CN109020933A - A kind of purification process of Mycophenolic Acid - Google Patents
A kind of purification process of Mycophenolic Acid Download PDFInfo
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- CN109020933A CN109020933A CN201710434441.6A CN201710434441A CN109020933A CN 109020933 A CN109020933 A CN 109020933A CN 201710434441 A CN201710434441 A CN 201710434441A CN 109020933 A CN109020933 A CN 109020933A
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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 methods of Mycophenolic Acid purifying.1) the method for the present invention is the following steps are included: Mycophenolic Acid is added in the mixed liquor of acetone and hydrochloric acid, heating stirring dissolution；2) active carbon, stirring decoloration is added；3) it filters；4) solvent B is added dropwise in filtrate；5) crystallization is kept the temperature；6) it filters, washs, it is dry, obtain Mycophenolic Acid sterling.This method significantly improves the purity of Mycophenolic Acid, and simple process, safety, at low cost, is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of purification process of Mycophenolic Acid.
Background technique
Mycophenolic Acid (Mycophenolic acid) also known as mycophenolic acid, chemical name are as follows: E-4- methyl -6- (1,3- bis-
Hydrogen -7- methyl -4- hydroxyl -6- methoxyl group -3- oxo -5- isobenzofuran-base) -4- hexenoic acid, molecular formula C17H20O6, molecular weight
320.34, CAS 24280-93-1, shown in structure such as formula (I).Mycophenolic Acid generates Mycophenolate Mofetil after esterification,
Mycophenolate Mofetil is a kind of neotype immunosuppressant, shown in structure such as formula (II).Nineteen ninety-five Mycophenolate Mofetil is ratified to use by FDA
In kidney transplant, it is approved for heart transplant within 1998.
Patent CN102399205A discloses a kind of purification process of Mycophenolic Acid: by Mycophenolic Acid crude product, at 50 DEG C -90
It is dissolved at DEG C in 18~22 times of (v/w) methanol, 6%~10% active carbon that Mycophenolic Acid crude product quality is added is taken off
Color, filtering, concentration, crystallization obtain the Mycophenolic Acid sterling that purity is 99% or more.The purification process is larger using quantity of solvent.
CN103880798A discloses a kind of method for purifying mycophenolic acid.The method comprising the steps of: 1) providing temperature is 50
DEG C to 70 DEG C of mycophenolic acid ethanol solution；2) ethanol solution described in step 1) is cooled to 10 DEG C to 30 DEG C, makes mycophenolic acid
Crystallization is precipitated, isolated mycophenolic acid crystal；3) ethyl alcohol dissolving step 2 is used) gained mycophenolic acid crystal, by acquired solution and temperature
It is mixed for 5 DEG C to 12 DEG C of water, mycophenolic acid recrystallization is precipitated, isolated mycophenolic acid recrystallizes crystal.What this method used
The amount of quantity of solvent and purified water is all bigger, and what is obtained is amorphous mycophenolic acid sterling.
Document " development of neotype immunosuppressant mycophenolic acid and mycophenolate " (Zhejiang University's master thesis, it is glad
Rong, 2006) disclose the purification process of another Mycophenolic Acid: 7%~10% diatomite, stirring are added in fermentation liquid
30min, filtering, obtains thallus；Thallus is impregnated with ethyl alcohol, filtering obtains soak, is concentrated to dryness, obtains mycophenolic acid solid, will
Its ethyl acetate for being dissolved in 2 times of volumes is added the stirring decoloration of 5% active carbon, filters, concentration, places crystallization, and filtering obtains mould phenol
Gained crude product is dissolved in the ethyl alcohol of 5 times of volumes by acid crude at 40 DEG C, and -4 DEG C are placed for 24 hours, are filtered, dry, is obtained content and is reached
99% mycophenolic acid sterling.Yield is about 45%.This process requirement frozen cooling crystallizes, and consumes energy in industrial production larger, it is difficult to
It implements, and has used multi-solvents, increase recovery difficult.
Summary of the invention
We have found the more difficult removing of impurity A, we have carried out in detail impurity A during purifying Mycophenolic Acid
Research derives that its structure such as (III) is shown:
To solve problems of the prior art, impurity A is removed, the present invention provides a kind of purifying sides of Mycophenolic Acid
Method.This purification process includes the following steps:
1) Mycophenolic Acid is added in the mixed liquor of acetone and hydrochloric acid, heating stirring dissolution；Heating temperature is at 40 DEG C or more；
2) active carbon, stirring decoloration is added；
3) it filters；
4) solvent B is added dropwise in filtrate；
5) cool down crystallization；
6) it filters, washs, it is dry, obtain Mycophenolic Acid sterling.
In step 1), the volume ratio of acetone and hydrochloric acid is (7~10) in mixed liquor: 1；Mycophenolic Acid crude product and acetone salt
The ratio of sour mixed liquor is 1:(5~9) (w/v)；It is preferred that the volume ratio of acetone and hydrochloric acid is (8~10) in mixed liquor: 1；It is preferred that
The ratio of Mycophenolic Acid crude product and acetone hydrochloric acid mixed solution is 1:(6~9) (w/v)；It is preferred that solution temperature control is 45 DEG C~55
℃；It is preferred that the concentration of hydrochloric acid is 0.1M~3M (substance withdrawl syndrome is 0.1~3mol/L)；
In step 2), the amount that active carbon is added is about 3~5% (mass percents) of Mycophenolic Acid crude product；Further,
The amount that active carbon is added is 5% (mass percent) of Mycophenolic Acid crude product.
In step 4), solvent B is one or more of petroleum ether, n-hexane, heptane, the dosage and Mai Kao of solvent B
The ratio of phenolic acid crude product is (5~10): 1 (v/w)；The dosage of preferred solvent B and the ratio of Mycophenolic Acid crude product are (8~10): 1 (v/
w)；
In step 5), the temperature for keeping the temperature crystallization is controlled at 15 DEG C~35 DEG C；It is preferred that the temperature of heat preservation crystallization is controlled 15
DEG C~30 DEG C.
Method of the invention has the advantages that compared with prior art:
1. the present invention uses mixed solvent, the purifying purpose to Mycophenolic Acid is preferably realized, Mycophenolic Acid sterling is made
Purity be higher than 99.6%, impurity A is less than 0.05%；Yield is higher than 85%.`
2. the present invention, without carrying out frozen cooling, reduces energy consumption in crystallization and recrystallization process.
3. method and process of the invention is simple, safety, at low cost, it is suitable for large-scale industrial production.
Specific embodiment
By the description of specific embodiment, the invention will be further described, but this is not a limitation of the present invention,
Those skilled in the art can be made various modifications or improvements, with basic thought according to the present invention without departing from of the invention
Basic thought is all within the scope of the present invention.
Embodiment 1
540ml acetone and 60ml 1M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, adds after dissolved clarification
Enter 5g active carbon, insulated and stirred 30 minutes, filters；Under stirring, 800ml n-hexane is added dropwise in filtrate at 30 DEG C, and drop finishes；15 DEG C of guarantors
Warm stirring and crystallizing 2.5 hours, filtering, filter cake are beaten with 50ml purified water and are washed；It is dried in vacuo at 40 DEG C, obtains 87.6g sterling,
Purity is 99.68%, impurity A 0.017%.
The detection of Mycophenolic Acid uses following HPLC analysis condition:
110 high performance liquid chromatograph of instrument Agilent
Phosphorylating reagent potassium dihydrogen, concentrated phosphoric acid, purified water, methanol and acetonitrile
10 μ L of sample volume
Chromatographic column Agilent XDB-C8 4.6mm × 15cm chromatographic column
Flow velocity 1.5ml/min
45 DEG C of column temperature
Detection wavelength 250nm
Mobile phase PH=3.0 phosphate buffer: acetonitrile: methanol=60:35:11
Diluent acetonitrile
Without illustrating, the detection method in the present invention carries out the detection of Mycophenolic Acid in this way.
Embodiment 2
550ml acetone and 55ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 55 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, 800ml petroleum ether is added dropwise in filtrate at 30 DEG C, and drop finishes；20℃
Insulated and stirred crystallization 3 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 86.2g sterling,
Purity is 99.63%, impurity A 0.022%.
Embodiment 3
800ml acetone and 100ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, 800ml petroleum ether is added dropwise in filtrate at 35 DEG C, and drop finishes；25℃
Insulated and stirred crystallization 3 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 85.6g sterling,
Purity is 99.74%, impurity A 0.028%.
Embodiment 4
800ml acetone and 100ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, 1000ml n-hexane is added dropwise in filtrate at 35 DEG C, and drop finishes；15
DEG C insulated and stirred crystallization 2.5 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 88.1g
Sterling, purity 99.62%, impurity A 0.017%.
Embodiment 5
800ml acetone and 80ml 2M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, adds after dissolved clarification
Enter 5g active carbon, insulated and stirred 30 minutes, filters；Under stirring, 500ml n-hexane and heptane (volume is added dropwise in filtrate at 35 DEG C
Than 1:1) mixed liquor, drop finish；15 DEG C insulated and stirred crystallization 2.5 hours, filtering, filter cake with 50ml purified water be beaten wash；40
It is dried in vacuo at DEG C, obtains 88.3g sterling, purity 99.68%, impurity A 0.025%.
Embodiment 6
800ml acetone and 100ml 2M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, adds after dissolved clarification
Enter 5g active carbon, insulated and stirred 30 minutes, filters；Under stirring, 800ml petroleum ether is added dropwise in filtrate at 35 DEG C, and drop finishes；25 DEG C of guarantors
Warm stirring and crystallizing 3 hours, filtering, filter cake are beaten with 50ml purified water and are washed；It is dried in vacuo at 40 DEG C, obtains 87.6g sterling, it is pure
Degree is 99.79%, impurity A 0.031%.
Embodiment 7
800ml acetone and 100ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, filtrate is cooled to 15 DEG C of insulated and stirred crystallizations 3 hours, filtering,
Filter cake is beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 45.7g sterling, purity 94.79%, impurity A is
0.069%.
Embodiment 8
550ml ethyl alcohol and 50ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 55 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, 800ml ethyl acetate is added dropwise in filtrate at 30 DEG C, and drop finishes；20
DEG C insulated and stirred crystallization 3 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, it is pure to obtain 66.2g
Product, purity 95.93%, impurity A 0.091%.
Embodiment 9
540ml acetone and 60ml purified water is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, is added after dissolved clarification
5g active carbon, insulated and stirred 30 minutes, filtering；Under stirring, 800ml n-hexane is added dropwise in filtrate at 30 DEG C, and drop finishes；15 DEG C of heat preservations
Stirring and crystallizing 2.5 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 75.6g sterling, it is pure
Degree is 96.08%, impurity A 0.087%.
Embodiment 10
550ml ethyl alcohol and 50ml 0.5M hydrochloric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 55 DEG C, after dissolved clarification
5g active carbon is added, insulated and stirred 30 minutes, filters；Under stirring, 800ml petroleum ether is added dropwise in filtrate at 30 DEG C, and drop finishes；20℃
Insulated and stirred crystallization 3 hours, filtering, filter cake was beaten with 50ml purified water and is washed；It is dried in vacuo at 40 DEG C, obtains 73.9g sterling,
Purity is 94.19%, impurity A 0.121%.
Embodiment 11
540ml acetone and 60ml 1M phosphoric acid is added in 100g Mycophenolic Acid crude product, stirring is warming up to 45 DEG C, adds after dissolved clarification
Enter 5g active carbon, insulated and stirred 30 minutes, filters；Under stirring, 800ml n-hexane is added dropwise in filtrate at 30 DEG C, and drop finishes；15 DEG C of guarantors
Warm stirring and crystallizing 2.5 hours, filtering, filter cake are beaten with 50ml purified water and are washed；It is dried in vacuo at 40 DEG C, obtains 71.2g sterling,
Purity is 95.69%, impurity A 0.103%.
Claims (10)
1. a kind of method of Mycophenolic Acid purifying, which is characterized in that the described method comprises the following steps:
1) Mycophenolic Acid is added in the mixed liquor of acetone and hydrochloric acid, heating stirring dissolution；Heating temperature is at 40 DEG C or more；
2) active carbon, stirring decoloration is added；
3) it filters；
4) solvent B is added dropwise in filtrate；
5) cool down crystallization；
6) it filters, washs, it is dry, obtain Mycophenolic Acid sterling；
In step 1), the volume ratio of acetone and hydrochloric acid is (7~10) in mixed liquor: 1；Mycophenolic Acid crude product and acetone salt acid-mixed
The ratio for closing liquid is 1:(5~9) (w/v)；
In step 4), solvent B is one or more of petroleum ether, n-hexane, heptane, the dosage and Mycophenolic Acid of solvent B
The ratio of crude product is (5~10): 1 (v/w)；
In step 5), the temperature of crystallization is controlled at 35 DEG C or less.
2. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 1), the solution temperature
Control is at 45 DEG C~55 DEG C.
3. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 1), in the mixed liquor
The volume ratio of acetone and hydrochloric acid is (8~10): 1.
4. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 1), the Mycophenolic Acid
The ratio of crude product and acetone hydrochloric acid mixed solution is 1:(6~9) (w/v).
5. the method for Mycophenolic Acid as described in claim 1 purifying, which is characterized in that in step 1), the hydrochloric acid it is dense
Degree is 0.1M~3M.
6. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 2), active carbon is added
Amount is 3~5% (mass percents) of Mycophenolic Acid crude product.
7. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 2), active carbon is added
Amount is 5% (mass percent) of Mycophenolic Acid crude product.
8. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 4), solvent B is positive oneself
One or both of alkane, heptane.
9. the method for Mycophenolic Acid purifying as described in claim 1, which is characterized in that in step 4), the amount of solvent B is added dropwise
It is (8~10): 1 (v/w) with the ratio between the amount of Mycophenolic Acid crude product.
10. the method for Mycophenolic Acid purifying as claim in any one of claims 1 to 9, which is characterized in that in step 5),
The temperature for keeping the temperature crystallization is controlled at 15 DEG C~30 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115838363A (en) * | 2023-01-09 | 2023-03-24 | 广东蓝宝制药有限公司 | Method for purifying mycophenolic acid |
| CN115889420A (en) * | 2022-12-23 | 2023-04-04 | 青岛农业大学 | Method for removing mycophenolic acid from alkaline mycophenolic acid residues |
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| WO2010041269A1 (en) * | 2008-09-10 | 2010-04-15 | Ipca Laboratories Limited | Process for preparation of mycophenolic acid, its salt and ester derivatives |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103880798A (en) * | 2012-12-19 | 2014-06-25 | 北大方正集团有限公司 | Mycophenolic acid purification method |
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2017
- 2017-06-09 CN CN201710434441.6A patent/CN109020933B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010041269A1 (en) * | 2008-09-10 | 2010-04-15 | Ipca Laboratories Limited | Process for preparation of mycophenolic acid, its salt and ester derivatives |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103880798A (en) * | 2012-12-19 | 2014-06-25 | 北大方正集团有限公司 | Mycophenolic acid purification method |
Non-Patent Citations (2)
| Title |
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| CAMPBELL IAIN MALCOLM ET AL.: "Some new metabolites related to mycophenolic acid", 《TETRAHEDRON LETTERS》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115889420A (en) * | 2022-12-23 | 2023-04-04 | 青岛农业大学 | Method for removing mycophenolic acid from alkaline mycophenolic acid residues |
| CN115838363A (en) * | 2023-01-09 | 2023-03-24 | 广东蓝宝制药有限公司 | Method for purifying mycophenolic acid |
| CN115838363B (en) * | 2023-01-09 | 2024-04-23 | 广东蓝宝制药有限公司 | Purification method of mycophenolic acid |
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Denomination of invention: A purification method of mycophenolic acid Effective date of registration: 20230117 Granted publication date: 20210525 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |