WO2008003637A2 - Isolation et utilisation de sels aminés d'acide mycophénolique - Google Patents

Isolation et utilisation de sels aminés d'acide mycophénolique Download PDF

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Publication number
WO2008003637A2
WO2008003637A2 PCT/EP2007/056486 EP2007056486W WO2008003637A2 WO 2008003637 A2 WO2008003637 A2 WO 2008003637A2 EP 2007056486 W EP2007056486 W EP 2007056486W WO 2008003637 A2 WO2008003637 A2 WO 2008003637A2
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Prior art keywords
mpa
water
amine
mycophenolic acid
solvent
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PCT/EP2007/056486
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English (en)
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WO2008003637B1 (fr
WO2008003637A3 (fr
Inventor
De Robertus Mattheus Pater
Van De Emilius Johannes Albertus Xaverius Sandt
Pieter Gijsbert Weber
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Dsm Ip Assets B.V.
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Publication of WO2008003637A2 publication Critical patent/WO2008003637A2/fr
Publication of WO2008003637A3 publication Critical patent/WO2008003637A3/fr
Publication of WO2008003637B1 publication Critical patent/WO2008003637B1/fr

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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

Definitions

  • the present invention relates to a method for the isolation of mycophenolic acid derivatives, especially amine salts of mycophenolic acid and the use thereof.
  • MPA Mycophenolic acid
  • 6-(4-hydroxy-6-methoxy-7-methyl-3- oxo-5-phthalanyl)-4-methyl-4-hexenoic acid 6-(1 ,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid
  • Ci 7 H 2 o0 6 and CAS 24280-93-1 is a compound with various advantageous properties.
  • MPA also displays antifungal, antiviral and antitumor properties and the compound has been used in the treatment of psoriasis and recently as immunosuppressant.
  • the chemical structure of MPA is:
  • MPA is most economically obtainable from microorganisms, such as Penicillium brevicompactum, Penicillium stoloniferum and related species. From the free acid two products are produced, which are commercially being applied as immunosuppressant, namely the salt mycophenolate sodium and the ester mycophenolate mofetil. In order to obtain these latter products in as pure as possible form it is necessary to isolate MPA from the fermentation broth with high purity in a form that can be used in the synthesis of said two final products. Unfortunately, direct crystallization of MPA from a fermentation broth does not lead to a product with a purity that is sufficient for subsequent steps. One way to overcome this problem is to recrystallize said MPA crystals.
  • a method for the isolation of amine salts of mycophenolic acid from a fermentation broth comprising less steps than known from prior art methods, i.e.:
  • a solution comprising MPA is mixed with an amine to form a precipitate of the amine salt of MPA.
  • the solution comprising MPA is a solution derived from a bioprocess in which MPA is formed.
  • the broth resulting from a bioprocess in which MPA is formed is mixed with a water-immiscible solvent, preferably at a pH value ranging from 1 to 7, more preferably ranging from 3 to 6.5, most preferably ranging from 4 to 6.
  • the water-immiscible phase also referred to as extract
  • an amine is added to the water-immiscible phase.
  • the amine salt of MPA precipitates and the precipitate can then be isolated with any of the methods available to the person skilled in the art, such as, but not limited to, filtration, sedimentation, decantation and centrifugation or combinations thereof.
  • the mixture comprising the amine salt of MPA is cooled to a temperature ranging from -20 to 50°C, more preferably ranging from -10 to 10°C, most preferably ranging from 0 to 5°C, which usually results in an improved recovery yield.
  • Suitable amines are primary, secondary and tertiary amines such as terf-butylamine, cyclohexylamine, dibenzylamine, N,N-di/sopropylethylamine, N,N-dimethylisopropyl- amine, N-methylpiperidine, morpholine, terf-octylamine, /so-propylamine, N,N,N',N'-tetramethylethylenediamine, tributylamine, triethylamine and tripropylamine.
  • the most preferred amine is triethylamine.
  • triethylamine Using triethylamine, the resulting MPA-triethylamine salt crystallizes with one molecule of triethylamine per molecule MPA whereas most other amines form crystals having two molecules amine per molecule MPA.
  • triethylamine has the advantage that less amine is needed, which is advantageous from an economic and a waste-stream point of view.
  • Another advantage is the high crystallization yield when triethylamine is used compared to other amines.
  • suitable water-immiscible solvents are alcohols, alkanes, benzene and derivatives thereof, esters, ethers and ketones. Particularly suitable alcohols are butanol and /so-butanol.
  • Suitable benzene derivatives are toluene and xylene.
  • Suitable esters are butyl acetate, ethyl acetate, methyl acetate and propyl acetate.
  • Suitable ethers are diethyl ether and methyl tert-butyl ether.
  • the broth obtained from the bioprocess is filtered and/or centrifuged prior to the addition of the water-immiscible solvent.
  • a filtration and/or centrifugation step allows for the removal of biomass, which normally results in improved separation of the aqueous phase and the water-immiscible solvent phase.
  • adjusting the pH of the aqueous phase with an alkaline solution prior to filtration and/or centrifugation can be advantageous in view of the overall yield, as undissolved MPA is thus dissolved and will no longer be retained by the filter.
  • Preferred pH values are those ranging from 6 to 12, more preferably ranging from 7 to 1 1 , most preferably ranging from 8 to 10.5, still most preferably ranging from 8.5 to 10.
  • the water-immiscible phase is treated with color- adsorbing material that can be removed by means of filtration or centrifugation.
  • treatment with color-adsorbing material is carried out using a means comprising said color-adsorbing material that can be removed and/or replaced, such as for instance a cartridge.
  • Treatment with color-adsorbing material has the advantage that less color is retained in the end-product, which in turn usually leads to a higher purity of the end-product.
  • Carbon is a preferred example of color-adsorbing material.
  • Other suitable examples are alumina, resins and silica.
  • the water-immiscible phase is concentrated, for instance by evaporation.
  • Concentration of the water-immiscible phase results in a higher yield and usually also facilitates the treatment with color-adsorbing material.
  • the water-immiscible phase is treated such that the amount of water present is reduced. Suitable methods for reducing the amount of water are treatment with a water-adsorbing agent such as molecular sieves, CaCI 2 , MgSO 4 , Na 2 SO 4 , and similar compounds, or by means of evaporation. Lowering the amount of water has the advantage that a higher yield is obtained.
  • MPA amine salts are used in the production of the derivatives of MPA.
  • the amine salts are converted to metal salts by dissolving the amine salt in a suitable solvent and then adding a suitable metal salt.
  • a suitable metal salt is an alkali metal salt such as the sodium salt.
  • a suitable solvent dissolves the amine salt of MPA, but -where the metal in question is for example sodium- does not dissolve the sodium salt of MPA.
  • Suitable solvents can be solvents like alcohols, alkanes, benzene and derivatives thereof, esters, ethers and ketones. Particularly suitable solvents are acetone, ethyl acetate, methyl ethyl ketone and methyl /so-butyl ketone.
  • the amine salts are converted into esters of MPA.
  • esterification of MPA has been described. For instance, in US 4,753,935 an acid halide condensation route has been described. This is a two-step process requiring toxic reagents for forming the halide of MPA and/or of the alcohol, which in this case was 2-morpholinoethanol.
  • the use of the amines of the present invention circumvents the necessity for acid halide formation as they react with alcohols without any further activation.
  • esterification of MPA is accomplished by reaction of an amine salt of MPA with an alcohol or an activated alcohol.
  • the alcohol is a primary alcohol having the general formula HOCH 2 CH 2 R, wherein R is hydrogen, (substituted) alkyl or substituted nitrogen, non-limiting examples of which are butanol, ethanol, /so-butanol, /so-propanol, propanol, and sec-butanol.
  • R is hydrogen, (substituted) alkyl or substituted nitrogen, non-limiting examples of which are butanol, ethanol, /so-butanol, /so-propanol, propanol, and sec-butanol.
  • 2-morpholinoethanol as one of the most preferred MPA esters is the 2-morpholinoethyl ester of MPA, or mycophenolate mofetil (MPM), as this ester is widely used as pro-drug of MPA.
  • MPM is prepared starting from the amine salt of MPA and 2-morpholino ethanol.
  • Amine salts suitable for the conversion of MPA into esters of MPA are amines as mentioned above, and in particular amines such as dibenzylamine, cyclohexylamine, /so-propylamine, terf-butylamine, terf-octylamine, triethylamine and N,N,N',N'-tetramethylethylene- diamine.
  • Esterification can be carried out in a solvent, preferably an inert solvent.
  • inert solvent means a solvent inert under the conditions of the reaction being described in conjunction therewith. Examples of inert solvents in the context of the present invention are alkanes, benzene, cycloalkanes, ethers, ethylbenzene, methylene chloride, toluene and xylene.
  • esterification of the amine salt of MPA is carried out in a non-inert solvent.
  • a route was disclosed concerning refluxing MPA with 2-morpholinoethanol in an inert organic solvent capable of azeotropic removal of water, without the use of additional reagents.
  • This method wherein MPA was used as free acid, is limited to solvents that are inert.
  • the amine salts of MPA of the present invention however also allow for successful esterification in non-inert solvents.
  • non-inert solvent means a solvent not being inert under the conditions of the reaction being described in conjunction therewith.
  • Non-inert solvents can be classified in relation to the degree in which the solvent in question suffers degradation during the reaction in question.
  • a suitable parameter for this is the loss of solvent due to reaction with any material (including the solvent itself) in %.h “1 .
  • a non-inert solvent has a degradation rate of 0.01 %.h "1 or higher.
  • the amine of MPA is esterified with a primary alcohol in a non-inert solvent having a degradation rate higher than 0.01 %.h "1 .
  • esterification of MPA can be accomplished in non-inert solvents with a degradation rate higher than 0.01 %.h “1 with results that are similar, or in some cases surprisingly even better, than prior art methods using inert solvents.
  • said non-inert solvent has a degradation rate under the reaction conditions of 0.3-0.01 %.h “1 , more preferably of 0.2-0.01 %.h “1 , most preferably 0.1-0.01 %.h “1 , still most preferably 0.05-0.01 %.h “1 .
  • Suitable non-inert solvents in this respect are ketones such as acetone, cyclohexanone, cyclopentanone, dipropyl ketone, methylisobutyl ketone, methylpropyl ketone, N-methylpyrrolidone and mixtures thereof.
  • esterification of the amine salt of MPA is carried out under non-boiling conditions.
  • EP 649,422 B1 mentioned above limits the esterification of MPA to reaction at reflux.
  • the amine salts of MPA of the present invention however also allow for successful esterification under non-boiling conditions, i.e. in a non-boiling mixture.
  • non-boiling mixture refers to a given conversion or process that is carried out at a temperature below the boiling point that the mixture in question has at that specific pressure.
  • the term “mixture” comprises at least one solvent.
  • the boiling point of a mixture refers to the boiling point of said solvent per se or to the boiling point of the solvent as changed by the presence of other components, i.e. through the formation of one or more azeotropes, whichever is lower. If there are components present, other than the solvent, which have lower boiling points than the solvent and which do not form an azeotrope with the solvent, the mixture will boil first at the temperature of that or those components. This or these first boiling points are not included in the term "non-boiling mixture".
  • such components which may be catalysts, reactants, reaction products or even co-solvents and the like, are usually present in minor amounts compared to the solvent, for instance 0.01-10% (w/w), 0.1-5% (w/w) or 1-3% (w/w).
  • the amine of MPA is esterified in a conversion with a primary alcohol in a solvent at a temperature that is at least 0.2% below the boiling point of the mixture comprising MPA, primary alcohol and solvent. This temperature is maintained at the value of 0.2% below the boiling point of the mixture, or even below that value, throughout the duration of the conversion.
  • the time during which the temperature is maintained at said value is, for example, 30 min for a conversion that takes 30 min, 1 h for a conversion that takes 1 h, 5 h for a conversion that takes 5 h, 10 h for a conversion that takes 10 h, 2O h for a conversion that takes 20 h, 40 h for a conversion that takes 40 h, 80 h for a conversion that takes 80 h, and so on and so forth.
  • the advantages of esterification at a temperature below the boiling point are already manifest at temperatures only slightly below the boiling point: equipment for condensing solvent vapors and returning these condensed vapors are no longer required and the energy input required to reach and maintain the boiling point, which normally is substantial, can be circumvented. Furthermore, formation of unwanted by-products generally is lower at lower reaction temperatures. On the one hand, typical temperatures below the boiling point are temperatures that are 0.2-10% below the boiling point, preferably 0.5-5% below the boiling point.
  • esterification of amines of MPA can be positively influenced (i.e. reduction of reaction time, increase of maximum conversion) by the addition of substances that are capable of adsorbing water.
  • substances that are capable of adsorbing water are for instance salts of alkali and earth alkali metals and usually these salts are carbonates, halides or sulfates. Suitable examples are CaCI 2 , CaSO 4 , K 2 CO 3 , K 2 SO 4 , MgSO 4 , Na 2 CO 3 , Na 2 SO 4 and the like.
  • Preferred other substances are molecular sieves, preferably those with pore sizes ranging from 0.1-0.6 nm, more preferably ranging from 0.2-0.5 nm, most preferably ranging from 0.3-0.4 nm.
  • impurities for instance the so-called impurity B (as defined in the European Pharmacopoeia) in the case of MPM
  • impurity B as defined in the European Pharmacopoeia
  • adsorbents such as silica, alumina, aluminosilicates or carbon.
  • impurity B which is the esterification product of a mycophenolate impurity produced during fermentation, is difficult to remove.
  • treatment with silica can either be done using column chromatography or by addition of silica to a solution of MPM followed by removal of the silica by means known to those skilled in the art. Treatment can be repeated to reduce the impurity levels even further.
  • said treatment is performed using a column, where an MPM solution, for example a solution of MPM in ethyl acetate but other solvents may also be used, is treated with silica, for example Silica gel 60 but other silica's may also be used.
  • Treatment with adsorbents such as silica can be done at various stages of the esterification process.
  • the silica can be regenerated using suitable solvents, for example alcohols such as methanol or ethanol, to remove the adsorbed impurities from the silica and therewith regenerating the silica to be able to reuse the silica.
  • the MPA esters obtainable from the MPA amines of the present invention can be used in pharmaceutical compositions, for instance in antifungal, antiviral and/or antitumor compositions, but also in compositions useful in the treatment of psoriasis and as immunosuppressant. Particularly suitable is a pharmaceutical composition comprising MPM.
  • HPLC analysis was performed on a Waters Atlantis dC-i ⁇ column (5 ⁇ m; 4.6x150 mm; W 32371 X 12), using as mobile phase A MiIIiQ water with 0.1 vol% formic acid and as mobile phase B CH 3 CN with 0.1 vol% HCO 2 H.
  • the run time was 13 minutes and the flow 1.5 mL. min "1 .
  • Detection wavelength was at 251 nm.
  • the following gradient was applied:
  • Example 2 Crystallization of MPA-isopropylamine salt (MPA-IPA) from MPA extract From an MPA ethyl acetate extract (200 ml_, containing 8.12 mmol MPA) obtained analogous to Example 1 , 1 10 ml. were distilled off over a period of 1 h at 79°C. The residue was cooled to 55°C and a mixture of ethyl acetate (10 ml.) and isopropyl amine (6 ml.) were added. During cooling at ca 48°C crystallization started, further cooled to 1 1 °C and stirred for 1 h.
  • MPA-IPA MPA-isopropylamine salt
  • Example 3 Crystallization of MPA-t-butylamine salt (MPA-TBA) from MPA extract
  • Example 3.1 From an MPA ethyl acetate extract (200 ml_, containing 8.12 mmol MPA) obtained analogous to Example 1 , 1 18 ml. were distilled off over a period of 1 h at 80°C. The residue was cooled to 60°C and a mixture of ethyl acetate (18 ml.) and t-butyl amine (12 ml.) were added. During the addition crystallization started. The suspension was further cooled to 22°C and stirred for 1 h.
  • MPA-t-butylamine salt MPA-TBA
  • Example 3.2 As Example 3.1 , however with 170 ml. extract (containing 6.90 mmol MPA) and 4 ml. tert-butyl amine to give 2.952 g of the title compound with a purity of 80%; yield: 86.8%.
  • Example 4.1 From an MPA ethyl acetate extract (200 ml_, containing 8.12 mmol MPA) obtained analogous to Example 1 , 100 ml. were distilled off over a period of 1 h at 79°C. The residue was cooled to 60°C and a mixture of ethyl acetate (10 ml.) and triethyl amine (6 ml.) were added. During cooling at ca 42°C crystallization started, further cooled to 10°C and stirred for 1 h. The precipitate was filtered off and washed/replaced with ethyl acetate (15 ml_).
  • Example 4.2 As Example 4.1 , however with 163 ml. extract (containing 6.62 mmol MPA) and 7 ml. triethyl amine to give 2.676 g of the title compound with a purity of 92%; yield: 88.4%.
  • the reaction mixture was diluted with 25 mL ort/70-xylene and with water and the pH was adjusted to 1.8 with 2M H 2 SO 4 .
  • the phases were separated. Ethyl acetate was added to the aqueous phase and under stirring the pH was adjusted to 8 with diluted NaOH. The phases were separated and the ethyl acetate phase was washed twice with water and then concentrated under vacuum.
  • the concentrate was decolorized with 1.5 g SX-ultra carbon. After filtration the filtrate was evaporated under vacuum to dryness. The residue was dissolved in 4 mL ethyl acetate and 20 mL 2-propanol at 45°C. The solution was gradually cooled to 0°C and left in the refrigerator overnight.
  • Example 7 Determination of solvent degradation rate (D) of cyclohexanone 150 ml (143 g) of cyclohexanone was heated under reflux (155°C) for 44 h. The mixture was evaporated under vacuum at 70°C, yielding 6.2 g of oil and thus the remaining solvent was 136.8 g.
  • the solvent degradation rate (D) of cyclohexanone at 155 0 C is:
  • MPA-TEA MPA-triethylamine salt
  • the reaction mixture was filtered with dicalite 4108 and the filter cake was washed with cyclohexanone.
  • the filtrate was extracted three times with water at pH 1.8 (acidification with 2M H 2 SO 4 ).
  • the aqueous phases were combined.
  • Ethyl acetate was added and under stirring the pH was adjusted to 8 with diluted NaOH.
  • the phases were separated and the ethyl acetate phase was washed twice with water and then evaporated under vacuum.
  • the purple residue was purified over 20 g silica gel 60 using ethyl acetate/ethanol 20/1 (v/v). The eluate was evaporated under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé servant à isoler de l'acide mycophénolique d'un bouillon de fermentation et consistant à: (a) effectuer l'apport d'un solvant immiscible dans l'eau à ce bouillon de fermentation; (b) séparer la phase immiscible dans l'eau de la phase aqueuse et (c) ajouter une amine à la phase immiscible dans l'eau obtenue à l'étape (b). Elle concerne, de plus, l'utilisation d'amines de mycophénolate afin de préparer des esters de mycophénolate, en particulier, mofétil de mycophénolate et des sels de mycophénolate, en particulier, un sel de sodium de mycophénolate.
PCT/EP2007/056486 2006-07-05 2007-06-28 Isolation et utilisation de sels aminés d'acide mycophénolique WO2008003637A2 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
EP06116622.9 2006-07-05
EP06116622 2006-07-05
EP06116623.7 2006-07-05
EP06116621 2006-07-05
EP06116621.1 2006-07-05
EP06116623 2006-07-05
EP06120381 2006-09-08
EP06120381.6 2006-09-08

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WO2008003637A2 true WO2008003637A2 (fr) 2008-01-10
WO2008003637A3 WO2008003637A3 (fr) 2008-05-08
WO2008003637B1 WO2008003637B1 (fr) 2008-07-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009096668A3 (fr) * 2008-02-01 2010-05-27 Ckd Bio Corp Procédé amélioré de préparation de mycophénolate de mofetil
EP2321421A1 (fr) * 2008-09-10 2011-05-18 IPCA Laboratories Limited Procédé de préparation d acide mycophénolique, son sel et ses dérivés esters
CN115838363A (zh) * 2023-01-09 2023-03-24 广东蓝宝制药有限公司 一种麦考酚酸的纯化方法

Citations (7)

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Publication number Priority date Publication date Assignee Title
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
WO1994001427A1 (fr) * 1992-07-10 1994-01-20 Syntex (U.S.A.) Inc. Esterification directe d'acide mycophenolique
WO2001021607A2 (fr) * 1999-09-23 2001-03-29 Gyógyszerkutató Intézet Kft. Elaboration d'acide mycophenolique et de derives de cet acide
WO2004020426A1 (fr) * 2002-08-29 2004-03-11 Biocon Limited Procede de production d'un immunosuppresseur
WO2005023791A2 (fr) * 2003-09-11 2005-03-17 Sandoz Ag Procede de production de mycophenolate mofetil
WO2005033089A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel d'acide 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoique avec du diamide de n, n-dimethyl-imidodicarbonimidique
WO2005105768A2 (fr) * 2004-04-26 2005-11-10 Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg Processus de préparation d'acide mycophénolique et de dérivés d'ester

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
WO1994001427A1 (fr) * 1992-07-10 1994-01-20 Syntex (U.S.A.) Inc. Esterification directe d'acide mycophenolique
WO2001021607A2 (fr) * 1999-09-23 2001-03-29 Gyógyszerkutató Intézet Kft. Elaboration d'acide mycophenolique et de derives de cet acide
WO2004020426A1 (fr) * 2002-08-29 2004-03-11 Biocon Limited Procede de production d'un immunosuppresseur
WO2005023791A2 (fr) * 2003-09-11 2005-03-17 Sandoz Ag Procede de production de mycophenolate mofetil
WO2005033089A1 (fr) * 2003-10-07 2005-04-14 Biocon Limited Sel d'acide 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoique avec du diamide de n, n-dimethyl-imidodicarbonimidique
WO2005105768A2 (fr) * 2004-04-26 2005-11-10 Teva Gyógyszergyár Zàrtköruen Muködo Rèszvènytàrsasàg Processus de préparation d'acide mycophénolique et de dérivés d'ester

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Title
CARMAN ET AL: "Derivatives of Mycophenolic Acid" AUSTRALIAN JOURNAL OF CHEMISTRY, no. 31, 1978, pages 353-364, XP002075178 ISSN: 0004-9425 cited in the application *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009096668A3 (fr) * 2008-02-01 2010-05-27 Ckd Bio Corp Procédé amélioré de préparation de mycophénolate de mofetil
KR100975520B1 (ko) * 2008-02-01 2010-08-12 종근당바이오 주식회사 마이코페놀레이트 모페틸의 개선된 제조방법
EP2321421A1 (fr) * 2008-09-10 2011-05-18 IPCA Laboratories Limited Procédé de préparation d acide mycophénolique, son sel et ses dérivés esters
EP2321421A4 (fr) * 2008-09-10 2013-01-09 Ipca Lab Ltd Procédé de préparation d acide mycophénolique, son sel et ses dérivés esters
CN115838363A (zh) * 2023-01-09 2023-03-24 广东蓝宝制药有限公司 一种麦考酚酸的纯化方法
CN115838363B (zh) * 2023-01-09 2024-04-23 广东蓝宝制药有限公司 一种麦考酚酸的纯化方法

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