WO2007063107A1 - Procede de fabrication d'un sel de potassium de penicilline - Google Patents

Procede de fabrication d'un sel de potassium de penicilline Download PDF

Info

Publication number
WO2007063107A1
WO2007063107A1 PCT/EP2006/069146 EP2006069146W WO2007063107A1 WO 2007063107 A1 WO2007063107 A1 WO 2007063107A1 EP 2006069146 W EP2006069146 W EP 2006069146W WO 2007063107 A1 WO2007063107 A1 WO 2007063107A1
Authority
WO
WIPO (PCT)
Prior art keywords
penicillin
group
potassium salt
alcohol
organic solvent
Prior art date
Application number
PCT/EP2006/069146
Other languages
English (en)
Inventor
Van Der Thomas Does
Original Assignee
Dsm Ip Assets B.V.
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 Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Priority to EA200801491A priority Critical patent/EA017121B1/ru
Priority to EP06819870A priority patent/EP1957502A1/fr
Priority to CN2006800452303A priority patent/CN101321771B/zh
Priority to BRPI0619157-6A priority patent/BRPI0619157A2/pt
Publication of WO2007063107A1 publication Critical patent/WO2007063107A1/fr
Priority to HK09104818.3A priority patent/HK1126476A1/xx

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; 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 process for the preparation of a potassium salt of penicillin G (Pen G K) or penicillin V (Pen V K) in crystal form.
  • Penicillins are normally obtained from a fermentation process using microbial strains capable of producing penicillin in the presence of a suitable side chain precursor.
  • Penicillin G for instance is produced by selected strains of Penicillium chrysogenum in the presence of the side chain precursor phenyl acetic acid. After fermentation, the penicillin is recovered from the fermentation broth according to known methods depending on the type of penicillin.
  • the fermentation broth obtained is filtered and the filter cake washed after which the penicillin G present in the collected filtrate is extracted to an organic solvent such as n-butylacetate or methyl isobutyl ketone after acidification of the filtrate.
  • the extract thus obtained may then be decolorized with aid of active carbon and the penicillin G acid is back extracted to water upon neutralization with an aqueous potassium salt solution such as potassium acetate.
  • This solution is admixed with a sufficient amount of a second solvent such as n-butanol after which the water content is reduced using evaporation of the n-butanol-water azeotrope, whereupon the penicillin G K crystals formed are recovered by filtration and subsequent washing and drying.
  • a second solvent such as n-butanol
  • penicillin G K crystals formed are recovered by filtration and subsequent washing and drying.
  • a disadvantage of this prior art recovery process is that during evaporation of the n-butanol- water azeotrope substantial losses of Pen G K occur due to degradation of Pen G K, resulting in a significantly reduced yield of Pen G K (e.g. ⁇ 92%).
  • crystalline Pen G K is directly obtained from the extract described above, by addition of potassium acetate or other suitable potassium sources followed by evaporation of the azeotrope, whereupon the Pen G K crystals that are formed are filtered, suspended in n-butanol, filtered and dried.
  • a disadvantage of this prior art recovery process is that after isolation of the final product (Pen G K) the mother liquor comprises both n-butanol and n-butylacetate. Both solvents need to be recovered; however, since n-butanol and n-butylacetate are difficult to separate, this solvent recovery step requires expensive equipment.
  • penicillin V in principle the same processes may be applied. However, due to better stability of penicillin V under acidic conditions, penicillin V can also be crystallized in the acid form instead of the potassium salt form, without economical unacceptable losses.
  • the aim of the present invention to provide a simplified and therefore economically more attractive process for the preparation of a potassium salt of a penicillin selected from the group of Penicillin G and Penicillin V in crystal form in sufficiently high and preferably improved yield and of good preferably improved quality.
  • Yield is defined herein as the %-yield of penicillin in the potassium salt of a penicillin selected from the group of Penicillin G and Penicillin V in crystal form relative to the penicillin present in the extract.
  • Sufficiently high is defined herein as being preferably at least 90%, more preferably at least 92%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, most preferably at least 98%.
  • Good quality is defined herein as that the final potassium salt of a penicillin selected from the group of Penicillin G and Penicillin V in crystal form contains very little or no impurities, e.g. less than 5% (w/w), more preferably less than 4%, more preferably less than 3%, more preferably less than 2%, more preferably less than 1 %, more preferably less than 0,5%, more preferably less than 0,25%, even more preferably less than 0,1%.
  • Impurities may for instance be 6-amino-penicillanic acid (6-APA), phenylacetic acid (PA), parahydroxy-penicillin G, penicillic acid of penicillin G, penicilloic acids of penicillin G and penilloic acids of penicillin G and corresponding impurities for penicillin V.
  • 6-APA 6-amino-penicillanic acid
  • PA phenylacetic acid
  • parahydroxy-penicillin G parahydroxy-penicillin G
  • penicillic acid of penicillin G penicillic acid of penicillin G
  • penicilloic acids of penicillin G and penilloic acids of penicillin G and corresponding impurities for penicillin V 6-amino-penicillanic acid
  • the invention provides a process for the preparation of a potassium salt of a penicillin selected from the group of Penicillin G and Penicillin V in crystal form from a suspension comprising the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V, an organic solvent and an alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol.
  • the penicillin is Penicillin G.
  • the yield of the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V in crystal form in the process according to the present invention was sufficiently high as defined hereinbefore and as high as, or even higher than in the processes known in the art, while at the same time the quality of the crystals obtained was good as defined hereinbefore.
  • Another advantage of the process of the present invention is that only one isolation step of the crystals is required which not only contributes to the sufficiently high yields but also to a substantial economic advantage.
  • the organic solvent in the process according to the present invention may be any suitable organic solvent known by the man skilled in the art.
  • suitable organic solvents are amylacetate, n-butylacetate, ethyl acetate, methyl isobutyl ketone, cyclohexanone, iso-butanol or n-butanol.
  • the organic solvent is n-butylacetate.
  • the alcohol in the process according to the present invention is selected from the group consisting of a Ci, C 2 and C 3 and is preferably methanol, ethanol, n-propanol or iso-propanol. Most preferably, the alcohol is methanol.
  • the penicillin in the process for the preparation of the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V in crystal form according to the present invention may be obtained from any suitable production process known in the art.
  • Penicillin G may for instance be produced by fermenting a penicillin G-producing microorganism e.g. a strain of Penicillium chrysogenum preferably in the presence of the side chain precursor phenylacetic acid according to methods known in the art.
  • the biomass may be separated from the fermentation broth using any suitable technology, such as centrifugation or filtration, thus yielding a penicillin containing fermentation fluid.
  • a filtration step is applied to separate the biomass from the broth.
  • the residual solids are washed.
  • the fermentation broth or fluid is acidified to a pH within a range of 2 to 4, preferably to a pH within a range of 2.5 to 3, by addition of at least one acid, such as sulphuric acid, hydrochloric acid or nitric acid or any combination of any of them.
  • the penicillin is then separated from the acidified aqueous phase by extraction to an organic solvent.
  • Any suitable organic solvent may be used, for instance, amylacetate, n-butylacetate, ethyl acetate, methyl isobutyl ketone, cyclohexanone, iso-butanol or n-butanol.
  • the organic solvent is n-butylacetate.
  • the addition of a suitable de-emulsifier may improve the extraction significantly.
  • Extract is defined herein as the organic solvent to which the penicillin selected from the group of Penicillin G and Penicillin V has been extracted.
  • the extract comprising the penicillin may optionally be treated with activated carbon to remove impurities according to methods known in the art.
  • the extract comprising the penicillin selected from the group of Penicillin G and Penicillin V as defined herein before, optionally treated with activated carbon may subsequently be mixed with a suitable potassium source to convert the penicillin selected from the group of Penicillin G and Penicillin V into the corresponding potassium salt of the penicillin thereby obtaining a mixture comprising the organic solvent and potassium salt of the penicillin.
  • the amount of the suitable potassium source mixed with the extract comprising the penicillin selected from the group of Penicillin G and Penicillin V is preferably such that between 0.4 and 3 mole-equivalents of potassium are added with regard to the penicillin.
  • Most preferably 1 mole-equivalent of potassium is added with regard to the penicillin.
  • a suitable potassium source is any potassium salt of a preferably weak acid. Examples of such suitable potassium sources are potassium acetate or potassium carbonate.
  • the potassium source may be used in solid form or may first be dissolved in water to form an aqueous solution of the potassium source.
  • a suitable concentration of the potassium source in aqueous solution is for instance between 10 to 60% w/v, for instance between 15 to 55% w/v, for instance between 20 to 50%.
  • part of the water or part of an azeotrope comprising water and the organic solvent e.g. an azeotrope of water and n-butylacetate, may be removed from the mixture comprising the organic solvent and the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V.
  • the water which is present in the mixture may origin from the fermentation broth or from the organic solvent or may have been introduced with the aqueous solution of potassium source.
  • the water content of the mixture comprising the organic solvent and the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V after removal of part of the water or the azeotrope is ⁇ 10% (v/v), more preferably ⁇ 5% (v/v), more preferably ⁇ 2.5% (v/v), more preferably ⁇ 1 % (v/v), more preferably ⁇ 0.5% (v/v) and most preferably ⁇ 0.2% (v/v).
  • an alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol is added to the mixture to obtain a suspension comprising a potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V, an organic solvent and the alcohol.
  • the alcohol may be methanol, ethanol, n-propanol or iso- propanol.
  • the alcohol is methanol.
  • the alcohol selected from the group consisting of a C 1 , C 2 and C 3 alcohol is dry.
  • dry means that the alcohol contains less than 10% (v/v) of water, preferably less than 5% (v/v) of water, preferably less than 2% (v/v). Most preferably, the dry alcohol contains 0% (v/v) of water.
  • the suspension comprising the potassium salt of a penicillin selected from the group of Penicillin G and Penicillin V, the organic solvent and the alcohol may be agitated during a certain period of time after having been brought into contact with each other.
  • the suspension is agitated during a period of time of between 5 min to 24 hours, preferably of between 10 min to 12 h, more preferably of between 20 min to 8 h, more preferably of between 0.5 h and 6h, more preferably of between 45 min and 3 h.
  • the suspension is agitated until white crystals of the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V are formed.
  • the suspension is agitated until white crystals of the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V are formed without lumps.
  • the suspension may be agitated at any suitable temperature, preferably between 0 and 4CO, more preferably between 5 and 30 °C, most preferably between 10 and 25 °C.
  • the ratio of the volume of the alcohol to the volume of the mixture comprising an organic solvent and the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V may be any suitable ratio. Preferably this ratio is between 1 :20 to 1 :3, preferably between 1 :15 to 1 :4, preferably between 1 :10 to 1 :6.
  • Penicillin V may crystallise partly or wholly during the process of the present invention.
  • the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V may start to crystallise upon addition of the suitable potassium source to the extract comprising the penicillin and/or during evaporation of part of the water or part of the azeotrope of water/organic solvent from the mixture comprising the organic solvent and the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V.
  • the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V may also crystallise further or recrystallise when the mixture comprising the organic solvent and the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V, optionally partly or wholly crystallized, is brought into contact with the alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol and/or during agitation of the suspension comprising the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V, the organic solvent and the alcohol.
  • crystals of the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V obtained after addition of a suitable potassium source to an extract containing a penicillin selected from the group of Penicillin G and Penicillin V obtained and defined as described hereinbefore and evaporation of the azeotrope comprising the organic solvent and water are collected, e.g. by filtration.
  • the crystals thus obtained are resuspended in a mixture comprising the organic solvent as described hereinbefore and the alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol under the same conditions (e.g. with respect to the ratio of alcohol/organic solvent, time, temperature) as described in the previous embodiment.
  • the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V in crystal form may be isolated from the suspension in any embodiment of the invention by any suitable method known in the art, for instance by centrifugation or filtration. A wet cake of the potassium salt of the penicillin in crystal form may then be obtained. Optionally the wet cake is washed with organic solvent or a mixture of organic solvent and the alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol. If a washing step is applied, the organic solvent is preferably the same organic solvent as used in the extract and the alcohol selected from the group consisting of a Ci, C 2 and C 3 alcohol is preferably the same as used in the suspension.
  • the wet cake of the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V in crystal form may be dried using any suitable technology known in the art. In this embodiment of the invention, the penicillin is preferably penicillin G.
  • the wet cake comprising the crystals of the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V is mixed with water to obtain an aqueous solution of the potassium salt of penicillin selected from the group of Penicillin G and Penicillin V.
  • the aqueous solution may then be stripped to remove traces of organic solvent and/or the alcohol selected from the group consisting of a C 1 , C 2 and C 3 alcohol. Stripping comprises evaporation of water, the organic solvent and/or the alcohol.
  • the aqueous solution of the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V may be used for enzymatic conversion to 6-amino penicillanic acid (6-APA) by known methods described in the art, for instance as described in EP 0977 883.
  • the solution comprising the dissolved the potassium salt of the penicillin selected from the group of Penicillin G and Penicillin V may be treated with a suitable penicillin acylase, e.g. a suitable penicillin G acylase to deacylate penicillin G and a suitable penicillin V acylase to deacylate penicillin V.
  • Organisms that have been found to produce suitable penicillin acylases are, for example, Acetobacter, Aeromonas, Alcaligenes, Aphanocladium, Bacillus sp., Cephalosporium, Escherichia, Flavobacterium, Kluyvera, Mycoplana, Protaminobacter, Providentia, Pseudomonas or Xanthomonas species.
  • Enzymes derived from Acetobacter pasteurioanum, Alcaligenes faecalis, Bacillus megaterium, Escherichia coli, Providentia rettgeri and Xanthomonas citrii have particularly proven to be successful in a method according to the invention.
  • penicillin acylases have also been referred to as penicillin amidases.
  • the penicillin acylase may be used as a free enzyme, but also in any suitable immobilised form, for instance as has been described in EP 0 222 462 and WO 97/04086.
  • the enzymatic conversion of dissolved Pen G K by a penicillin acylase results in the formation of 6-amino penicillanic acid (6-APA) and phenyl acetic acid.
  • the volume evaporated is the total volume evaporated and the value in brackets represents the volume of the water layer in the distillate.
  • the column with the water content represents the water content of the residue after evaporation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication d'un sel de potassium de pénicilline G (Pen G K) ou de pénicilline V (Pen V K) sous forme cristalline à partir d'une suspension comprenant de la Pen G K ou de la pénicilline V (Pen V K), un solvant organique et un alcool en C1 à C3.
PCT/EP2006/069146 2005-12-02 2006-11-30 Procede de fabrication d'un sel de potassium de penicilline WO2007063107A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EA200801491A EA017121B1 (ru) 2005-12-02 2006-11-30 Способ получения калиевой соли пенициллина g
EP06819870A EP1957502A1 (fr) 2005-12-02 2006-11-30 Procede de fabrication d' un sel de potassium de penicilline
CN2006800452303A CN101321771B (zh) 2005-12-02 2006-11-30 青霉素钾盐的制备工艺
BRPI0619157-6A BRPI0619157A2 (pt) 2005-12-02 2006-11-30 processo para a preparação de um sal de potássio de penicilina
HK09104818.3A HK1126476A1 (en) 2005-12-02 2009-05-27 Process for the preparation of a potassium salt of penicillin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05111630.9 2005-12-02
EP05111630 2005-12-02
EP06110094 2006-02-17
EP06110094.7 2006-02-17

Publications (1)

Publication Number Publication Date
WO2007063107A1 true WO2007063107A1 (fr) 2007-06-07

Family

ID=37684994

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2006/069146 WO2007063107A1 (fr) 2005-12-02 2006-11-30 Procede de fabrication d'un sel de potassium de penicilline

Country Status (5)

Country Link
EP (1) EP1957502A1 (fr)
BR (1) BRPI0619157A2 (fr)
EA (1) EA017121B1 (fr)
HK (1) HK1126476A1 (fr)
WO (1) WO2007063107A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159782A (zh) * 2011-12-08 2013-06-19 胡先念 从青霉素水溶液中萃取青霉素的方法及其应用和青霉素的提取方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2599401A (en) 1947-08-15 1952-06-03 Lilly Co Eli Process of obtaining crystalline penicillin salts
WO1998048039A1 (fr) 1997-04-22 1998-10-29 Dsm N.V. Procede ameliore de production fermentative de penicilline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2599401A (en) 1947-08-15 1952-06-03 Lilly Co Eli Process of obtaining crystalline penicillin salts
WO1998048039A1 (fr) 1997-04-22 1998-10-29 Dsm N.V. Procede ameliore de production fermentative de penicilline
EP0977883A1 (fr) * 1997-04-22 2000-02-09 Dsm N.V. Procede ameliore de production fermentative de penicilline

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOTECHNOL. BIOENG., vol. 78, 2002, pages 785
DATABASE WPI Section Ch Week 199131, Derwent World Patents Index; Class B05, AN 1991-225295, XP002368211 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159782A (zh) * 2011-12-08 2013-06-19 胡先念 从青霉素水溶液中萃取青霉素的方法及其应用和青霉素的提取方法
CN103159782B (zh) * 2011-12-08 2015-10-21 湖南中创化工股份有限公司 从青霉素水溶液中萃取青霉素的方法及其应用和青霉素的提取方法

Also Published As

Publication number Publication date
EP1957502A1 (fr) 2008-08-20
EA017121B1 (ru) 2012-10-30
EA200801491A1 (ru) 2008-10-30
HK1126476A1 (en) 2009-09-04
BRPI0619157A2 (pt) 2011-09-20

Similar Documents

Publication Publication Date Title
JP5022913B2 (ja) セファクロルの合成方法
US20090162905A1 (en) Method for Purification of Hyaluronic Acid Salt
US6503727B1 (en) Process for the preparation of an antibiotic
US8067195B2 (en) Process for producing 7-methoxy-3-desacetylcefalotin
EP0977883B1 (fr) Procede ameliore de production fermentative de penicilline
EP1957502A1 (fr) Procede de fabrication d' un sel de potassium de penicilline
JPH11503408A (ja) セファレキシンの回収方法
TW565612B (en) Improved process for the fermentative production of cephalosporin
CA2168923C (fr) Methode pour la synthese enzymatique d'antibiotiques de type .beta.-lactames en presence d'inhibiteurs enzymatiques
KR20010034700A (ko) 세팔로스포린을 발효성 제조하기 위한 신규한 방법
MX2008007066A (en) Process for the preparation of a potassium salt of penicillin
CN101321771B (zh) 青霉素钾盐的制备工艺
JPH11502832A (ja) アンピシリンの回収法
CN101906052B (zh) 一种制备d-间羟基苯甘氨酸的方法
US5916762A (en) Process for the recovery of ampicillin
MXPA98010768A (en) Improved process for the fermentative production of cephalosporin

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680045230.3

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 3932/DELNP/2008

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2006819870

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: MX/a/2008/007066

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 200801491

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 2006819870

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0619157

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20080602