CN102532078A - Method for directly preparing mycophenolate sodium from mycophenolic acid fermentation broth - Google Patents
Method for directly preparing mycophenolate sodium from mycophenolic acid fermentation broth Download PDFInfo
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- CN102532078A CN102532078A CN2012100057782A CN201210005778A CN102532078A CN 102532078 A CN102532078 A CN 102532078A CN 2012100057782 A CN2012100057782 A CN 2012100057782A CN 201210005778 A CN201210005778 A CN 201210005778A CN 102532078 A CN102532078 A CN 102532078A
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- mycophenolic acid
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- sodium mycophenolate
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Abstract
The invention provides a method for directly preparing mycophenolate sodium from mycophenolic acid fermentation broth. Soda is added into the mycophenolic acid fermentation broth, so that mycophenolate sodium liquor is produced, and after filtration and drying, mycophenolate sodium powder is prepared. The method directly prepares the mycophenolate sodium from the mycophenolic acid fermentation broth, the middle process in the preparation of the mycophenolate sodium powder is dispensed with, and organic solvent is not used, so that pollution is reduced and the production cost is saved, so the industrial production is facilitated.
Description
Technical field
The present invention relates to a kind of method for preparing Sodium mycophenolate from mycophenolic acid fermented liquid direct production.
Background technology
Nineteen sixty for the end, Eli lilly discloses mycophenolic acid sodium salt (MPS) restraining effect to the growth of warm-blooded animal malignant cell.Nowadays Novartis has developed a kind of enteric coating preparation of Sodium mycophenolate, is called Myfortic
Sodium mycophenolate (Mycophenolate sodium, MPS), molecular formula is Cl7Hl9Na06, molecular weight is 342.32.Existing current research shows: Sodium mycophenolate is to work through suppressing inosine monophosphate dehydrogenase; MPS has better tolerance, and the bioavailability and the stability that merit attention are arranged, and needs the unitary dose of administration littler than MMF; Make patient Geng Yi accept, improve compliance of patients.And the gi tract tolerance is the major issue of immunosuppressant therapy, implants the organ viability because it can influence, thereby influences patient's chance of surviving.As immunosuppressor of new generation, MPS shows few side effects in the research of the U.S., helps the kidney transplantation patient light newborn excessively.
Strait Pharmaceutical Journal l9 in 2007 rolled up for the 8th phase and mentions mycophenolic acid and sodium hydroxide in " preparation of Sodium mycophenolate and chemical analysis measure and to synthetic " and add successively and react in the methyl alcohol; Be cooled to after the room temperature in 5 ℃ of following crystallizations; Washing with acetone behind the crystal suction filtration can obtain Sodium mycophenolate after vacuum drying and the grinding.
South african patent No.6804959 has also described the preparation of mycophenolic acid one sodium and disodium.After the sodium methylate of a molar equivalent and mycophenolic acid reacted in the mixture of methyl alcohol and chloroform, mycophenolic acid one sodium can be through using the Skellysolve A precipitate and separate.The preparation of corresponding disodium has also been described.In this case, the sodium methylate of two molar equivalents is joined in the 2:1 benzene-chloroform mixture solution of mycophenolic acid, the material after the evaporation is used the acetone crystallization.
That describes among the synthetic route of WO 97/38689 and the south african patent NO.6804959 is identical.Compound can obtain (m.p 189-191 ℃) with crystallized form through recrystallization in acetone (if being necessary water).
The above-mentioned method of utilizing mycophenolic acid to prepare Sodium mycophenolate, its weak point has: above-mentioned technology is raw materials used to be the mycophenolic acid powder, prepares a large amount of organic solvent of process need consumption of mycophenolic acid powder from the mycophenolic acid fermented liquid; Preparation process from the mycophenolic acid powder to Sodium mycophenolate also need be used a large amount of solvents, and production cost is high, and environmental pollution is serious.
Summary of the invention
For overcoming the above problems, the present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, add in the mycophenolic acid fermented liquid soda generate the Sodium mycophenolate feed liquid through filter, dry back prepares becomes the Sodium mycophenolate powder; Its concrete operations step is following:
1, the mycophenolic acid fermented liquid adds soda: the mycophenolic acid fermented liquid under agitation slowly flows and adds soda, transfers fermented liquid pH value, continues to stir 30-60 minutes;
2, the Sodium mycophenolate feed liquid is filtered: the Sodium mycophenolate feed liquid through sheet frame or micropore ceramics membrane filtration to clarifying feed liquid, operating temperature≤40 ℃;
3, the clarification feed liquid is further removed macromole impurity such as protein, polysaccharide and colour former through ultrafiltration;
4, ultrafiltrated through the nf membrane desalination, concentrate 3～5 times, the volume of liquid concentrator is about 20～30% of ultrafiltrated;
5, nf membrane is collected liquid becomes the Sodium mycophenolate powder through vacuum concentration drying or spraying drying.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the indication soda is a kind of of liquid sodium hydroxide or solid sodium hydroxide in its operation steps 1.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, transfers fermented liquid pH value to 8.0-11.0 in its operation steps 1, preferentially selects pH8-9.5.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the plate-and-frame filter press working pressure is 5.0～6.0bar in its operation steps 2.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and ceramic membrane membrane flux 30～50L/h ㎡ preferentially selects 35～45 L/h ㎡ in its operation steps 2.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, ceramic membrane operating pressure 0.15-0.35Mpa in its operation steps 2, preferentially selects 0.2-0.3Mpa.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and ceramic membrane aperture 0.03-0.5um preferentially selects 0.05-0.15um in its operation steps 2.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the ultra-filtration membrane working pressure is 1.5～6.0bar in its operation steps 3, preferentially selects 3.0～6.0bar working pressure.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the ultra-filtration membrane molecular weight cut-off is 5000～100000 in its operation steps 3, preferentially selects 6000～8000.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the membrane flux of used ultra-filtration membrane is 30L/h ㎡～45 L/h ㎡ in its operation steps 3, preferentially selects 40L/h ㎡～45 L/h ㎡.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the service temperature of ultra-filtration membrane feed liquid is 5 ℃～35 ℃ in its operation steps 3, preferentially selects 25～30 ℃.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the feed liquid of handling well in its operation steps 2 also can directly be carried out operation steps 5 and handled.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and used ultra-filtration membrane is one or more in inorganic (containing stupalith, metal, alloy and other non-metallic material) class, polysulfones, polyvinylidene difluoride, aromatic polyamides class, FM class, the composite package class mould material in its operation steps 3.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the nf membrane working pressure is 6.0～12.0bar in its operation steps 4, preferentially selects 8.0～12.0bar working pressure.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the nf membrane molecular weight cut-off is 300～800 in its operation steps 4, preferentially selects 600～800.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the membrane flux of used nf membrane is 20L/h ㎡～40 L/h ㎡ in its operation steps 4, preferentially selects 30L/h ㎡～35 L/h ㎡.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and the service temperature of nf membrane feed liquid is 5 ℃～35 ℃ in its operation steps 4, preferentially selects 25～30 ℃.
The present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, and used nf membrane is one or more in polyvinylidene difluoride, aromatic polyamides class, FM class, the composite package class mould material in its operation steps 4.
Through test, the off-white powder of this method preparation is water-soluble, is insoluble to absolute ethyl alcohol, and fusing point is 189.6-192.1 ℃, and is consistent with the Sodium mycophenolate fusing point (189-191 ℃) that document is reported, different with the fusing point (141 ℃) of mycophenolic acid.
Compare with existing Technology, the present invention has outstanding feature:
1. present method has been removed the pilot process of preparation mycophenolic acid powder directly from mycophenolic acid fermentative prepn Sodium mycophenolate;
2. present method prepares in the process of Sodium mycophenolate and does not use organic solvent, has saved production cost;
3. present method benefit is that technology is simple, the energy consumption material consumption is low, green cleaning, be convenient to implement, and the activity duration is short, has reduced the pollution of environment, has improved the quality of product.
Embodiment
The present invention is a kind of to prepare the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production in order better to set forth, and below through specific embodiment the present invention is described further, but does not limit the present invention in any way.
Embodiment 1
To contain mycophenolic acid concentration is that the ferment filtrate 260L of 7.5g/L is a raw material; Slowly flow hydro-oxidation sodium liquid while stirring and regulate pH to 9.0; Continue to stir 35 minutes, adopting the aperture afterwards is the ceramic membrane of 0.05um again, and the ceramic membrane flux is 35L/h ㎡; Working pressure is 0.20Mpa, and macrobead is removed in 30 ℃ of operations of service temperature; It is the composite package of 5000Da that filtrating is adopted molecular weight cut-off, is 30 L/h ㎡ at the ultra-filtration membrane flux, and working pressure is 5.0bar, through the ultra-filtration membrane removal of impurities, removes protein, polysaccharide and colour former etc. under the operational condition that service temperature is 25 ℃.Ultrafiltration sees through liquid, and to adopt molecular weight cut-off be that the composite package of 300Da carries out nanofiltration and handles; At the nf membrane flux is 30 L/h ㎡; Working pressure is 10.0bar, under the operational condition that service temperature is 25 ℃, passes through the nanofiltration desalination, concentrates 3 times; Vacuum-drying gets off-white color Sodium mycophenolate 1.98kg, and yield is 95%.
Embodiment 2
To contain mycophenolic acid concentration is that the fermented liquid 270L of 7.8g/L is a raw material; Slowly flow hydro-oxidation sodium liquid while stirring and regulate pH to 9.3; Continue to stir 40 minutes, adopting the aperture afterwards is the ceramic membrane of 0.05um again, and the ceramic membrane flux is 35L/h ㎡; Working pressure is 0.20Mpa, and macrobead is removed in 35 ℃ of operations of service temperature; It is the composite package of 50000Da that filtrating is adopted molecular weight cut-off, is 40 L/h ㎡ at the ultra-filtration membrane flux, and working pressure is 5.0bar, through the ultrafiltration removal of impurities, removes protein, polysaccharide and colour former etc. under the operational condition that service temperature is 30 ℃.Ultrafiltration sees through liquid, and to adopt molecular weight cut-off be that the composite package of 300Da carries out nanofiltration and handles; At the nf membrane flux is 30 L/h ㎡; Working pressure is 10.0bar, under the operational condition that service temperature is 30 ℃, passes through the nanofiltration desalination, concentrates 4 times;-0.08Mpa vacuum-drying gets off-white color Sodium mycophenolate 2.12kg, and the recovery is 94.2%.
Embodiment 3
To contain mycophenolic acid concentration is that the fermented liquid 250L of 8.5g/L is a raw material; Slowly flow hydro-oxidation sodium liquid while stirring and regulate pH to 8.5; Continue to stir 35 minutes, adopting the aperture afterwards is the ceramic membrane of 0.05um again, and the ceramic membrane flux is 40L/h ㎡; Working pressure is 0.20Mpa, and macrobead is removed in 30 ℃ of operations of service temperature; It is the composite package of 50000Da that filtrating is adopted molecular weight cut-off, is 35 L/h ㎡ at the ultra-filtration membrane flux, and working pressure is 5.0bar, through the ultrafiltration removal of impurities, removes protein, polysaccharide and colour former etc. under the operational condition that service temperature is 35 ℃.Ultrafiltration sees through liquid, and to adopt molecular weight cut-off be that the composite package of 500Da carries out nanofiltration and handles; At the nf membrane flux is 40 L/h ㎡; Working pressure is 10.0bar, under the operational condition that service temperature is 40 ℃, passes through the nanofiltration desalination, concentrates 3 times;-0.09Mpa vacuum-drying gets off-white color Sodium mycophenolate 2.12kg, and the recovery is 93.2%.
Embodiment 4
To contain mycophenolic acid concentration is that the fermented liquid 270L of 7.0g/L is a raw material; Slowly flow hydro-oxidation sodium liquid while stirring and regulate pH to 8.9; Continue again to stir 55 minutes; Adopting plate-and-frame filter press press filtration working pressure afterwards is 5.0bar, and filtered liq gets off-white color Sodium mycophenolate 1.89kg in-0.07Mpa vacuum-drying, and the recovery is 93.5%.
Embodiment 5
To contain mycophenolic acid concentration is that the fermented liquid 260L of 7.2g/L is a raw material, slowly flows hydro-oxidation sodium liquid while stirring and regulates pH to 8.7, continues to stir 46 minutes again; Adopting plate-and-frame filter press press filtration working pressure afterwards is 6.0bar; Filtering back employing molecular weight cut-off is the composite package of 8000Da, is 40L/h ㎡ at the ultra-filtration membrane flux, and working pressure is 3.0bar; Through the ultrafiltration removal of impurities, remove protein, polysaccharide and colour former etc. under the operational condition that service temperature is 35 ℃.Ultrafiltration sees through liquid, and to adopt molecular weight cut-off be that the composite package of 800Da carries out nanofiltration and handles; At the nf membrane flux is 40 L/h ㎡; Working pressure is 8.0bar, under the operational condition that service temperature is 40 ℃, passes through the nanofiltration desalination, concentrates 3 times;-0.07Mpa vacuum-drying gets off-white color Sodium mycophenolate 1.86kg, and the recovery is 93.0%.
Claims (11)
1. the present invention provides a kind of and prepares the method for Sodium mycophenolate from mycophenolic acid fermented liquid direct production, add in the mycophenolic acid fermented liquid soda generate the Sodium mycophenolate feed liquid through filter, dry back prepares becomes the Sodium mycophenolate powder; It is characterized in that operation steps is following:
A, mycophenolic acid fermented liquid add soda: the mycophenolic acid fermented liquid under agitation slowly flows and adds soda, transfers fermented liquid pH value, continues to stir 30-60 minutes;
B, Sodium mycophenolate feed liquid filter: the Sodium mycophenolate feed liquid through sheet frame or micropore ceramics membrane filtration to clarifying feed liquid, operating temperature≤40 ℃;
C, clarification feed liquid are further removed macromole impurity such as protein, polysaccharide and colour former through ultrafiltration;
D, ultrafiltrated through the nf membrane desalination, concentrate 3～5 times, the volume of liquid concentrator is about 20～30% of ultrafiltrated;
E, nf membrane collection liquid become the Sodium mycophenolate powder through vacuum concentration, drying.
2. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that the indication soda is a kind of of liquid sodium hydroxide or solid sodium hydroxide among the operation steps a.
3. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that transferring fermented liquid pH value to 8.0-10.0 among the operation steps a, preferentially select pH8-9.5.
4. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that plate-and-frame filter press press filtration working pressure is 5.0～6.0bar among the operation steps b.
5. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that ceramic membrane membrane flux 30～50L/h ㎡ among the operation steps b, preferentially select 35～45 L/h ㎡; Operating pressure 0.15-0.35Mpa preferentially selects 0.2-0.3Mpa; Aperture 0.03-0.5um preferentially selects 0.05-0.15um.
6. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that the ultra-filtration membrane working pressure is 1.5～6.0bar among the operation steps c, preferentially select 3.0～6.0bar working pressure; Molecular weight cut-off is 5000～100000, preferentially selects 6000～8000; Membrane flux is 30L/h ㎡～45 L/h ㎡, preferentially selects 40L/h ㎡～45 L/h ㎡.
7. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that ultra-filtration membrane in the operation steps, the service temperature of nf membrane feed liquid is 5 ℃～35 ℃, preferentially selects 25～30 ℃.
8. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that used ultra-filtration membrane among the operation steps c is one or more in inorganic (containing stupalith, metal, alloy and other non-metallic material) class, polysulfones, polyvinylidene difluoride, aromatic polyamides class, FM class, the composite package class mould material.
9. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that the nf membrane working pressure is 6.0～12.0bar among the operation steps d, preferentially select 8.0～12.0bar; Molecular weight cut-off is 300～800, preferentially selects 600～800; Membrane flux is 20L/h ㎡～40 L/h ㎡, preferentially selects 30L/h ㎡～35 L/h ㎡.
10. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that used nf membrane among the operation steps d is one or more in polyvinylidene difluoride, aromatic polyamides class, FM class, the composite package class mould material.
11. prepare the method for Sodium mycophenolate according to 1 one kinds of claims from mycophenolic acid fermented liquid direct production, it is characterized in that the feed liquid of handling well among its operation steps b also can directly carry out operation steps e and handle.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103664848A (en) * | 2012-09-13 | 2014-03-26 | 北大方正集团有限公司 | Extracting method of mycophenolic acid |
| CN116041293A (en) * | 2023-02-08 | 2023-05-02 | 丽珠集团新北江制药股份有限公司 | Method for purifying mycophenolic acid |
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| CN1974564A (en) * | 2006-12-15 | 2007-06-06 | 丽珠集团新北江制药股份有限公司 | Prepn process of Mycophenolate mofetil |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1974564A (en) * | 2006-12-15 | 2007-06-06 | 丽珠集团新北江制药股份有限公司 | Prepn process of Mycophenolate mofetil |
Non-Patent Citations (1)
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| 张斌等: "膜分离技术应用于霉酚酸生产的工艺研究", 《食品与发酵工业》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103570655B (en) * | 2012-07-31 | 2015-08-05 | 北大方正集团有限公司 | A kind of method extracting mycophenolic acid |
| CN103664848A (en) * | 2012-09-13 | 2014-03-26 | 北大方正集团有限公司 | Extracting method of mycophenolic acid |
| CN103664848B (en) * | 2012-09-13 | 2016-03-23 | 北大方正集团有限公司 | A kind of extracting method of mycophenolic acid |
| CN116041293A (en) * | 2023-02-08 | 2023-05-02 | 丽珠集团新北江制药股份有限公司 | Method for purifying mycophenolic acid |
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Application publication date: 20120704 |