WO1994012504A1 - Procede pour purifier de l'acide 7-aminocephalosporanique - Google Patents

Procede pour purifier de l'acide 7-aminocephalosporanique Download PDF

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Publication number
WO1994012504A1
WO1994012504A1 PCT/JP1993/001734 JP9301734W WO9412504A1 WO 1994012504 A1 WO1994012504 A1 WO 1994012504A1 JP 9301734 W JP9301734 W JP 9301734W WO 9412504 A1 WO9412504 A1 WO 9412504A1
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WO
WIPO (PCT)
Prior art keywords
acid
aca
styrene
exchange resin
type
Prior art date
Application number
PCT/JP1993/001734
Other languages
English (en)
Japanese (ja)
Inventor
Katsushi Asai
Fumihiko Nakamura
Tomio Miyawaki
Katsuhiko Itoh
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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 Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1994012504A1 publication Critical patent/WO1994012504A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a method for purifying 7-aminophosphoronic acid (hereinafter abbreviated as 7ACA). More specifically, an aqueous solution of 7 ACA containing ⁇ -amino diapic acid as an impurity is treated with a styrene-based strong basic anion-exchange resin to obtain ⁇ -aminoadipic acid.
  • the present invention relates to a method for purifying 7 ACA, which involves removing aminoadipic acid.
  • the enzymatic cleavage of cephalosporin C includes D-amino acid oxidase and glutaryl 7 ACA (hereinafter abbreviated as GL-7AC).
  • GL-7AC glutaryl 7 ACA
  • a two-stage cleavage method using sylase is known, a single-stage cleavage method using cephalosporin C acylase has not been extensively studied. Although it has been done, it has not been industrialized yet.
  • One of the reasons for this is that it is not possible to efficiently remove ct-aminopydinoic acid, which is a by-product of the cleavage reaction solution, and produces high yields. This means that 7 ACA crystals with a purity cannot be obtained.
  • GL-7 ACA is produced from cephalosporin C by a synthetic method or an enzymatic method, and then the side chain (glutaryl acid) is produced by an acylase. ) Can be easily removed from glutaric acid only by isoelectric focusing after concentration according to a known method. Of 7 ACA is obtained. Or however, when isoelectric focusing was performed after concentration from the solution after direct cleavage reaction with cephalosporin C acylase, ct-aminodipic acid Eliminating it was associated with significant difficulties, and as a result, it was not possible to obtain high purity 7 ACA in high yield.
  • the present inventors have conducted intensive studies in order to establish a method for purifying 7ACA having a high purity at a high yield from an aqueous solution of 7ACA containing ⁇ -aminoaminodipic acid. It is very efficient if a 7 ACA aqueous solution containing ⁇ -aminoadipic acid as an impurity is treated with a styrene-based strong anion-ion exchange resin. We have surprisingly found that ⁇ -aminodipic acid can be fractionated and removed, and as a result of further research, we have completed the present invention.
  • the 7-ACA aqueous solution containing ⁇ -aminodipic acid used in the present invention cleaves cephalosporin C at the 7-position of ct monoaminodivinic acid. It is obtained by doing so.
  • a solution of Cephalosporin C in an aqueous solution of Cephalosporin C for example, pseudomonas' diminimeter N 17 Cephalosporin C acylases of Escherichia coli 6 and Espy SE83 (Microorganism Depositary No. 7649), respectively (European Patent Application Publication No. 47, respectively) Reaction liquid obtained by enzymatic digestion to generate 7 ACA using 5 6 5 2 publication and USP 4 7 7 4 1 7 9 And so on.
  • styrene-based strongly basic anion exchange resin used in the present invention include, for example, Diaion SA11A, PA306.
  • PA406 and PA408 (trademark, manufactured by Mitsubishi Kasei Co., Ltd.), Announcement IRA401 (trademark, room-and-node) Styrene-based strongly basic anion with low degree of cross-linking such as Lenox MP500 and MP500OA (trademark, manufactured by Bayer).
  • Exchange resins are listed. Also, it is preferable to use these resins in C1 type, CH3C00 type or P04 type.
  • ACA aqueous solution with a styrene-based strong basic anion-exchange resin that is, adsorption and desorption of 7 ACA by a column method or a notch method according to a conventional method.
  • the type of eluate used for ACA elution is not particularly limited.
  • a resin solution is prepared by converting it into a water solution containing the same salt as the resin type. Can be used repeatedly without.
  • Preferable examples of such an eluate include, for example, when the resin is a C1 type, a CH3COO type, and a P04 type, respectively.
  • Aqueous solutions such as salt, sodium acetate, and phosphate buffer are listed.
  • a mixed solution of an aqueous solution containing a salt and a water-miscible organic solvent as described above is mentioned.
  • the water-miscible organic solvent include methanol, ethanol, isopronole, and acetone.
  • a 7-aqueous ACA solution containing ⁇ -aminopyridinic acid as an impurity can be converted to a styrene-based strong basic anion-exchange resin.
  • a 7 ACA aqueous solution from which ⁇ -aminoaminodipic acid has been removed is required to obtain a 7 ACA aqueous solution.
  • ⁇ -Aminoadipic acid removal ratio in solution that is, the conversion of ⁇ -aminodidivic acid to 7 ACA It is preferable to set the content mole ratio to 0.3 or less, and it is most preferable to set it to 0.24 or less. Therefore, the amount of the resin is appropriately increased or decreased.
  • 7-Aminose aprosporic acid obtained by this method can be further purified into 7ACA crystals by crystallization and other operations. It can.
  • the crystallization method is as follows: a 7-ACA aqueous solution containing ⁇ -amino didipic acid from which ⁇ -amino didipic acid has been removed is applied with an isoelectric force of 3 to 4 to give an isoelectric current. Just do a spot precipitation. Further, for example, after performing a concentration operation such as concentration under reduced pressure and concentration of a reverse osmosis membrane, isoelectric point precipitation can be performed.
  • ⁇ -amino diaponic acid-containing 7 ACA aqueous solution (7 ACA concentration: 1.5 mg Z ml, ct-amino Dipynic acid concentration: 0.75 mg Z ml) was adsorbed to each resin loaded on a column (inner diameter: 2 cm, height: 30 cm), and 7 ACA Measure the concentration of 7 ACA and ⁇ -aminoadipic acid contained in the flow-through liquid when the load is 30 g of normal resin, and determine the ratio to the load liquid. are shown in Table 1.
  • the resin used for the test was Diaion ⁇ 408 (trademark, manufactured by Mitsubishi Kasei Co., Ltd.), Amberlite 1 RA401 (trademark, mouth and mouth) ⁇ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 AP 4 AP It is.
  • Resin name Resin acid, salt type 7 ACA Amino Adipi Matrix Basic leakage rate Acid leakage rate
  • the method of the present invention has a remarkably superior ability to fractionate and purify ACA and ct-aminodiadipic acid compared to other methods. And became illuminated.
  • Cephalosporin C sodium aqueous solution (5.0 mg / m) 2 Add 2 liters of pseudomonas' dimminator N176 Add cephalosporin C acylase to a concentration of 2 mg / m1, and add sodium hydroxide aqueous solution at pH 8.5--9 at 25 ° C. The mixture was stirred for 1 hour under 0 control. After completion of the reaction, the cephalosporin acylase was removed quickly using an ultrafiltration membrane (molecular weight cut-off: 600,000), and 7 ACA and -amino Four liters of an aqueous solution containing adipic acid in an equimolar amount were obtained as an ultrafiltration solution.
  • an ultrafiltration membrane molecular weight cut-off: 600,000
  • Cephalosporin C sodium aqueous solution (5.0 mg / m 1) Same as Example 1 in two liters of Cephalosporin C acylase Was adjusted to 2 mg / m 1, and the mixture was stirred at 25 ° C with an aqueous sodium hydroxide solution under PH 8.5 control for 1 hour. After the reaction is completed, the cephalosporin C acylase is quickly removed using an ultrafiltration membrane (molecular weight cut-off: 600,000), and the ultrafiltration membrane and the permeated liquid are separated. I got it.
  • an ultrafiltration membrane molecular weight cut-off: 600,000
  • the eluted activity (540 ml) was adjusted to pH 3.5 with 17.5% hydrochloric acid with stirring to precipitate 7 ACA. After allowing to stand for 2 hours under cooling, the mixture was separated and dried under vacuum to obtain 5.0 g of crystals having a purity of 7 ACA of 90% and containing no ⁇ -aminodipic acid.
  • Cephalosporin C sodium aqueous solution (5.0 mg / m1) 2 liters of the same Cephalosporin C acylase as in Example 1 was added to a concentration of 2 mg / m 1, and the mixture was stirred with sodium hydroxide aqueous solution at 25 ° C under ⁇ ⁇ 8.5-9.0 control for 1 hour. . After completion of the reaction, the cephalosporin C 'acylase was quickly removed using an ultrafiltration membrane (molecular weight cut-off: 600,000), and the resulting solution was used as the permeate of the ultrafiltration membrane. Obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention se rapporte à un procédé permettant d'obtenir de l'acide 7-aminocéphalosporanique de haute pureté à partir d'une solution aqueuse de cet acide, laquelle est contaminée avec de l'acide α-aminoadipique. Ce procédé consiste à traiter la solution aqueuse avec une résine d'échange anionique à base de styrène fortement basique, afin de débarrasser la solution aqueuse de l'acide α-aminoadipique.
PCT/JP1993/001734 1992-12-02 1993-11-29 Procede pour purifier de l'acide 7-aminocephalosporanique WO1994012504A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/323051 1992-12-02
JP32305192 1992-12-02

Publications (1)

Publication Number Publication Date
WO1994012504A1 true WO1994012504A1 (fr) 1994-06-09

Family

ID=18150559

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001734 WO1994012504A1 (fr) 1992-12-02 1993-11-29 Procede pour purifier de l'acide 7-aminocephalosporanique

Country Status (1)

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WO (1) WO1994012504A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055484A1 (fr) * 1997-06-04 1998-12-10 Biochemie Gesellschaft Mbh Procede de precipitation ameliore d'un acide 7-aminocephalosporanique (7-aca)
CN101768169B (zh) * 2008-12-30 2011-09-21 焦作健康元生物制品有限公司 用于7-氨基头孢烷酸生产中的母液回收工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49284A (fr) * 1972-03-09 1974-01-05
JPS4913195A (fr) * 1972-06-01 1974-02-05
JPS49126692A (fr) * 1973-04-16 1974-12-04

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49284A (fr) * 1972-03-09 1974-01-05
JPS4913195A (fr) * 1972-06-01 1974-02-05
JPS49126692A (fr) * 1973-04-16 1974-12-04

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055484A1 (fr) * 1997-06-04 1998-12-10 Biochemie Gesellschaft Mbh Procede de precipitation ameliore d'un acide 7-aminocephalosporanique (7-aca)
CN101768169B (zh) * 2008-12-30 2011-09-21 焦作健康元生物制品有限公司 用于7-氨基头孢烷酸生产中的母液回收工艺

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