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WO2007013017A1 - Processus de purification de macrolides - Google Patents

Processus de purification de macrolides Download PDF

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Publication number
WO2007013017A1
WO2007013017A1 PCT/IB2006/052518 IB2006052518W WO2007013017A1 WO 2007013017 A1 WO2007013017 A1 WO 2007013017A1 IB 2006052518 W IB2006052518 W IB 2006052518W WO 2007013017 A1 WO2007013017 A1 WO 2007013017A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
macrolide
ether
silica gel
tacrolimus
Prior art date
Application number
PCT/IB2006/052518
Other languages
English (en)
Inventor
Parveen Kumar
Ashoke Mitra
Original Assignee
Ranbaxy Laboratories 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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2007013017A1 publication Critical patent/WO2007013017A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to purification of macrolides from analogous compounds by using silver-impregnated silica gel.
  • macrolides refers to neutral non-polyeptide macrolides, which are lactone-containing high molecular weight compounds.
  • a variety of macrolide compounds such as tacrolimus, rapamycin, ascomycin and their analogs find use as immunosuppressive agents for prevention of graft rejection in bone marrow and organ transplants and in the treatment of various auto-immune diseases.
  • Tacrolimus and its derivatives have been shown to be effective in treating a number of diseases like asthma (PCT Application WO 90/14826), inflammatory and hyperproliferative skin disease and cutaneous manifestations of immunologically-induced illness (EP 0 315 978).
  • Macrolides are usually produced by microbial fermentation whereby there is formation of analogous compounds from which the desired component has to be separated and purified.
  • the separation and purification of macrolide from analogous compounds produced by fermentation methods is often complicated as they have same or almost the same number of carbon atoms and are similar to each other in physical properties such as solubility and affinity to solvents.
  • U.S. Patent No. 4,894,366 discloses a method for production of tacrolimus by fermentation using Streptomyces species wherein tacrolimus is isolated and purified from the fermentation broth by subjecting the treated broth to silica gel column chromatography.
  • U.S. Patent No. 4,894,366 discloses a method for production of tacrolimus by fermentation using Streptomyces species wherein tacrolimus is isolated and purified from the fermentation broth by subjecting the treated broth to silica gel column chromatography.
  • 5,508,398 discloses a process for recovering a neutral macrolide antibiotic such as rapamycin from concentrates of fermentation broth extracts or mother liquors whereby acidic and/or basic components formed in the fermentation process are removed by means of aqueous base or acid extraction from a water-immiscible solution of said concentrate and non-polar components are separated from the neutral macrolide by selective solubility.
  • a neutral macrolide antibiotic such as rapamycin
  • U.S. Patent No. 5,616,595 discloses a process for recovering tacrolimus from a single apparatus from fermentation broth by tangential filtration of raw fermentation broth across a solvent-compatible porous filtration membrane.
  • U.S. Patent No. 6,492,513 discloses a method for separating a lactone-containing high molecular weight compound having an alkyl side chain from a lactone-containing high molecular weight compound having an alkenyl side chain, by using a sulphonic acid group containing cation exchange resin treated with silver ions.
  • U.S. Patent No. 6,881,341 discloses a method for separating a lactone-containing high molecular weight compound from a mixture with its analogues by adsorbing the mixture onto basic active alumina and eluting with an organic solvent to separate the compounds.
  • U.S. Patent No. 6,576,135 discloses a method for separating a macrolide from a mixture of macrolide and its analogous compounds by adsorbing the mixture onto a nonionic adsorption resin and eluting with an aqueous solvent containing silver ions, or adsorbing the mixture onto basic active alumina and eluting with an organic solvent or carrying out both the steps.
  • U.S. Patent Application No. 2004/0226501 discloses a method of crystallizing a macrolide from a macrolide starting material and from a concentrate residue from whole - broth extraction of macrolide-containing biomatter by combining the macrolide, a polar solvent like ethyl acetate, a hydrocarbon solvent like n-hexane and water and sodium hydroxide to attain a pH of 7 or above.
  • PCT Application WO 05/010015 discloses a method of purifying tacrolimus from impurities by loading onto a bed of sorption resin or a macroreticular resin and eluting with a combination of water and tetrahydrofuran.
  • PCT Application WO 05/019226 discloses a process for recovery of a macrolide by treating the macrolide with water-immiscible solvent, followed by mixing with water- miscible solvent, performing hydrophobic interaction chromatography, extracting the fraction containing macrolide with water-immiscible solvent, adding water-miscible solvent to effect separation of impurities from the macrolide compound and then performing silica gel chromatography to obtain the microlide.
  • the present inventors have found that macrolides can be purified from fermentation broth or mother liquors thereof by using silver- impregnated silica gel chromatography.
  • the present process shows unexpected efficiency in separating the macrolide from analogous compounds and enables isolation of pure macrolide.
  • the present process is easily scalable and industrially advantageous.
  • the macrolides that can be purified by the present process include, for example, lactone-containing high molecular weight compounds, for example, those having molecular weight of 400 or more. They may be monocyclic, bicyclic or tricyclic macrolides or the like. Monocyclic macrolides can include, for example, erythromycin, leucomycin, methymycins and the like. Tricyclic lactone containing compounds include, for example, those disclosed in EP 0 184 162, EP 0427 680, EP 0 532 088 or PCT Application WO 93/04680.
  • macrolides that can be purified by the present process include, but are not limited to, tacrolimus (FK-506) of Formula I, dihydro FK-506, ascomycin (FK-520), rapamycin, 32-desmethylrapamycin, immunomycin, everolimus, pimecrolimus and homologs, analogs or isomers therof.
  • Tacrolimus (FK-506) when subjected to purification by the present process was found to contain 1% or less of dihydro FK-506 and FK-520.
  • FIG. 1 Elution profile of tacrolimus (FK-506) purified from the analogous compounds FK-520 and dihydro FK-506 by silver- impregnated silica gel chromatography.
  • processes for separation of a macrolide from homologs, analogs or isomers thereof comprising: a) adsorbing a mixture comprising a macrolide onto silver-impregnated silica gel; and b) eluting the mixture of step a) using water-immiscible organic solvent.
  • the mixture comprising the macrolide along with analogs, homologs or isomers thereof used for separation of the macrolide can be the fermentation broth or mother liquors comprising the macrolide or it can be an isolated crude mixture of the macrolide obtained by the methods known in the art.
  • the mixture of macrolide and analogous compounds can be dissolved in a suitable solvent and subjected to column chromatography using silver-impregnated silica gel having a mesh size of 60-400.
  • the mixture adsorbed on the column can be successively eluted with water-immiscible organic solvent(s) at a temperature of about 10 0 C to about 30 0 C.
  • the fractions comprising the macrolide can be pooled to recover the macrolide.
  • the water-immiscible organic solvent for elution can be, for example, an aliphatic hydrocarbon, a C 2-1 O ester, a chlorinated hydrocarbon, C4-8 ethers or mixtures thereof.
  • the C 2-1 O esters can be, for example, ethyl acetate, n-propyl acetate, n-butyl acetate, iso-butyl acetate and the like or mixtures thereof.
  • Aliphatic hydrocarbons can be, for example, n-pentane, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof. Elution can also be carried out using a gradient of organic solvents.
  • Example 1 Purification of Tacrolimus (Fk-506) by Silver- Impregnated Silica Gel Chromato graphy
  • a silver-impregnated silica gel column (26 X 1.3 cm; bed volume 30 ml) was prepared in hexanes.
  • silver- impregnated silica gel (1 g) was added and concentrated under vacuum at 40 0 C.
  • hexanes (20 ml) were added and again concentrated under vacuum at 40 0 C to get a dry slurry.
  • the dry slurry was loaded onto the column at 2O 0 C at a loading of 5 g per litre of silica gel.
  • the elution was carried out with a gradient mobile phase of ethyl acetate and hexanes (100% n-hexanes 30 ml; 40% ethylacetate-60% hexanes 60 ml; 50%ethylacetate-50% hexanes 60 ml; 60%ethylacetate-40% hexanes 120 ml; 70%ethylacetate-30% hexanes 120 ml).
  • a flow rate of 1.0 bed volume per hour (0.5ml per minute) was maintained and fractions of 15 ml each were collected. The collected fractions were pooled and concentrated under vacuum at 40 0 C and the residue so obtained was crystallized from diisopropyl ether to afford the title compound.
  • Purity 96% by HPLC FK-520 and Dihydro FK506 content: ⁇ 1.0 % by HPLC Elution profile as in Figure 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne un processus de séparation d'un macrolide d'un mélange comprenant des homologues, des analogues ou des isomères de celui-ci via l'utilisation d'une chromatographie sur gel de silice imprégné d'argent.
PCT/IB2006/052518 2005-07-29 2006-07-21 Processus de purification de macrolides WO2007013017A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2016DE2005 2005-07-29
IN2016/DEL/2005 2005-07-29

Publications (1)

Publication Number Publication Date
WO2007013017A1 true WO2007013017A1 (fr) 2007-02-01

Family

ID=37441959

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/052518 WO2007013017A1 (fr) 2005-07-29 2006-07-21 Processus de purification de macrolides

Country Status (1)

Country Link
WO (1) WO2007013017A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007106587A3 (fr) * 2006-03-15 2008-01-17 Teva Gyogyszergyar Zartkoruen Procede de purification de tacrolimus
CN108929335A (zh) * 2018-08-31 2018-12-04 福建省微生物研究所 一种他克莫司粗晶的制备方法
CN114516884A (zh) * 2022-01-05 2022-05-20 福建省微生物研究所 一种高纯度他克莫司的提纯方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) * 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
WO2000071546A1 (fr) * 1999-05-25 2000-11-30 Fujisawa Pharmaceutical Co., Ltd. Procede de separation de composes organiques analogues
WO2001018007A2 (fr) * 1999-09-08 2001-03-15 Fujisawa Pharmaceutical Co., Ltd. Technique de separation de composes de poids moleculaire eleve contenant de la lactone
WO2005019226A1 (fr) * 2003-08-26 2005-03-03 Biocon Limited Processus de recuperation d'un macrolide tricyclique pratiquement pur
WO2005054253A1 (fr) * 2003-12-05 2005-06-16 Biocon Limited Procede de purification de macrolides
WO2005098011A1 (fr) * 2004-04-12 2005-10-20 Biocon Limited Procede de production de macrolides au moyen d'une nouvelle souche de streptomyces espece bicc 7752
WO2006048145A1 (fr) * 2004-11-03 2006-05-11 Antibioticos S.P.A. Procede de purification de tacrolimus

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184162A2 (fr) * 1984-12-03 1986-06-11 Fujisawa Pharmaceutical Co., Ltd. Composés tricycliques, procédé pour leur préparation et composition pharmaceutique les contenant
WO2000071546A1 (fr) * 1999-05-25 2000-11-30 Fujisawa Pharmaceutical Co., Ltd. Procede de separation de composes organiques analogues
WO2001018007A2 (fr) * 1999-09-08 2001-03-15 Fujisawa Pharmaceutical Co., Ltd. Technique de separation de composes de poids moleculaire eleve contenant de la lactone
US6576135B1 (en) * 1999-09-08 2003-06-10 Fujisawa Pharmaceutical Co., Ltd. Method for separating lactone-containing high-molecular weight compounds
WO2005019226A1 (fr) * 2003-08-26 2005-03-03 Biocon Limited Processus de recuperation d'un macrolide tricyclique pratiquement pur
WO2005054253A1 (fr) * 2003-12-05 2005-06-16 Biocon Limited Procede de purification de macrolides
WO2005098011A1 (fr) * 2004-04-12 2005-10-20 Biocon Limited Procede de production de macrolides au moyen d'une nouvelle souche de streptomyces espece bicc 7752
WO2006048145A1 (fr) * 2004-11-03 2006-05-11 Antibioticos S.P.A. Procede de purification de tacrolimus

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007106587A3 (fr) * 2006-03-15 2008-01-17 Teva Gyogyszergyar Zartkoruen Procede de purification de tacrolimus
CN108929335A (zh) * 2018-08-31 2018-12-04 福建省微生物研究所 一种他克莫司粗晶的制备方法
CN114516884A (zh) * 2022-01-05 2022-05-20 福建省微生物研究所 一种高纯度他克莫司的提纯方法
CN114516884B (zh) * 2022-01-05 2024-03-19 福建省微生物研究所 一种高纯度他克莫司的提纯方法

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