 0.790g/ml is 0.830g/ml; Stir 1h, leave standstill 3h after, filtration, washing, drying obtain the 46.27g mecobalamin.
The mecobalamin that present embodiment obtains is according to the check of Japanese Pharmacopoeia detection method, and content is 99.74%, and related substance is 0.86%, and the yield of mecobalamin is 92.54%.
Embodiment 2
A kind of preparation method of mecobalamin, its step comprises:
A, in retort, 50g Vitral, 7g NSC 51149,15g Trimethylsulfoxonium Iodide are dissolved in the 4L deionized water, fully stir, question response liquid, feed nitrogen deoxygenation 40 minutes, the purity of nitrogen >=99.99%;
B, the 18g Peng Qinghuana is dissolved in the 400ml absolute ethyl alcohol, moisture in this absolute ethyl alcohol≤3%, the nitrogen deoxygenation added retort with it again and reacts after 25 minutes, the purity of nitrogen>=99.99% wherein, temperature of reaction is controlled at 20-40 ℃;
C, go up after the step, reaction finished, PH is 10.39, and the acetic acid with 20% is adjusted to 5.97 with reaction solution PH;
D, on to go on foot the gained reaction solution be that the whizzer of 12000rpm is crossed and filtered filtered liq through rotating speed;
E, on go on foot the gained filtered liq and under 65-70 ℃ temperature condition, carry out vacuum-evaporation, obtain the 3170ml liquid concentrator;
F, will go up step gained liquid concentrator be adsorbed on the flow velocity of 1L/h on the macroporous resin column of dress 4L CAD45; Washing back is that the aqueous acetone solution of 0.985g/ml is opened up layer with the flow of 500ml/h with density; After liquid to be exported becomes colorless; Flow with 700ml/h uses density to resolve as the aqueous acetone solution of 0.935g/ml, obtains 1640ml crystallization stoste; Under agitation, in crystallization stoste, adding density is that the density of acetone to the solution of 0.790g/ml is 0.830g/ml; Stir 1h, leave standstill 3h after, filtration, washing, drying obtain the 46.73g mecobalamin.
The mecobalamin that present embodiment obtains is according to the check of Japanese Pharmacopoeia detection method, and content is 99.81%, and related substance is 0.74%, and the yield of mecobalamin is 93.46%.
Embodiment 3
A kind of preparation method of mecobalamin, its step comprises:
A, in retort, 50g Vitral, 8.5g NSC 51149,15.7g Trimethylsulfoxonium Iodide are dissolved in the 4L deionized water, fully stir, question response liquid, feed nitrogen deoxygenation 40 minutes, the purity of nitrogen >=99.99%;
B, the 19.1g Peng Qinghuana is dissolved in the 400ml absolute ethyl alcohol, moisture in this absolute ethyl alcohol≤3%, the nitrogen deoxygenation added retort with it again and reacts after 25 minutes, the purity of nitrogen>=99.99% wherein, temperature of reaction is controlled at 20-40 ℃;
C, go up after the step, reaction finished, PH is 10.51, and the acetic acid with 20% is adjusted to 6.15 with reaction solution PH;
D, on to go on foot the gained reaction solution be that the whizzer of 12000rpm is crossed and filtered filtered liq through rotating speed;
E, on go on foot the gained filtered liq and under 65-70 ℃ temperature condition, carry out vacuum-evaporation, obtain the 3170ml liquid concentrator;
F, will go up step gained liquid concentrator be adsorbed on the flow velocity of 1L/h on the macroporous resin column of dress 4L XAD1180; Washing back is that the aqueous acetone solution of 0.990g/ml is opened up layer with the flow of 500ml/h with density; After liquid to be exported becomes colorless; Flow with 700ml/h uses density to resolve as the aqueous acetone solution of 0.935g/ml, obtains 1550ml crystallization stoste; Under agitation, in crystallization stoste, adding density is that the density of acetone to the solution of 0.795g/ml is 0.830g/ml; Stir 1h, leave standstill 3h after, filtration, washing, drying obtain the 46.77g mecobalamin.
The mecobalamin that present embodiment obtains is according to the check of Japanese Pharmacopoeia detection method, and content is 99.62%, and related substance is 0.75%, and the yield of mecobalamin is 93.54%.
Foregoing description only proposes as the enforceable technical scheme of the present invention, not as the single restricted condition to its technical scheme itself.
Claims (10)
1. the preparation method of a mecobalamin, its characterization step comprises:
A, Vitral, NSC 51149, Trimethylsulfoxonium Iodide are dissolved in the deionized water, fully stir, question response liquid;
B, Peng Qinghuana is dissolved in absolute ethyl alcohol, the gained ethanol solution of sodium borohydride adds to be gone up step gained question response liquid and reacts;
C, go up after the step, reaction finished, the PH of regulator solution is 5.0-7.0;
D, on go on foot the gained reaction solution through centrifugal filtered liq;
Go on foot the gained filtered liq in E, the vacuum-evaporation and get liquid concentrator;
F, on go on foot the gained liquid concentrator through macroporous resin column absorption, washing, exhibition layer, resolve crystallization stoste; In crystallization stoste, add acetone, through dynamically, behind the stationary crystallization, filtration, washing, dry mecobalamin finished product.
2. the preparation method of mecobalamin according to claim 1; It is characterized in that: in the steps A; The concentration of said Vitral is 0.010-0.013g/ml; The consumption weight ratio of said NSC 51149 and Vitral is (0.12-0.17): 1, and the consumption weight ratio of said Trimethylsulfoxonium Iodide and Vitral is (0.25-0.32): 1.
3. the preparation method of mecobalamin according to claim 1, it is characterized in that: in the steps A, gained question response liquid is at first used the nitrogen deoxygenation, carries out next step reaction again.
4. the preparation method of mecobalamin according to claim 1, it is characterized in that: among the step B, the consumption weight ratio of said Peng Qinghuana and Vitral is (0.34-0.39): 1, the weightmeasurement ratio of Peng Qinghuana and absolute ethyl alcohol (0.042-0.048) g: 1ml.
5. the preparation method of mecobalamin according to claim 1 is characterized in that: among the step B, Peng Qinghuana is dissolved in absolute ethyl alcohol after, the gained ethanol solution of sodium borohydride is at first used the nitrogen deoxygenation, carries out next step reaction again; Temperature when ethanol solution of sodium borohydride and steps A gained question response liquid react is 20-40 ℃.
6. the preparation method of mecobalamin according to claim 1, it is characterized in that: among the step C, the used reagent of regulator solution PH is acetic acid.
7. the preparation method of mecobalamin according to claim 1, it is characterized in that: developing agent described in the step F is that proportion is the aqueous acetone solution of 0.980-0.990g/ml.
8. the preparation method of mecobalamin according to claim 1 is characterized in that: resolving agent described in the step F is the aqueous acetone solution of 0.920-0.940g/ml.
9. the preparation method of mecobalamin according to claim 1; It is characterized in that: in the step F; Obtain after the crystallization stoste to its carry out dynamically, the concrete operation method of stationary crystallization is that under agitation the acetone of adding 0.79-0.80g/ml in crystallization stoste makes that the density of solution is 0.820-0.840g/ml; Stir 1-2h and carry out dynamic crystallization, leave standstill 2-4h and carry out stationary crystallization.
10. the preparation method of mecobalamin according to claim 1, it is characterized in that: in the step F, the concrete model of said macroporous resin column is CAD45 or XAD1180.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113443A (en) * | 2013-02-01 | 2013-05-22 | 山东省医药工业研究所 | Novel chemical synthesis method for preparing mecobalamine |
| CN105218608A (en) * | 2015-10-29 | 2016-01-06 | 无锡福祈制药有限公司 | A kind of preparation method of mecobalamin |
| CN106349313A (en) * | 2016-08-23 | 2017-01-25 | 宁夏泰瑞制药股份有限公司 | Method for synthesizing crude product of methylcobalamin by using cyanocobalamin |
| CN107698642A (en) * | 2017-10-09 | 2018-02-16 | 广州普星药业有限公司 | A kind of method for preparing Mecobalamin |
| CN108329373A (en) * | 2018-04-24 | 2018-07-27 | 江苏四环生物制药有限公司 | A kind of synthetic method of Mecobalamin |
| CN108948116A (en) * | 2018-08-30 | 2018-12-07 | 上海应用技术大学 | A kind of green synthesis process of Mecobalamin |
| CN111303228A (en) * | 2020-04-02 | 2020-06-19 | 河北玉星生物工程股份有限公司 | Method for synthesizing cobamamide |
| CN113959805A (en) * | 2021-10-25 | 2022-01-21 | 淄博高新技术产业开发区生物医药研究院 | Method for analyzing and detecting cobalt chloride impurity in mecobalamin bulk drug |
| CN114874276A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
| CN114874274A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113443A (en) * | 2013-02-01 | 2013-05-22 | 山东省医药工业研究所 | Novel chemical synthesis method for preparing mecobalamine |
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| CN105218608A (en) * | 2015-10-29 | 2016-01-06 | 无锡福祈制药有限公司 | A kind of preparation method of mecobalamin |
| CN106349313A (en) * | 2016-08-23 | 2017-01-25 | 宁夏泰瑞制药股份有限公司 | Method for synthesizing crude product of methylcobalamin by using cyanocobalamin |
| CN107698642A (en) * | 2017-10-09 | 2018-02-16 | 广州普星药业有限公司 | A kind of method for preparing Mecobalamin |
| CN108329373A (en) * | 2018-04-24 | 2018-07-27 | 江苏四环生物制药有限公司 | A kind of synthetic method of Mecobalamin |
| CN108948116A (en) * | 2018-08-30 | 2018-12-07 | 上海应用技术大学 | A kind of green synthesis process of Mecobalamin |
| CN111303228A (en) * | 2020-04-02 | 2020-06-19 | 河北玉星生物工程股份有限公司 | Method for synthesizing cobamamide |
| CN113959805A (en) * | 2021-10-25 | 2022-01-21 | 淄博高新技术产业开发区生物医药研究院 | Method for analyzing and detecting cobalt chloride impurity in mecobalamin bulk drug |
| CN114874276A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
| CN114874274A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
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