WO2004089946A1 - Synthese de mycophenolate-mofetil par irradiation par micro-ondes - Google Patents

Synthese de mycophenolate-mofetil par irradiation par micro-ondes Download PDF

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Publication number
WO2004089946A1
WO2004089946A1 PCT/IN2003/000143 IN0300143W WO2004089946A1 WO 2004089946 A1 WO2004089946 A1 WO 2004089946A1 IN 0300143 W IN0300143 W IN 0300143W WO 2004089946 A1 WO2004089946 A1 WO 2004089946A1
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WO
WIPO (PCT)
Prior art keywords
synthesis
acid
solvent
catalyst
carried out
Prior art date
Application number
PCT/IN2003/000143
Other languages
English (en)
Inventor
Laxmi Adhikary
Shrikumar Suryanarayan
Original Assignee
Biocon Limited
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 Biocon Limited filed Critical Biocon Limited
Priority to AU2003231924A priority Critical patent/AU2003231924A1/en
Priority to PCT/IN2003/000143 priority patent/WO2004089946A1/fr
Publication of WO2004089946A1 publication Critical patent/WO2004089946A1/fr

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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

  • This invention relates to a method for chemical synthesis of mycophenolate mofetil (MMF) using microwave. More particularly, the present invention relates to a process for synthesis of MMF by reacting mycophenolic acid (MPA) and 2-hydroxy ethyl morpholine (HEM) under microwave irradiation.
  • MPA mycophenolic acid
  • HEM 2-hydroxy ethyl morpholine
  • MMF is the morpholino ethyl derivative of MPA.
  • MMF is an immunosuppressant. It is derived from MPA, which was isolated from a fungus and chemically modified to improve oral absorption. MMF is used as an immunosuppressive agent, anti- inflammatory, anti-tumor and anti-viral agent.
  • WO 00/34503 discloses biochemical synthesis of MMF as well as chemical synthesis of MMF without the use of catalyst and a third solvent, but the synthesis takes a long time i.e. in hours or days to completion.
  • MMF which gives purer product with high yields in less time and wherein the reactants, reagents, catalyst and support material are recycled resulting in economy of the cost.
  • Use of high concentrations of reactants also increases the economy of the cost per batch.
  • Microwave ovens have been utilized for rapid heating domestically for several years, it is only recently that their use for batch-wise organic synthesis has been reported. It has been demonstrated that microwave heating can provide a means for dramatically increasing the rate of reactions.
  • US 3,535,482 discloses microwave apparatus for rapidly heating fluids, namely foods such as fruit juice, soup, puree, etc. for blanching, concentrating, pasteurization and sterilization.
  • GB 1 425 624 discloses chemical modification of starch which is carried out by subjecting a mixture of starch and modifying agents to microwave energy such that the water content during radiation is ⁇ 10 wt. % of the starch, or is reduced to this value.
  • US 4,599,365 discloses preparation of polyimide foam by (a) reacting an aromatic di-anhydride with an oximine in a mole ratio of
  • (1I): of 0.05-1.5:1 (x 2-4) to form an N-substituted aliphatic imide; (b) dissolving the imide in a reactive solvent esterifying agent; (c) adding a diamine to the esterified imide; (d) drying the resulting solution.; and (e) exposing the material to microwave energy at a level of 5-80 KW, pref. at an optimum level of 10 KW for 10 min to spontaneously foam and cure the material.
  • WO 92/19390 discloses production of an adhesive mass composition
  • an adhesive mass composition comprising reacting by microwave heating of (pref. 5-50 wt. %) of a first component of a copolymer of formula ( with (pref. 5-50 wt. %) of a second component comprising a hydroxylated compound capable of hydrolyzing or esterifying the first component in the presence of water and optionally a surfactant.
  • GB 2 361 918 discloses activation of mono- and bi-saccharides and hydrolysis of triglycerides contained in natural chemical substances, which involves irradiating the substances with microwaves. The reactions are performed in absence of solvent. There are no reports on synthesis of MMF using microwave.
  • the process of instant invention is advantageous in following ways a) very less synthesis time e.g. in minutes to a few hours, b) eco- friendly process c) economic process d) non-corrosive process e) pure product and f) high yields.
  • the present invention provides a process for the synthesis of MMF (FORMULA I).
  • FORMULA I Said process comprises treating the MPA and HEM in a solvent or solvent free system under the microwave radiation in the absence or presence of a catalyst and a support.
  • the said process comprises a) treating MPA and HEM in a solvent or solvent free system b) optionally, treating mixture of MPA and HEM with a catalyst c) optionally, treating MPA and HEM with a solid support DETAILED DESCRIPTION OF THE INVENTION
  • This invention relates to a process of preparation of MMF by treating MPA and HEM under microwave irradiation.
  • MMF is synthesized by treatment of MPA with HEM in absence or presence of solvent system in absence or presence of catalyst and solid support.
  • the synthesis is carried out in a solvent system.
  • the solvent used is anhydrous.
  • the solvent used is a mixture of solvents.
  • the solvent is selected from a group comprising C 2 to C 12 hydrocarbon, aliphatic or cyclic or heterocyclic solvents.
  • the solvent is selected from one or more among benzene, toluene,, xylene, hexane, pentane, heptane, or pyridine.
  • the synthesis is carried out in solvent free system.
  • the catalyst used is acidic.
  • the catalyst is selected from a group comprising mineral acid, carboxylic acid, and phenol.
  • the catalyst is selected from a group comprising hydrochloric acid, sulphuric acid, nitric acid, sulphonic acid, phosphoric acid or derivatives thereof.
  • the support used is selected from a group comprising diatomaceous earth, polymeric material or carbon.
  • the support is selected from a group comprising bentonite, zeolite, silica, charcoal, carbon or Montmorrillonite.
  • the synthesis is carried out for a time period between 1 to 600 minutes.
  • the yields of the synthesis were higher than yields of a synthesis without solvent system.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de synthèse d'un composé correspondant à la formule (I), lequel fait appel à une irradiation par micro-ondes.
PCT/IN2003/000143 2003-04-07 2003-04-07 Synthese de mycophenolate-mofetil par irradiation par micro-ondes WO2004089946A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003231924A AU2003231924A1 (en) 2003-04-07 2003-04-07 Microwave synthesis of mycophenolate
PCT/IN2003/000143 WO2004089946A1 (fr) 2003-04-07 2003-04-07 Synthese de mycophenolate-mofetil par irradiation par micro-ondes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000143 WO2004089946A1 (fr) 2003-04-07 2003-04-07 Synthese de mycophenolate-mofetil par irradiation par micro-ondes

Publications (1)

Publication Number Publication Date
WO2004089946A1 true WO2004089946A1 (fr) 2004-10-21

Family

ID=33156188

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000143 WO2004089946A1 (fr) 2003-04-07 2003-04-07 Synthese de mycophenolate-mofetil par irradiation par micro-ondes

Country Status (2)

Country Link
AU (1) AU2003231924A1 (fr)
WO (1) WO2004089946A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010503A1 (fr) * 2007-07-18 2009-01-22 Dsm Ip Assets B.V. Recyclage d'acide mycophénolique dans un procédé de préparation de mycophénolate mofétil

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599365A (en) * 1983-12-27 1986-07-08 John Gagliani Foaming and curing polyimide resins by application of microwave energy
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
WO1992019390A1 (fr) * 1991-04-26 1992-11-12 Isp Investments Inc. Procede en continu permettant de produire des compositions de pâte adhesive autocollante et articles produits avec ce procede

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599365A (en) * 1983-12-27 1986-07-08 John Gagliani Foaming and curing polyimide resins by application of microwave energy
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
WO1992019390A1 (fr) * 1991-04-26 1992-11-12 Isp Investments Inc. Procede en continu permettant de produire des compositions de pâte adhesive autocollante et articles produits avec ce procede

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010503A1 (fr) * 2007-07-18 2009-01-22 Dsm Ip Assets B.V. Recyclage d'acide mycophénolique dans un procédé de préparation de mycophénolate mofétil

Also Published As

Publication number Publication date
AU2003231924A1 (en) 2004-11-01

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