WO1996030376A1 - Process for the recovery of ampicillin - Google Patents
Process for the recovery of ampicillinInfo
- Publication number
- WO1996030376A1 WO1996030376A1 PCT/NL1996/000128 NL9600128W WO9630376A1 WO 1996030376 A1 WO1996030376 A1 WO 1996030376A1 NL 9600128 W NL9600128 W NL 9600128W WO 9630376 A1 WO9630376 A1 WO 9630376A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ampicillin
- apa
- mixture
- process according
- solid substance
- Prior art date
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
- C07D499/04—Preparation
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P37/00—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin
- C12P37/04—Preparation of compounds having a 4-thia-1-azabicyclo [3.2.0] heptane ring system, e.g. penicillin by acylation of the substituent in the 6 position
-
- 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 invention relates to a process for the recovery of ampicillin from a mixture containing ampicillin and 6-aminopenicillic acid (6-APA).
- the object of the invention is to provide a simple, industrially practicable process allowing ampicillin to be recovered in pure form without making use of said organic solvents that are alien to the process.
- This is achieved according to the invention in that a mixture containing ampicillin and 6-APA and having a pH higher than 7, which, apart from any solid ampicillin that is present, is homogeneous at a pH between 7 and 8.5, is subjected to a pH lowering to a pH lower than 8.2, and that the solid substance present is recovered.
- the applicant has found that by lowering the pH of the mixture to a value lower than 8.2, for instance between 5 and 8, in particular between 5.5 and 7.8, depending on the composition of the reaction mixture, it is possible to cause ampicillin to be crystallized out with a purity of more than 90 mass%, in particular more than 98 mass%, even if a large amount of 6-APA is present in the mixture, after which it can be recovered.
- the reaction mixture often contains other valuable components, such as for instance the 6-APA. In order to get a commercially attractive process it is consequently important also to minimize the 6-APA and ampicillin losses.
- the process according to the invention is in particular suitable to be applied in the working up of the reaction mixture which is obtained after the enzymatic acylation reaction in which 6-APA is acylated with D-phenylglycine amide (PGA) or esters of D- phenylglycine.
- the process according to the invention can for instance be applied to a starting mixture that is obtained by successively filtering, with isolation of (immobilized) enzyme, the reaction mixture of an enzymatic acylation reaction carried out at a relatively high pH, for instance a pH between 7.5 and 10, in particular between 8 and 10, lowering the pH to a value between 7 and 9.
- the starting mixture used is the mixture obtained after an enzymatic acylation reaction that ends at a relatively low pH, for instance a pH between 7 and 8.8, preferably between 7.5 and 8.8, and after isolation of the solid substance which mainly contains the immobilized enzyme and D- phenylglycine.
- 6-APA In the starting mixture containing 6-APA and ampicillin, a significant quantity of 6-APA may be present.
- the quantity of 6-APA is mostly less than 75 mol% relative to the total amount of 6-APA plus ampicillin, preferably 2-60%, in particular 5-50%.
- the pH may be lowered in several ways in the framework of the invention, for instance chemically by adding an acid, for instance a mineral acid, in particular sulphuric acid, hydrochloric acid or nitric acid.
- an acid for instance a mineral acid, in particular sulphuric acid, hydrochloric acid or nitric acid.
- Another possibility is for instance, if PGA has been used as acylation agent in the acylation reaction or if an ester of PG has been used and the pH has been kept constant by means of titration with ammonia during the acylation reaction, to lower the pH through physical removal of ammonia.
- Suitable physical removal methods are for instance stripping with steam or an inert gas; (steam) distillation at reduced pressure, in particular thin-film evaporation; evaporation in a spray tower; gas membrane separation or electrodialysis.
- the optimum pH at which ampicillin is recovered depends on the composition of the mixture and is chosen such that optimum separation of 6-APA and ampicillin is achieved.
- the optimum pH is a compromise between on the one hand high purity of the ampicillin recovered, which is achieved if the pH at which the ampicillin is recovered is relatively high, so that the ampicillin is still partly in solution and the 6-APA still completely in solution, and on the other hand a high yield, which is achieved if the pH at which the ampicillin is recovered is relatively low so that the ampicillin has been precipitated virtually completely, while at the same time part of the 6-APA has also been precipitated.
- the temperature at which the working up is performed is mostly lower than 35°C, preferably between 0 and 30°C, in particular between 10 and 30°C.
- the process according to the invention for recovery of pure ampicillin in combination with recirculation of the mixture of 6-APA and ampicillin obtained after further pH lowering, applied to the mixture obtained after enzymatic acylation of 6-APA with PGA enables an overall high selectivity towards 6- APA to be achieved, in particular higher than 80%.
- the remaining filtrate which mainly contains minor residual amounts of PGA, may optionally be worked up further, for instance by bringing it to a pH higher than 8, in particular between 8.5 and 10. If desired, it is possible to apply further concentration and cooling to a temperature lower than 10°C, for instance between 0 and 8°C.
- PGA or esters of PGA for instance may be used as acylation agent.
- any enzyme can be used that is suitable as catalyst in the coupling reaction.
- Such enzymes are for instance the enzymes that are known under the general designations 'penicillin amidase' and 'penicillin acylase'.
- suitable enzymes are enzymes derived from Acetobacter, Aeromonas. Alcali ⁇ enes, Alcali ⁇ enes, Aphanocladium, Bacillus sp.
- Cephalosporium Cephalosporium, Escherichia, Flavobacterium, Kluvvera, Mvcoplana, Protaminobacter, Pseudomonas and Xanthomonas, in particular Acetobaxter pasteurianum.
- an immobilized enzyme is used, since the enzyme can be easily isolated and re-used then.
- Immobilized enzymes are known as such and are commercially available.
- suitable enzymes are the Escherichia coli enzyme from Boehringer Mannheim GmbH, which is commercially available under the name 'Enzygel®', the immobilized Penicillin-G acylase from Recordati, the immobilized Penicillin-G acylase from Phar a Biotechnology Hannover, and an Escherichia coli penicilline acylase isolated as described in WO-A- 92/12782 and immobilised as described in EP-A-222462.
- the enzymatic acylation reaction is mostly carried out at a temperature lower than 35°C, preferably between 0 and 28°C.
- the pH at which the enzymatic acylation reaction is carried out is mostly between 5.5 and 10, preferably between 6 and 9.
- the reaction mixture may also contain an organic solvent or a mixture of organic solvents, preferably less than 30 vol.%.
- organic solvents that can be used are alcohols with 1-7 carbon atoms, for instance a monoalcohol, in particular methanol or ethanol; a diol, in particular ethylene glycol or a triol, in particular glycerol .
- the various components may be present in the reaction mixture in the free form or as salts.
- the pH values mentioned are in all cases the pH values measured at room temperature.
- AM I ampici11in
- the combined filtrate was acidified to pH 6.8 at 5°C in 10 minutes by means of concentrated H 2 S0 4 .
- This solid substance contained a mixture of APA and AMPI in a molar ratio of 94:6.
- the combined filtrate was worked up as follows: by means of a rotary film evaporator 510 ml of liquid was distilled off at 20°C (in about 45-60 minutes), after which 510 ml of water was added. This procedure was repeated one time.
- the resulting suspension was filtered through a G-3 glass filter and washed with 2 x 30 ml of water (5°C) and dried, which yielded 22.2 g of AMPI.3H 2 0 of a chemical purity (on a water-free basis) of > 99%.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Manufacturing Of Electric Cables (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Mechanical Coupling Of Light Guides (AREA)
- Ticket-Dispensing Machines (AREA)
- Bipolar Transistors (AREA)
- Superconductors And Manufacturing Methods Therefor (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU49582/96A AU4958296A (en) | 1995-03-31 | 1996-03-25 | Process for the recovery of ampicillin |
MX9707550A MX9707550A (en) | 1995-03-31 | 1996-03-25 | Process for the recovery of ampicillin. |
AT96906103T ATE220069T1 (en) | 1995-03-31 | 1996-03-25 | METHOD FOR OBTAINING AMPICILLIN |
EP96906103A EP0869960B1 (en) | 1995-03-31 | 1996-03-25 | Process for the recovery of ampicillin |
JP8529208A JPH11502832A (en) | 1995-03-31 | 1996-03-25 | Recovery of ampicillin |
DE69622193T DE69622193T2 (en) | 1995-03-31 | 1996-03-25 | METHOD FOR WINNING AMPICILLIN |
US08/940,984 US5916762A (en) | 1995-03-31 | 1997-09-30 | Process for the recovery of ampicillin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BE9500291A BE1009264A3 (en) | 1995-03-31 | 1995-03-31 | Process for the extraction of ampicillin. |
BE9500291 | 1995-03-31 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/940,984 Continuation US5916762A (en) | 1995-03-31 | 1997-09-30 | Process for the recovery of ampicillin |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996030376A1 true WO1996030376A1 (en) | 1996-10-03 |
Family
ID=3888891
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL1996/000128 WO1996030376A1 (en) | 1995-03-31 | 1996-03-25 | Process for the recovery of ampicillin |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0869960B1 (en) |
JP (1) | JPH11502832A (en) |
KR (1) | KR100442040B1 (en) |
CN (1) | CN1103777C (en) |
AT (1) | ATE220069T1 (en) |
AU (1) | AU4958296A (en) |
BE (1) | BE1009264A3 (en) |
CZ (1) | CZ307497A3 (en) |
DE (1) | DE69622193T2 (en) |
ES (1) | ES2179180T3 (en) |
IN (1) | IN183010B (en) |
MX (1) | MX9707550A (en) |
WO (1) | WO1996030376A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL1006266C2 (en) * | 1997-06-10 | 1998-12-14 | Chemferm Vof | Method for the preparation of ampicillin. |
NL1007076C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
NL1007077C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
WO1999055710A1 (en) * | 1998-04-29 | 1999-11-04 | Dsm N.V. | A METHOD FOR CRYSTALLIZING A β-LACTAM ANTIBIOTIC |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB994402A (en) * | 1962-09-04 | 1965-06-10 | Bayer Ag | Process for the separation of 6-aminopenicillanic acid and ampicillin |
FR2188608A5 (en) * | 1972-06-14 | 1974-01-18 | Aries Robert | Penicillins prepn by acylating 6-apa - in presence of catalytic enzymes using free acids |
DE2611286A1 (en) * | 1975-03-17 | 1976-09-23 | Bristol Myers Co | PROCESS FOR THE PRODUCTION OF AMOXICILLIN TRIHYDRATE |
US4354971A (en) * | 1981-06-22 | 1982-10-19 | Eli Lilly And Company | Non-extractive penicillin V recovery process |
WO1995003420A1 (en) * | 1993-07-19 | 1995-02-02 | Dsm N.V. | Process for the enzymatic preparation of a beta-lactam derivative |
-
1995
- 1995-03-31 BE BE9500291A patent/BE1009264A3/en not_active IP Right Cessation
-
1996
- 1996-03-25 AU AU49582/96A patent/AU4958296A/en not_active Abandoned
- 1996-03-25 DE DE69622193T patent/DE69622193T2/en not_active Expired - Fee Related
- 1996-03-25 CN CN96194145A patent/CN1103777C/en not_active Expired - Fee Related
- 1996-03-25 AT AT96906103T patent/ATE220069T1/en not_active IP Right Cessation
- 1996-03-25 KR KR1019970707021A patent/KR100442040B1/en not_active IP Right Cessation
- 1996-03-25 EP EP96906103A patent/EP0869960B1/en not_active Expired - Lifetime
- 1996-03-25 MX MX9707550A patent/MX9707550A/en not_active IP Right Cessation
- 1996-03-25 WO PCT/NL1996/000128 patent/WO1996030376A1/en active IP Right Grant
- 1996-03-25 CZ CZ973074A patent/CZ307497A3/en unknown
- 1996-03-25 ES ES96906103T patent/ES2179180T3/en not_active Expired - Lifetime
- 1996-03-25 JP JP8529208A patent/JPH11502832A/en active Pending
- 1996-03-26 IN IN483MA1996 patent/IN183010B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB994402A (en) * | 1962-09-04 | 1965-06-10 | Bayer Ag | Process for the separation of 6-aminopenicillanic acid and ampicillin |
FR2188608A5 (en) * | 1972-06-14 | 1974-01-18 | Aries Robert | Penicillins prepn by acylating 6-apa - in presence of catalytic enzymes using free acids |
DE2611286A1 (en) * | 1975-03-17 | 1976-09-23 | Bristol Myers Co | PROCESS FOR THE PRODUCTION OF AMOXICILLIN TRIHYDRATE |
US4354971A (en) * | 1981-06-22 | 1982-10-19 | Eli Lilly And Company | Non-extractive penicillin V recovery process |
WO1995003420A1 (en) * | 1993-07-19 | 1995-02-02 | Dsm N.V. | Process for the enzymatic preparation of a beta-lactam derivative |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL1006266C2 (en) * | 1997-06-10 | 1998-12-14 | Chemferm Vof | Method for the preparation of ampicillin. |
WO1998056946A1 (en) * | 1997-06-10 | 1998-12-17 | Dsm N.V. | Process for the preparation of ampicillin |
CN1115417C (en) * | 1997-06-10 | 2003-07-23 | Dsm有限公司 | Process for preparation of ampicillin |
US7029885B2 (en) | 1997-06-10 | 2006-04-18 | Dsm Ip Assests B.V. | Process for the preparation of ampicillin |
NL1007076C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
NL1007077C2 (en) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Method for the recovery of a ß-lactam antibiotic. |
WO1999015531A1 (en) * | 1997-09-19 | 1999-04-01 | Dsm N.V. | PROCEDE FOR RECOVERY OF A β-LACTAM ANTIBIOTIC |
WO1999015532A1 (en) * | 1997-09-19 | 1999-04-01 | Dsm N.V. | PROCESS FOR RECOVERY OF A β-LACTAM ANTIBIOTIC |
WO1999055710A1 (en) * | 1998-04-29 | 1999-11-04 | Dsm N.V. | A METHOD FOR CRYSTALLIZING A β-LACTAM ANTIBIOTIC |
Also Published As
Publication number | Publication date |
---|---|
EP0869960B1 (en) | 2002-07-03 |
KR100442040B1 (en) | 2005-08-05 |
BE1009264A3 (en) | 1997-01-07 |
ATE220069T1 (en) | 2002-07-15 |
ES2179180T3 (en) | 2003-01-16 |
DE69622193D1 (en) | 2002-08-08 |
MX9707550A (en) | 1997-11-29 |
KR19980703622A (en) | 1998-12-05 |
JPH11502832A (en) | 1999-03-09 |
EP0869960A1 (en) | 1998-10-14 |
CN1103777C (en) | 2003-03-26 |
IN183010B (en) | 1999-08-21 |
CZ307497A3 (en) | 1998-01-14 |
DE69622193T2 (en) | 2003-03-20 |
CN1185157A (en) | 1998-06-17 |
AU4958296A (en) | 1996-10-16 |
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