WO2019138299A1 - Procédé amélioré pour la préparation de micafungine sodique - Google Patents

Procédé amélioré pour la préparation de micafungine sodique Download PDF

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Publication number
WO2019138299A1
WO2019138299A1 PCT/IB2019/050016 IB2019050016W WO2019138299A1 WO 2019138299 A1 WO2019138299 A1 WO 2019138299A1 IB 2019050016 W IB2019050016 W IB 2019050016W WO 2019138299 A1 WO2019138299 A1 WO 2019138299A1
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WIPO (PCT)
Prior art keywords
sodium
micafungin
compound
formula
salt
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Application number
PCT/IB2019/050016
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English (en)
Inventor
William Wiffen Jonathan
Roy DIPAK KUMAR
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Aurozymes
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.)
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Publication date
Application filed by Aurozymes filed Critical Aurozymes
Publication of WO2019138299A1 publication Critical patent/WO2019138299A1/fr
Priority to ZA2021/05263A priority Critical patent/ZA202105263B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the present invention relates to an improved process for the preparation of Micafungin sodium of a Structural Compound of Formula (I).
  • Micafungin sodium is chemically known as Pneumocandin AO, l-[(4R,5R)- 4,5-dihydroxy-N2-[4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl]-Lornithine]-4- [(4S)-4-hydroxy-4-[4-hydroxy-3-(sulfooxy)phenyl]-L-threonine]-, monosodium salt.
  • Micafungin sodium is a light-sensitive, hygroscopic white powder that is freely soluble in water, isotonic sodium chloride solution, N,N-dimethylformamide and dimethylsulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane.
  • Micafungin sodium is a semisynthetic lipopeptide (echinocandin) synthesized by a chemical modification of a fermentation product of Coleophoma empetri F- 11899. Micafungin inhibits the synthesis of 1, 3-beta-D-glucan, an integral component of the fungal cell wall.
  • Micafungin sodium is marketed under the brand name MYCAMINE ® .
  • Micafungin sodium is an echinocandin indicated in adult and pediatric patients 4 months and older for the Treatment of Patients with Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses.
  • Micafungin sodium (I) was disclosed first time in US 6107458. This patent reported a process of Micafungin sodium from a natural product of FR-901379 (Compound of Formula III) isolated from the fungus Coleophoma empetri F- 11899. By removing the N-acyl group side chain of precursor FR-901379 through an enzymatic deacylation to obtain a Compound of Formula II (FR- 179642). The Compound of Formula II is further reacted with 4-[5-(4-Pentyloxyphenyl)isoxazolyl- 3-yl]benzoic acid (Compound of Formula IV) or its reactive derivative to obtain Micafungin
  • US 7,199,248 also discloses variant process for the preparation of Micafungin sodium (I).
  • the process involves condensing FR- 179642 (II) with l-[4-[5-(4- Pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole-3-oxide (HOBT-Isoxazole adduct) (V) in the presence of DIPEA (N,N-Diisopropylethylamine) and N,N- Dimethylformamide (DMF) to obtain Micafungin DIPEA salt. Later conversion of Micafungin DIPEA salt to Micafungin sodium using aqueous sodium hydroxide.
  • DIPEA N,N-Diisopropylethylamine
  • DMF N,N- Dimethylformamide
  • US‘248 discloses a process wherein a crude DIPEA salt of Micafungin is purified by filtration and chromatographic separation using a regenerated g Alumina in a 1350-L column and eluting Micafungin DIPEA with methanol.
  • the Micafungin containing fraction is further purified using ion exchange resin UBK510L.
  • Sodium salt of micafungin was prepared by treatment of aqueous sodium hydroxide followed by precipitation using acetone and ethyl acetate mixture. Inventors found that, the above reported methods for obtaining the sodium salt by using aqueous sodium hydroxide which is a strong base. It is difficult to control the pH value of the product using said method.
  • the process involves condensing FR-179642 (II) with 4-[5-(4-Pentyloxyphenyl)isoxazolyl-3-yl]benzoic acid of a Compound of Formula IV in the presence of TEA (Triethylamine), pivalic acid chloride and DMF to obtain Micafungin TEA salt. Conversion of Micafungin TEA salt to Micafungin sodium using ion exchange resin (CG 120 I; counter ion sodium).
  • TEA Triethylamine
  • ion exchange resin CG 120 I; counter ion sodium
  • miceafungin sodium (1) res ‘ n Micafungin TEA salt
  • the process require ion exchange column to prepare sodium salt using a mixture of organic and aqueous eluent. Yield of the process is low.
  • US 9,115,177 reported a method for the preparation of Micafungin sodium, wherein said method comprises: mixing a weak base solution with a water solution containing Micafungin or a mixture solution of water and organic solvent(s) containing Micafungin to obtain Micafungin sodium, wherein said weak base is selected from the group consisting of disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, sodium butyrate, sodium isobutyrate, sodium tartrate, sodium oxalate, sodium benzoate, sodium sorbate, sodium malate, monosodium succinate, disodium succinate, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium borate, sodium sulfite or sodium hydrosulfide.
  • said weak base is selected from the group consisting of disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, sodium butyrate, sodium isobutyrate, sodium tartrate, sodium oxalate, sodium benzoate, sodium sorbate
  • IN 201621007136 reported a process for the preparation of Micafungin sodium, the process comprises: treating sodium source with one or more solvents to obtain a mixture, reacting the obtained mixture with FR- 179642 and a compound of Formula V in one or more solvents, wherein said sodium source is selected from one or more of disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, sodium butyrate, sodium isobutyrate, sodium tartrate, sodium oxalate, sodium benzoate, sodium sorbate, sodium malate, monosodium succinate, disodium succinate, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium borate, sodium sulfite or sodium hydrosulfide.
  • said sodium source is selected from one or more of disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, sodium butyrate, sodium isobutyrate, sodium tartrate, sodium oxalate, sodium benzoate, sodium sorbate, sodium malate, monos
  • the main objective of the present invention is to provide a simple and cost effective process for the preparation of Micafungin sodium (I) with high purity and good yield on commercial scale.
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • step (b) optionally adding a base to the step (a) to obtain base addition salt of a Compound of formula (la);
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • Micafungin of a compound of formula la or a salt thereof is specifically base addition salts.
  • the base is organic base such as tri(lower)alkylamine (e.g., N,N-diisopropylethylamine, triethylamine etc.), pyridine, di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.) N,N- di(lower)alkylbenzylamine, or the like.
  • the base is preferably N,N-diisopropylethylamine
  • base addition salt is preferably Micafungin DIPEA salt.
  • longer chain fatty acid sodium salt is selected from the group consisting of Sodium hexanoate, sodium decanoate or Sodium oleate or Sodium palmitate or Sodium stearate. In still another embodiment, the longer chain fatty acid sodium salt is preferably sodium decanoate.
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • longer chain fatty acid sodium salts is selected from the group consisting of Sodium hexanoate, sodium decanoate or Sodium oleate or Sodium palmitate or Sodium stearate.
  • the longer chain fatty acid sodium salt is preferably sodium decanoate.
  • reaction is usually carried out in the presence of an organic solvent or mixture of organic solvents.
  • This organic solvent is alcohol (e.g. methanol, ethanol, propanol, etc.), ether (diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE)), N,N- dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, l,2-dimethoxy ethane, dioxane, ethyl acetate, etc., or the mixture thereof.
  • the long chain fatty acid salt comprises sodium decanoate in non-aqueous solvent media like methanol. Unreacted fatty acid sodium salt can be washed out using less polar organic solvent without losing Micafungin sodium.
  • Micafungin before treating with fatty acid sodium salt, Micafungin is treated with sulphonic acid resin.
  • sulphonic acid resin selected from DIAION SK104H.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the temperature is preferably 10 to 50° C., and more preferably 5 to 10° C for a time period of 1-5 hours.
  • One advantage of using sodium salt of long chain fatty acid is that unreacted fatty acid sodium salt can be washed out using less polar organic solvent in which micafungin sodium is insoluble thereby avoiding the loss of product during washing.
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • R is hydrogen or protecting group
  • Compound of formula (II) is obtained by removing the N-acyl group side chain of precursor Compound of Formula III (FR- 90139) through an enzymatic deacylation.
  • FR-901379 is a natural product isolated from the fungus Coleophoma empetri F-l 1899.
  • R is selected from hydrogen or suitable reactive derivative at the carboxy group is an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1 -hydroxy- lH-benzotriazole (HOBt).
  • the reactive derivative of Isoxazole carboxylic acid of a Compound of formula (VI) is HOBt Isoxazole adduct of a Compound of formula (V).
  • reaction of a Compound of Formula (II) with Compound of formula (VI) i.e, step (a) and step (b) is carried out in the presence of a base and a solvent.
  • the base is organic base such as tri(lower)alkylamine (e.g., N,N-diisopropylethylamine, triethylamine etc.), pyridine, di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.) N,N-di(lower)alkyl benzylamine, or the like.
  • organic base such as tri(lower)alkylamine (e.g., N,N-diisopropylethylamine, triethylamine etc.), pyridine, di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.) N,N-di(lower)alkyl benzylamine, or the like.
  • the base is preferably N,N-diisopropylethylamine
  • the solvent used in the reaction step comprises polar aprotic solvent or non-polar solvents and/or mixtures thereof.
  • polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone and/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, l,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2C12) and/or mixtures thereof.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • acetonitrile acetone
  • ethyl acetate N-methylpyrrolidone and/or mixtures thereof
  • non-polar solvents comprises hexane, benzene, toluene, l,4-dioxane, chloroform, diethyl ether, m
  • the solvent is preferably N,N-dimethylformamide
  • reaction (DMF).
  • the reaction is usually carried out at low temperature or room temperature.
  • the temperature is preferably -10 to lO°C, and more preferably -5 to 0°C.
  • the compound obtained by the process of the present invention can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, reprecipitation or the like.
  • a conventional method such as pulverization, recrystallization, column-chromatography, reprecipitation or the like.
  • treating Micafungin or its base addition salt obtained in Step (a) or Step (b) with longer chain fatty acid sodium salts can be administered in Step (a) or Step (b) with longer chain fatty acid sodium salts.
  • longer chain fatty acid sodium salts is selected from the group consisting of Sodium hexanoate, sodium decanoate or Sodium oleate or Sodium palmitate or Sodium stearate. In still another embodiment, the longer chain fatty acid sodium salts is preferably sodium decanoate.
  • miceafungin before treating with fatty acid sodium salt, Micafungin is treated with sulphonic acid resin selected from DIAION SK104H.
  • sulphonic acid resin selected from DIAION SK104H.
  • inventors are using long chain fatty acid salt like sodium decanoate in non-aqueous solvent like methanol. Unreacted fatty acid sodium salt can be washed out using less polar organic solvent without losing Micafungin sodium.
  • the present invention provides an improved process for the preparation of Micafungin sodium of a Compound of Formula (I):
  • Step (b) treating Micafungin DIPEA salt obtained in Step (a) with resin followed by longer chain fatty acid sodium salts, selected from sodium decanoate;
  • reaction of a Compound of Formula (II) with Compound of formula (V) in step (a) is carried out in the presence of a base selected from DIPEA and a solvent.
  • a base selected from DIPEA and a solvent.
  • inventors are using long chain fatty acid salt like sodium decanoate in non-aqueous solvent like methanol. Unreacted fatty acid sodium salt can be washed out using less polar organic solvent without losing Micafungin sodium.
  • Compound (I) is isolated by conventional methods such as by removing the solvent under reduced pressure.
  • Compound (I) is optionally purified by conventional methods.
  • purification is carried out by crystallization using a solvent or mixture of solvents.
  • the inventors have repeated the method reported in US 7,199,248 for multiple times and analyzed and validated the reported method from the point of view of local pH value.
  • the inventors have found that during the course of pH adjusting, regarding the whole solution system, 0.1 mol/L NaOH solution has a relatively low concentration and the overall pH value can be managed at 6-8, however, during the course of adding NaOH solution dropwise, the local base concentration gets too high, i.e. local pH value in the solution gets overly high, therefore, partial degradation occurred in Micafungin.
  • the inventors have conducted further and intensive researches and have unexpectedly found that by using fatty acid sodium salt in an organic media, the compound of formula I (Micafungin sodium) can be obtained with higher yield and without generating any additional impurities.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 5-micafungine sodique d'un composé de formule (I), par traitement de micafungine ou de son sel d'addition de base avec un sel de sodium d'acide gras à chaîne plus longue. ON OHO OHOHO N H HH N 3CH3CH N N O O2O HNOHO HO NH O CH3H N Formule I O N OHHOOOH. NaHO3SOOH
PCT/IB2019/050016 2018-01-09 2019-01-02 Procédé amélioré pour la préparation de micafungine sodique WO2019138299A1 (fr)

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ZA2021/05263A ZA202105263B (en) 2018-01-09 2021-07-26 A lighting system and method of use thereof

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IN201841000938 2018-01-09
IN201841000938 2018-01-09

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199248B2 (en) * 2002-08-08 2007-04-03 Astellas Pharma Inc. Process
WO2016056023A2 (fr) * 2014-10-07 2016-04-14 Alaparthi Lakshmi Prasad Produits intermédiaires et procédés de préparation de micafungine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199248B2 (en) * 2002-08-08 2007-04-03 Astellas Pharma Inc. Process
WO2016056023A2 (fr) * 2014-10-07 2016-04-14 Alaparthi Lakshmi Prasad Produits intermédiaires et procédés de préparation de micafungine

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