CN1238776A - 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
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- CN1238776A CN1238776A CN97180163A CN97180163A CN1238776A CN 1238776 A CN1238776 A CN 1238776A CN 97180163 A CN97180163 A CN 97180163A CN 97180163 A CN97180163 A CN 97180163A CN 1238776 A CN1238776 A CN 1238776A
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- clavulanic acid
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- 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
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- 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
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- Animal Behavior & Ethology (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract
An improved process for the preparation of pharmaceutically acceptable alkali metal salts or esters of clavulanic acid has been provided for. Furthermore, also potassium clavulanate with an extremely low amine content and pharmaceutical compositions comprising the same have been provided for.
Description
The present invention relates to prepare the especially method of Potassium clavulanate of the pharmaceutically acceptable alkali metal salt of clavulanic acid and ester.
Clavulanic acid and an alkali metal salt thereof and ester are the inhibitor of β-Nei Xiananmei, and it can improve the effect of penicillin and cephalosporin antibiotics.
The preparation of clavulanic acid generally is that fermentation can produce the microorganism of clavulanic acid such as streptomyces bacterial strain as being with excellent streptomycete.Generally resulting moisture meat soup is carried out conventional purifying and concentration method, as disclosed among the GB-1508977.
EP-A-26044 discloses the purposes of the tert-butylamine salt of clavulanic acid as preparation clavulanic acid intermediate.At for example WO93/25557, WO94/22873, EP-A-0387178, EP-A-562583 discloses other amine salt of clavulanic acid among WO96/26944 and the WO96/20199.Also disclosed two amidogen ethers in the application of back are thought amine in this application.All these reference papers that are cited insert among the application as a reference.
The objective of the invention is to prepare clavulanic acid and pharmacy acceptable salt class thereof,, wherein obtain required material with high yield and high purity as sylvite.
We have been surprised to find the many improvement to method.The meat soup extraction is to removing seemingly a kind of useful selection of solids from fermenting broth at first, entirely.Further improvement relates to the amine that use can form clavulanic acid amine with clavulanic acid, and this clavulanic acid amine can adhere on the wall in general used ethyl acetate/acetone soln.Add miscible organic solvent of entry such as alcohols, preferred dehydrated alcohol can avoid adhering to the trend on the two amine crystallization walls in the crystallization test tube, and this adhesion can cause the loss of productive rate.And, can influence the crystal habit of final product by being adjusted in the amount that adds water in the crystallisation stage.
According to the present invention, the pharmacy acceptable salt of preparation clavulanic acid or the method for ester are provided, it comprises one or more the following steps:
-the microbial fermentation that produces clavulanic acid;
-acidifying contains the meat soup of clavulanic acid;
-selectivity adds the miscible solvent of a spot of water;
-use the meat soup that contains clavulanic acid with water-insoluble organic solvent extraction acidifying;
-contain the clavulanic acid of water-insoluble organic solvent by evaporation concentration;
The spissated clavulanic acid solution of-usefulness purification via adsorption-based process;
-filter stick acid solution;
-selectivity adds one or more water miscibles organic solvents;
-selectivity adds the clavulanate that amine prepares this amine with the miscible solvent of water;
-selectivity is the clavulanate recrystallization of this amine that forms;
-be converted into the clavulanic acid of purifying or be converted into pharmaceutically acceptable clavulanate or ester by acidifying by the thing source that adds corresponding salt or ester;
-from this solution, isolate pharmacy acceptable salt or ester.
This paper points out for example N particularly of use, N, N ', N '-Tetramethyl Ethylene Diamine, 1, the amine of two (the dimethylamino)-2-propyl alcohol of 3-, tert-butylamine, uncle's octyl amine, benzhydrylamine and two (2-(dimethylamino) ethyl) ether.
In nearly all art methods, all emphasize before solvent extraction, to need to remove the solid of any suspension.Although filter or ultra-filtration can access useful result, the result is whole meat soups extractions is all having a proximate net result aspect the productive rate of final product and the purity.Yes by removing the big method efficient that a method steps produces to remove the important benefits of filtration step.The solvent of a small amount of by adding (be up to fermenting broth cumulative volume about 25%) such as the miscible ketone of water or alcohol and/or pH regulator make in the meat soup protein denaturation and/or add the difficulty that an amount of de-emulsifier can overcome the meat soup unstable and the emulsification that may exist forms, and improve the performance of whole meat soup extraction thus.
In the crystallisation stage of the clavulanate of amine, find that adding a spot of alcohol in the mixture that contains clavulanic acid and this extraction solvent ethyl acetate and the preferred acetone of recrystallisation solvent is useful as dehydrated alcohol.In a preferred embodiment, before adding amine or add alcohol simultaneously.The use of the solvent mixture of these three kinds of components has reduced crystallization and has sticked to phenomenon that causes loss of yield on the wall and the performance that has also unexpectedly improved purity and whole quality.All methods that add amine in the mixture that contains clavulanic acid have all caused favourable crystallization effect, for example add this amine and this clavulanic acid mixture in the reactor together simultaneously the amine and adding clavulanic acid mixture in this amine except adding in containing the clavulanic acid mixture.And, select by with activated carbon treatment separately or part with the amine clavulanate aqueous solution of solvent cut, the resulting solution of sterile filtration comes recrystallization before aseptic crystallization then.
In the Potassium clavulanate forming process, found to be incorporated in solvent then by slurry amine salt in miscible ketone of solvent preferably water or alcohol, also in miscible ketone of preferably water or the alcohol the preferred thylhexoic acid potassium in potassium source to form this material be useful.The use of slurry systems has significantly reduced required quantity of solvent, thereby has reduced cost and improved the productive rate of end product.
And, found that it is useful adding a spot of water in this (slurry) solvent.Be to have now found that to do the crystal habit that can influence end product so astoundingly.Can obtain easier cleaning like this and crystallization that have improved filtration and drying property.In this method, can form rose-shaped or acicular moulding crystallization, preferably a kind of acicular moulding crystallization.
And particularly when ether was made amine, the residual amine in the end product was very low, is lower than 0.05%w/w, preferably was lower than 0.02%w/w when using two (2-(dimethylamino) ethyl), and this content than the tert-butylamine that British Pharmacopoeia allowed hangs down 10 times.Low amine content in clavulanic acid amine intermediate is an ideal, because it can form more stable end product.Therefore, it is useful really using the Potassium clavulanate by this method preparation in the pharmaceutical composition that contains Potassium clavulanate and amoxycillin trihydrate.
Provide the following example just for goal of the invention is described better.EXAMPLE Example 1 contains the full meat soup extract of clavulanic acid meat soup
Being cooled to 2 ℃ with the meat soup (3.5 liters contain the 13.3g clavulanic acid) that obtains with excellent streptomycete fermentation.While stirring this meat soup is added in 10.5 liters of ethyl acetate at 1-3 ℃.After adding this meat soup, the sulfuric acid of using 3M is the pH regulator to 1.6 of mixture.This mixture is left standstill 5 minutes, and separate each layer.Collect 9.25 liters of ethyl acetate layers, contain the clavulanic acid of 7.5g.Embodiment 2 contains the evaporation of clavulanic acid ethyl acetate solution
With a neutral circulating evaporator, the ethyl acetate solution (9.25 liters) that obtains at the 30-35 ℃ of previous embodiment of vacuum-evaporation.Obtain containing the concentrated solution (0.88 liter) of the clavulanic acid of 7.5g.Concentrate this solution (vacuum, 30-35 ℃) with rotary film evaporator.Obtain containing the enriched material (0.11 liter) of 7.4g clavulanic acid.The two clavulanate crystalline preparation of 3 pairs of (2-(dimethylamino) ethyl) ethers of embodiment
Put into ethanol (50ml) in 1 liter of three neck round-bottomed flask, this flask is furnished with thermometer, two dropping funnels and agitator.Temperature is controlled to 10 ℃ and stirring the thick solution (400ml of ethyl acetate of clavulanic acid; 32.9g clavulanic acid/liter) under, add the ethanolic soln (230ml) of two (2-(dimethylamino) ethyl) ethers (13.5g) simultaneously.In adition process, temperature is remained between 10-15 ℃.Add back (15-20 minute), mixture was stirred 1 hour at 5 ℃.Filtering for crystallizing is with 40ml ethyl acetate washed twice and vacuum-drying at room temperature.Obtain two clavulanate of two (2-(dimethylamino) ethyl) ethers of 16g.Embodiment 4 usefulness activated carbon treatment are come purification of clavulanic acid solution
The spissated ethyl acetate solution of embodiment 2 (7.4g clavulanic acid in 110ml) is carried out activated carbon treatment.Solution is cooled to 5 ℃, and adds gac (16.5g, Norit SXUltra).At 5-10 ℃ mixture was stirred two hours.The adding flocculating aids (Dicalite, 5g), and filtering mixt.Is 185ml with ethyl acetate washing solid cake up to collected filtrate volume.The crystallization of two clavulanate from the ethyl acetate solution of spissated clavulanic acid of 5 pairs of (2-(dimethylamino) ethyl) ethers of embodiment
Under nitrogen, carry out following test.In the ethyl acetate solution of clavulanic acid (900ml, concentration 40g clavulanic acid/liter), add dehydrated alcohol (450ml).Stirred solution, and be cooled to 10 ℃, add two (2-(dimethylamino) ethyl) ethers (35.1ml, 0.18 mole).Mixture is cooled to 3 ℃, and stirred 1 hour.Filtering for crystallizing suspension, and use 200ml acetone earlier, use 200ml washing with acetone filter cake again.This wet cake of vacuum-drying at room temperature.Obtain two clavulanate of two (2-(dimethylamino) ethyl) ethers of 45g.Embodiment 6 is from two (2-(dimethylamino) ethyl) ether two clavulanate crystallization initiation Potassium clavulanates
Under nitrogen, carry out following test.Two (2-(dimethylamino) ethyl) ether two clavulanate (10g) are suspended in the mixed solution of acetone (300ml) and water (6ml).Stir this mixed solution and be cooled to 12 ℃, in 10 minutes, add the acetone soln (the 0.34M solution of 125ml) of 2 ethyl hexanoic acid potassium.Mixed solution is cooled to 5 ℃, and stirred 1 hour.Filtering for crystallizing suspension is also used filter cake volume triple washing with acetone filter cake.Dry this wet cake under 20 ℃ of vacuum.Obtain the Potassium clavulanate of 8.22g.Embodiment 7 is by two (2-(dimethylamino) ethyl) ether two clavulanate of recrystallization purifying
Under nitrogen, carry out following test.At 20 ℃ two (2-(dimethylamino) ethyl) ether two clavulanate (10g) are dissolved in the mixed solution of dehydrated alcohol (45ml) and water (5ml).In 20 minutes, in transparent solution, add acetone (250ml) and stir this mixed solution down at 20 ℃ simultaneously.This mixed solution is cooled to 5 ℃ and stirred 30 minutes.Filter this crystallization suspension, and with this filter cake of washing with acetone of filter cake volume twice.20 ℃ of these crystallizations of vacuum-drying.Obtain two (2-(dimethylamino) ethyl) ether two clavulanate of 9.44g.Embodiment 8 comes the crystallization Potassium clavulanate from two (2-(dimethylamino) ethyl) initial centre of ether two clavulanate with activated carbon treatment
Under nitrogen, carry out following test.At 20 ℃ two (2-(dimethylamino) ethyl) ether two clavulanate (10g) are dissolved in the mixed solution of dehydrated alcohol (45ml) and water (5ml).With 2 ethyl hexanoic acid the pH regulator to 6.5 of this mixed solution.Add gac (1g), at 30 minutes these mixed solutions of inner filtration.(Dicalite 0.3g), filters this mixed solution to add flocculating aids.Filter cake washs with dehydrated alcohol (5ml) and acetone (10ml).At 10 ℃ the filtrate that merges is added in the acetone (250ml).Obtain crystallization suspension.The acetone soln (125ml, the solution of 0.34M) that in 10 minutes, adds 2 ethyl hexanoic acid potassium.Mixed solution is cooled to 5 ℃, stirred 1 hour.Filter this crystallization suspension and use three times of washing with acetone filter cakes of filter cake volume.At 20 ℃ of these wet cakes of vacuum-drying.Obtain the Potassium clavulanate needle crystal of 7.56g.
Claims (16)
1. prepare the method for clavulanic acid pharmaceutically acceptable alkali metal salt or ester, it comprises the following steps:
-the microbial fermentation that produces clavulanic acid;
-acidifying contains the meat soup of clavulanic acid;
-selectivity adds the miscible solvent of a spot of water;
-use the meat soup that contains clavulanic acid with water-insoluble organic solvent extraction acidifying;
-contain the clavulanic acid of water-insoluble organic solvent by evaporation concentration;
The spissated clavulanic acid solution of-usefulness purification via adsorption-based process;
-filter stick acid solution;
-selectivity adds one or more water miscibles organic solvents;
-selectivity adds the clavulanate that amine prepares this amine with the miscible solvent of water;
-selectivity is the clavulanate recrystallization of this amine that forms;
-be converted into the clavulanic acid of purifying or be converted into pharmaceutically acceptable clavulanate or ester by acidifying by the thing source that adds corresponding salt or ester;
-from this solution, isolate pharmacy acceptable salt or ester.
2. in accordance with the method for claim 1, wherein use following any amine of doing: N, N, N ', N '-Tetramethyl Ethylene Diamine, 1, two (the dimethylamino)-2-propyl alcohol of 3-, tert-butylamine, uncle's octyl amine, benzhydrylamine and two (2-(dimethylamino) ethyl) ether.
3. according to any one described method of claim 1 and 2, wherein before extraction, from contain the clavulanic acid fermenting broth, remove solids.
4. according to the described method of any one claim, it is characterized in that in this fermenting broth, adding water miscibility ketone and/or alcohol.
5. according to any one described method of claim 1-4, it is characterized in that containing the meat soup of clavulanic acid with the ethyl acetate extraction acidifying.
6. according to any one described method of claim 1-5, it is characterized in that coming the spissated clavulanic acid solution of purifying with activated carbon treatment.
7. according to any one described method of claim 1-6, it is characterized in that behind purifying and filtration step, in clavulanic acid solution, add water-miscible solvent acetone.
8. according to any one described method of claim 1-7, it is characterized in that before adding amine or the while, in the solution that contains clavulanic acid, add the clavulanate that water-miscible solvent ethanol prepares this amine.
9. according to any one described method of claim 1-8, it is characterized in that by in slurry solvent, providing this amine salt slurry and adding the solution of potassium ion that the clavulanate of amine is converted into Potassium clavulanate.
10. in accordance with the method for claim 9, it is characterized in that in slurry solvent, adding a spot of water.
11. any one the described method according among the claim 1-10 is characterized in that in the mixed solution of second alcohol and water, selectivity is with activated carbon treatment and add the clavulanate that the acetone crystallization comes this amine of recrystallization.
12. prepare the method for Potassium clavulanate, it is characterized in that:
-the band rod streptomycete fermentation that produces clavulanic acid;
The meat soup that the spissated acid solution of-adding comes acidifying to contain clavulanic acid is between 1 to 3 to pH;
-selectivity is removed solids from fermenting broth;
-selectivity adds a spot of water-miscible solvent ketone or alcohol;
-contain the meat soup of clavulanic acid with the ethyl acetate extraction acidifying;
-contain the ethyl acetate solution of clavulanic acid by evaporation concentration;
-come this solution of purifying with activated carbon treatment;
The resulting clavulanic acid solution of-filtration;
-selectivity adds acetone;
-add ethanol and be selected from N, N, N ', N '-Tetramethyl Ethylene Diamine, 1, any in the amine of two (the dimethylamino)-2-propyl alcohol of 3-, tert-butylamine, uncle's octyl amine, benzhydrylamine and two (2-(dimethylamino) ethyl) ether;
-Potassium clavulanate is dissolved in the mixed solution of second alcohol and water, selectivity with activated carbon treatment and in acetone crystallization come selectivity recrystallization Potassium clavulanate;
-be converted into Potassium clavulanate by adding thylhexoic acid potassium;
-isolation of clavulanic acid potassium from slurry.
13. in accordance with the method for claim 12, it is characterized in that by in water miscibility ketone or alcohol this amine clavulanate pulp and optional in this pulp solvent, add a spot of water and be converted into Potassium clavulanate.
14. amine content is lower than the Potassium clavulanate of 0.05%w/w.
15. according to the described Potassium clavulanate of claim 14, wherein amine content is lower than 0.02%w/w.
16. pharmaceutical composition, it contains the Potassium clavulanate and the amoxycillin trihydrate of claim 14 or 15 definition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96203117.5 | 1996-11-11 | ||
| EP96203117 | 1996-11-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1238776A true CN1238776A (en) | 1999-12-15 |
Family
ID=8224563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97180163A Pending CN1238776A (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) | NO992225D0 (en) |
| PL (1) | PL333247A1 (en) |
| TR (1) | TR199901631T2 (en) |
| WO (1) | WO1998021212A1 (en) |
| ZA (1) | ZA9710141B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT400033B (en) | 1992-03-10 | 1995-09-25 | Biochemie Gmbh | NEW METHOD FOR ISOLATING AND PURIFYING CLAVULANIC ACID AND FOR PRODUCING PHARMACOLOGICALLY COMPATIBLE SALTS THEREOF |
| SI9500134B (en) * | 1995-04-20 | 2004-04-30 | Lek, | Preparation procedure of pure alkali salts of clavulanic acid |
| AT403375B (en) * | 1995-11-15 | 1998-01-26 | Biochemie Gmbh | METHOD FOR FILLING ALKALINE SALTS 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 |
| CN1209099C (en) * | 1999-04-01 | 2005-07-06 | Dsm公司 | Agglomerates by crystallisation |
| DE60105016T3 (en) * | 2000-05-13 | 2009-06-25 | Smithkline Beecham P.L.C., Brentford | PROCESS FOR CLEANING A SALT OF CLAVLANIC ACID |
| WO2008065160A1 (en) * | 2006-12-01 | 2008-06-05 | Dsm Ip Assets B.V. | Process for the production of clavulanic acid |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI9300296B (en) * | 1992-06-11 | 1998-06-30 | Smithkline Beecham P.L.C. | Process and intermediates for the preparation of clavulanic acid |
| KR100200239B1 (en) * | 1992-10-21 | 1999-06-15 | 김충환 | Process for preparing salts of clavulanic acid |
| GB9305565D0 (en) * | 1993-03-18 | 1993-05-05 | Smithkline Beecham Plc | Novel compounds and processes |
| SI9400107A (en) * | 1994-03-02 | 1995-10-31 | Lek Tovarna Farmacevtskih | New process of the isolation of clavulanic acid and its pharmaceutical salts from fermented broth of streptomyces sp.p 6621 ferm p 2804. |
| GB9426261D0 (en) * | 1994-12-24 | 1995-02-22 | Spurcourt Ltd | Clavulanic acid salts |
| SI9500074A (en) * | 1995-03-10 | 1996-10-31 | Lek Tovarna Farmacevtskih | Process for preparation of alkani salts of clavulanic acid. |
| SI9500134B (en) * | 1995-04-20 | 2004-04-30 | Lek, | Preparation procedure of pure alkali salts of clavulanic acid |
| KR100200242B1 (en) * | 1995-05-16 | 1999-06-15 | 김충환 | Process for preparing clavulanic acid salt |
-
1997
- 1997-11-10 WO PCT/EP1997/006263 patent/WO1998021212A1/en not_active Application Discontinuation
- 1997-11-10 PL PL97333247A patent/PL333247A1/en unknown
- 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 JP JP52216798A patent/JP2001503763A/en active Pending
- 1997-11-10 CN CN97180163A patent/CN1238776A/en active Pending
- 1997-11-10 BR BR9713339-6A patent/BR9713339A/en not_active Application Discontinuation
- 1997-11-10 EP EP97951881A patent/EP0937084A1/en not_active Withdrawn
- 1997-11-10 TR TR1999/01631T patent/TR199901631T2/en unknown
- 1997-11-11 ZA ZA9710141A patent/ZA9710141B/en unknown
-
1999
- 1999-05-07 NO NO992225A patent/NO992225D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU5551698A (en) | 1998-06-03 |
| NO992225L (en) | 1999-05-07 |
| BR9713339A (en) | 2000-05-09 |
| CA2271847A1 (en) | 1998-05-22 |
| EP0937084A1 (en) | 1999-08-25 |
| JP2001503763A (en) | 2001-03-21 |
| PL333247A1 (en) | 1999-11-22 |
| ZA9710141B (en) | 1998-06-25 |
| NO992225D0 (en) | 1999-05-07 |
| TR199901631T2 (en) | 1999-09-21 |
| WO1998021212A1 (en) | 1998-05-22 |
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