CN108546278A - The process for purification of Mecobalamin - Google Patents
The process for purification of Mecobalamin Download PDFInfo
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- CN108546278A CN108546278A CN201810221253.XA CN201810221253A CN108546278A CN 108546278 A CN108546278 A CN 108546278A CN 201810221253 A CN201810221253 A CN 201810221253A CN 108546278 A CN108546278 A CN 108546278A
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- mecobalamin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The process for purification of Mecobalamin of the present invention, belong to technical field of medicine synthesis, it is refined using mixed solvent recrystallization, at 20~60 DEG C, Mecobalamin crude product is added to the in the mixed solvent of water~organic solvent, is heated to 50~60 DEG C, stirring and dissolving 0.5~2 hour, add acid for adjusting pH value to 4.5~6.5, add activated carbon decolorizing 0.5~1 hour, filtering, which decolourizes to obtain, clarifies feed liquid；Organic solvent is added into clarification feed liquid, filtered after stirring cooling crystallization under thermostatic control, dry high-purity Mecobalamin.The present invention adjusts pH value, increases the stability of Mecobalamin, reduces the possibility for generating new impurity in subtractive process；Using suitable dissolving bleaching temperature, the inorganic salts introduced in Mecobalamin production process are effectively removed；Using suitable mixing speed and recrystallization temperature, speed, rate of charge effectively controls crystalline rate, reduces the precipitation of impurity, make its maximum single miscellaneous control 0.3% hereinafter, the sum of each impurity 1.5% hereinafter, ensure that the controllability of product quality.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of process for purification of Mecobalamin.
Background technology
Mecobalamin, English name：Mecobalamin, chemical name：Cobalt-α-[α-(5,6- dimethylbenzimidazoles base)]-cobalt-
Beta-methyl cobalt amide, structure are as follows：
Mecobalamin is dark red crystalline or crystalline powder, and hygroscopicity is strong, and light-exposed easy decomposition, it is vitamin B12In vivo
One of two kinds of coenzyme active forms can directly participate in being metabolized in vivo for anti-peripheral nerve disease medicine.Mecobalamin is turned by methyl
With the stabilization for maintaining internal cellular morphology and function, clinically apply this product treatment neurological disorder caused by diabetes, more more
The peripheral nerve diseases such as inflammation nerve, the especially such as numb, pain and fiber crops are thin apparent effect to the complication of diabetes.
In addition, some researches show that Mecobalamin is effective treatment parkinsonism, alzheimer syndrome, muscular atrophy and neurasthenia
Potential drug.
It is mostly two steps that restore and methylate to have Mecobalamin synthetic method, and by retrieval, discovery has numerous patents to describe
To Mecobalamin preparation method, the accurate process arrived involved in method is only the simple supplement to synthetic method, unspecial right
Subtractive process is studied, and particular content is as follows：A kind of preparation method (patent No. of Mecobalamin：201510726286.6), it adopts
With water water dissolution, chromatography, concentration；Produce the new method (patent No. of methylcobalamin：200680009228.0), using acetone
Water process, concentration, resin treatment；A kind of preparation method (patent No. of Mecobalamin：201110336279.7), using concentration, tree
Fat adsorbs.
By comparison it is found that although the method purification effect for the resin treatment column chromatography that the above patent utilizes is good, receive
Rate is low, the period is long, of high cost, is unfavorable for industrialized production.Wherein thickening temperature is higher is easy so that Mecobalamin decomposition, influences
Yield.
It is found after Mecobalamin synthesising process research simultaneously, the control of Mecobalamin reduction process condition is very strict, very
The reaction for being susceptible to by-product, and being susceptible to one valence state of reduzate and divalent state cobalt in methylation procedure not exclusively has residual
Situation about being deposited in crude product, it is very difficult to remove so that related substance is higher；Existing recrystallizing technology is to inorganic miscellaneous simultaneously
Matter impurity-eliminating effect is also limited, influences product content.Therefore handled in subtractive process it is bad have to product final mass it is very big
It influences.
Invention content
The purpose of the present invention is to provide a kind of simple and effective, low cost that can effectively control impurity in bulk pharmaceutical chemicals, height
The process for purification of the Mecobalamin of purity and suitable industrialized production.
To achieve the goals above, the technical solution adopted by the present invention is：
The process for purification of Mecobalamin of the present invention is refined using mixed solvent recrystallization, is as follows：
1) at 20~60 DEG C, Mecobalamin crude product is added to the in the mixed solvent of water~organic solvent, it is heated to 50~
60 DEG C, stirring and dissolving 0.5~2 hour adds acid for adjusting pH value to 4.5~6.5, adds activated carbon decolorizing 0.5~1 hour, mistake
Filter, which decolourizes to obtain, clarifies feed liquid；
2) organic solvent is added into clarification feed liquid under thermostatic control, is filtered after stirring cooling crystallization, it is high-purityly dry
Spend Mecobalamin.
The organic solvent is the combination of one or more of methanol, ethyl alcohol, isopropanol, acetone, acetonitrile, butanone.
The mass ratio of the in the mixed solvent water of water~organic solvent and organic solvent is 1 in step 1)：(1~3).
The mass ratio of Mecobalamin crude product and the mixed solvent of water~organic solvent is 1 in step 2)：(5~60).
The mass ratio of Mecobalamin crude product and the mixed solvent of water~organic solvent is 1 in step 2)：(10~20).
The acid that pH is used is adjusted in step 1) as one or several kinds of combinations in acetic acid, hydrochloric acid, phosphoric acid.
The mass ratio of Mecobalamin crude product and activated carbon is 1 in step 2):0.01~0.001.
Speed of agitator is 100~300rpm.
Cooling Crystallization Process is cooled down using program in step 2), first 35~50 DEG C of crystallizations 1~2 hour, then 15~35 DEG C of analysis
It is 1~2 hour brilliant, final 0~15 DEG C of crystallization 3~10 hours.
Compared with prior art, beneficial effects of the present invention are：
1) process for purification of Mecobalamin of the present invention carries out pH value adjusting before refining, increases the stability of Mecobalamin, being allowed to can
To exist in solution for a long time, reduce the possibility that new impurity is generated in subtractive process；
2) present invention can effectively remove Mecobalamin production process using suitable dissolving bleaching temperature in subtractive process
The inorganic salts of middle introducing；
3) present invention uses suitable mixing speed and recrystallization temperature, speed, rate of charge effectively to control in Crystallization Process
Crystalline rate, reduces the precipitation of impurity, make its maximum single miscellaneous control 0.3% hereinafter, the sum of each impurity 1.5% with
Under, it ensure that the controllability of product quality；
4) crystallization of the present invention, drying time extend the stability for not influencing product quality, and yield can reach 85% or more.
Description of the drawings
Fig. 1 is the HPLC figures of 1 Mecobalamin impurity test solution of the embodiment of the present invention；
Fig. 2 is the HPLC figures of 2 Mecobalamin impurity test solution of the embodiment of the present invention；
Fig. 3 is the HPLC figures of 3 Mecobalamin impurity test solution of the embodiment of the present invention.
Specific implementation mode
In order to better understand the content of the present invention, it is further illustrated below in conjunction with specific embodiment to make.But
These embodiments cannot constitute the limitation to protection scope of the present invention.
Embodiment 1
Under the conditions of dark red light, Mecobalamin crude product 5g is added to 60g50% boiling ethyl alcohol under the conditions of 45~50 DEG C
(acetone：Ethyl alcohol=4:1) in the mixed solvent, temperature control stirring dissolve 1 hour, and enriching salt acid for adjusting pH to 4.5 adds activity
Charcoal 0.05g filters decoloration, and filter cake is washed with water to clarify feed liquid.150g acetone second is added into clarification feed liquid in 45 DEG C of temperature control
Alcohol (acetone：Ethyl alcohol=4:1) mixed solvent, 45 DEG C are stirred 1 hour, are cooled to 35 DEG C and are stirred 1 hour, are cooled to 10 DEG C of stirrings
3 hours, filtering and washing was dried in vacuo the high-purity Mecobalamin 4.32g that weighs to obtain, yield 86.4%.Maximum single miscellaneous 0.17%, it is each miscellaneous
The sum of matter 0.47%.
The HPLC integral result tables of 1 embodiment of table, 1 Mecobalamin impurity test solution
Embodiment 2
Under the conditions of dark red light, Mecobalamin crude product 5g is added to 50g50% boiling butanone under the conditions of 40~45 DEG C
(acetone：Butanone=5:1) in the mixed solvent, temperature control stirring dissolve 1 hour, add vinegar acid for adjusting pH to 5.0, add activated carbon
0.05g filters decoloration, and filter cake is washed with water to clarify feed liquid.200g acetone butanone is added into clarification feed liquid in 40 DEG C of temperature control
(acetone：Butanone=5:1) mixed solvent, 40 DEG C are stirred 2 hours, are cooled to 30 DEG C and are stirred 2 hours, and it is small to be cooled to 5 DEG C of stirrings 3
When, filtering and washing is dried in vacuo the high-purity Mecobalamin 4.46g that weighs to obtain, yield 89.2%.Maximum single miscellaneous 0.16%, each impurity
The sum of 0.47%.
The HPLC integral result tables of 2 embodiment of table, 2 Mecobalamin impurity test solution
Embodiment 3
Under the conditions of dark red light, Mecobalamin crude product 5g is added to 80g50% boiling ethyl alcohol under the conditions of 50~60 DEG C
(acetone：Ethyl alcohol=3:2) in the mixed solvent, temperature control stirring dissolve 1 hour, and enriching salt acid for adjusting pH to 5.5 adds activity
Charcoal 0.05g filters decoloration, and filter cake is washed with water to clarify feed liquid.150g acetone second is added into clarification feed liquid in 45 DEG C of temperature control
Alcohol (acetone：Ethyl alcohol=3:2) mixed solvent, 45 DEG C are stirred 1.5 hours, are cooled to 35 DEG C and are stirred 1.5 hours, are cooled to 10 DEG C
Stirring 5 hours, filtering and washing are dried in vacuo the high-purity Mecobalamin 4.27g that weighs to obtain, yield 85.4%.Maximum single miscellaneous 0.15%,
The sum of each impurity 0.45%.
The HPLC integral result tables of 3 embodiment of table, 3 Mecobalamin impurity test solution
Claims (9)
1. a kind of process for purification of Mecobalamin, which is characterized in that refined using mixed solvent recrystallization, specific steps are such as
Under：
1) at 20~60 DEG C, Mecobalamin crude product is added to the in the mixed solvent of water~organic solvent, is heated to 50~60 DEG C,
Stirring and dissolving 0.5~2 hour adds acid for adjusting pH value to 4.5~6.5, adds activated carbon decolorizing 0.5~1 hour, filtering decoloration
Feed liquid must be clarified；
2) organic solvent is added into clarification feed liquid, filtered after stirring cooling crystallization under thermostatic control, dry high-purity first
Cobalt amine.
2. the process for purification of Mecobalamin according to claim 1, which is characterized in that the organic solvent be methanol, ethyl alcohol,
The combination of one or more of isopropanol, acetone, acetonitrile, butanone.
3. the process for purification of Mecobalamin according to claim 1, which is characterized in that water~organic solvent is mixed in step 1)
The mass ratio of water and organic solvent is 1 in bonding solvent：(1~3).
4. the process for purification of Mecobalamin according to claim 1, which is characterized in that Mecobalamin crude product and water in step 2)~
The mass ratio of the mixed solvent of organic solvent is 1：(5~60).
5. the process for purification of Mecobalamin according to claim 4, which is characterized in that Mecobalamin crude product and water in step 2)~
The mass ratio of the mixed solvent of organic solvent is 1：(10~20).
6. the process for purification of Mecobalamin according to claim 1, which is characterized in that adjust in step 1) acid that pH is used for
One or several kinds of combinations in acetic acid, hydrochloric acid, phosphoric acid.
7. the process for purification of Mecobalamin according to claim 1, which is characterized in that Mecobalamin crude product and activity in step 2)
The mass ratio of charcoal is 1:0.01~0.001.
8. the process for purification of Mecobalamin according to claim 1, which is characterized in that speed of agitator is 100~300rpm.
9. the process for purification of Mecobalamin according to claim 1, which is characterized in that cooling Crystallization Process uses in step 2)
Program cools down, first 35~50 DEG C of crystallizations 1~2 hour, then 15~35 DEG C of crystallizations 1~2 hour, and final 0~15 DEG C of crystallization 3~10 is small
When.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111808158A (en) * | 2020-07-23 | 2020-10-23 | 宁夏金维制药股份有限公司 | Preparation method of vitamin B12 crude product |
| CN111808159A (en) * | 2020-07-23 | 2020-10-23 | 宁夏金维制药股份有限公司 | Preparation method of cobamamide crude product |
Citations (7)
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|---|---|---|---|---|
| JPH08143590A (en) * | 1994-11-24 | 1996-06-04 | Meiji Seika Kaisha Ltd | Production of high-purity methylcobalamin |
| CN1409723A (en) * | 1999-12-09 | 2003-04-09 | 卫材株式会社 | Process for production of methylcobalamin |
| WO2012165934A1 (en) * | 2011-05-30 | 2012-12-06 | Interquim, S.A. De C.V. | Methylcobalamin synthesis process |
| 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 |
| WO2018007035A1 (en) * | 2016-07-08 | 2018-01-11 | Interquim, S.A. | Process for the purification of methylcobalamin |
| 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 |
| CN107805267A (en) * | 2016-09-08 | 2018-03-16 | 重庆莱美隆宇药业有限公司 | A kind of purification process of Mecobalamin and its derivative |
-
2018
- 2018-03-17 CN CN201810221253.XA patent/CN108546278A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08143590A (en) * | 1994-11-24 | 1996-06-04 | Meiji Seika Kaisha Ltd | Production of high-purity methylcobalamin |
| CN1409723A (en) * | 1999-12-09 | 2003-04-09 | 卫材株式会社 | Process for production of methylcobalamin |
| WO2012165934A1 (en) * | 2011-05-30 | 2012-12-06 | Interquim, S.A. De C.V. | Methylcobalamin synthesis process |
| 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 |
| WO2018007035A1 (en) * | 2016-07-08 | 2018-01-11 | Interquim, S.A. | Process for the purification of methylcobalamin |
| CN107805267A (en) * | 2016-09-08 | 2018-03-16 | 重庆莱美隆宇药业有限公司 | A kind of purification process of Mecobalamin and its derivative |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111808158A (en) * | 2020-07-23 | 2020-10-23 | 宁夏金维制药股份有限公司 | Preparation method of vitamin B12 crude product |
| CN111808159A (en) * | 2020-07-23 | 2020-10-23 | 宁夏金维制药股份有限公司 | Preparation method of cobamamide crude product |
| CN111808159B (en) * | 2020-07-23 | 2023-02-17 | 宁夏金维制药股份有限公司 | Preparation method of cobamamide crude product |
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