Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
  • Y10T436/141111—Diverse hetero atoms in same or different rings [e.g., alkaloids, opiates, etc.]

Definitions

• Mycophenolic acid has the chemical name 6-[4-Hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl]-4-methyl-hex-4-enoic acid, 6-[1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid, molecular formula of C 17 H 20 O 6 , molecular weight of 320.35, CAS Registry number of 24280-93-1 and a structure of:
• Mycophenolic acid isolated by Gosio in 1893, is the first well characterized antibiotic (Bentley 2001). It is produced by several species of Penicillium , including P. brevi - compactum, P. scabrum, P. nagemi, P. roqueforti, P. patris - mei and P. viridicatum (Clutterbuck et al. 1932, Jens and Filtenborg 1983).
• MPA in addition to its antibiotic activity (Abraham 1945), also has antifungal (Gilliver 1946), antiviral (Ando et al. 1968) and antitumor properties (Noto et al. 1969), and has been used clinically in the treatment of psoriasis (Johnson 1972). More recently, it has been recognized as a powerful immunosuppressant (Bentley 2000).
• IMPD inosine monophosphate dehydrogenase
• MPA was withdrawn due to its high incidence of side effects (primarily infections such as herpes zoster and gastrointestinal side effects such as stomach discomfort).
• the 2-morpholinoethyl ester derivative, mycophenolate mofetil (CellCept®) does not have these drawbacks, and has a better bioavailability than mycophenolic acid.
• Mycophenolate mofetil was recently approved (in the United States in 1995 and in Europe in 1996) for prophylaxis of organ rejection in patients receiving allogeneic renal transplants (Shaw and Nowak 1995, Sollinger 1995). After oral administration the ester form rapidly hydrolyzes to free acid.
• MPA is then converted mainly to an inactive glucuronide metabolite, which is eliminated by urinary excretion (Bentley 2001, Wiwattanawongsa et al. 2001).
• the present invention provides a process for preparing an ester of mycophenolic acid comprising: reacting a mycophenolic acid of formula: with a C 1 to C 4 alcohol or 4-(2-hydroxyethyl)morpholine in the presence of a catalyst, to obtain an ester of mycophenolic acid of formula: wherein R is C 1 to C 4 alkyl or a group.
• the reaction is carried out in the absence of a solvent.
• the alcohol is 4-(2-hydroxyethyl)morpholine.
• the alcohol is a C 1 to C 4 alkanol.
• the alcohol is methanol, ethanol, isopropanol, or isobutanol.
• alcohol is present in an amount of about 1 to about 6 molar equivalents of the mycophenolic acid. In one embodiment, the alcohol is present in an amount of about 3 to about 6 molar equivalents of the mycophenolic acid.
• the present invention provides a process for preparing mycophenolate mofetil, comprising the step of reacting mycophenolate C 1 to C 4 alkyl ester with with 4-(2-hydroxyethyl)morpholine, in the presence of a catalyst and without a solvent.
• the catalyst for the processes of the present invention may be selected from the group consisting of: tin(II) chloride, iron(II) chloride, zinc sulfate, camphorsulfonic acid, and potassium dihydrogenphosphate. More preferably the catalyst is selected from the group consisting of tin(II) chloride, iron(II) chloride and zinc sulfate. Most preferably the catalyst is tin(II) chloride. In one embodiment the catalyst is present in an amount of about 0.005 to about 0.2 molar equivalents of the mycophenolic acid. In one embodiment, the catalyst is present in an amount of about 0.15 molar equivalents of the mycophenolic acid. In one embodiment, the reaction is carried out under inert atmosphere.
• the reaction is carried out at a temperature of about room temperature to about reflux temperature. In one embodiment, the reaction is carried out at a temperature of about 30° C. to about 200° C. In one embodiment, the reaction is carried out at a temperature of about 140° C. to about 180° C.
• the present invention provides a process for preparing mycophenolate mofetil comprising:
• mixture includes both heterogeneous and homogenous mixtures, such as, for example, a solution, suspension, or slurry.
• a heterogeneous mixture may be formed, for example, during extraction, where mycophenolic acid is dissolved in a solvent by basification.
• alkaline or “basic” refers to a pH of greater than 7.
• the term “acidic” refers to a pH of less than 7.
• the invention encompasses processes for preparing mycophenolate mofetil and other esters of MPA in a catalytic reaction.
• the catalyst used may be a particular Lewis acid catalyst.
• Certain Lewis acid catalysts are able to change the direction of the process in such a way that an advanced conversion of mycophenolic acid can be achieved while maintaining at the same time the impurity 2-(4-morpholinyl)ethyl (E)-6-(1,3-dihydro-4-[2-(4-morpholinyl)ethoxy]-6-methoxy-7-methyl-3-oxo-isobenzofuran-5-yl)-4-methyl-hex-4-enoate, (designated Compound 1) at a level which facilitates its subsequent removal from the drug.
• the catalytic process for preparing esters of mycophenolic acid is performed with or without a solvent, under an inert atmosphere.
• This process comprises: reacting a mycophenolic acid of formula (I): with a C 1 to C 4 alcohol or 4-(2-hydroxyethyl)morpholine in the presence of a catalyst, to obtain an ester of mycophenolic acid of formula (II): wherein R is C 1 to C 4 alkyl or a group.
• inert atmosphere refers to unreactive atmospheres, which includes, for example, nitrogen or argon atmosphere
• the reaction is carried out neat, i.e. in the absence of a solvent.
• a preferable C 1 to C 4 alcohol is methanol, ethanol, isopropanol or isobutanol.
• the C 1 to C 4 alcohol or 4-(2-hydroxyethyl)morpholine used should be in an amount sufficient to produce mycophenolate esters of the invention.
• mycophenolate mofetil is prepared by reaction of a C 1 to C 4 alkyl ester of mycophenolic acid with 4-(2-hydroxyethyl)morpholine without a solvent in the presence of a catalyst.
• the 4-(2-hydroxyethyl)morpholine should be in an amount sufficient to produce the mycophenolate mofetil.
• the 4-(2-hydroxyethyl)morpholine is in an amount of about 1 to about 6 molar equivalents of the mycophenolic acid, and more preferably about 3 to about 6 molar equivalents.
• Acid catalysts favor an esterification reaction.
• not all acid catalysts have the same effect on the reaction selectivity of mycophenolic acid with morpholine ethanol.
• catalysts such as tin(II) chloride, iron(III) chloride, or zinc sulfate; or organic acids such as camphorsulfonic acid; or other inorganic salts such as potassium dihydrogenphosphate; can be used to promote the esterification reaction, not all catalysts favor the conversion and increase the selectivity of the esterification reaction towards the desired compound.
• Catalysts that do favor conversion and increase selectivity include certain Lewis acid catalysts such as, for example, tin(II) chloride, iron(III) chloride, or zinc sulfate.
• a most preferable catalyst is tin(II) chloride.
• the catalyst should be in an amount sufficient to increase the reaction speed and selectivity.
• the catalyst is present in an amount of about 0.005 to about 0.2 molar equivalents of the mycophenolic acid, and more preferably about 0.15 molar equivalents.
• the reaction should be at a suitable temperature to move the reaction forward.
• the reaction temperature may be from room temperature to about reflux temperature.
• the reaction temperature is about 30° C. to about 200° C., and more preferably about 140° C. to about 180° C.
• reaction time depends on factors such as the reagents, temperature, or the amount of reagents.
• the reaction time is about 1.5 to about 10 hours, and more preferably about 4 to about 9 hours.
• the reaction mixture may undergo various treatments, such as, for example, extraction, washing, decolorization, or filtration, to obtain a crude product.
• the crude product is then crystallized at least once from a suitable solvent or solvent mixture.
• Removal of impurities refers to reducing the levels of impurities as defined by European Pharmacopoeia.
• Unreacted mycophenolic acid may be removed, for example, by alkaline extraction.
• the alkaline extraction may be carried out, for example, by admixing the mycophenolate ester with a water-immiscible solvent and extracting the ester with an alkaline aqueous solution.
• Any water-immiscible solvent suitable for extracting the mycophenolate ester may be used.
• suitable solvents include, but are not limited to, at least one of ethyl acetate, isobutyl acetate, methyl ethyl ketone, or toluene.
• An alkaline aqueous solution may be prepared, for example, from sodium bicarbonate, sodium carbonate, or sodium hydroxide.
• the alkaline extraction is carried out at a pH of about 7 to about 12, and preferably at about 8 to about 10.
• the impurity designated Compound 1 may be removed by acidic extraction, as described in commonly-owned U.S. application Ser. No. 11/_______ [K&K ref: 2664/58504 filed 26 Apr. 2005.
• the U.S. Ser. No. ______ will be completed when available].
• This acidic extraction method comprises: admixing the mycophenolate ester with a water-immiscible solvent; washing the mycophenolate mofetil admixture with an aqueous acidic solution to obtain a two-phase system; separating the organic phase containing mycophenolate mofetil from the aqueous acidic phase; adding an aqueous basic solution to the aqueous acidic phase; and recovering Compound 1.
• a residue is obtained by concentration, and is crystallized from at least one solvent.
• the residue may be obtained by evaporation at atmospheric or reduced pressure, preferably at below 1 atm, and more preferably at below about 100 mm Hg.
• An anti-solvent such as isopropanol may be added to the mixture of the mycophenolate ester in the water-immiscible solvent obtained after extraction for optimum crystallization.
• the anti-solvent may also be added after concentration into the residue.
• Water may also be added to the reaction mixture obtained from the extraction, and the mixture is seeded.
• Crystallization helps remove other known significant impurities such as, for example, impurity A as defined by European Pharmacopoeia, or the lactone or Z-isomer of the mycophenolic ester.
• Any solvent suitable for crystallization may be used.
• suitable solvents include, but are not limited to, ketones (such as acetone or methyl ethyl ketone), alcohols (such as methanol, ethanol, n-propanol, or isopropanol), esters (such as ethyl acetate or isobutyl acetate), ethers (such as diisopropyl ether or tert-butyl methyl ether), or other solvents such as acetonitrile or toluene.
• the above solvents may also be mixed with ethers, alcohols, or alkanes (such as n-heptane, n-hexane or cyclohexane).
• Preferred solvents include acetone/isopropanol, isobutyl acetate, isobutyl acetate/isopropanol, isobutyl acetate/acetone/isopropanol, acetonitrile/isopropanol, or toluene/isopropanol.
• Crystallization is carried out a suitable temperature to dissolve the crude product.
• the solution may be heated, preferably at about 30° C. to about 60° C., and more preferably at about 40° C. to about 45° C.
• the solution may then be cooled, preferably at about ⁇ 10° C. to about 10° C., and more preferably at about ⁇ 5° C. to about 0° C.
• the cooling time may vary depending on the crystallization conditions.
• the solution is cooled for about 2 to about 10 hours, and more preferably about 6 hours.
• the solution is then allowed to crystallize, preferably for about 2 to about 20 hours, and more preferably for about 10 to about 12 hours.
• the recovered solid may be dried at atmospheric or reduced pressure, preferably at about 40° C. to about 80° C., and more preferably at about 60° C.
• Mycophenolic acid used to prepare the ester in the present invention may be prepared by any methods known in the art. See, e.g., WO 01/21607, WO 01/64931 and GB 1158387.
• MPA may be also prepared by the processes disclosed in commonly-owned U.S. application Ser. No. 11/_______ [K&K ref: 2664/60903, which is filed on Apr. 26, 2005. The U.S. Ser. No. ______ will be completed when available], which process comprises:
• the second water-immiscible phase in step e) is preferably concentrated by membrane filtration.
• the concentrated alkaline mixture in step a) may be prepared from a fermentation broth by various methods. Preferably, it is obtained by the method comprising: basifying a fermentation broth containing mycophenolic acid, and removing the mycelia to obtain a basic mixture; acidifying the basic mixture to obtain an acidic mixture; and filtering and basifying the acidic mixture, to obtain the concentrated alkaline mixture.
• the mycophenolate mofetil prepared by the processes of the present invention has about 0.01 to about 0.1% of Compound 1 as measured by HPLC area percentage.
• the processes provided in the present invention further comprise the step of formulating the ester of mycophenolic acid with one or more pharmaceutical acceptable excipients.
• compositions of the invention contain mycophenolic acid ester, and preferably the mofetil ester. Also included are pharmaceutically acceptable salts of the mofetil ester such as, for example, acetic, benzoic, fumaric, maleic, citric, tartaric, gentisic, methane-sulfonic, ethanesulfonic, benzenesulfonic and laurylsulfonic, taurocholat, hydrobromide, or hydrochloride salts.
• the pharmaceutical composition may contain a single polymorphic form, or a mixture of various crystalline forms, with or without amorphous form.
• the pharmaceutical composition may contain one or more excipients or adjuvants. Selection of excipients and the amounts may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
• Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
• Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
• microcrystalline cellulose e.g. Avicel®
• microfine cellulose lactose
• starch pregelatinized starch
• calcium carbonate calcium sulfate
• sugar dextrates
• dextrin
• Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
• Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
• carbomer e.g. carbopol
• carboxymethylcellulose sodium, dextrin ethyl cellulose
• gelatin
• the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
• Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
• alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®
• Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
• Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
• a dosage form such as a tablet
• the composition is subjected to pressure from a punch and dye.
• Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
• a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
• Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
• Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
• Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
• Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
• liquid pharmaceutical compositions of the present invention nateglinide and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
• a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
• Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
• Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
• Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
• a viscosity enhancing agent include acacia, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
• Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
• Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
• a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
• a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
• the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
• the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
• the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
• Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
• the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
• the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
• compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
• a composition for tableting or capsule filling may be prepared by wet granulation.
• wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
• the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
• the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
• a tableting composition may be prepared conventionally by dry blending.
• the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
• a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
• Direct compression produces a more uniform tablet without granules.
• Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
• a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
• the invention also encompasses a method of suppressing the immune system of a mammal by administering a therapeutically effective amount of the pharmaceutical composition to a mammal in need thereof.
• An assay is a determination of the purity or presence of a quantity of a substance, as described by the European Pharmacopoeia (“EP”). EUROPEAN PHARMACOPOEIA, 4 th ed., Council of Europe, France, 2001.
• the assay is performed by high pressure liquid chromatography (“HPLC”). HPLC methods are carried out according to Pharmaeuropa.
• HPLC analysis was conducted using a Discovery ciano or Zorbax C 8 column.
• the eluent was a water-acetonitrile mixture containing phosphoric acid and the potassium salt of phosphoric acid.
• the triethylamine salt of phosphoric acid may be used in place of the potassium salt of phosphoric acid.
• the pH of the eluent was 3.0-5.9.
• the eluent flow was approximately 1.5 ml/min.
• the temperature for elution was 20-45° C.
• MPA level 2.4 area %.
• the crude compound (172 g) was dissolved in acetone (344 ml) and isopropanol (3.27 l) at 40-45° C.
• the warmed solution was treated with charcoal (17.2 g, 10%). After filtration the solution was cooled to ⁇ 5° C. over 6 hours and stirred at this temperature for 10-12 hours.
• the precipitated crystals were filtered off and washed with 2:19 acetone/isopropanol mixture (361 ml).
• the crystallized compound was dried under vacuum at 60° C. The solid was 155-164 g (85-90%).
• the crude compound (5 g) was dissolved in isobutyl acetate (10 ml) and isopropanol (90 ml) at 40-45° C.
• the warmed solution was treated with charcoal (0.5 g, 10%). After filtration the solution was cooled to ⁇ 5° C. over 6 hours and stirred at this temperature for 10-12 hours.
• the precipitated crystals were filtered off and washed with 1:9 isobutyl acetate/isopropanol mixture (10 ml).
• the crystallized compound was dried under vacuum at 60° C. The compound was 4.1-4.3 g (82-86%).
• the crude compound (5 g) was dissolved in isobutyl acetate (100 ml) at 40-45° C. The warmed solution was treated with charcoal (0.5 g, 10%). After filtration the solution was cooled to ⁇ 5° C. during 6 hours and stirred at this temperature for 10-12 hours. The precipitated crystals were filtered off and washed with isobutyl acetate (10 ml). The crystallized compound was dried in vacuum at 60° C. The solid was 3.55-3.80 g (71-76%). MPA level: 0.11 area %. Assay: 99.7%.
• the crude compound (5 g) was dissolved in isobutyl acetate (10 ml), acetone (9 ml) and isopropanol (86 ml) at 40-45° C.
• the warmed solution was treated with charcoal (0.5 g, 10%). After filtration the solution was cooled to ⁇ 5° C. over 6 hours and stirred at this temperature for 10-12 hours.
• the precipitated crystals were filtered off and washed with isobutyl acetate/acetone/isopropanol mixture (10 ml).
• the crystallized compound was dried under vacuum at 60° C. The solid was 4.05-4.3 g (81-86%).
• Concentrated mycophenolic acid suspension of 140 kg (produced from 620 kg fermented broth) was pH adjusted with 800 ml conc. ammonium hydroxide solution. The achieved pH was 8.3-8.5.
• the alkaline solution was purified with 80 liters ethylacetate. The ethylacetate was mixed with the alkaline solution, stirred for 30 minutes, and the phases were separated.
• the crystals were recrystallized from ethylacetate after charcoal treatment. Assay: 99.6%. HPLC purity: 99.8 area %. Any impurity is less than 0.1 area %.

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• 2005
  • 2005-04-26 MX MXPA06005658A patent/MXPA06005658A/es unknown
  • 2005-04-26 US US11/115,820 patent/US20050250773A1/en not_active Abandoned
  • 2005-04-26 EP EP05744402A patent/EP1675841A1/en not_active Withdrawn
  • 2005-04-26 EP EP05739984A patent/EP1740563A2/en not_active Withdrawn
  • 2005-04-26 JP JP2006549718A patent/JP2007522117A/ja active Pending
  • 2005-04-26 CA CA002555461A patent/CA2555461A1/en not_active Abandoned
  • 2005-04-26 JP JP2007509732A patent/JP2007534697A/ja active Pending
  • 2005-04-26 WO PCT/US2005/014238 patent/WO2005105771A1/en not_active Application Discontinuation
  • 2005-04-26 MX MXPA06005660A patent/MXPA06005660A/es active IP Right Grant
  • 2005-04-26 US US11/115,593 patent/US7358247B2/en not_active Expired - Fee Related
  • 2005-04-26 CA CA002555454A patent/CA2555454C/en not_active Expired - Fee Related
  • 2005-04-26 WO PCT/US2005/014354 patent/WO2005105769A2/en not_active Application Discontinuation
  • 2005-04-27 TW TW094113530A patent/TWI338006B/zh not_active IP Right Cessation
  • 2005-04-27 TW TW094113507A patent/TW200606160A/zh unknown
• 2006
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