CN108329373A - A kind of synthetic method of Mecobalamin - Google Patents
A kind of synthetic method of Mecobalamin Download PDFInfo
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- CN108329373A CN108329373A CN201810373844.9A CN201810373844A CN108329373A CN 108329373 A CN108329373 A CN 108329373A CN 201810373844 A CN201810373844 A CN 201810373844A CN 108329373 A CN108329373 A CN 108329373A
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- CN
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- Prior art keywords
- mecobalamin
- added
- synthetic method
- dichloromethane
- phenol
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The present invention provides a kind of synthetic methods of Mecobalamin, including：Under the protection of high pure nitrogen, cyanocobalamin, NaBH is added4And CH3I；Using the mixed extractant solvent reaction solution of phenol and dichloromethane, collected organic layer, water layer continues the mixed extractant solvent with phenol and dichloromethane, merges organic layer, and after being diluted using dichloromethane, it is plain to be stripped the Mecobalamin in organic layer with purified water；Concentrate crystallisation by cooling obtains Mecobalamin crude product；Mecobalamin crude product is taken, the mixed solution heating of ethyl alcohol and purified water, which is added, makes dissolving, and the activated carbon of 0.1wt% is added, recrystallizes to obtain Mecobalamin sterling and drying.A kind of synthetic method of disclosed Mecobalamin need not be eluted using resin absorbing column, so as to avoid the uncontrollable caused risk of its adsorption effect of resin adsorption major gene, the yield and quality of Mecobalamin can be effectively improved, while can also effectively reduce the synthesis cost of Mecobalamin.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of synthetic methods of Mecobalamin.
Background technology
Mecobalamin is the cobamamide class drug that Japanese Eisai Co., Ltd develops, and is anti-anemia action new drug, uses
In diabete peripheral herve disease and due to a lack of megaloblastic anemia caused by vitamin B12, existing peripheral nerve disease is controlled
It treats.Compared with other vitamin B12 class drugs, Mecobalamin transitivity in nervous system is good；It can promote nucleic acid, albumen and fat
Metabolism；Pharmacologically by promoting the synthesis of nerve cell nucleic acid and protein and neural myelin, to repairing damage
Peripheral nerve.Clinically to peripheral nerve diseases such as diabetes nerve obstacle, polyneuritis especially to numb, pain and
Paralysis has positive effect, is the active drug of current such disease of clinical treatment, and side effect is minimum.In addition, there is research
Show that Mecobalamin is effective treatment parkinsonism, alzheimer syndrome, muscular atrophy and neurasthenic potential drug.
Authorization Notice No. provides a kind of chemical synthesis preparing Mecobalamin for the Chinese invention patent of CN103113443B
Method.In the prior art, cyanocobalamin, cobalt chloride hexahydrate are dissolved in deionized water, obtain reaction solution, to the reaction solution
In simultaneously sodium borohydride aqueous solution, formaldehyde methanol solution is added dropwise, by reduction methylate, a step generate Mecobalamin.Reaction finishes
Afterwards, it is 6.0 to adjust pH value of solution, centrifuges to obtain filtrate, then concentrated concentrate.Concentrate is through macroporous resin adsorption, washing, third
Ketone-water mixed solution elution, the elution of acetone-water mixed solution, crystallizes to obtain crude product Mecobalamin at neutral alumina absorption；Crude product adds
Enter acetone and purified water is recrystallized, Mecobalamin fine work is obtained after centrifugal drying.
Applicant thinks that in the above prior art after reaction, elution processes program is complicated for the first step, and resin column exists
It needs to activate before use, and resin column is to reuse in actual production, to its adsorption effect, there may be uncontrollable wind
Danger, to influence product yield and product quality.
In view of this, it is necessary to the synthetic method of Mecobalamin in the prior art be improved, to solve the above problems.
Invention content
It is an object of the invention to disclose a kind of synthetic method of Mecobalamin, during overcoming chemical synthesis Mecobalamin
Need using resin adsorbed present in because resin adsorption ability unstable existing Mecobalamin yield and quality is relatively low
Technological deficiency, and reduce the synthesis cost of Mecobalamin.
To achieve the above object, the present invention provides a kind of synthetic method of Mecobalamin, include the following steps：
S1, purified water is added in reaction pot and is passed through high pure nitrogen, cyanocobalamin is added and is warming up to after 40 ± 2 DEG C successively
NaBH is added4And CH3I is simultaneously stirred, and obtains reaction solution；
S2, using the mixed extractant solvent reaction solution of phenol and dichloromethane, collected organic layer, water layer continue with phenol with
The mixed extractant solvent of dichloromethane merges organic layer, after being diluted using dichloromethane, is stripped in organic layer with purified water
Mecobalamin element；
Acetone is added until slight turbid occurs in solution after S3, concentrate cooling, stands cooling, filtering for crystallizing, with third
Ketone washs, and obtains Mecobalamin crude product；
S4, Mecobalamin crude product is taken, the mixed solution that ethyl alcohol and purified water is added is heated and dissolved, and the work of 0.1wt% is added
Property charcoal, recrystallizes to obtain Mecobalamin sterling and drying.
As a further improvement on the present invention, in the step S2, the in the mixed solvent phenol and dichloro of reaction solution are extracted
The proportioning of methane is 100g phenol：100ml dichloromethane.
As a further improvement on the present invention, in the step S2, in the Mecobalamin being stripped with purified water in organic layer
Further include being washed with dichloromethane after element, remove the phenol of trace, is concentrated under reduced pressure.
As a further improvement on the present invention, in the step S4, the molar ratio of ethyl alcohol and purified water is 1:1.
As a further improvement on the present invention, in the step S4, further include after the activated carbon of 0.1wt% is added：60
± 2 DEG C of stirrings keep the temperature 30 minutes.
As a further improvement on the present invention, it in the step S4, Mecobalamin crude product and is made of ethyl alcohol and purified water
The mass ratio of mixed solution is 1:10.
As a further improvement on the present invention, in the step S1, cyanocobalamin and NaBH4And CH3The rate of charge of I is：0.4:
4.3:0.9。
As a further improvement on the present invention, in the step S4, dry temperature is 60~70 DEG C, drying time 3
Hour.
Compared with prior art, the beneficial effects of the invention are as follows：A kind of synthetic method of disclosed Mecobalamin
Need not be eluted using resin absorbing column, so as to avoid resin adsorption major gene its adsorption effect it is uncontrollable caused by
Risk can effectively improve the yield and quality of Mecobalamin, while can also effectively reduce the synthesis cost of Mecobalamin.
Specific implementation mode
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in function, method or structure made by these embodiments
Equivalent transformation or replacement, all belong to the scope of protection of the present invention within.
Unless otherwise specified, the room temperature in each embodiment of this specification is specially 23 DEG C；" h " is specially time measurement list
Position：Hour；" min " is specially time measurement unit：Minute；" ml " is specially volume unit：Milliliter；" L " is specially volume list
Position：It rises；" concentration " is specially mass percent concentration.
In the present embodiment, the synthetic method of the Mecobalamin specifically includes following steps S1~step S4.
Step S1, methylation reaction is restored；Wherein, in the present embodiment, cyanocobalamin and NaBH4And CH3The rate of charge of I
For：0.4:4.3:0.9.
Purified water 40L is added in the reaction pot of 200L, being passed through high pure nitrogen, (purity can be 80%~90%, to reduce
Use the cost of nitrogen) it is protected as protective gas to entirely restoring methylation reaction.Blender is started, cyanogen is slowly added into
Cobalt amine 400g.Charging finishes, and is warming up to 40 ± 2 DEG C, and the NaBH of 4L is added4Solution (80g → 4l).At this point, reaction solution is in greyish black
The CH of 0.4L is added in color3I solution, stirring after twenty minutes, stop reduction methylation reaction, obtain reaction solution, for use.
Step S2, extraction Mecobalamin element.
(proportioning is 100g phenol to the mixed solvent being made of phenol and dichloromethane using 10L:100ml dichloromethane)
Extract reaction solution.Collected organic layer, (proportioning is for mixed solvent that water layer continues to be made of with dichloromethane phenol with 10L
100g phenol:100ml dichloromethane) extraction, until extract liquor is colourless.Merge organic layer, dichloromethane is used in combination (about
After 120L) being diluted to 5 times, with the Mecobalamin element in the purified water back extraction organic layer of about 10L.Mixed Mecobalamin element is water-soluble
Liquid is washed with dichloromethane (about 30L), to remove the phenol of trace, is concentrated under reduced pressure into about 4L.
Step S3, it crystallizes.
After concentrate slightly cools down, acetone is added until slight turbid occurs in solution, stands cooling.Filtering for crystallizing, with third
Ketone washs, and obtains Mecobalamin crude product, for use.
Step S4, Mecobalamin sterling is made in polishing purification.
It takes Mecobalamin crude product 420g, addition to be heated and dissolved by the mixed solution of ethyl alcohol and purified water, is added 0.1wt%'s
Activated carbon recrystallizes to obtain Mecobalamin sterling 390g and drying；Wherein, which is specially：In the activated carbon that 0.1wt% is added
Afterwards, it stirs and keeps the temperature 30 minutes in 60 ± 2 DEG C, filtering is quiet until slight turbid shape occurs in addition acetone to solution after slightly cooling down
Cooling is set, filtering for crystallizing is washed with acetone, after being filtered dry, is set in baking oven, 60~70 DEG C of dryings about 3 hours, after obtaining polishing purification
Mecobalamin about 396.76g.In the present embodiment, the molar ratio of ethyl alcohol and purified water is in ethyl alcohol and the mixed solution of purified water
1:1.The mass ratio of Mecobalamin crude product and the mixed solution being made of ethyl alcohol and purified water is 1:10.
In the present embodiment, it is computed, cyanocobalamin molecular weight is 1355.37, and Mecobalamin molecular weight is 1344.4, by anti-
Answer 100% completely, the comprehensive yield by the Mecobalamin obtained by this synthetic method is 98%, compared with the existing technology middle first cobalt
Tool is improved to some extent for the technique effect that the comprehensive yield of amine is about 90%.
The series of detailed descriptions listed above only for the present invention feasible embodiment specifically
Bright, they are all without departing from equivalent implementations made by technical spirit of the present invention not to limit the scope of the invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Profit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent requirements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiment being appreciated that.
Claims (8)
1. a kind of synthetic method of Mecobalamin, which is characterized in that include the following steps：
S1, purified water is added in reaction pot and is passed through high pure nitrogen, cyanocobalamin is added and is sequentially added after being warming up to 40 ± 2 DEG C
NaBH4And CH3I is simultaneously stirred, and obtains reaction solution；
S2, using the mixed extractant solvent reaction solution of phenol and dichloromethane, collected organic layer, water layer continues to use phenol and dichloro
The mixed extractant solvent of methane merges organic layer, and after being diluted using dichloromethane, the first cobalt in organic layer is stripped with purified water
Amine element；
Acetone is added until slight turbid occurs in solution after S3, concentrate cooling, stands cooling, filtering for crystallizing is washed with acetone
It washs, obtains Mecobalamin crude product；
S4, Mecobalamin crude product being taken, the mixed solution that ethyl alcohol and purified water is added is heated and is dissolved, and the activated carbon of 0.1wt% is added,
Recrystallize to obtain Mecobalamin sterling and drying.
2. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S2, extract reaction solution
In the mixed solvent phenol and dichloromethane proportioning be 100g phenol：100ml dichloromethane.
3. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S2, with purified water
The Mecobalamin element being stripped in organic layer further includes later being washed with dichloromethane, removes the phenol of trace, is concentrated under reduced pressure.
4. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S4, ethyl alcohol and purifying
The molar ratio of water is 1:1.
5. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S4, work as addition
Further include after the activated carbon of 0.1wt%：60 ± 2 DEG C of stirrings keep the temperature 30 minutes.
6. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S4, Mecobalamin crude product
Mass ratio with the mixed solution being made of ethyl alcohol and purified water is 1:10.
7. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S1, cyanocobalamin with
NaBH4And CH3The rate of charge of I is：0.4:4.3:0.9.
8. the synthetic method of Mecobalamin according to claim 1, which is characterized in that in the step S4, dry temperature
It it is 60~70 DEG C, drying time is 3 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810373844.9A CN108329373A (en) | 2018-04-24 | 2018-04-24 | A kind of synthetic method of Mecobalamin |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810373844.9A CN108329373A (en) | 2018-04-24 | 2018-04-24 | A kind of synthetic method of Mecobalamin |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4538059B1 (en) * | 1967-07-27 | 1970-12-02 | ||
| CN102391340A (en) * | 2011-10-31 | 2012-03-28 | 河北玉星生物工程有限公司 | Preparation method of mecobalamin |
| 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 |
-
2018
- 2018-04-24 CN CN201810373844.9A patent/CN108329373A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4538059B1 (en) * | 1967-07-27 | 1970-12-02 | ||
| CN102391340A (en) * | 2011-10-31 | 2012-03-28 | 河北玉星生物工程有限公司 | Preparation method of mecobalamin |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 赵临襄等，: "《化学制药工艺学》", 31 January 2003 * |
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