CN107903228A - A kind of high-purity mycophenolic acid production technology - Google Patents
A kind of high-purity mycophenolic acid production technology Download PDFInfo
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- CN107903228A CN107903228A CN201711252596.4A CN201711252596A CN107903228A CN 107903228 A CN107903228 A CN 107903228A CN 201711252596 A CN201711252596 A CN 201711252596A CN 107903228 A CN107903228 A CN 107903228A
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- mycophenolic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The present invention relates to a kind of high-purity mycophenolic acid production technology, including zymotic fluid to modulate, separation of solid and liquid, extraction, five steps such as crystallization and the purification of mycophenolic acid crude product.Simple production process of the present invention is easily grasped, universal normalization is good, on the one hand mycophenolic acid production preparation work efficiency and product purity stability can effectively be improved, so as to effectively improve the quality and quality of mycophenolic acid product, on the other hand in mycophenolic acid produces preparation process, material loss and energy consumption can be effectively reduced, and used contamination of raw material and toxicity are low, so as to effectively reduce the cost and environmental contamination of mycophenolic acid production activity.
Description
Technical field
The present invention relates to a kind of high-purity mycophenolic acid production technology, belongs to technical field of chemical chemistry.
Background technology
Mycophenolic acid is one of raw material important in current biological medical product, and usage amount is huge, is currently carrying out mycophenolic acid
Product is prepared in operation, is extracted when main by carrying out the organic matters such as the adjusting of progress acid-base value, toluene to mycophenolic acid fermentation broth, is dense
Sheepshank is brilliant, and then the crystal after crystallization is dissolved in toluene again, is then filtered again, takes out impurity and decolorization,
The technique such as low temperature crystallization is finally carried out again and carries out production preparation, although the preparation process of this quasi-tradition can effectively meet pair
Needs prepared by mycophenolic acid production, but production efficiency is relatively low, needs to use in complex production process and production process
The intermediary larger to substantial amounts of pollution and toxicity, also easily causes environmental pollution while material loss is big, while also easy
Cause the objectionable impurities in mycophenolic acid product relatively more, in addition, in current mycophenolic acid production process, operation energy consumption
It is of a relatively high, so as to cause current mycophenolic acid production efficiency, product quality and cost cannot effectively meet to actually use
Needs, therefore this present situation is directed to, there is an urgent need to develop a kind of mycophenolic acid preparation process, to meet the needs of actual use.
The content of the invention
The object of the invention, which is that, overcomes above-mentioned deficiency, there is provided a kind of high-purity mycophenolic acid production technology.
To achieve the above object, the present invention is to be achieved through the following technical solutions：
A kind of high-purity mycophenolic acid production technology, comprises the following steps：
The first step, zymotic fluid modulation, mycophenolic acid fermentation broth temperature was increased to 30 DEG C-60 DEG C in 10-30 minutes first, then
Sulfide is added into mycophenolic acid and stirs evenly mixed liquor is prepared, and the sulfide content in mixed liquor for 0.005-
0.5mol/L, and acid-base value is pH7.5-12；
Second step, separation of solid and liquid, passes through filtering by the mixed liquor being prepared in the first step under 30 DEG C -60 DEG C isoperibols
Device carries out separation of solid and liquid, and spare and constant temperature is collected to the filtrate after filtering and is preserved；
3rd step, extraction, adds into the filtered fluid of second step and accounts for the organic solvent of 1-6 times of filtered fluid total amount and stir evenly,
Filtered fluid and organic solvent mixed liquor acid-base value are adjusted to pH1-6 at the same time, and keep the temperature standing 30-180 minutes, is then filtered
Separating and filtering liquid and the organic phase in organic solvent mixed liquor are spare；
4th step, crystallization, the organic phase of filtered fluid prepared by the 3rd step, which is delivered in crystallizer, carries out crystallization operation, and right
Crystal after crystallization is collected, and obtains mycophenolic acid crude product；
5th step, the purification of mycophenolic acid crude product, it is mycophenolic acid crude product that the mycophenolic acid crude product that the 4th step is prepared is added to total amount
In the deionized water at normal temperature of 10-30 times of total amount and stir evenly, mycophenolic acid crude product aqueous solution is then warming up to 35 DEG C-90
DEG C, insulation stands 5-20 minutes, and then addition accounts for active carbon particle and the stirring of mycophenolic acid crude product aqueous solution total amount 3%-15%
Uniformly, then insulation stands 5-20 minutes, leads to after mycophenolic acid crude product aqueous solution then is pressurized to 1.5-5 times of standard atmospheric pressures
Cross vertical sheet frame filter plant to be separated by filtration, filtrate can be so collected spare；
6th step, recrystallization, when by the filtered fluid that the 5th step obtains, crystallisation by cooling 5-24 is small under-5 DEG C-5 DEG C isoperibols,
Then separation of solid and liquid is carried out by sedimentation centrifuge to the filtered fluid after crystallization under thermal environment, and crystalline solid is collected
Obtain finished product high-purity mycophenolic acid.
Further, in the first step, sulfide is metal sulphide salt, its double salt or monohydric salt, hydrogen sulfide, vulcanization
Any one in ammonia and polysulfide.
Further, the metal sulphide salt is in vulcanized sodium, potassium sulfide, rubidium sulfide, vulcanization ammonia and NaHS
Any one.
Further, in the 3rd step, organic solvent is ethyl acetate, methyl acetate, Ethyl formate, acetic acid third
In ester, propyl formate, ethyl propionate, methyl propionate, propyl propionate any one or any several made with arbitrary proportion mixing
With.
Further, in the 5th step, mycophenolic acid crude product aqueous solution is filtering work by vertical sheet frame filter plant
Before industry, vacuum rising film concentration is carried out first, wherein it is 300-800L/h to rise diaphragm flow, and the mycophenolic acid after concentration is thick
Product aqueous solution volume is 40% -60% of mycophenolic acid crude product aqueous solution volume before filtering.
Simple production process of the present invention is easily grasped, and universal normalization is good, on the one hand can effectively improve mycophenolic acid production
Preparation work efficiency and product purity stability, so as to effectively improve the quality and quality of mycophenolic acid product, on the other hand exist
In mycophenolic acid production preparation process, material loss and energy consumption can be effectively reduced, and used contamination of raw material and toxicity are low,
So as to effectively reduce the cost and environmental contamination of mycophenolic acid production activity.
Brief description of the drawings
Fig. 1 is the preparation technology flow chart of the present invention.
Embodiment
Embodiment 1
As shown in Figure 1, a kind of high-purity mycophenolic acid production technology, comprises the following steps：
The first step, zymotic fluid modulation, mycophenolic acid fermentation broth temperature was increased to 60 DEG C in 30 minutes first, then into mycophenolic acid
Addition hydrogen sulfide simultaneously stirs evenly mixed liquor is prepared, and the sulfide content in mixed liquor is 0.3mol/L, and acid-base value
For pH12；
Second step, separation of solid and liquid, by the mixed liquor being prepared in the first step under 50 DEG C of isoperibols by filtration apparatus into
Row separation of solid and liquid, and spare and constant temperature is collected to the filtrate after filtering and is preserved；
3rd step, extraction, adds into the filtered fluid of second step and accounts for the propyl propionate of 3 times of filtered fluid total amount and stir evenly, together
When filtered fluid and will there is propyl propionate mixed liquor acid-base value to be adjusted to pH16, and keep the temperature standing 30-180 minutes, then filtering point
From filtered fluid with there is the organic phase in propyl propionate mixed liquor spare；
4th step, crystallization, the organic phase of filtered fluid prepared by the 3rd step, which is delivered in crystallizer, carries out crystallization operation, and right
Crystal after crystallization is collected, and obtains mycophenolic acid crude product；
5th step, the purification of mycophenolic acid crude product, it is mycophenolic acid crude product that the mycophenolic acid crude product that the 4th step is prepared is added to total amount
In the deionized water at normal temperature of 10-30 times of total amount and stir evenly, mycophenolic acid crude product aqueous solution is then warming up to 35 DEG C-90
DEG C, insulation stands 5-20 minutes, and then addition accounts for active carbon particle and the stirring of mycophenolic acid crude product aqueous solution total amount 3%-15%
Uniformly, then insulation stands 5-20 minutes, then mycophenolic acid crude product aqueous solution is carried out vacuum rising film concentration, wherein rising film
Device flow is 800L/h, and the mycophenolic acid crude product aqueous solution volume after concentration is mycophenolic acid crude product aqueous solution volume before filtering
60%, then mycophenolic acid crude product aqueous solution is pressurized to after 5 times of standard atmospheric pressures filtering point is carried out by vertical sheet frame filter plant
From can be so collected to filtrate spare；
Then 6th step, recrystallization, the filtered fluid that the 5th step is obtained are being protected when crystallisation by cooling 24 is small under -5 DEG C of isoperibols
Separation of solid and liquid is carried out by sedimentation centrifuge to the filtered fluid after crystallization under warm environment, and crystalline solid is collected and can obtain finished product
High-purity mycophenolic acid.
Embodiment 2
As shown in Figure 1, a kind of high-purity mycophenolic acid production technology, comprises the following steps：
The first step, zymotic fluid modulation, mycophenolic acid fermentation broth temperature was increased to 40 DEG C in 10 minutes first, then into mycophenolic acid
Addition vulcanized sodium simultaneously stirs evenly mixed liquor is prepared, and the sulfide content in mixed liquor is 0.5mol/L, and acid-base value
For pH8；
Second step, separation of solid and liquid, by the mixed liquor being prepared in the first step under 60 DEG C of isoperibols by filtration apparatus into
Row separation of solid and liquid, and spare and constant temperature is collected to the filtrate after filtering and is preserved；
3rd step, extraction, adds into the filtered fluid of second step and accounts for the ethyl acetate of 6 times of filtered fluid total amount and stir evenly, together
When filtered fluid and ethyl acetate mixtures acid-base value be adjusted to pH3, and keep the temperature standing 40 minutes, be then separated by filtration filtered fluid
It is spare with the organic phase in ethyl acetate mixtures；
4th step, crystallization, the organic phase of filtered fluid prepared by the 3rd step, which is delivered in crystallizer, carries out crystallization operation, and right
Crystal after crystallization is collected, and obtains mycophenolic acid crude product；
5th step, the purification of mycophenolic acid crude product, it is mycophenolic acid crude product that the mycophenolic acid crude product that the 4th step is prepared is added to total amount
In the deionized water at normal temperature that 20 times of total amount and stir evenly, mycophenolic acid crude product aqueous solution is then warming up to 90 DEG C, insulation is stood
10 minutes, then addition accounted for the active carbon particle of mycophenolic acid crude product aqueous solution total amount 8% and stirs evenly, and then insulation stands 20
Minute, mycophenolic acid crude product aqueous solution is then subjected to vacuum rising film concentration, wherein it is 450L/h to rise diaphragm flow, and is concentrated
Mycophenolic acid crude product aqueous solution volume afterwards is 40% of mycophenolic acid crude product aqueous solution volume before filtering, then by mycophenolic acid crude product water
Solution is separated by filtration after being pressurized to 5 times of standard atmospheric pressures by vertical sheet frame filter plant, and so filtrate can be collected
It is spare；
Then 6th step, recrystallization, the filtered fluid that the 5th step is obtained are being protected when crystallisation by cooling 24 is small under 0 DEG C of isoperibol
Separation of solid and liquid is carried out by sedimentation centrifuge to the filtered fluid after crystallization under warm environment, and crystalline solid is collected and can obtain finished product
High-purity mycophenolic acid.
Simple production process of the present invention is easily grasped, and universal normalization is good, on the one hand can effectively improve mycophenolic acid production
Preparation work efficiency and product purity stability, so as to effectively improve the quality and quality of mycophenolic acid product, on the other hand exist
In mycophenolic acid production preparation process, material loss and energy consumption can be effectively reduced, and used contamination of raw material and toxicity are low,
So as to effectively reduce the cost and environmental contamination of mycophenolic acid production activity.
The basic principles, main features and the advantages of the invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (5)
- A kind of 1. high-purity mycophenolic acid production technology, it is characterised in that：The high-purity mycophenolic acid production technology includes following Step：The first step, zymotic fluid modulation, mycophenolic acid fermentation broth temperature was increased to 30 DEG C-60 DEG C in 10-30 minutes first, then Sulfide is added into mycophenolic acid and stirs evenly mixed liquor is prepared, and the sulfide content in mixed liquor for 0.005- 0.5mol/L, and acid-base value is pH7.5-12；Second step, separation of solid and liquid, passes through filtering by the mixed liquor being prepared in the first step under 30 DEG C -60 DEG C isoperibols Device carries out separation of solid and liquid, and spare and constant temperature is collected to the filtrate after filtering and is preserved；3rd step, extraction, adds into the filtered fluid of second step and accounts for the organic solvent of 1-6 times of filtered fluid total amount and stir evenly, Filtered fluid and organic solvent mixed liquor acid-base value are adjusted to pH1-6 at the same time, and keep the temperature standing 30-180 minutes, is then filtered Separating and filtering liquid and the organic phase in organic solvent mixed liquor are spare；4th step, crystallization, the organic phase of filtered fluid prepared by the 3rd step, which is delivered in crystallizer, carries out crystallization operation, and right Crystal after crystallization is collected, and obtains mycophenolic acid crude product；5th step, the purification of mycophenolic acid crude product, it is mycophenolic acid crude product that the mycophenolic acid crude product that the 4th step is prepared is added to total amount In the deionized water at normal temperature of 10-30 times of total amount and stir evenly, mycophenolic acid crude product aqueous solution is then warming up to 35 DEG C-90 DEG C, insulation stands 5-20 minutes, and then addition accounts for active carbon particle and the stirring of mycophenolic acid crude product aqueous solution total amount 3%-15% Uniformly, then insulation stands 5-20 minutes, leads to after mycophenolic acid crude product aqueous solution then is pressurized to 1.5-5 times of standard atmospheric pressures Cross vertical sheet frame filter plant to be separated by filtration, filtrate can be so collected spare；6th step, recrystallization, when by the filtered fluid that the 5th step obtains, crystallisation by cooling 5-24 is small under-5 DEG C-5 DEG C isoperibols, Then separation of solid and liquid is carried out by sedimentation centrifuge to the filtered fluid after crystallization under thermal environment, and crystalline solid is collected Obtain finished product high-purity mycophenolic acid.
- A kind of 2. high-purity mycophenolic acid production technology according to claim 1, it is characterised in that：In the first step, Sulfide for metal sulphide salt, its double salt or monohydric salt, hydrogen sulfide, vulcanization ammonia and polysulfide in any one.
- A kind of 3. high-purity mycophenolic acid production technology according to claim 2, it is characterised in that：The metal sulphide salt For any one in vulcanized sodium, potassium sulfide, rubidium sulfide, vulcanization ammonia and NaHS.
- A kind of 4. high-purity mycophenolic acid production technology according to claim 1, it is characterised in that：In 3rd step, Organic solvent is ethyl acetate, methyl acetate, Ethyl formate, propyl acetate, propyl formate, ethyl propionate, methyl propionate, propionic acid In propyl ester any one or any several be used in mixed way with arbitrary proportion.
- A kind of 5. high-purity mycophenolic acid production technology according to claim 1, it is characterised in that：In 5th step, Mycophenolic acid crude product aqueous solution carries out vacuum rising film concentration first before by vertical sheet frame filter plant filtration operation, its Middle liter of diaphragm flow is 300-800L/h, and the mycophenolic acid crude product aqueous solution volume after concentration is mycophenolic acid crude product water before filtering 40%-the 60% of liquor capacity.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111378704A (en) * | 2020-03-23 | 2020-07-07 | 焦作健康元生物制品有限公司 | Method for producing 4-AA intermediate by ketoreductase |
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| US20090240069A1 (en) * | 2004-04-26 | 2009-09-24 | Vilmos Keri | Process for preparation of mycophenolic acid and ester derivatives thereof |
| CN102399205A (en) * | 2011-12-13 | 2012-04-04 | 福建和泉生物科技有限公司 | Mycophenolic acid purification process |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
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2017
- 2017-12-01 CN CN201711252596.4A patent/CN107903228A/en active Pending
Patent Citations (3)
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|---|---|---|---|---|
| US20090240069A1 (en) * | 2004-04-26 | 2009-09-24 | Vilmos Keri | Process for preparation of mycophenolic acid and ester derivatives thereof |
| CN102399205A (en) * | 2011-12-13 | 2012-04-04 | 福建和泉生物科技有限公司 | Mycophenolic acid purification process |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
Non-Patent Citations (1)
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| CN111378704A (en) * | 2020-03-23 | 2020-07-07 | 焦作健康元生物制品有限公司 | Method for producing 4-AA intermediate by ketoreductase |
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