WO1998021212A1 - Process for the preparation of salts and esters of clavulanic acid - Google Patents
Process for the preparation of salts and esters of clavulanic acid Download PDFInfo
- Publication number
- WO1998021212A1 WO1998021212A1 PCT/EP1997/006263 EP9706263W WO9821212A1 WO 1998021212 A1 WO1998021212 A1 WO 1998021212A1 EP 9706263 W EP9706263 W EP 9706263W WO 9821212 A1 WO9821212 A1 WO 9821212A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- clavulanic acid
- amine
- clavulanate
- addition
- process according
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to a process for the preparation of pharmaceutically acceptable alkali metal salts and esters of clavulanic acid, especially potassium clavulanate.
- Clavulanic acid and its alkali metal salts and esters are ⁇ -lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins .
- Clavulanic acid is normally prepared by the fermentation of a microorganism which produces clavulanic acid as for instance Streptomyces strains such as Strepto vces clavuliger- us .
- the resulting aqueous broth is normally subjected to conventional purification and concentration processes, such as disclosed in GB-1508977.
- EP-A-26044 discloses the use of the tertiary butylamine salt of clavulanic acid as an useful intermediate in the preparation of clavulanic acid.
- Other amine salts of clavulanic acid are disclosed in for example WO 93/25557, WO 94/22873, EP-A-0387178, EP-A-562583, WO 96/26944 and WO 96/20199.
- diamino ethers as disclosed in the latter application are considered as amines. All these cited references are incorporated in the present application by reference.
- the aim of this invention is to prepare clavulanic acid and its pharmaceutically acceptable salts, such as potassium, wherein the desired substance is obtained in a high yield and of high purity.
- a lot of process improvements were surprisingly found.
- whole broth extraction appears to be an advantageous alternative for removing solids from the fermentation broth.
- a further improvement relates to the application of an amine which forms with clavulanic acid an amine clavulanate, which sticks to the walls in the normally applied ethylacetate /acetone solution.
- a water miscible organic solvent like an alcohol, preferably absolute alcohol, avoids the tendency to stick to the walls of the diamine crystals of the crystallising vessel which results in a yield loss.
- it appears to be possible to influence the crys- tal morphology of the end product by regulating the amount of water added during the crystallisation stage.
- the potassium clavulanate it has been found advantageous to form the same by slurrying the amine salt in a solvent, preferably a water miscible ketone or alcohol and then adding a potassium source, preferably potassium ethyl hexanoate in a solvent, also preferably a water miscible ketone or alcohol.
- a potassium source preferably potassium ethyl hexanoate in a solvent, also preferably a water miscible ketone or alcohol.
- the residual amine in the endproduct is extremely low, lower than 0.05% w/w, preferably lower than 0.02% w/w appears to be possible, viz. ten times lower than the level of tertiary butylamine permitted by the British Pharmacopoeia.
- a low amine content in the amine clavulanate intermediate is desirable since it results in a more stable endproduct. Therefore, it is really advantageous to apply potassium clavulanate, prepared in this way, in a pharmaceutical composition comprising potassium clavulanate and amoxycillin trihydrate.
- Example 1 Whole broth extraction of a clavulanic acid containing broth
- the ethylacetate solution (9.25 1) from the preceding example was evaporated in vacuo at 30-35 °C, using a natural circulation evaporator.
- a concentrated solution (0.88 1) was obtained, containing 7.5 g of clavulanic acid.
- This solution was concentrated using a rotatory thin film evaporator (vacuum, 30-35 °C) .
- a concentrate (0.11 1) was obtained, containing 7.4 g of clavulanic acid.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002271847A CA2271847A1 (en) | 1996-11-11 | 1997-11-10 | Process for the preparation of salts and esters of clavulanic acid |
JP52216798A JP2001503763A (en) | 1996-11-11 | 1997-11-10 | Preparation of salts and esters of clavulanic acid |
EP97951881A EP0937084A1 (en) | 1996-11-11 | 1997-11-10 | Process for the preparation of salts and esters of clavulanic acid |
BR9713339-6A BR9713339A (en) | 1996-11-11 | 1997-11-10 | Process for preparing salts and esters of clavulanic acid. |
AU55516/98A AU5551698A (en) | 1996-11-11 | 1997-11-10 | Process for the preparation of salts and esters of clavulanic acid |
NO992225A NO992225L (en) | 1996-11-11 | 1999-05-07 | Process for the preparation of salts and esters of clavulanic acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96203117 | 1996-11-11 | ||
EP96203117.5 | 1996-11-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998021212A1 true WO1998021212A1 (en) | 1998-05-22 |
Family
ID=8224563
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/006263 WO1998021212A1 (en) | 1996-11-11 | 1997-11-10 | Process for the preparation of salts and esters of clavulanic acid |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0937084A1 (en) |
JP (1) | JP2001503763A (en) |
CN (1) | CN1238776A (en) |
AU (1) | AU5551698A (en) |
BR (1) | BR9713339A (en) |
CA (1) | CA2271847A1 (en) |
NO (1) | NO992225L (en) |
PL (1) | PL333247A1 (en) |
TR (1) | TR199901631T2 (en) |
WO (1) | WO1998021212A1 (en) |
ZA (1) | ZA9710141B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000004028A1 (en) * | 1998-07-16 | 2000-01-27 | Dsm N.V. | Improved process for the preparation of salts and esters of clavulanic acid |
WO2000041478A2 (en) * | 1999-04-01 | 2000-07-20 | Dsm N.V. | Agglomerates by crystallisation |
US6133441A (en) * | 1995-11-15 | 2000-10-17 | Biochemie Gesellschaft M.B.H. | Production of a salt of clavulanic acid |
US6180782B1 (en) * | 1995-04-20 | 2001-01-30 | Lek Pharmaceutical & Chemical Co., Dd | Preparation of clavulanate salts |
WO2001087891A1 (en) * | 2000-05-13 | 2001-11-22 | Smithkline Beecham P.L.C. | Process for the purification of a salt of clavulanic acid |
USH2158H1 (en) | 1992-03-10 | 2006-06-06 | Sandoz Ag | Process for the production of clavulanic acid salts |
WO2008065160A1 (en) * | 2006-12-01 | 2008-06-05 | Dsm Ip Assets B.V. | Process for the production of clavulanic acid |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993025557A1 (en) * | 1992-06-11 | 1993-12-23 | Smithkline Beecham Plc | Process for the preparation of clavulanic acid |
EP0594099A1 (en) * | 1992-10-21 | 1994-04-27 | Pharma Development Ltd. | Process for the purification of crude clavulanic acid |
WO1994021647A1 (en) * | 1993-03-18 | 1994-09-29 | Smithkline Beecham Plc | Diclavulanate salt with a diamine and process of preparation |
WO1995023870A1 (en) * | 1994-03-02 | 1995-09-08 | Lek, Tovarna Farmacevtskih In Kemic^¿Nih Izdelkov, D.D. | Novel process for the isolation of clavulanic acid and of pharmaceutically acceptable salts thereof from the fermentation broth of streptomyces sp. p 6621 ferm p 2804 |
WO1995034194A2 (en) * | 1995-05-16 | 1995-12-21 | Chong Kun Dang Corp. | Process for manufacturing clavulanic acid salt |
WO1996020199A2 (en) * | 1994-12-24 | 1996-07-04 | Spurcourt Limited | Diclavulanate salt with a diamino ether and process of preparation |
WO1996028452A1 (en) * | 1995-03-10 | 1996-09-19 | Lek Pharmaceutical And Chemical Co. D.D. | Process for the preparation of pharmaceutically acceptable salts of clavulanic acid |
WO1996033197A1 (en) * | 1995-04-20 | 1996-10-24 | Lek Pharmaceutical And Chemical Co. D.D. | Preparation of clavulanate salts |
-
1997
- 1997-11-10 BR BR9713339-6A patent/BR9713339A/en not_active Application Discontinuation
- 1997-11-10 AU AU55516/98A patent/AU5551698A/en not_active Abandoned
- 1997-11-10 CA CA002271847A patent/CA2271847A1/en not_active Abandoned
- 1997-11-10 PL PL97333247A patent/PL333247A1/en unknown
- 1997-11-10 JP JP52216798A patent/JP2001503763A/en active Pending
- 1997-11-10 EP EP97951881A patent/EP0937084A1/en not_active Withdrawn
- 1997-11-10 TR TR1999/01631T patent/TR199901631T2/en unknown
- 1997-11-10 CN CN97180163A patent/CN1238776A/en active Pending
- 1997-11-10 WO PCT/EP1997/006263 patent/WO1998021212A1/en not_active Application Discontinuation
- 1997-11-11 ZA ZA9710141A patent/ZA9710141B/en unknown
-
1999
- 1999-05-07 NO NO992225A patent/NO992225L/en not_active Application Discontinuation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993025557A1 (en) * | 1992-06-11 | 1993-12-23 | Smithkline Beecham Plc | Process for the preparation of clavulanic acid |
EP0594099A1 (en) * | 1992-10-21 | 1994-04-27 | Pharma Development Ltd. | Process for the purification of crude clavulanic acid |
WO1994021647A1 (en) * | 1993-03-18 | 1994-09-29 | Smithkline Beecham Plc | Diclavulanate salt with a diamine and process of preparation |
WO1995023870A1 (en) * | 1994-03-02 | 1995-09-08 | Lek, Tovarna Farmacevtskih In Kemic^¿Nih Izdelkov, D.D. | Novel process for the isolation of clavulanic acid and of pharmaceutically acceptable salts thereof from the fermentation broth of streptomyces sp. p 6621 ferm p 2804 |
WO1996020199A2 (en) * | 1994-12-24 | 1996-07-04 | Spurcourt Limited | Diclavulanate salt with a diamino ether and process of preparation |
WO1996028452A1 (en) * | 1995-03-10 | 1996-09-19 | Lek Pharmaceutical And Chemical Co. D.D. | Process for the preparation of pharmaceutically acceptable salts of clavulanic acid |
WO1996033197A1 (en) * | 1995-04-20 | 1996-10-24 | Lek Pharmaceutical And Chemical Co. D.D. | Preparation of clavulanate salts |
WO1995034194A2 (en) * | 1995-05-16 | 1995-12-21 | Chong Kun Dang Corp. | Process for manufacturing clavulanic acid salt |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USH2158H1 (en) | 1992-03-10 | 2006-06-06 | Sandoz Ag | Process for the production of clavulanic acid salts |
US6180782B1 (en) * | 1995-04-20 | 2001-01-30 | Lek Pharmaceutical & Chemical Co., Dd | Preparation of clavulanate salts |
US6133441A (en) * | 1995-11-15 | 2000-10-17 | Biochemie Gesellschaft M.B.H. | Production of a salt of clavulanic acid |
WO2000004028A1 (en) * | 1998-07-16 | 2000-01-27 | Dsm N.V. | Improved process for the preparation of salts and esters of clavulanic acid |
WO2000041478A2 (en) * | 1999-04-01 | 2000-07-20 | Dsm N.V. | Agglomerates by crystallisation |
WO2000041478A3 (en) * | 1999-04-01 | 2000-11-02 | Dsm Nv | Agglomerates by crystallisation |
US6979735B1 (en) | 1999-04-01 | 2005-12-27 | Dsm N.V. | Agglomerates by crystallization |
WO2001087891A1 (en) * | 2000-05-13 | 2001-11-22 | Smithkline Beecham P.L.C. | Process for the purification of a salt of clavulanic acid |
US7767823B2 (en) | 2000-05-13 | 2010-08-03 | Smithkline Beecham Limited | Process for the purification of a salt of clavulanic acid |
CZ304775B6 (en) * | 2000-05-13 | 2014-10-15 | Smithkline Beecham Plc | Process for preparing potassium clavulanate |
WO2008065160A1 (en) * | 2006-12-01 | 2008-06-05 | Dsm Ip Assets B.V. | Process for the production of clavulanic acid |
Also Published As
Publication number | Publication date |
---|---|
NO992225D0 (en) | 1999-05-07 |
JP2001503763A (en) | 2001-03-21 |
AU5551698A (en) | 1998-06-03 |
ZA9710141B (en) | 1998-06-25 |
CA2271847A1 (en) | 1998-05-22 |
PL333247A1 (en) | 1999-11-22 |
BR9713339A (en) | 2000-05-09 |
CN1238776A (en) | 1999-12-15 |
NO992225L (en) | 1999-05-07 |
TR199901631T2 (en) | 1999-09-21 |
EP0937084A1 (en) | 1999-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5184465B2 (en) | Method for producing potassium clavulanate | |
HU212583B (en) | New process for producing potassium salt of clavulanic acid | |
RU2206613C2 (en) | Method of isolation of clavulanic acid | |
EP0813536B1 (en) | Process for the preparation of pharmaceutically acceptable salts of clavulanic acid | |
EP0937084A1 (en) | Process for the preparation of salts and esters of clavulanic acid | |
EP0821687B1 (en) | Preparation of clavulanate salts | |
JPH11501023A (en) | Clavulanate | |
EP0941229B1 (en) | Purification of fermented clavulanic acid | |
US6417352B1 (en) | Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid | |
CA2337072A1 (en) | Improved process for the preparation of salts and esters of clavulanic acid | |
MXPA99004322A (en) | Process for the preparation of salts and esters of clavulanic acid | |
US20010029038A1 (en) | Purification of fermented clavulanic acid | |
WO1998042858A1 (en) | Process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid | |
RU2522806C1 (en) | Improved method of purification of pravastatin | |
AU692091C (en) | Preparation of clavulanate salts |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 97180163.0 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
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: 1997951881 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1999/004322 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2271847 Country of ref document: CA Ref document number: 1998 522167 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09308002 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999/01631 Country of ref document: TR |
|
WWP | Wipo information: published in national office |
Ref document number: 1997951881 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1997951881 Country of ref document: EP |