WO1998026085A1 - Procedes de fabrication de vancomycine - Google Patents

Procedes de fabrication de vancomycine Download PDF

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Publication number
WO1998026085A1
WO1998026085A1 PCT/JP1997/004460 JP9704460W WO9826085A1 WO 1998026085 A1 WO1998026085 A1 WO 1998026085A1 JP 9704460 W JP9704460 W JP 9704460W WO 9826085 A1 WO9826085 A1 WO 9826085A1
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WIPO (PCT)
Prior art keywords
vancomycin
solution
phenol
resin
passed
Prior art date
Application number
PCT/JP1997/004460
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English (en)
Japanese (ja)
Inventor
Hiroaki Nishiyama
Hajime Asada
Original Assignee
Nippon Kayaku Kabushiki Kaisha
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 Nippon Kayaku Kabushiki Kaisha filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO1998026085A1 publication Critical patent/WO1998026085A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin

Definitions

  • the present invention relates to a method for decolorizing vancomycin, which comprises bringing vancomycin into contact with a phenol-based adsorption resin.
  • Noncomimycin is a glycopeptide antibiotic produced in fermentation broth by Nocardia orientalis (see, for example, US Pat. 7 0 9 9). Purification of vancomycin from fermentation broth is carried out by first adsorbing and recovering vancomycin from the fermentation filtrate using an ion exchange resin or the like, then crystallizing the free base, and if necessary It is common practice to perform chromatography, and finally decolorize with activated carbon and then separate as a hydrochloride.
  • Activated carbon is generally used for decolorization of koncomisin, and its purpose is to remove impurities including dyes coming from the fermentation broth. It is generally said that activated carbon is neutral to weakly acidic and has the highest decolorization ability, but this liquid property has a good decolorization rate.Bancomycin is also adsorbed and the recovery rate decreases. (See Reference Example 1). On the other hand, if the treatment is performed with more acidic or basic to improve the recovery, the recovery rate is better, but the decolorization ability decreases. (See Reference Examples 2 and 3.) Therefore, the desired degree of decolorization cannot be achieved without increasing the amount of activated carbon used.
  • a method for producing vancomycin comprising a step of contacting an aqueous solution containing vancomycin with a phenol-based adsorption resin.
  • the phenolic adsorption resin has a pore size of 15 to 35 nm and a pore volume of 0.9 to 1.6 ml / g. Manufacturing method described in,
  • the vancomycin aqueous solution passed through the phenol-based adsorption resin is passed through the phenol-based adsorption resin again to allow the vancomycin to pass through, or adsorb and elute.
  • the phenol-based adsorption resin is a macroporous adsorption resin having a crosslinked structure composed of a phenol-formalin condensate and having a bore of 15 to 15 mm. Those having 35 nm and a pore volume of 0.9 to 1.6 mLZg are preferred.
  • the trademark is Amber X (Amb er 1 ite) X AD-716, which is a trademark of Rohm and Haas Company of the United States and supplied by Sumitomo Chemical Co., Ltd. in Japan.
  • This resin was previously known as Duolite S-30, Duolite S-761, and Duolite XAD-761. is there.
  • phenolic adsorption resins are easy to adsorb and desorb, unlike activated carbon, and can be used repeatedly by regeneration.
  • Styrene vinylbenzene-based adsorption resin which is currently the most commonly used adsorption resin, is an acidic or alkaline water in which the regenerant contains 50% (V / V) or more of an organic solvent.
  • the phenol-based adsorption resin can be regenerated with acid or alkali that does not contain any organic solvent.
  • the present invention there are two methods for decolorizing vancomycin using a phenol-based adsorption resin.
  • One method is to pass the vancomycin solution through a cellulose-based adsorption resin packed in a column, and obtain the passing solution as a decolorizing solution.
  • the other is to allow the vancomycin solution to pass through a phenol-based adsorption resin packed in a column, adsorb the vancomycin, and elute with an appropriate eluent. Is obtained as a decolorizing solution.
  • the pH of the bancomicin solution is adjusted to 3.0 to 5.0, preferably to pH 3.5 to 4.5.
  • the concentration of vancomycin at this time is 3 to 15 g / L, and preferably 6 to 12 g / L.
  • the transit velocity is between 1.0 and 3.0, preferably between 1.5 and 2.5.
  • the degree of coloration of the koncomicin solution is 45 O nm absorption per vancomycin concentration (gZ liter).
  • Evaluate by luminosity hereinafter abbreviated as AZC
  • This method is effective for specifically adsorbing and removing impurities that cannot be removed by the method for obtaining an eluate described below.
  • the pH of the vancomycin solution adjusts the pH of the vancomycin solution to 7.0 to 8.5, preferably 7.5 to 8.0.
  • the concentration of vancomycin at this time is 3 to 15 g ZL, preferably 5 to 11 g ZL.
  • SV space Ve1ocity 2.0.
  • the lower alcohols include, but are not limited to, methanol, ethanol, proso, 'nor' and isopopen, but in the present application, methanol is preferred.
  • hydrochloric acid contains 10% of methanol, 50% to 50%, preferably 25 to 35% (V / V), and has a pH of 1.0 to 3.0, preferably 5 to 2%.
  • V / V the pH of 1.0 to 3.0
  • elution rate is from 0.3 to 0.7 spacevelosity (SV).
  • Dye removal rates range from 90 to 95%.
  • the recovery rate of corn mycin ranges from 85 to 95%. This method is Not only color but also desalting, it can be used in place of other adsorption resins.
  • vancomycin is obtained through a step such as concentration, preferably as a hydrochloride.
  • the vancomycin aqueous solution to be brought into contact with the phenol-based adsorption resin is prepared by adjusting the pH of the vancomycin aqueous solution containing urea to near the isoelectric point. It is preferably a solution in which a precipitate obtained by crystallizing vancomycin is dissolved.
  • aqueous vancomycin solution containing urea The pH of aqueous vancomycin solution containing urea is adjusted to near the isoelectric point to crystallize noncomicin as follows.
  • the acid or base used for pH adjustment is preferably hydrochloric acid or sulfuric acid, and the base is preferably sodium hydroxide or ammonia. If the stirring is continued after the pH adjustment, precipitation (vancomycin base) occurs for a while. Crystallization recoveries range from 91 to 98%.
  • the sediment is collected from this batch using a centrifuge or a press filter.
  • This precipitate is filtered at a reasonable speed with a filter cloth (twill weave) with an air permeability (cc / min / cm 2 ) of around 100, which is used when filtering a precipitate that is not crystalline. It is possible.
  • the collected precipitate is dissolved, and the above-mentioned crystallization method is repeated to further purify vancomycin. You can also get it.
  • the solution of the precipitate obtained is passed through a phenol-based adsorption resin, for example, Amberlite (Ambrer1ite) XAD-761, or is adsorbed and eluted to decolorize.
  • a phenol-based adsorption resin for example, Amberlite (Ambrer1ite) XAD-761
  • the absorbance value (AC value) at 450 nm per vancomycin concentration (g liter) is not more than 0.005, preferably not more than 0.005. It is possible to obtain a decolorization method with an extremely low degree of coloration of vancomycin.
  • the A / C value can be obtained with a smaller degree of coloring by repeating contact with the phenol-based adsorption resin.
  • the bacterial cells were removed from the fermentation broth by using a pre-coated filter and the like to obtain a fermentation filtrate.
  • the fermentation filtrate is passed through a strongly acidic ion-exchange resin Dion PK 208 (Mitsubishi Chemical) at a load of 20 g of Bancoma Eisin ZL resin, washed with water, and washed with 0.25 N Elution was carried out with ammonia water to obtain 60 L of eluate.
  • the eluate had a vancomycin concentration of 18.2 g / L and a pH of 10.3.
  • Add 6 kg (10% W / V) of powdered urea to the eluate and dissolve. Adjust the pH to 8.3 with 6 N hydrochloric acid, keep stirring at 18 ° C for 2 hours, and filter with a press filter.
  • the concentration of vancomycin in the filtrate was 1.6 g /.
  • the recovery rate of the obtained vancomycin was 91.2%, and the HPLC purity was 94.2%.
  • the obtained nokomycin precipitate was dissolved with hydrochloric acid to obtain a solution.
  • the pigment removal rate was 87.9%.
  • Example 1 The vancomycin precipitate obtained in Example 1 was dissolved with hydrochloric acid in the same manner as in Example 1 to obtain a solution.
  • the eluate had a recovery of 93.2% and an AZC of 0.0015.
  • the pigment removal rate was 92.9%.
  • Example 1 The vancomycin precipitate obtained in Example 1 was dissolved with hydrochloric acid in the same manner as in Example 1 to obtain a solution.
  • the lysate used in Reference Example 1 was adjusted to pH 6.0.
  • AZC was 0.0173 and the concentration i 0.4 g / L.
  • This was passed through activated carbon (Shirasagi KL, Takeda Pharmaceutical Co., Ltd.) at a load of 180 g of Bancomai Shinno L resin at SV 2.0, and the passed liquid was collected.
  • the recovery rate from the solution was 48.2%, and A / C was 0.001.
  • the pigment removal rate was 99.4%.
  • a concentration of 10.4 g / A and a pH of 7.8 with a A / C 0.013 solution of the cocomicin solution at a load of 26 g
  • the solution was passed through activated carbon (Shirasagi KL, Takeda Pharmaceutical), adsorbed vancomycin, washed with water, and eluted with hydrochloric acid-acid 50% ethanol water. The recovery was 79.2% and the dye removal rate was 72.1%.
  • a vancomycin decolorizing method suitable for economical industrial production that achieves both a decolorizing effect and a good recovery rate without using activated carbon in the vancomycin production method.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Compounds Of Unknown Constitution (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne des procédés de décoloration qui sont adaptés à la production économique de vancomycine à l'échelle industrielle et qui permettent à la fois d'obtenir un bon effet décolorant et d'assurer un rendement élevé. Lesdits procédés se caractérisent par la mise en contact de la vancomycine avec des résines phénoliques adsorbantes pouvant être régénérées sans recours à aucun solvant organique; ils comprennent un procédé qui consiste à faire passer une solution acide de vancomycine à travers une résine phénolique adsorbante pour obtenir l'éluat, un autre procédé consistant à faire passer une solution faiblement alcaline de vancomycine à travers une résine phénolique adsorbante et à éluer la vancomycine ainsi absorbée dans un alcool inférieur acidifié pour obtenir l'éluat.
PCT/JP1997/004460 1996-12-11 1997-12-05 Procedes de fabrication de vancomycine WO1998026085A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/346568 1996-12-11
JP34656896 1996-12-11

Publications (1)

Publication Number Publication Date
WO1998026085A1 true WO1998026085A1 (fr) 1998-06-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7015307B2 (en) 2001-08-24 2006-03-21 Theravance, Inc. Process for purifying glycopeptide phosphonate derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57141253A (en) * 1981-01-22 1982-09-01 Lilly Co Eli Feedstuff utilizing efficiency enhancer
US4440753A (en) * 1982-03-15 1984-04-03 Eli Lilly And Company Purification of glycopeptide antibiotics using non-functional resins
EP0528117A2 (fr) * 1991-08-15 1993-02-24 American Cyanamid Company Procédé de précipitation de vancomycine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57141253A (en) * 1981-01-22 1982-09-01 Lilly Co Eli Feedstuff utilizing efficiency enhancer
US4440753A (en) * 1982-03-15 1984-04-03 Eli Lilly And Company Purification of glycopeptide antibiotics using non-functional resins
EP0528117A2 (fr) * 1991-08-15 1993-02-24 American Cyanamid Company Procédé de précipitation de vancomycine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ENCYCLOPAEDIA CHIMICA 5 (Reduced-Size Edition 30th Printing), KYORITSU SHUPPAN K.K., 1987, page 649, "Decolorizing Resin". *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7015307B2 (en) 2001-08-24 2006-03-21 Theravance, Inc. Process for purifying glycopeptide phosphonate derivatives
US7375181B2 (en) 2001-08-24 2008-05-20 Theravance, Inc. Process for purifying glycopeptide phosphonate derivatives
US7468420B2 (en) 2001-08-24 2008-12-23 Theravance, Inc. Process for purifying glycopeptide phosphonate derivatives
US7858583B2 (en) 2001-08-24 2010-12-28 Theravance, Inc. Process for purifying glycopeptide phosphonate derivatives

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