CN106350550A - Method for preparing mycophenolate sodium from mycophenolic acid strains - Google Patents
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Abstract
The invention provides a method for preparingmycophenolate sodium from mycophenolic acid strains, comprising the following steps: selecting the mycophenolic acid strains to produce strain spore suspension liquid, inoculating the strain spore suspension liquid in a seed medium and cultivating for 2-4 days at a temperature of 26-28 DEG C; inoculating the seed medium in a fermentation tank, adding a fermentation medium, and fermenting for 9-11 days at a temperature of 26-28 DEG C; adding acid into fermentation liquid in such a manner that pH value of the fermentation liquid is 3-4, adding a sodium hydroxide solution into the fermentation liquid in such a manner that pH value of the fermentation liquid is 8-9, decolorizing and recrystallizing to obtain mycophenolic acid; and synthesizing the mycophenolic acid and sodium hydroxide or sodium methylate in alcohols solvent to obtain the mycophenolate sodium. According to the method provided by the invention, the fermentation liquid obtained by cultivating the mycophenolic acid strains is subjected to acid and alkali treatment, and the sodium hydroxide or the sodium methylate is adopted to synthesize the mycophenolate sodium; and therefore the method has the advantages of short preparation route, simple operating procedure and lower production cost; meanwhile, the application of ketones organic solvent is avoided, and harm to the environment and human body is reduced.
Description
Technical field
The present invention relates to biological pharmacy technical field, more particularly, to a kind of side examining phenol sodium from Mycophenolic Acid bacterial strain preparation wheat
Method.
Background technology
Wheat examines phenol sodium also known as mycophenolate sodium, is a kind of immunosuppressant being obtained by synthesis from Mycophenolic Acid, molecular formula:
c17h19nao6, molecular weight: 342.3.Wheat is examined shown in the chemical structural formula such as following formula (1) of phenol sodium.
Wheat examines the sodium salt that phenol sodium (mps) is Mycophenolic Acid (mpa).Mycophenolic Acid is a kind of selectivity, noncompetitive, reversible
Hypoxanthine monophosphate dehydrogenase (impdh) inhibitor, the classical route of synthesis of guanylic acid can be suppressed not damage
Hinder the synthesis of dna.Wheat is examined phenol sodium and is applied to and shared with ciclosporin and corticosteroid, for accepting allograft renal transplantation
The prevention of year patients acuity rejection.The research and development of immunosuppressant and application are that in organ transplantation development history one is important
Milestone, it promotes and has promoted the raising of clinical renal transplantation quantity and the improvement of quality.Renal transplantation is made to become now because each
Plant the conventional treatments that primary disease causes renal failure.
At present, preparation wheat is examined phenol sodium and mainly includes solid state fermentation and liquid fermentation method.But there is conjunction in solid state fermentation
Become the low defect of stability.The liquid fermentation method phase after incubation, culture medium can be subsided and can be collapsed hardening, be unfavorable for mass transfer and biography
Heat.The Chinese invention patent of notification number cn101348810b discloses " solid state fermentation of Mai Kaofen acid ", and it needs using non-
Inert carrier.This non-inert carrier is crossed in car in commercial application and can be produced substantial amounts of waste material, thus leading to environment is caused
Certain pollution；On the other hand this existing also cannot directly prepare whole product " wheat examines phenol sodium ", thus leading to synthetic route relatively
Long.Meanwhile, in current liquid fermentation method, the metabolite of microbial cell and microbial environment also can examine phenol sodium to wheat
Precursor (i.e. " Mycophenolic Acid ") has undesirable effect.
In view of this it is necessary to the preparation method examining phenol sodium to wheat of the prior art is improved, to solve above-mentioned asking
Topic.
Content of the invention
It is an object of the invention to disclosing a kind of method examining phenol sodium from Mycophenolic Acid bacterial strain preparation wheat, in order to realize shortening
Synthetic route, reduce manufacturing cost, reduce preparation wheat examine phenol sodium during produced side-product to the dirt caused by environment
Dye, and improve repeatability.
For achieving the above object, the invention provides preparing, from Mycophenolic Acid bacterial strain, the method that wheat examines phenol sodium, including
Following steps:
Step (1), take Mycophenolic Acid bacterial strain producing strains spore suspension, be inoculated on seed culture medium at 26～28 DEG C
Culture 2～4 days；
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, 26～28 DEG C of bottom fermentations 9～11
My god, carry out after the completion of fermentation putting tank to extract fermentation liquid；
Step (3), in fermentation liquid add acid make fermentation liquid ph be in 3～4, then in fermentation liquid add sodium hydroxide
It is in 8～9 that solution makes the ph of fermentation liquid, plate-and-frame filtration, and it is in 2～3 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid crude product,
Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid；
Step (4), Mycophenolic Acid and sodium hydroxide or Feldalat NM are synthesized wheat in alcohols solvent examine phenol sodium, wherein, instead
Temperature is answered to be 40～60 DEG C, 1～3 hour response time；
Step (5), the reactant liquor obtaining step (4) crystallize after concentrating, and filter, are dried.
As a further improvement on the present invention, the consisting of of the seed culture medium in described step (1): soybean cake powder 5～
15g/l, Lactose 40～60g/l, Dried Corn Steep Liquor Powder 20～40g/l, ammonium nitrate 1～3g/l, potassium dihydrogen phosphate 1～3g/l, carbonic acid
Calcium 1～3g/l.
As a further improvement on the present invention, the consisting of of the fermentation medium in described step (2): soybean cake powder 15～
25g/l, corn starch 5～15g/l, glucose 45～65g/l, Fructose 70～90g/l, Dried Corn Steep Liquor Powder 45～55g/l, carbonic acid
Calcium 1～3g/l, Methionine 2～4g/l, potassium dihydrogen phosphate 0.5～1.5g/l.
As a further improvement on the present invention, the acid in described step (3) be selected from hydrochloric acid or sulphuric acid, concentration be 6～
12mol/l, the alcohols solvent in described step (3) is selected from ethanol or methanol.
As a further improvement on the present invention, the alcohols solvent in described step (4) be selected from methanol, ethanol, normal propyl alcohol or
N-butyl alcohol.
As a further improvement on the present invention, the crystallization mode in described step (5) is condensing crystallizing or crystallisation by cooling；Its
In, the temperature of condensing crystallizing is 40～60 DEG C, and the temperature of crystallisation by cooling is 0～10 DEG C.
As a further improvement on the present invention, the drying mode in described step (5) is vacuum drying, vacuum drying temperature
Spend for 40～50 DEG C, vacuum drying vacuum is 0.1～0.5mpa.
Compared with prior art, the invention has the beneficial effects as follows: in the present invention, Mai Kaofen acid bacterial strain through culture after
The fermentation liquid arriving is through acid-alkali treatment, and is synthetically generated wheat with sodium hydroxide or Feldalat NM and examines phenol sodium, and it is short to have a syntheti c route,
Operation sequence is simple, the relatively low advantage of manufacturing cost；Simultaneously, it is to avoid using organic solvent of ketone, reduce to environment and human body
Harm.
Specific embodiment
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 these embodiment institute work energy, method or structure
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless there is specified otherwise in description, the component in each embodiment in the present invention, raw material are all pure using analyzing
Rank.In addition, " g " in each embodiment is unit of weight " gram "；" h " is unit of time " hour "；" ml " be volume unit " in the least
Rise "；" room temperature " is 23 DEG C；" hplc " is " high performance liquid chromatography ".
Embodiment one:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated on seed culture medium, cultivate 4 days at 28 DEG C.Should
Each group in seed culture medium is divided into (unit: g/l): soybean cake powder 5, Lactose 40, Dried Corn Steep Liquor Powder 20, ammonium nitrate 1, di(2-ethylhexyl)phosphate
Hydrogen potassium 1, Calcium Carbonate 1, balance of water.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 10 days for 26 DEG C.Fermentation training
Each component (unit: g/l) in foster base: soybean cake powder 15, corn starch 5, glucose 45, Fructose 70, Dried Corn Steep Liquor Powder 45, carbon
Sour calcium 1, Methionine 2, potassium dihydrogen phosphate 0.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 3.0, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 8.0.Plate-and-frame filtration, it is in 2.0 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid thick
Product；Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used
For the dilute sulfuric acid for 10wt% for the mass concentration.
Step (4), Mycophenolic Acid and sodium hydroxide are carried out synthetic reaction in methanol, examine phenol sodium, reaction temperature to generate wheat
50 DEG C of degree, 2 hours response time.
Step (5), by step (4) reactant liquor crystallization, filter, be dried, obtain final product whole product wheat and examine phenol sodium.In the present embodiment
In, crystallization mode is 0 DEG C of crystallisation by cooling.40 DEG C of baking temperature.
Through Physico-chemical tests, fusing point meets pertinent literature regulation to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
189～191 DEG C, and fusing point is 189.5～190.1 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.91%.
Embodiment two:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated in culture medium, cultivate 3 days at 26 DEG C；This seed
Each group in culture medium is divided into (unit: g/l): soybean cake powder 10, Lactose 50, Dried Corn Steep Liquor Powder 25, ammonium nitrate 2, biphosphate
Potassium 2, Calcium Carbonate 2, balance of water.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 9 days for 26 DEG C.Fermentation culture
Each group in base is divided into (unit: g/l): soybean cake powder 20, corn starch 10, glucose 50, Fructose 80, Dried Corn Steep Liquor Powder 50,
Calcium Carbonate 1, Methionine 3, potassium dihydrogen phosphate 0.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 4.0, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 9.0.Plate-and-frame filtration, it is in 3.0 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid thick
Product；Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used
For the dilute sulfuric acid for 5wt% for the mass concentration.
Step (4), Mycophenolic Acid and sodium hydroxide are carried out in ethanol synthetic reaction and examine phenol sodium to produce wheat, reaction temperature
40 DEG C of degree, 3 hours response time.
Step (5), the reactant liquor obtaining step (4) concentrate, and crystallization is dried, obtains final product whole product wheat and examine phenol sodium.Crystallization mode
For 40 DEG C of condensing crystallizings.Vacuum drying temperature is 40 DEG C, and vacuum drying vacuum is 0.1mpa.
Through Physico-chemical tests, fusing point meets pertinent literature regulation 189 to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
～191 DEG C, fusing point is 189.9～190.5 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.83%.
Embodiment three:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated in culture medium, cultivate 4 days at 28 DEG C；This seed
Each group in culture medium is divided into (unit: g/l) soybean cake powder 15, Lactose 60, Dried Corn Steep Liquor Powder 40, ammonium nitrate 3, potassium dihydrogen phosphate
3, Calcium Carbonate 3, balance of water.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 11 days for 28 DEG C.Fermentation training
Each group in foster base is divided into (unit: g/l): soybean cake powder 25, corn starch 15, glucose 65, Fructose 90, Dried Corn Steep Liquor Powder
55, Calcium Carbonate 3, Methionine 4, potassium dihydrogen phosphate 1.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 4.0, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 8.5.Plate-and-frame filtration, it is in 2.5 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid thick
Product；Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used
For the dilute hydrochloric acid for 10wt% for the mass concentration.
Step (4), the Mycophenolic Acid obtaining and Feldalat NM carry out synthetic reaction in methanol, examine phenol sodium to generate wheat, instead
Answer temperature 60 C, 3 hours response time.
Step (5), the reactant liquor of step (4) gained is concentrated, crystallization, be dried, obtain final product whole product wheat and examine phenol sodium.Crystallization mode
For 10 DEG C of crystallisation by cooling.Vacuum drying temperature is 50 DEG C, and vacuum drying vacuum is 0.5mpa.
Through Physico-chemical tests, fusing point meets pertinent literature regulation 189 to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
～191 DEG C, fusing point is 190.3～190.9 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.85%.
Example IV:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated in culture medium, cultivate 3 days at 26 DEG C.Seed is trained
Each group in foster base is divided into (unit: g/l): soybean cake powder 10, Lactose 50, Dried Corn Steep Liquor Powder 25, ammonium nitrate 2, potassium dihydrogen phosphate
2, Calcium Carbonate 2, balance of water.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 9 days for 26 DEG C.Fermentation medium
In each group be divided into (unit: g/l): soybean cake powder 20, corn starch 10, glucose 50, Fructose 80, Semen Maydis pulp 50, Calcium Carbonate
1, Methionine 3, potassium dihydrogen phosphate 0.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 3.0, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 9.Plate-and-frame filtration, it is in 2.0 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid crude product；
Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used is matter
Amount concentration is the dilute hydrochloric acid of 8wt%.
Step (4), Mycophenolic Acid and Feldalat NM are carried out synthetic reaction in ethanol, examine phenol sodium, reaction temperature to generate wheat
40 DEG C of degree, 3 hours response time.
Step (5), the reactant liquor of step (4) gained is concentrated, crystallization, be dried.Crystallization mode is 60 DEG C of condensing crystallizings.Very
The empty temperature being dried is 50 DEG C, and vacuum drying vacuum is 0.2mpa.
Through Physico-chemical tests, fusing point meets pertinent literature regulation 189 to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
～191 DEG C, fusing point is 190.2～190.9 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.89%.
Embodiment five:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated in culture medium, cultivate 3 days at 26 DEG C.Seed is trained
Each group in foster base is divided into (unit: g/l): soybean cake powder 10, Lactose 50, Dried Corn Steep Liquor Powder 25, ammonium nitrate 2, potassium dihydrogen phosphate
2, Calcium Carbonate 2, balance of water.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 9 days for 26 DEG C；Fermentation medium
In each group be divided into (unit: g/l): soybean cake powder 20, corn starch 10, glucose 50, Fructose 80, Dried Corn Steep Liquor Powder 50, carbon
Sour calcium 1, Methionine 3, potassium dihydrogen phosphate 0.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 4.0, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 8.8.Plate-and-frame filtration, it is in 2.2 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid thick
Product；Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used
For the dilute sulfuric acid for 5wt% for the mass concentration.
Step (4), Mycophenolic Acid and sodium hydroxide are carried out synthetic reaction in normal propyl alcohol, examine phenol sodium to generate wheat.Instead
Answer 40 DEG C of temperature, 3 hours response time.
Step (5), the reactant liquor of step (4) gained is concentrated, crystallization, be dried, obtain final product whole product wheat and examine phenol sodium.Crystallization mode
For 40 DEG C of condensing crystallizings.Vacuum drying temperature is 45 DEG C, and vacuum drying vacuum is -0.15mpa.
Through Physico-chemical tests, fusing point meets pertinent literature regulation 189 to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
～191 DEG C, fusing point is 189.7～190.3 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.88%.
Embodiment six:
The method that phenol sodium should be examined from Mycophenolic Acid bacterial strain preparation wheat comprises the following steps.
Step (1), take Mycophenolic Acid producing strains spore suspension, be inoculated in culture medium, cultivate 4 days at 28 DEG C；Seed is trained
Support basis set point (g/l): soybean cake powder 15, Lactose 60, Dried Corn Steep Liquor Powder 40, ammonium nitrate 3, potassium dihydrogen phosphate 3, Calcium Carbonate 3.
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, cultivate 11 days for 28 DEG C.Fermentation culture
Each group in base is divided into (unit: g/l): soybean cake powder 25, corn starch 15, glucose 65, Fructose 90, Dried Corn Steep Liquor Powder 55,
Calcium Carbonate 3, Methionine 4, potassium dihydrogen phosphate 1.5, balance of water.Fermentation carries out putting tank to extract fermentation liquid after finishing.
Step (3), in fermentation liquid add acid make fermentation liquid be acidified to ph be in 2.1, then in fermentation liquid add hydrogen-oxygen
Change sodium solution to make the ph of fermentation liquid is in 8.7.Plate-and-frame filtration, it is in 2.6 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid thick
Product；Mycophenolic Acid crude product is dissolved in alcohols solvent rear decoloring, after recrystallization, obtains Mycophenolic Acid.In the present embodiment, acid used
For the dilute hydrochloric acid for 5wt% for the mass concentration.
Step (4), Mycophenolic Acid and Feldalat NM are carried out synthetic reaction in n-butyl alcohol, examine phenol sodium to generate wheat.Reaction
Temperature 60 C, 3 hours response time.
Step (5), by step (4) reactant liquor concentrate, crystallization, be dried.Crystallization mode is 10 DEG C of crystallisation by cooling.Vacuum
The temperature being dried is 42 DEG C, and vacuum drying vacuum is 0.32mpa.
Through Physico-chemical tests, fusing point meets pertinent literature regulation 189 to solid (i.e. " wheat examines phenol sodium ") obtained by the present embodiment
～191 DEG C, fusing point is 190.2～190.8 DEG C, through hplc detection, by the purity that the wheat that this method is obtained examines phenol sodium is
99.86%.
The a series of detailed description of those listed above is only for the feasibility embodiment of the present invention specifically
Bright, they simultaneously are not used to limit the scope of the invention, all equivalent implementations made without departing from skill spirit of the present invention
Or change should be included within the scope of the present invention.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of the spirit or essential attributes of the present invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although this specification is been described by according to embodiment, not each embodiment only wraps
Containing an independent technical scheme, only for clarity, those skilled in the art should for this narrating mode of description
Using description as an entirety, the technical scheme in each embodiment can also form those skilled in the art through appropriately combined
Understandable other embodiment.
Claims (7)
1. examine the method for phenol sodium it is characterised in that comprising the following steps from Mycophenolic Acid bacterial strain preparation wheat:
Step (1), take Mycophenolic Acid bacterial strain producing strains spore suspension, be inoculated in and cultivate at 26～28 DEG C on seed culture medium
2～4 days；
Step (2), seed culture medium are inoculated in fermentation tank and add fermentation medium, 26～28 DEG C of bottom fermentations 9～11 days, send out
Carry out after the completion of ferment putting tank to extract fermentation liquid；
Step (3), in fermentation liquid add acid make fermentation liquid ph be in 3～4, then in fermentation liquid add sodium hydroxide solution
The ph making fermentation liquid is in 8～9, plate-and-frame filtration, and it is in 2～3 that filtrate is adjusted to ph with acid again, filters, obtains Mycophenolic Acid crude product, by wheat
Examine phenolic acid crude product and be dissolved in alcohols solvent rear decoloring, after recrystallization, obtain Mycophenolic Acid；
Step (4), Mycophenolic Acid and sodium hydroxide or Feldalat NM are synthesized wheat in alcohols solvent examine phenol sodium, wherein, reaction temperature
Spend for 40～60 DEG C, 1～3 hour response time；
Step (5), the reactant liquor obtaining step (4) crystallize after concentrating, and filter, are dried.
2. method according to claim 1, the consisting of of the seed culture medium in described step (1): soybean cake powder 5～
15g/l, Lactose 40～60g/l, Dried Corn Steep Liquor Powder 20～40g/l, ammonium nitrate 1～3g/l, potassium dihydrogen phosphate 1～3g/l, carbonic acid
Calcium 1～3g/l.
3. method according to claim 1, the consisting of of the fermentation medium in described step (2): soybean cake powder 15～
25g/l, corn starch 5～15g/l, glucose 45～65g/l, Fructose 70～90g/l, Dried Corn Steep Liquor Powder 45～55g/l, carbonic acid
Calcium 1～3g/l, Methionine 2～4g/l, potassium dihydrogen phosphate 0.5～1.5g/l.
4. method according to claim 1, the acid in described step (3) is selected from hydrochloric acid or sulphuric acid, and concentration is 6～12mol/
L, the alcohols solvent in described step (3) is selected from ethanol or methanol.
5. method according to claim 1, the alcohols solvent in described step (4) is selected from methanol, ethanol, normal propyl alcohol or just
Butanol.
6. method according to claim 1, the crystallization mode in described step (5) is condensing crystallizing or crystallisation by cooling；Its
In, the temperature of condensing crystallizing is 40～60 DEG C, and the temperature of crystallisation by cooling is 0～10 DEG C.
7. method according to claim 1, the drying mode in described step (5) is vacuum drying, vacuum drying temperature
Spend for 40～50 DEG C, vacuum drying vacuum is 0.1～0.5mpa.
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Cited By (2)
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| CN106866594A (en) * | 2017-02-17 | 2017-06-20 | 上海华源医药科技发展有限公司 | The optimize technique of phenol sodium industrialized production is examined suitable for wheat |
| CN112645912A (en) * | 2020-12-27 | 2021-04-13 | 广东蓝宝制药有限公司 | Preparation method of high-purity M2 crystal form meclofenol sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866594A (en) * | 2017-02-17 | 2017-06-20 | 上海华源医药科技发展有限公司 | The optimize technique of phenol sodium industrialized production is examined suitable for wheat |
| CN112645912A (en) * | 2020-12-27 | 2021-04-13 | 广东蓝宝制药有限公司 | Preparation method of high-purity M2 crystal form meclofenol sodium |
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