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WO2009003878A1 - Procédé de préparation de mycophénolate mofétil - Google Patents

Procédé de préparation de mycophénolate mofétil Download PDF

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Publication number
WO2009003878A1
WO2009003878A1 PCT/EP2008/058024 EP2008058024W WO2009003878A1 WO 2009003878 A1 WO2009003878 A1 WO 2009003878A1 EP 2008058024 W EP2008058024 W EP 2008058024W WO 2009003878 A1 WO2009003878 A1 WO 2009003878A1
Authority
WO
WIPO (PCT)
Prior art keywords
mpa
esterification
mpm
chelating agent
mycophenolate mofetil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/058024
Other languages
English (en)
Inventor
De Robertus Mattheus Pater
De Erik Vos Burchart
Neeraj Tewari
Bhausaheb Nana Ghogare
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of WO2009003878A1 publication Critical patent/WO2009003878A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the present invention relates to a method for the preparation of mycophenolate mofetil.
  • 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 OO 6 , 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 2-morpholinoethyl ester of MPA also known as mycophenolate mofetil (MPM, C 2 3H 31 NO 7 , CAS 128794-94-5), is a prodrug of MPA and has similar advantageous properties.
  • MPM mycophenolate mofetil
  • MPM can be prepared by esterification of MPA with 2-morpholinoethanol.
  • 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 2-morpholinoethanol.
  • EP 649,422 B1 an improved 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 represents advantages over the method as described in US 4,753,935, it still has drawbacks, one of which is the unwanted formation of color in the end product as mentioned in WO 2002/100855, a problem that is particularly pronounced in industrial-scale synthesis.
  • MPM is prepared from MPA and 2-morpholinoethanol by esterification in a refluxing solvent followed by downstream processing in the presence of a chelating agent.
  • Said chelating agent can be added before and/or during and/or after said esterification.
  • chelating agent refers to a substance whose molecules can form several bonds to a positively charged ion.
  • a chelating agent is a multidentate ligand.
  • An example of a chelating agent is ethylenediamine, a single molecule of which can form two bonds to, for instance, a transition-metal ion such as Ni 2+ .
  • Substituted derivatives of ethylenediamine can also serve as chelating agent and a well-known example that proved to be well-suited in the context of the present invention is ethylenediamine tetraacetic acid (EDTA) or a salt thereof.
  • EDTA salts are alkaline or alkaline earth metal salts such as for instance the di- or tetra sodium salt.
  • Other suitable examples of chelating agents are diamines wherein the nitrogen atoms are connected with 1-6 carbon atoms, preferably 2-4 carbon atoms and wherein the amine groups are independently substituted with formyl, acetyl, propionyl or similar substituents.
  • Another suitable chelating agent in the context of the present invention is porphine and derivatives thereof such as the porphyrins. Still other suitable chelating agents are dithiols, notably 1 ,2-dithiols such as dimercaprol (2,3-dimercapto-1-propanol).
  • the amount of chelating agent to be used is from 0.001 to 10 mmol per mol of MPA, preferably from 0.005 to 5 mmol per mol of MPA, more preferably from 0.01 to 1 mmol per mol of MPA, most preferably from 0.1 to 0.8 mmol per mol of MPA.
  • the chelating agent can be added during the esterification reaction but can preferably also be added after the esterification reaction, i.e. to the reaction mixture after a certain degree of conversion has been reached or to any of the aqueous or organic phases in which MPM is present during downstream processing and/or crystallization.
  • the solvent used for esterification of MPA can be a solvent such as benzene and substituted benzenes like ethyl benzene, mefa-xylene, orf/?o-xylene, para-xylene and toluene, chloroform, methylene chloride, ethers such as dialkyl ethers like dibutyl ether and diisopropyl ether, ketones such as acetone, cyclohexanone, cyclopentanone, dipropyl ketone, methylisobutyl ketone, methylpropyl ketone and mixtures of these solvents.
  • Preferred solvents are xylene, dibutyl ether and cyclohexanone.
  • the esterification is carried out under azeotropic separation of water and under use of an excess of 2-morpholinoethanol, for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.
  • 2-morpholinoethanol for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.
  • 2-morpholinoethanol for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.
  • esterification at a temperature below the boiling point are that equipment for condensing solvent vapors and returning these condensed vapors are no longer required and the energy input required for reaching and maintaining the boiling point, which normally is substantial, can be circumvented. Furthermore, formation of unwanted by-products generally is lower at lower reaction temperatures. Following conversion of MPA to MPM, downstream processing can be carried out, for instance by direct crystallization of the product from the reaction mixture.
  • the MPM is extracted from the reaction mixture to water at low pH and back-extracted to an organic solvent at higher pH after which crystallization is effected.
  • MPA is used in the form of a salt.
  • Suitable salts are amines and alkali metal salts.
  • an acid should be present in a molar amount that is at least equal to that of the molar amount of the MPA alkali metal salt.
  • addition of acid is not mandatory, although acid can also be added in order to decrease conversion times and/or increase yields.
  • Suitable amine salts of MPA are, but are not limited to, salts from amines such as te/t-butylamine, cyclohexylamine, dibenzylamine, N,N-di/sopropyl- ethylamine, N ⁇ -dimethylcyclohexylamine, N,N-dimethylisopropylamine, N-methyl- piperidine, morpholine, te/t-octylamine, piperidine, /so-propylamine, N,N,N',N'-tetra- methylbutylenediamine, N,N,N',N'-tetramethylethylenediamine, tributylamine, triethyl- amine and tripropylamine.
  • Suitable alkali metal salts of MPA are salts from lithium and potassium, preferably from sodium.
  • esterification of MPA can be positively influenced (Ae. reduction of reaction time, increase of maximum conversion) by the addition of substances that are capable of absorbing water.
  • substances that are capable of absorbing water can be present in the mixture of MPA, solvent and 2-morpholinoethanol.
  • these substances may also be present in the vapor phase of said mixture; despite the fact that the present invention deals with a method for esterification in non-boiling mixtures, a vapor phase nevertheless is usually present above such non-boiling mixtures.
  • Substances that are capable of absorbing water are for instance salts of alkali and earth alkali metals and usually these salts are carbonates, halides or sulfates.
  • MPM obtained according to the first aspect 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. Accordingly, said pharmaceutical compositions have the advantage that color-generating components are absent resulting in the absence of unwanted impurities but also in the absence of color.
  • HPLC analysis was performed on a Waters HPLCWIS system (Alliance HT 2795 separation module; Diode array detector, model 996) with the following specifics:
  • the chemicals are water (MiIIi-Q purified or HPLC grade), acetonitrile (ACN, gradient grade, Merck 1.00030), KH 2 PO 4 (p.a., Merck 1.04873), Na 2 HPO 4 .2H 2 O (p.a., Merck 1.06580).
  • Phosphate solution A 3.026 g of KH 2 PO 4 was dissolved in 1 L MiIIiQ water.
  • Phosphate solution B 3.9587 g of Na 2 HPO 4 .2H 2 O was dissolved in 1 L MiIIiQ water.
  • Sorensen buffer (0.022 M, pH 6.4): 700 mL phosphate solution A was mixed with 300 mL phosphate solution B.
  • the pH was adjusted to 4.2 with 4N NaOH and a purple color developed in the organic phase. After stirring for 15 min the phases were separated. The organic phase was washed with water (50 L) at pH 4.2. After stirring for 15 min the phases were separated. Water (50 L) was added to the organic phase and the pH was adjusted to 8 with 4N NaOH. After stirring for 15 min the layers were separated. Water (50 L) was added to the organic phase and the pH was adjusted to 7 with diluted H 2 SO 4 . After stirring for 15 min the phases were separated. The solution was partially decolorized with active carbon. Under stirring the extract was concentrated under vacuum to dryness.
  • the crystals were filtered off, washed with 1-propanol (21 L) of 0-5 0 C, and dried under vacuum at 40-45 0 C, giving 6.5 kg MPM as white to off-white crystals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de mycophénolate mofétil, caractérisé en ce que l'acide mycophénolique ou un sel d'amine de l'acide mycophénolique est estérifié avec du 2-morpholinoéthanol, cette estérification étant suivie d'un traitement en aval en présence d'un chélateur (formule (I)).
PCT/EP2008/058024 2007-06-29 2008-06-24 Procédé de préparation de mycophénolate mofétil Ceased WO2009003878A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1396DE2007 2007-06-29
IN1396/DEL/2007 2007-06-29
EP07115724 2007-09-05
EP07115724.2 2007-09-05

Publications (1)

Publication Number Publication Date
WO2009003878A1 true WO2009003878A1 (fr) 2009-01-08

Family

ID=39884792

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/058024 Ceased WO2009003878A1 (fr) 2007-06-29 2008-06-24 Procédé de préparation de mycophénolate mofétil

Country Status (1)

Country Link
WO (1) WO2009003878A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265514A (zh) * 2013-06-08 2013-08-28 重庆理工大学 一种制备吗替麦考酚酯的方法
CN103755671A (zh) * 2014-01-29 2014-04-30 江苏九阳生物制药有限公司 一种去除吗替麦考酚酯和麦考酚酸料液紫色的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5247083A (en) * 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
WO2002100855A1 (fr) * 2001-06-08 2002-12-19 Ivax Corporation Methode de preparation de mofetilmycophenolate
CN1772745A (zh) * 2005-10-18 2006-05-17 深圳市东阳光实业发展有限公司 一种霉酚酸莫啡酯的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5247083A (en) * 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
WO2002100855A1 (fr) * 2001-06-08 2002-12-19 Ivax Corporation Methode de preparation de mofetilmycophenolate
CN1772745A (zh) * 2005-10-18 2006-05-17 深圳市东阳光实业发展有限公司 一种霉酚酸莫啡酯的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARMAN ET AL: "Derivatives of Mycophenolic Acid", AUSTRALIAN JOURNAL OF CHEMISTRY, no. 31, 1978, pages 353 - 364, XP002075178, ISSN: 0004-9425 *
DATABASE WPI Week 200682, Derwent World Patents Index; AN 2006-799131, XP002454114 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265514A (zh) * 2013-06-08 2013-08-28 重庆理工大学 一种制备吗替麦考酚酯的方法
CN103265514B (zh) * 2013-06-08 2016-01-13 重庆理工大学 一种制备吗替麦考酚酯的方法
CN103755671A (zh) * 2014-01-29 2014-04-30 江苏九阳生物制药有限公司 一种去除吗替麦考酚酯和麦考酚酸料液紫色的方法

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