CN102924413B - Method for purifying and decolorizing mycophenolate mofetil - Google Patents
Method for purifying and decolorizing mycophenolate mofetil Download PDFInfo
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- CN102924413B CN102924413B CN201210411931.1A CN201210411931A CN102924413B CN 102924413 B CN102924413 B CN 102924413B CN 201210411931 A CN201210411931 A CN 201210411931A CN 102924413 B CN102924413 B CN 102924413B
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Abstract
The invention provides a method for purifying and decolorizing mycophenolate mofetil. The method for purifying and decolorizing mycophenolate mofetil comprises the following steps of dissolving mycophenolate mofetil reaction raw products by utilizing a mixed solvent; carrying out continuous decolorizing and purifying by enabling the solution to pass through a device containing a decolorizing medium; eluting collected liquid, removing residual mycophenolic acid, dewatering, concentrating and crystallizing to obtain purified and decolorized mycophenolate mofetil; and flushing 3-4 volumes of the device containing the decolorizing medium by utilizing acetone, and flushing two volumes by utilizing the mixed solvent. According to the method for purifying and decolorizing mycophenolate mofetil, disclosed by the invention, the process is simple, the industrial continuous production can be carried out, the yield is high, the product purity is high, and the prepared products are white samples so that problems of purity and appearance color of the products are solved.
Description
[technical field]
The present invention is specifically related to a kind of mycophenolate mofetil Purification decolorization method.
[background technology]
1896, Gosio found mycophenolic acid (Mycophenolic acid, MPA) from Penicillium notatum nutrient solution.The early stage research of MPA mainly concentrates on its antibacterium and antimycotic aspect, finds the effects such as its antiviral, antitumor and immunosuppression subsequently.Along with the development of medical science, Allison, Giblett etc. infer and demonstrate lymphocytic propagation and mainly rely on the classical route of synthesis of purine, find the effect of MPA specific suppression T, bone-marrow-derived lymphocyte thus, and enter rapidly experimental stress resistance graft-rejection research.
Mycophenolate mofetil (Mycophenolate Mofetil, MMF, mycophenolate mofetile) is the MPA structural compounds that the bioavailability of nineteen ninety discovery is higher.May nineteen ninety-five, MMF started through FDA approval the treatment being applied to renal transplantation, I, II clinical trial phase display MMF can the graft rejection of effectively the prevention and therapy heart, liver, renal transplant patient, contribute to the arterial disease alleviating graft chronic rejection, in the treatment of the autoimmune disorders such as rheumatoid arthritis, psoriatic, systemic lupus erythematous, chronic glomerulonephritis, also obtain preliminary curative effect.
Existing mycophenolate mofetil reaction product, often along with pigments interferes, cannot effectively be removed in crystallisation process, but the product appearance of mycophenolate mofetil is an important Testing index.Traditional technology employing adds large carbon content active and decolours, with saturated sodium bicarbonate water washing removing mycophenolic acid, again in combination with 2 crystallizations, but also cannot remove pigments interferes preferably, obtained product is with lilac red, and gac extremely adsorbs, reduce product yield, the yield obtaining product is only 70 ~ 85%, and adds a large amount of activated carbon filtration inconvenience, high-pressure filteration is high to equipment requirements.
Chinese Patent Application No. 200510100489.0 disclosed in 17 days Mays in 2006, name is called in " a kind of mycophenolate mofetil preparation method " that introducing antioxidant vitamin C reaches the object removing pigment, participate in reacting the effect reached by reductive agent, this patent introduces new reaction in pharmaceutical production, and causes and detect to latter products the problem brought.Because the vitamins C micromolecular compound that to be polarity larger, its maximal ultraviolet absorption is different from mycophenolate mofetil, and Simultaneously test vitamins C is needed for the new bulk drug product detection introduced, pH value close relation because of ascorbic ultraviolet maximum absorption wavelength and solution: when pH=2.0, the maximum absorption wavelength of solution is at 245nm; When pH=12, the maximum absorption wavelength of solution is at 300nm; When pH=5 ~ 10 scope, the maximum absorption wavelength of solution is at 267nm, moreover absorb angle value when pH=6.0 maximum.So cause the testing conditions of vitamins C and mycophenolate mofetil different, and if sample can be caused again to turn yellow after placing for some time containing residual ascorbic mycophenolate mofetil, certain impact can be formed on last quality product again.
[summary of the invention]
Technical problem to be solved by this invention is to provide a kind of mycophenolate mofetil Purification decolorization method, and technique is simple, can carry out suitability for industrialized production, yield is high, product purity is high.
The present invention solves the problems of the technologies described above by the following technical programs: a kind of mycophenolate mofetil Purification decolorization method, comprises the following steps:
(1) take the reaction product crude product containing mycophenolate mofetil containing 1000g, dissolve with mixed solvent 6000ml; Described mixed solvent is the mixture of organic solvent and ethyl acetate, and described organic solvent is any one in normal hexane, hexanaphthene, sherwood oil;
(2) decoloring medium being loaded on height is 8 ~ 3:1 with internal diameter ratio, and bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is one or several the mixture in 200 ~ 300 order silica gel, diatomite, aluminum oxide, Microcrystalline Cellulose;
(3) will process after the mixed solvent obtained flows through the decoloration device obtained in (2) through (1), and collect colourless peritoneal effluent, decoloring medium is rinsed again with the described mixed solvent of 1 ~ 2 times of volume of decoloration device, collect colourless permeate, and merge colourless permeate;
(4) wash colourless permeate of obtaining in (3) with 5% sodium hydrogen carbonate solution 3300ml to remove remaining mycophenolic acid, then be washed with distilled water to neutrality, desiccant dehydration, concentrated successively, obtain enriched material;
(5) in enriched material, add 850ml ethyl acetate, crystallization at 5 DEG C, then use cold ethyl acetate washing crystal, then dry abrasive dust and namely obtain white finished product.
Further, also comprise step (6): with the acetone rinsing decoloration device of described decoloration device 3 ~ 4 times of volumes, then rinse decoloration device with the n-hexane-ethyl acetate mixed solvent of the volume ratio 1:1 of 2 times of volumes of described decoloration device.
Further, the volume ratio of described mixed solvent is organic solvent: ethyl acetate=10 ~ 40:90 ~ 60.
Further, described mixed solvent is the n-hexane-ethyl acetate of volume ratio 20:80.
Further, the weight ratio of described decoloring medium and described reaction product crude product is 1:3 ~ 10.
Further, the height of described decoloration device is 4:1 with internal diameter ratio.
Beneficial effect of the present invention is: present invention process is simple, can carry out suitability for industrialized production, yield is high, product purity is high, and obtained product is white pigmented samples, solves product purity and appearance luster problem.
[embodiment]
A kind of mycophenolate mofetil Purification decolorization method, comprises the following steps:
(1) take the reaction product crude product containing mycophenolate mofetil containing 1000g, dissolve with mixed solvent 6000ml; Described mixed solvent is the mixture of organic solvent and ethyl acetate; The volume ratio of described mixed solvent is organic solvent: ethyl acetate=10 ~ 40:90 ~ 60, and described organic solvent is any one in normal hexane, hexanaphthene, sherwood oil; Described mixed solvent is preferably the n-hexane-ethyl acetate of volume ratio 20:80.
(2) decoloring medium being loaded on height is 8 ~ 3:1 with internal diameter ratio, and bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is one or several the mixture in 200 ~ 300 order silica gel, diatomite, aluminum oxide, Microcrystalline Cellulose; The weight ratio of described decoloring medium and described reaction product crude product is 1:3 ~ 10; The height of described decoloration device is preferably 4:1 with internal diameter ratio.
(3) will process after the mixed solvent obtained flows through the decoloration device obtained in (2) through (1), and collect colourless peritoneal effluent, rinse silica gel with the described mixed solvent of 1 ~ 2 times of volume of decoloration device again, collect colourless permeate, and merge colourless permeate;
(4) wash colourless permeate of obtaining in (3) with 5% sodium hydrogen carbonate solution 3300ml to remove remaining mycophenolic acid, more successively with distilled water to neutrality, desiccant dehydration, concentrate, obtain enriched material;
(5) in enriched material, add 850ml ethyl acetate, crystallization at 5 DEG C, then with cold ethyl acetate washing, then dry abrasive dust and namely obtain white finished product and mycophenolate mofetil.
(6) with decoloration device 3 ~ 4 volumes described in acetone rinsing, then rinse 2 volumes with the n-hexane-ethyl acetate mixed solvent of volume ratio 1:1, decoloring medium can reuse.
Embodiment 1
A kind of mycophenolate mofetil Purification decolorization method, comprises the following steps:
(1) take the reaction product crude product containing mycophenolate mofetil containing 1000g, dissolve with mixed solvent 6000ml; Described mixed solvent is n-hexane-ethyl acetate, and the volume ratio of described mixed solvent is normal hexane: ethyl acetate=10:90.
(2) decoloring medium is loaded on height with internal diameter than being 8:1, bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is 200 ~ 300 order micropowder silica gels, and the weight ratio of described decoloring medium and described reaction product crude product is 1:3.
(3) will process after the mixed solvent obtained flows through the decoloration device obtained in (2) through (1), and collect colourless peritoneal effluent, rinse silica gel with the described mixed solvent of 1 times of volume of decoloration device again, collect colourless permeate, and merge colourless permeate.
(4) wash colourless permeate of obtaining in (3) to remove remaining mycophenolic acid with the sodium hydrogen carbonate solution 3300ml of 5, then be washed with distilled water to neutrality, desiccant dehydration, concentrated successively, obtain enriched material;
(5) in enriched material, add 850ml ethyl acetate, crystallization at 5 DEG C, then wash with cold ethyl acetate, then oven dry abrasive dust obtains white finished product 880g, HPLC detection purity is 99.7%, and yield is 88%.
(6) with decoloration device 3 volumes described in acetone rinsing, then rinse 2 volumes with the n-hexane-ethyl acetate mixed solvent of volume ratio 1:1, decoloring medium can reuse.
Embodiment 2
This part difference from Example 1 is:
(1) described mixed solvent is cyclohexane-ethyl acetate, and the volume ratio of described mixed solvent is hexanaphthene: ethyl acetate=40:60;
(2) decoloring medium is loaded on height with internal diameter than being 3:1, bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is diatomite, and the weight ratio of described decoloring medium and described reaction product crude product is 1:10.
(3) diatomite is rinsed with the described mixed solvent of 2 times of volumes of decoloration device again,
(6) with decoloration device 4 volumes described in acetone rinsing;
It is 99.5% that HPLC detects purity, and product yield is 90.2%.
Embodiment 3
This part difference from Example 1 is:
(1) described mixed solvent is petroleum ether-ethyl acetate, and the volume ratio of described mixed solvent is sherwood oil: ethyl acetate=30:70;
(2) decoloring medium is loaded on height with internal diameter than being 5:1, bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is aluminum oxide, and the weight ratio of described decoloring medium and described reaction product crude product is 1:6.
(3) aluminum oxide is rinsed with the described mixed solvent of 1.5 times of volumes of decoloration device again;
It is 99.7% that HPLC detects purity, and product yield is 93.2%.
Embodiment 4
This part difference from Example 1 is:
(1) described mixed solvent is n-hexane-ethyl acetate, and the volume ratio of described mixed solvent is normal hexane: ethyl acetate=20:80;
(3) Microcrystalline Cellulose is rinsed with the described mixed solvent of 1.5 times of volumes of decoloration device again.
It is 99.7% that HPLC detects purity, and product yield is 94%.
Favorable reproducibility of the present invention, in production several times to 30 feather weight that workshop is carried out, circulation ratio is all fine, add with tradition the effect that activated carbon combined repeatedly crystallization and recrystallization reach and have larger difference, the obtained product of traditional activated carbon decolorizing method is often with lilac red, and the product that the present invention obtains is white powder, the present invention has good operability, can carry out suitability for industrialized production, all right repetitive operation continuously, can reach continuous seepage requirement.Instant invention overcomes the deficiency of current mycophenolate mofetil color and purity, improve purity and the appearance luster of mycophenolate mofetil, foundation one is simultaneously pollution-free and energy quantity-produced mode, realizes large-scale mycophenolate mofetil Purification decolorization method.
The present invention also has the following advantages:
1, avoid adding new reaction thing vitamins C to the impact of end product quality, avoid the new reaction raw material introduced to cause unnecessary trouble to final product quality examination.
2, the quality product obtained improves, and high performance liquid chromatography detects purity and reaches more than 99.5%, and yield can reach 88% ~ 94%; Vitamins C method is only the oxidized byproduct reduced in side reaction, larger effect can not be had to final product purity, the vitamins C that removing additionally adds to be washed need to wash with a large amount of water simultaneously, because acetic acid ethyl dissolution liquid has certain solvability in water, product loss can be caused to reduce yield.
3, to the invention solves in old technology residual red-purple pigment outward appearance and the lower problem of product purity.
4, tradition can be avoided to add fluctuation of service between activated carbon decolorizing method brings batch, under sample purity Qualification, still has pigments interferes; Reduce discarded activated charcoal solid to pollute simultaneously; Reduce the energy consumption that repeatedly crystallization consumes.
5, the organic solvent used in producing all belongs to the affine solvent of hypotoxicity environment, and decolouring chromatography media can be reused repeatedly, reduces waste solid discharge.
Claims (6)
1. a mycophenolate mofetil Purification decolorization method, is characterized in that: comprise the following steps:
(1) take the reaction product crude product containing mycophenolate mofetil containing 1000g, dissolve with mixed solvent 6000ml; Described mixed solvent is the mixture of organic solvent and ethyl acetate, and described organic solvent is any one in normal hexane, hexanaphthene, sherwood oil;
(2) decoloring medium being loaded on height is 8 ~ 3:1 with internal diameter ratio, and bottom has in two decoloration devices led to up and down of degreasing cotton filtering layer; Described decoloring medium is one or several the mixture in 200 ~ 300 order silica gel, diatomite, aluminum oxide, Microcrystalline Cellulose;
(3) will process after the mixed solvent obtained flows through the decoloration device obtained in (2) through (1), and collect colourless peritoneal effluent, decoloring medium is rinsed again with the described mixed solvent of 1 ~ 2 times of volume of decoloration device, collect colourless permeate, and merge colourless permeate;
(4) wash colourless permeate of obtaining in (3) with 5% sodium hydrogen carbonate solution 3300ml to remove remaining mycophenolic acid, then be washed with distilled water to neutrality, desiccant dehydration, concentrated successively, obtain enriched material;
(5) in enriched material, add 850ml ethyl acetate, crystallization at 5 DEG C, then use cold ethyl acetate washing crystal, then dry abrasive dust and namely obtain white finished product.
2. a kind of mycophenolate mofetil Purification decolorization method as claimed in claim 1, it is characterized in that: also comprise step (6): with the acetone rinsing decoloration device of described decoloration device 3 ~ 4 times of volumes, then rinse decoloration device with the n-hexane-ethyl acetate mixed solvent of the volume ratio 1:1 of 2 times of volumes of described decoloration device.
3. a kind of mycophenolate mofetil Purification decolorization method as claimed in claim 1, is characterized in that: the volume ratio of described mixed solvent is organic solvent: ethyl acetate=10 ~ 40:90 ~ 60.
4. a kind of mycophenolate mofetil Purification decolorization method as described in claim 1 or 3, is characterized in that: described mixed solvent is the n-hexane-ethyl acetate of volume ratio 20:80.
5. a kind of mycophenolate mofetil Purification decolorization method as claimed in claim 1, is characterized in that: the weight ratio of described decoloring medium and described reaction product crude product is 1:3 ~ 10.
6. a kind of mycophenolate mofetil Purification decolorization method as claimed in claim 1, is characterized in that: the height of described decoloration device and internal diameter are than being 4:1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1772745A (en) * | 2005-10-18 | 2006-05-17 | 深圳市东阳光实业发展有限公司 | Prepn process of mofe-til mycophenolate |
| WO2006076802A1 (en) * | 2005-01-20 | 2006-07-27 | Apotex Fermentation Inc. | An improved process for the preparation of mycophenolate mofetil |
| CN101035904A (en) * | 2004-09-03 | 2007-09-12 | 波利工业化学公司 | Method for the preparation of mycophenolate mofetil by enzimatic transesterification |
| CN101037427A (en) * | 2007-03-16 | 2007-09-19 | 北大方正集团有限公司 | Preparation method of tested and reference mycophenolate mofetil |
| WO2009000834A1 (en) * | 2007-06-27 | 2008-12-31 | Dsm Ip Assets B.V. | Method for the purification of mycophenolate mofetil |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035904A (en) * | 2004-09-03 | 2007-09-12 | 波利工业化学公司 | Method for the preparation of mycophenolate mofetil by enzimatic transesterification |
| WO2006076802A1 (en) * | 2005-01-20 | 2006-07-27 | Apotex Fermentation Inc. | An improved process for the preparation of mycophenolate mofetil |
| CN1772745A (en) * | 2005-10-18 | 2006-05-17 | 深圳市东阳光实业发展有限公司 | Prepn process of mofe-til mycophenolate |
| CN101037427A (en) * | 2007-03-16 | 2007-09-19 | 北大方正集团有限公司 | Preparation method of tested and reference mycophenolate mofetil |
| WO2009000834A1 (en) * | 2007-06-27 | 2008-12-31 | Dsm Ip Assets B.V. | Method for the purification of mycophenolate mofetil |
Non-Patent Citations (2)
| Title |
|---|
| Glenn T. Huang,等.synthesis of mycophenolate mofetil-[14C],RS-61443-14C.《Journal of Labelled Compounds and Radiopharmaceuticals》.1995,第36卷(第5期),449-456. * |
| 吗替麦考酚酯合成工艺研究;魏志波;《广东化工》;20100131;第37卷(第1期);39、41 * |
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